拉米夫定联合阿德福韦对慢性乙型肝炎近期疗效的影响
摘要
背景：慢性乙型肝炎是一个全球性的健康问题,预计约影响4亿人群。我国是乙肝病毒感染的高流行区,发病率列世界第一位。慢性乙肝占中国50%的慢性病毒性肝病病例,估计在中国有9千万乙肝携带者,其中80-85%处在慢性无症状阶段,大约有2千8百万处于有临床症状的慢性乙型肝炎阶段。每10万人中的患病率约为2770人,每年的新发病率约为每10万人中230人。在中国,绝大部分的肝硬化都是从慢性乙肝发展而来的；慢性乙肝的发病率分布与肝癌也存在密切相关性,在80%的肝癌患者中都能检测到乙肝病毒。至今为止,有效的抗病毒治疗乙肝的药物只有核苷类似物和干扰素(IFN)。而核苷类似物是近年来抗HBV药物研究的热点,进展很快。治疗慢性乙肝的核苷类似物主要有下面几种：拉米夫定(Lamivudine)、阿德福韦(Adefovir)、恩替卡韦(Entecavir)、左旋脱氧胸腺嘧啶(LdT)、替诺福韦(Viread tenofovir)、恩曲他滨(Emtritabine)。核苷类似物同其他抗病毒药一样,只能抑制HBV病毒复制而难以彻底清除病毒,且HBV易发生变异,变异病毒对抗病毒药易发生耐药,如拉米夫定治疗后的YMDD变异株可发生耐药等,治疗过程中出现的耐药性已成为影响其长期抗病毒治疗最大临床问题之一。如何提高核苷类药物的疗效,降低耐药的发生是目前临床治疗中最为关注的问题。
阿德福韦单用或拉米夫定联合阿德福韦是目前最常用的拉米夫定耐药的乙肝患者的挽救性治疗方案。大量临床研究表明,拉米夫定耐药后换用阿德福韦酯或两者联合均可取得较好的临床疗效,且有研究认为拉米夫定耐药后联合治疗的效果优于阿德福韦酯单用。拉米夫定和阿德福韦没有交叉耐药,有研究指出肝硬化患者初治时联合应用拉米夫定和阿德福韦抗病毒疗效优于拉米夫定耐药后换用阿德福韦酯或联合。目前初治联合抗病毒治疗已广泛应用于肝硬化、肝移植以及合并HIV等其他病毒感染的病人,而对慢性乙型肝炎初治患者使用拉米夫定联合阿德福韦酯的联合抗病毒的报道较少。
目的：通过拉米夫定联合阿德福韦治疗慢性乙型肝炎初治患者,观察两者联合抗病毒在慢性乙型肝炎患者的HBV-DNA抑制情况,同时观察两者联合对慢性乙型肝炎患者近期疗效的影响,以及两者联合抗病毒的耐药率及安全性,进一步探索核苷类药物的治疗方法,为慢乙肝的治疗提供更加合理的治疗策略及试验依据。
方法：选择2009年1月至2010年1月期间符合入组条件的e抗原阳性或e抗原阴性的慢性乙型肝炎初治患者给予拉米夫定联合阿德福韦抗病毒治疗(下称观察组),同时回顾性统计分析了30例拉米夫定单药抗病毒治疗的e抗原阳性或e抗原阴性的慢性乙型肝炎初治患者的相关资料(下称对照组)。观察的指标包括症状体征的变化,肝肾功能,DNA水平,乙肝的血清学标记物等,分别在治疗的0、2、4、8、12、24、36、48周测定,同时观察记录相关不良反应。入组病例严格按照入组标准和排除标准选择。
结果：观察组一共入组116例病例,其中完成了12周疗程有116例,DNA阴转率为50%,ALT复常率为44.7%,e抗原血清学转换率为0.86%；完成24周疗程的有79例,DNA阴转率为83.5%,ALT复常率为67.1%,e抗原血清学转换率为3.80%；完成48周疗程的有24,DNA阴转率为95.83%,ALT复常率为87.5%,e抗原血清学转换率为16.70%；所有病例均未发现病毒学突破,未发现严重不良反应。对照组一共30例,48周时DNA阴转率为43.3%,ALT复常率为76.7%,e抗原血清学转换率为19.0%,病毒学突破率为13.3%,未发现严重不良反应。48周时,观察组较对照组具有更高的DNA阴转率(P<0.05)。
结论：拉米夫定联合阿德福韦治疗慢性乙型肝炎初治患者可快速持久地抑制病毒复制,可降低病毒耐药的发生,而且具有良好的安全性。
Background:Hepatitis B (HBV) viral infection is a serious public health problem worldwide,there are almost 400 million people infected with HBV.China is the area where hepatitis B virus infection is in high prevalence,and the incidence has the first place in the world.Chronic hepatitis B accounted for 50% of chronic viral liver disease,it is estimated there are 90 million HBV carriers in China,of which 80-85% is in chronic asymptomatic stage,and about 28 million people is chronic hepatitis B patients who have clinical symptoms.The prevalence rate is about 2,770 pre 10 thousand,the annual new incidence rate is about 230 pre 10 thousand.In China,the vast majority of liver cirrhosis is developed from chronic hepatitis B,and primary hepatocellar carcinoma is related to Hepatitis B virus infection,of which 80% can be found hepatitis B virus in their blood.To date, the nucleoside analogues and interferon (IFN) are the effective anti-viral drug can be treated in hepatitis B infection.The nucleoside analogues is the research focus.Now the Nucleoside analogues for chronic hepatitis B has the following main categories:lamivudine, Adefovir, entecavir, L-deoxy-thymidine (LdT), Viread tenofovir and Emtritabine.Like other anti-viral drugs，the nucleoside analogues only can inhibit the HBV viral replication and can't completely remove the virus,and HBV is easy to variant, variant viruses resistant to the antiviral drugs such as ymdd variation after lamivudine can occur such drug resistance.drug resistance arising in the treatment has been the biggest clinical problems which effects the long-term anti-viral treatment. How to improve the efficacy of nucleoside drugs and reduce the incidence of resistance is the most concern in clinical treatment.
Lamivudine combined with adefovir or adefovir alone is the most commonly choice in hepatitis B patients with lamivudine resistant as salvage therapy. Many clinical studies have shown that both Lamivudine combined with adefovir and adefovir alone can achieve well clinical efficacy in hepatitis B patients with lamivudine resistant,and some studies show that in these cases Lamivudine combined with adefovir has better clinical efficacy than adefovir alone.These is no cross-resistance between lamivudine and adefovir,and some studies show that choosing Lamivudine combined with adefovir at the beginning has better clinical than choosing it after it is arealy resist to lamivudine.Now Combined antiretroviral therapy is widely used in cirrhosis, liver transplantation and patients wo has combined HIV or other virus-infected.But there is little reports about combined antiretroviral therapy using in chronic hepatitis B patients.
Objectives:We observe the HBV-DNA inhibition,the therapeutic effect,drug resistance and security of Lamivudine combined with adefovir treatment in the patients who haven't receive nucleoside analogues treatment before. And we want to further explore the treatment of nucleoside drugs and to offers a more rational and experimental basis for treatment strategies of chronic hepatitis B patients through our reasch.
Methods:We choose the untreated e-antigen positive or e antigen negative chronic hepatitis B patients who met the inclusion criteria to accepted antiviral therapy with Lamivudine combined adefovir from January 2009 to January 2010 (the experimental group),and retrospectively analyzed 30 untreated e-antigen positive or e-antigen negative chronic hepatitis B patients who accepted antiviral therapy with lamivudine monotherapy (the control group).Observed indicators including DNA levels, hepatitis B serological markers and transaminase,which were measured in the treatment of 0,2,4,8,12,24,36,48 week,and safety assessments were also conducted. We choose the enrolled patients into groups strictly according to selection criteria and exclusion criteria.
Results:Experimental group, a total of 116 cases of patients enrolled, of which completed 12-week of treatment were 116 cases, which DNA negative conversion rate was 50%, ALT normalization rate was 44.7% and e antigen seroconversion rates is 0.86%; completed 24 weeks of treatment were 79 cases, which DNA negative conversion rate was 83.5%,ALT normalization rate was 67.1% and e antigen seroconversion rates is 3.80%; completed 48 weeks of treatment were 24, which DNA negative conversion rate was 95.83%,ALT normalization rate was 87.5%,and e antigen seroconversion rates is 16.70%.Virological breakthrough weren't found in all cases, and no serious adverse reactions found. A total of 30 cases were enrolled in control group, after 48 weeks treatment, the DNA negative conversion rate was 43.3%, ALT normalization rate was 76.7%, e antigen seroconversion rates is 19.0%,virological breakthrough rate is 13.3%, no serious adverse reactions was found.After 48 weeks treatment, the experimental group compared with the control group had higher DNA negative conversion rate (P<0.05).
Conclusion:Lamivudine combined with adefovir treatment of chronic hepatitis B patients who is untreated with nucleoside analogues before can inhibit virus replication rapid and sustained, can significantly reduce the occurrence of drug resistance, and also has good security.
阿德福韦单用或拉米夫定联合阿德福韦是目前最常用的拉米夫定耐药的乙肝患者的挽救性治疗方案。大量临床研究表明,拉米夫定耐药后换用阿德福韦酯或两者联合均可取得较好的临床疗效,且有研究认为拉米夫定耐药后联合治疗的效果优于阿德福韦酯单用。拉米夫定和阿德福韦没有交叉耐药,有研究指出肝硬化患者初治时联合应用拉米夫定和阿德福韦抗病毒疗效优于拉米夫定耐药后换用阿德福韦酯或联合。目前初治联合抗病毒治疗已广泛应用于肝硬化、肝移植以及合并HIV等其他病毒感染的病人,而对慢性乙型肝炎初治患者使用拉米夫定联合阿德福韦酯的联合抗病毒的报道较少。
目的：通过拉米夫定联合阿德福韦治疗慢性乙型肝炎初治患者,观察两者联合抗病毒在慢性乙型肝炎患者的HBV-DNA抑制情况,同时观察两者联合对慢性乙型肝炎患者近期疗效的影响,以及两者联合抗病毒的耐药率及安全性,进一步探索核苷类药物的治疗方法,为慢乙肝的治疗提供更加合理的治疗策略及试验依据。
方法：选择2009年1月至2010年1月期间符合入组条件的e抗原阳性或e抗原阴性的慢性乙型肝炎初治患者给予拉米夫定联合阿德福韦抗病毒治疗(下称观察组),同时回顾性统计分析了30例拉米夫定单药抗病毒治疗的e抗原阳性或e抗原阴性的慢性乙型肝炎初治患者的相关资料(下称对照组)。观察的指标包括症状体征的变化,肝肾功能,DNA水平,乙肝的血清学标记物等,分别在治疗的0、2、4、8、12、24、36、48周测定,同时观察记录相关不良反应。入组病例严格按照入组标准和排除标准选择。
结果：观察组一共入组116例病例,其中完成了12周疗程有116例,DNA阴转率为50%,ALT复常率为44.7%,e抗原血清学转换率为0.86%；完成24周疗程的有79例,DNA阴转率为83.5%,ALT复常率为67.1%,e抗原血清学转换率为3.80%；完成48周疗程的有24,DNA阴转率为95.83%,ALT复常率为87.5%,e抗原血清学转换率为16.70%；所有病例均未发现病毒学突破,未发现严重不良反应。对照组一共30例,48周时DNA阴转率为43.3%,ALT复常率为76.7%,e抗原血清学转换率为19.0%,病毒学突破率为13.3%,未发现严重不良反应。48周时,观察组较对照组具有更高的DNA阴转率(P<0.05)。
结论：拉米夫定联合阿德福韦治疗慢性乙型肝炎初治患者可快速持久地抑制病毒复制,可降低病毒耐药的发生,而且具有良好的安全性。
Background:Hepatitis B (HBV) viral infection is a serious public health problem worldwide,there are almost 400 million people infected with HBV.China is the area where hepatitis B virus infection is in high prevalence,and the incidence has the first place in the world.Chronic hepatitis B accounted for 50% of chronic viral liver disease,it is estimated there are 90 million HBV carriers in China,of which 80-85% is in chronic asymptomatic stage,and about 28 million people is chronic hepatitis B patients who have clinical symptoms.The prevalence rate is about 2,770 pre 10 thousand,the annual new incidence rate is about 230 pre 10 thousand.In China,the vast majority of liver cirrhosis is developed from chronic hepatitis B,and primary hepatocellar carcinoma is related to Hepatitis B virus infection,of which 80% can be found hepatitis B virus in their blood.To date, the nucleoside analogues and interferon (IFN) are the effective anti-viral drug can be treated in hepatitis B infection.The nucleoside analogues is the research focus.Now the Nucleoside analogues for chronic hepatitis B has the following main categories:lamivudine, Adefovir, entecavir, L-deoxy-thymidine (LdT), Viread tenofovir and Emtritabine.Like other anti-viral drugs，the nucleoside analogues only can inhibit the HBV viral replication and can't completely remove the virus,and HBV is easy to variant, variant viruses resistant to the antiviral drugs such as ymdd variation after lamivudine can occur such drug resistance.drug resistance arising in the treatment has been the biggest clinical problems which effects the long-term anti-viral treatment. How to improve the efficacy of nucleoside drugs and reduce the incidence of resistance is the most concern in clinical treatment.
Lamivudine combined with adefovir or adefovir alone is the most commonly choice in hepatitis B patients with lamivudine resistant as salvage therapy. Many clinical studies have shown that both Lamivudine combined with adefovir and adefovir alone can achieve well clinical efficacy in hepatitis B patients with lamivudine resistant,and some studies show that in these cases Lamivudine combined with adefovir has better clinical efficacy than adefovir alone.These is no cross-resistance between lamivudine and adefovir,and some studies show that choosing Lamivudine combined with adefovir at the beginning has better clinical than choosing it after it is arealy resist to lamivudine.Now Combined antiretroviral therapy is widely used in cirrhosis, liver transplantation and patients wo has combined HIV or other virus-infected.But there is little reports about combined antiretroviral therapy using in chronic hepatitis B patients.
Objectives:We observe the HBV-DNA inhibition,the therapeutic effect,drug resistance and security of Lamivudine combined with adefovir treatment in the patients who haven't receive nucleoside analogues treatment before. And we want to further explore the treatment of nucleoside drugs and to offers a more rational and experimental basis for treatment strategies of chronic hepatitis B patients through our reasch.
Methods:We choose the untreated e-antigen positive or e antigen negative chronic hepatitis B patients who met the inclusion criteria to accepted antiviral therapy with Lamivudine combined adefovir from January 2009 to January 2010 (the experimental group),and retrospectively analyzed 30 untreated e-antigen positive or e-antigen negative chronic hepatitis B patients who accepted antiviral therapy with lamivudine monotherapy (the control group).Observed indicators including DNA levels, hepatitis B serological markers and transaminase,which were measured in the treatment of 0,2,4,8,12,24,36,48 week,and safety assessments were also conducted. We choose the enrolled patients into groups strictly according to selection criteria and exclusion criteria.
Results:Experimental group, a total of 116 cases of patients enrolled, of which completed 12-week of treatment were 116 cases, which DNA negative conversion rate was 50%, ALT normalization rate was 44.7% and e antigen seroconversion rates is 0.86%; completed 24 weeks of treatment were 79 cases, which DNA negative conversion rate was 83.5%,ALT normalization rate was 67.1% and e antigen seroconversion rates is 3.80%; completed 48 weeks of treatment were 24, which DNA negative conversion rate was 95.83%,ALT normalization rate was 87.5%,and e antigen seroconversion rates is 16.70%.Virological breakthrough weren't found in all cases, and no serious adverse reactions found. A total of 30 cases were enrolled in control group, after 48 weeks treatment, the DNA negative conversion rate was 43.3%, ALT normalization rate was 76.7%, e antigen seroconversion rates is 19.0%,virological breakthrough rate is 13.3%, no serious adverse reactions was found.After 48 weeks treatment, the experimental group compared with the control group had higher DNA negative conversion rate (P<0.05).
Conclusion:Lamivudine combined with adefovir treatment of chronic hepatitis B patients who is untreated with nucleoside analogues before can inhibit virus replication rapid and sustained, can significantly reduce the occurrence of drug resistance, and also has good security.
引文
1 姚碧连,张欣欣.慢性乙型肝炎抗病毒治疗规范进展.国际流行病学传染病学杂志,2007,34(2)：108-111.
2 中华医学会肝病学分会、感染病学分会.慢性乙型肝炎防治指南.中华肝脏病杂志,2005,13：881-891.
3 美国2006年慢性乙型肝炎病毒感染处理治疗规范简介.中华肝脏病杂志,2006,14：871-872.
4 Hui AY, Chan HL, Cheung AY, Cooksley G, Sung JY. Sistematic review:treatment of chronic hepatitis b virus infection by pegylated interferon. Aliment Pharmacol Ther.2005;22:519-28.
5 Dienstag J.L., Schiff E.R., Wright T.L., et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63.
6 Chang TT, Gish RG, De Man R, Gadano A, Sollano J, Chao YC, et al.A comparison of entecavir and lamivudine for HBe-Ag-positive chronic hepatitis B. N Engl J Med.2006;354:1001-10.
7 Ching-Lung Lai, Edward Gane, Yun-Fan Liaw,et al.Telbivudine versus Lamivudine in Patients with Chronic Hepatitis.BN Engl J Med 2007;357:2576-88.
8 Lai CL, Leung N. Teo EK, Tong M,Wong F, Hann HW, et al. A 1-year trial of telbivudine, lamivudine and the combination in patients with hepatitis B e antigen-positive. Gastroenterology.2005; 129:528-36.
9 R. Morillo Verdugo, A. Madrazo Berenguer,bM.V. Gil Navarro,at el.Drugs Treatment of Hepatitis B. Farm Hosp.2008;32(4):234-248.
10 Perrillo R. Hann HW, Mutimer D,et al.Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004:126:91-101.
11 Chang TT, Gish RG, de Man R, et al.A comparison of entecavir and lamivudine for HBe Ag-positive chronic hepatitis B. N Engl J Med.2006 Mar 9;354(10):1001-10.
12 Gish RG, Lok AS, Chang TT,et al.Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.Gastroenterology.2007 Nov;133(5):1437-44. Epub 2007 Aug 14.
13 Lai CL, Gane E, Liaw YF, et al.Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med.2007 Dec 20;357(25):2576-88.
14 Lai C-L, et al. Hepatology 2006;44(Suppl.1):222A (Abstract 91), and oral presentation at AASLD 2006.
15 Marcellin P, Chang TT, Lim SG,et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med.2003 Feb 27;348(9):808-16.
16 Lampertico P.Partial virological response to nucleos(t)ide analogues in naive patients with chronic hepatitis B:From guidelines to field practice. J Hepatol, 2009 Apr;50(4):644-7.
17 H. Pan,AASLD,2008,Abstract European Association For The Study Of The Liver.EASL Clinical Practice Guidelines:management of chronic hepatitis B. J Hepatol.2009 Feb; 50(2):227-42. Epub 2008 Oct 29.
18 Lai C.L., Chien R.N., Leung N.W., et al. A one year trial of lamivudine for chronic hepatitis B.N Engl J Med.1998;339:61-8.
19 Lau D.T., Khokhar F., Doo E., et al. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology 2000;32:828-34.
20 Hadziyannis SJ, Tassopoulos NC, Hiathcote EJ,et al.Long-term therapy with adefovir Dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006; 131:1743-1751.
21 Fung SK, Chae HB, Fontana RJ,et al.Virologic response and resistance toadefovir in patients with chronic hepatitis B.J Hepatol.2006;44:283-290.
22 Locarmini S,Ma.son WS,.Cellular and virological mechanisms of HBV drug resistance. J Hepatol 2006;44:422-431.
23 Dong J, Cheng J, Wang QH, Liu Y, Wang G, Shi SS, Xia XB, Shao Q, Si CW. The preliminary study on hepatitis B virus (HBV) quasispecies in patients with chronic HBV infection. Chin J Infect Dis,2001;19:199-203.
24 Sung JJ, Lai JY, Zeuzem S, et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol.2008 May;48(5):728-35.
1 Bernal W, Wendon J. Liver transplantation in adults with acute liver failure. J Hepatol 2004;40:192-197.
2 Li LJ, Yang Q, Huang JR, et al. Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases. World J Gastroenterol, 2004,10:2984-2988.
3 Tong YL, Huang JR, Chen YM. Effect observation of selective plasma exchange in treating chronic sever hepatitis. Zhonghua Chuanranbing Zazhi,2006,24:124-126.童娅玲,黄建荣,陈月美.选择性血浆置换治疗慢性重型肝炎临床疗效观察.中华传染病杂志,2006,24：124-126.
4 Huang JR, Du WB.A brief regarding the Fourth International Symposium on Hepatic Failure and Artificial Liver. CHINESE JOURNAL OF HEPATOLOGY.2007,15(7):551.
5.黄建荣,杜维波.第四届国际暨全国肝衰竭与人工肝学术会议纪要.中华肝脏病杂志,2007,15(7)：551.
6. Adham M. Extracorporeal liver support:waiting for the deciding vote [J]. ASAIO Journal,2003,621-632.
7 中华传染病与寄生虫病学会人工肝学组.人工肝支持系统治疗的操作指南[J].中华肝脏病杂志,2002,10(5)：329-333.
8. A Nishimura et al. Plasma Exchange-based Plasma Recycling Dialysis System as a Potential Platform for Artificial Liver Support. Artif Organs,2006, 30(8):629-633.
9. K Takahashi et al. Plasma Exchange-based Plasma Recycling Dialysis System as an Artificial Liver Support. Therapeutic Apheresis and Dialysis, 2008,12(4):264-270.
10. Stockmann HB, Hiemstra CA, Marquet RL, IJzermans JN. Extracorporeal perfusion for the treatment of acute liver failure. Ann Surg 2000;231:460-470.
11. Singer AL, Olthoff KM, Kim H, Rand E, Zamir G, Shaked A. Role of plasmapheresis in the management of acute hepatic failure in children. Ann Surg 2001;234:418-24.
12.黄建荣.非生物型人工肝支持系统新技术.药品评价,2007,4(1)：17-19.
13. Heemann U, Treichel U, Loock J, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury:a prospective, controlled study. Hepatology.2002; 36:949-958.
14. Khuroo MS, Farahat KL. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure:a meta-analysis. Liver Transpl 2004; 10:1099-1106.
15. Rifai K, Ernst T, Kretschmer U, Bahr MJ, Schneider A, Hafer C,et al. Prometheus-a new extracorporeal system for the treatmentof liver failure. J Hepatol 2003;39:984-990.
16. Evenepoel P, Laleman W, Wilmer A, et al. Detoxifying capacity and kinetics of Prometheus:a new extracorporeal system for the treatment of liver failure.Blood Purif 2005; 23:349-358.
17. Rifai K, Ernst T, Kretschmer U, et al. Prometheus:a new extracorporeal system for the treatment of liver failure. J Hepatol 2003; 39:984-990.
18. Krisper P, Haditsch B, Stauber R, et al. In vivo quantification of liver dialysis:comparison of albumin dialysis and fractionated plasma separation. J Hepatol2005; 43:451-457.
19. Laleman W, Wilmer A, Evenepoel P, et al. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure.Crit Care 2006; 10:R108.
20. Sauer IM, Goetz M, Steffen I, et al. In vitro comparison of the molecular adsorbent
recirculation system (MARS) and single-pass albumin dialysis(SPAD). Hepatology 2004; 39:1408-1414.
21. Rozga J. Liver support technology-an update. Xenotransplantation 2006; 13: 380-389.
22. Clemmesen JO, Kondrup J, Nielsen LB, Larsen FS, Ott P. Effects of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure. Am J Gastroenterol.2001;96:1217-1223.
23. Hisamitsu Shinohara et al. New Type of Artificial Liver Support System (ALSS) Using the Photocatalytic Effect of Titanium Oxide. Dig Dis Sci.2007, 52:2271-2275.
1 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.肝衰竭诊疗指南.中华临床感染病杂志.2008,4,1(1)：47-53.
2 Li LJ, Yang Q, Huang JR. et al. Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases. World J Gastroenterol, 2004,10:2984-2988.
3 Bernal W, Wendon J. Liver transplantation in adults with acute liver failure. J Hepatol 2004;40:192-197.
4 Rolando N, Wade J, Davalos M, et al. The systemic inflammatoryresponse syndrome in acute liver failure. Hepatology,2000; 32:734-739.
5 Vaquero J, Polson J, Chung C, et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology,2003; 125:755-764.
6 Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infection in acute liver failure. Semin Liver Dis 1996;16:389-402.
7 重型肝炎继发医院感染临床分析.王占军,柳忠生.现代中西医结合杂志,2008,17(5)：676-677.
8 程风英.抗病毒治疗慢性重型乙型肝炎165例临床分析.临床内科杂志,2008,25(7)：484-486.
9 肖光明,何凯茵,雷春亮等.慢性重型乙型肝炎抗病毒治疗的生存分析.中华传染病杂志,2009,27(7)：423-425.
10 Yu JW, Sun LJ, Zhao YH, et al. The Study of Efficacy of Lamivudine in Patients with Severe Acute Hepatitis B. Dig Dis Sci.2009 Dec 3. [Epub ahead of print].
11 Wong VW, Chan HL. Severe acute exacerbation of chronic hepatitis B:a unique presentation of a common disease.J Gastroenterol Hepatol.2009 Jul;24(7):1179-86.
12 Wang YM, Tang YZ.Antiviral therapy for hepatitis B virus associated hepatic failure. Hepatobiliary Pancreat Dis Int.2009,8:17.
13 Fujiwara K, Yasui S, Yonemitsu Y, et al.Efficacy of combination therapy of antiviral and immunosuppressive drugs for the treatment of severe acute exacerbation of chronic hepatitis B. J Gastroenterol.2008;43(9):711-9. Epub 2008 Sep 20.
14 李丽军,李铭,李卫等.使用激素治疗重型肝炎价值的再探讨.实用肝脏病杂志,2006,9(3)：163-164.
15 朱喜增,翟玉峰,张怀宏.拉米夫定联合胸腺素α1治疗慢性重型乙型肝炎疗效观察.医学信息,2007,20(12)：2093-2095.
16 高明宏,刘百坤.胸腺素α1治疗慢性重型乙型肝炎的临床观察.中国厂矿医学,2007,20(5)：481-482.
17 于强,席启辉,高世定.高压氧治疗亚急性重型肝炎的临床疗效分析.实用肝脏病杂志,2009,12(4)：283-284.
18 KIMURA M,OSUMI S,OGIHARA M. Prostaglandin E(EP1) receptor agonist-induced synthesis and proliferation in primary cultures of adult rat hepatocytes:the involvement of TGF-α J. Endocrinology,2001,142(10):4428-4440.
19 杨景毅,倪辉,冼永超等.前列地尔治疗慢性重型肝炎65例临床疗效观察.中国现代药物应用,2009,3(16)：101-103.
20 黄砚青,陈辉,王鲁文等.乙酰半胱氨酸治疗慢性重型乙型肝炎的临床疗效观察.中西医结合肝病杂志,2009,19(3)：140-142.
21 戴锴,杨丽华.N-乙酰半胱氨酸和还原型谷胱甘肽治疗重型肝炎的临床对比观察.临床内科杂志,2009,26(8)：535-537.
22 Song HY, Jiang CH, Yang JR. et al. The change of intestinal mucosa barrier in chronic severe hepatitis B patients and clinical intervention. Zhonghua Gan Zang Bing Za Zhi.2009 Oct;17(10):754-8.
23 Shawcross D,Jalan R.The pathophysiologic basis of hepatic encephaiopathy:entral role for ammonia and inflammation.Cellular and Molecular Life Sciences,2005,62:2295.
24 Alba L,Hay JE,Angulo P,et al.Lactulose therapy in acute liver failure.Journal of Hepatology,2002,36:33A.
25 Ahmad I, Khan AA, Alam A,et al.L-ornithine-L-aspartate infusion efficacy in hepatic encephalopathy. J Coll Physicians Surg Pak.2008,18(11):684-7.
26 Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora:effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology. 2004,39(5):1441-9.
27 Al Sibae MR, McGuire BM.Current trends in the treatment of hepatic encephalopathy.Ther Clin Risk Manag.2009,5(3):617-26.
28 Jalan R,Wright G,Davies NA,et al.L-ornithine phenylacetate (OP):a novel treatment for hyperammonemia and hepatic encephalopathy.Medical Hypotheses,2007,69:1064.
29 Gentile S, Guarino G, Romano M,et al.A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol.2005,3(2):184-91.
30 Malaguarnera M, Gargante MP, Cristaldi E, et al.Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci.2008,53(11):3018-25.
31 de Soarez PC, Oliveira AC, Padovan J, et al.A critical analysis of studies assessing L-ornithine-L-aspartate (LOLA) in hepatic encephalopathy treatment. Arq Gastroenterol.2009,46(3):241-7.
32 Stravitz RT,Kramer AH,D avern T.et al.Acute intensive care of patients with acute liver failure..Recommendations of the US.Acute Liver Failure Study Group.Critical Care Medicine,2007,35:2498.
33 MasA.Hepaticencephalopathy:from pathophysiology to treatment. Digestion 2006,73(Suppl 1):S86-S93.
34 Vaquero J,Polson J.Chung C,et al.Infection and the progression of encephalopathy in acute liver failure. Gastroenterology,2003,125:755.
35 Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in acute liver failure:an analysis of fifty patients. Hepatology 1990; 11:49-53.
36 吕晓峰,李保义,安凤霞等.重型肝炎并发医院内真菌感染168例临床分析.中西医结合肝病杂志,2009,19(2)：83-84.
37 重型肝炎并医院内真菌感染临床分析张岸平,佘长建,李超群.中国现代医药杂志,2008,10(3)：42-44.
38 Shami V,Caldwell SH,Hespenheide EE,et al. Recombinant activated factor Ⅶ for coagulopattthy in fulminant hepatic failure compared with conventional therapy.Liver Transplantation,2003,9:138.
39 中医药治疗重型肝炎疗效的Meta分析.刘国旺,曹武奎,唐克诚.天津医药,2009,37(3)：218-220.
40 曾岳祥,谭兰香,周泳昕等.重肝合剂保留灌肠阻抑重型肝炎内毒素血症的临床研究.中西医结合肝病杂志,2009,19(3)：134-136.
41 谭善忠,徐乾,杨觉民等.足三里穴位注射小剂量地塞米松小剂量地塞米松治疗肝衰竭早期疗效分析.中西医结合肝病杂志,2009,19(4)：241-243.
42 Dernertriou AA,Brown RS Jr,Busuttil RW,et al.Prospective randomized multicenter controlled trial of a bioartificial liver in treating acute liver failure.Ann surg,2004,239:660.
43 Sauer IM,Kardassis D,Zeillinger K,ea al.Clinical extracorporeal hybrid liver support-phase I study with primary porcine liver cells. Xenotransplantation, 2003,10:460.
44 李兰娟,杨芊,黄建荣等.混合型人工肝支持系统治疗慢性重型肝炎疗效研究.透析与人工器官,2004,1：21.
45 De Bartolo L,Morelli S,Piscioneri A,et al.Novel membranes and surface modification able to activate specific cellular responses.Biomo lecular Engineering,2007,24:23.
46陈志,王英杰,张世昌等.聚砜膜生物反应器实验系统构建及对重型肝炎患者血浆的影响.中国组织工程研究与临床康复,2008,12(6)：1175-1178.
47 Huang JR, Du WB.A brief regarding the Fourth International Symposium on Hepatic Failure and Artificial Liver. CHINESE JOURNAL OF HEPATOLOGY.2007,15(7):551.
48.黄建荣,杜维波.第四届国际暨全国肝衰竭与人工肝学术会议纪要.中华肝脏病杂志,2007,15(7)：551.
49.Tong YL, Huang JR, Chen YM. Effect observation of selective plasma exchange in treating chronic sever hepatitis. Zhonghua Chuanranbing Zazhi,2006,24:124-126.童娅玲,黄建荣,陈月美.选择性血浆置换治疗慢性重型肝炎临床疗效观察.中华传染病杂志,2006,24：124-126.
50.喻成波,杨京,曹红翠等.慢性重型乙型肝炎人工肝血浆置换疗法的临床研究2008,35(1)：4-6.
51.袁雯霞,黄建荣.非生物型人工肝治疗肝衰竭的现状.内科急危重症杂志,2009,15(3)：122-124.
52. Adham M. Extracorporeal liver support:waiting for the deciding vote J. ASAIO Journal,2003,621-632.
53.中华医学会感染病学分会肝衰竭与人工肝学组.非生物型人工肝支持系统治疗肝衰竭指南(2009年版).中华临床感染病杂志,2009,2(6)：321-325.
54.金洁,叶卫江,俞海燕等.缓慢性血浆置换同步并联血液滤过治疗慢性乙型重型肝炎.中华肝脏病杂志,2009,17(2)：95-98.
55.胡肖兵,高洪波,廖明儿等.不同物理型人工肝治疗模式早期救治慢性重型肝炎疗效比较.中国中西医结合急救杂志,2008,15(2)：117-119.
56. Singer AL, Olthoff KM, Kim H, Rand E, Zamir G, Shaked A. Role of plasmapheresis in the management of acute hepatic failure in children. Ann Surg 2001;234:418-24.
57. Heemann U, Treichel U, Loock J, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury:a prospective, controlled study. Hepatology.2002; 36:949-958.
58.刘国旺,曹武奎,唐克诚.改良Port配方在重型肝炎血液滤过治疗中的应用.天津医药,2009,37(3)：228-229.
59.郑树森.我国肝移植的现状和展望.中华外科杂志,2009,47(1)：27-29.
60. Xi ZF, Xia Q, Zhang JJ, et al.The role of entecavir in preventing hepatitis B recurrence after liver transplantation. J Dig Dis.2009,10(4):321-7.
61. Wu LM, Xu X, Zheng SS.Hepatitis B virus reinfection after liver transplantation: related risk factors and perspective. Hepatobiliary Pancreat Dis Int. 2005,4(4):502-8.
1 Li LJ, Yang Q, Huang JR, et al. Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases. World J Gastroenterol, 2004,10:2984-2988.
2 Tong YL, Huang JR, Chen YM. Effect observation of selective plasma exchange in treating chronic sever hepatitis. Zhonghua Chuanranbing Zazhi,2006,24:124-126.童娅玲,黄建荣,陈月美.选择性血浆置换治疗慢性重型肝炎临床疗效观察.中华传染病杂志,2006,24：124-126.
3 Yang YF, Wei LL, Zhang N, et al. The efficacy of artificial liver support system treatment on hepatic failure in China:a meta-analysis. Chin J Hepatol,2006, 14(10):732-734.
4.杨永峰,魏林玲,张宁等.国内人工肝支持系统治疗重型肝炎疗效的Meta分析.中华肝脏病杂志,2006,14(10)：732-734.
5. Splendiani G, Tancredi M, Daniele M, et al. Treatment of acute liver failure with hemodetoxification techniques J. Int J Artif Organs,1990-06,13(6):370-374.
6. Li LJ, Progress in clinical application of artificial liver support systems. Chin J Hepatol,2005,13(11):844-855.
7.李兰娟,人工肝临床应用若干进展.中华肝脏病杂志,2005,13(11)：844-855.
8.黄建荣.非生物型人工肝支持系统新技术.药品评价,2007,4(1)：17-19.
9. Adham M. Extracorporeal liver support:waiting for the deciding vote J. ASAIO Journal,2003,621-632.
10 中华传染病与寄生虫病学会人工肝学组.人工肝支持系统治疗的操作指南J中华肝脏病杂志,2002,10(5)：329-333.
11 Biancofiore G, Bindi LM, Urbani L, et al. Combined twice-dailv plasma exchange and continuous veno-venous hemodialiltration for bridsing severe acute liver failure. Transplant Proc,2003,35(8):3011-3014.
12. Xu B, Jiang JJ, Lin Z, et al. Easy method for separation and recovery of albumin and clearance of bilirubin from plasma. Chin J Clini Hepatol,2002,18(6):340-341.
13.徐兵,江家骥,林灼等.简便法分离回收血浆白蛋白并清除胆红素.临床肝胆病杂志,2002,18(6)：340-341.
2 中华医学会肝病学分会、感染病学分会.慢性乙型肝炎防治指南.中华肝脏病杂志,2005,13：881-891.
3 美国2006年慢性乙型肝炎病毒感染处理治疗规范简介.中华肝脏病杂志,2006,14：871-872.
4 Hui AY, Chan HL, Cheung AY, Cooksley G, Sung JY. Sistematic review:treatment of chronic hepatitis b virus infection by pegylated interferon. Aliment Pharmacol Ther.2005;22:519-28.
5 Dienstag J.L., Schiff E.R., Wright T.L., et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63.
6 Chang TT, Gish RG, De Man R, Gadano A, Sollano J, Chao YC, et al.A comparison of entecavir and lamivudine for HBe-Ag-positive chronic hepatitis B. N Engl J Med.2006;354:1001-10.
7 Ching-Lung Lai, Edward Gane, Yun-Fan Liaw,et al.Telbivudine versus Lamivudine in Patients with Chronic Hepatitis.BN Engl J Med 2007;357:2576-88.
8 Lai CL, Leung N. Teo EK, Tong M,Wong F, Hann HW, et al. A 1-year trial of telbivudine, lamivudine and the combination in patients with hepatitis B e antigen-positive. Gastroenterology.2005; 129:528-36.
9 R. Morillo Verdugo, A. Madrazo Berenguer,bM.V. Gil Navarro,at el.Drugs Treatment of Hepatitis B. Farm Hosp.2008;32(4):234-248.
10 Perrillo R. Hann HW, Mutimer D,et al.Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004:126:91-101.
11 Chang TT, Gish RG, de Man R, et al.A comparison of entecavir and lamivudine for HBe Ag-positive chronic hepatitis B. N Engl J Med.2006 Mar 9;354(10):1001-10.
12 Gish RG, Lok AS, Chang TT,et al.Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B.Gastroenterology.2007 Nov;133(5):1437-44. Epub 2007 Aug 14.
13 Lai CL, Gane E, Liaw YF, et al.Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med.2007 Dec 20;357(25):2576-88.
14 Lai C-L, et al. Hepatology 2006;44(Suppl.1):222A (Abstract 91), and oral presentation at AASLD 2006.
15 Marcellin P, Chang TT, Lim SG,et al.Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med.2003 Feb 27;348(9):808-16.
16 Lampertico P.Partial virological response to nucleos(t)ide analogues in naive patients with chronic hepatitis B:From guidelines to field practice. J Hepatol, 2009 Apr;50(4):644-7.
17 H. Pan,AASLD,2008,Abstract European Association For The Study Of The Liver.EASL Clinical Practice Guidelines:management of chronic hepatitis B. J Hepatol.2009 Feb; 50(2):227-42. Epub 2008 Oct 29.
18 Lai C.L., Chien R.N., Leung N.W., et al. A one year trial of lamivudine for chronic hepatitis B.N Engl J Med.1998;339:61-8.
19 Lau D.T., Khokhar F., Doo E., et al. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology 2000;32:828-34.
20 Hadziyannis SJ, Tassopoulos NC, Hiathcote EJ,et al.Long-term therapy with adefovir Dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006; 131:1743-1751.
21 Fung SK, Chae HB, Fontana RJ,et al.Virologic response and resistance toadefovir in patients with chronic hepatitis B.J Hepatol.2006;44:283-290.
22 Locarmini S,Ma.son WS,.Cellular and virological mechanisms of HBV drug resistance. J Hepatol 2006;44:422-431.
23 Dong J, Cheng J, Wang QH, Liu Y, Wang G, Shi SS, Xia XB, Shao Q, Si CW. The preliminary study on hepatitis B virus (HBV) quasispecies in patients with chronic HBV infection. Chin J Infect Dis,2001;19:199-203.
24 Sung JJ, Lai JY, Zeuzem S, et al.Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B.J Hepatol.2008 May;48(5):728-35.
1 Bernal W, Wendon J. Liver transplantation in adults with acute liver failure. J Hepatol 2004;40:192-197.
2 Li LJ, Yang Q, Huang JR, et al. Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases. World J Gastroenterol, 2004,10:2984-2988.
3 Tong YL, Huang JR, Chen YM. Effect observation of selective plasma exchange in treating chronic sever hepatitis. Zhonghua Chuanranbing Zazhi,2006,24:124-126.童娅玲,黄建荣,陈月美.选择性血浆置换治疗慢性重型肝炎临床疗效观察.中华传染病杂志,2006,24：124-126.
4 Huang JR, Du WB.A brief regarding the Fourth International Symposium on Hepatic Failure and Artificial Liver. CHINESE JOURNAL OF HEPATOLOGY.2007,15(7):551.
5.黄建荣,杜维波.第四届国际暨全国肝衰竭与人工肝学术会议纪要.中华肝脏病杂志,2007,15(7)：551.
6. Adham M. Extracorporeal liver support:waiting for the deciding vote [J]. ASAIO Journal,2003,621-632.
7 中华传染病与寄生虫病学会人工肝学组.人工肝支持系统治疗的操作指南[J].中华肝脏病杂志,2002,10(5)：329-333.
8. A Nishimura et al. Plasma Exchange-based Plasma Recycling Dialysis System as a Potential Platform for Artificial Liver Support. Artif Organs,2006, 30(8):629-633.
9. K Takahashi et al. Plasma Exchange-based Plasma Recycling Dialysis System as an Artificial Liver Support. Therapeutic Apheresis and Dialysis, 2008,12(4):264-270.
10. Stockmann HB, Hiemstra CA, Marquet RL, IJzermans JN. Extracorporeal perfusion for the treatment of acute liver failure. Ann Surg 2000;231:460-470.
11. Singer AL, Olthoff KM, Kim H, Rand E, Zamir G, Shaked A. Role of plasmapheresis in the management of acute hepatic failure in children. Ann Surg 2001;234:418-24.
12.黄建荣.非生物型人工肝支持系统新技术.药品评价,2007,4(1)：17-19.
13. Heemann U, Treichel U, Loock J, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury:a prospective, controlled study. Hepatology.2002; 36:949-958.
14. Khuroo MS, Farahat KL. Molecular adsorbent recirculating system for acute and acute-on-chronic liver failure:a meta-analysis. Liver Transpl 2004; 10:1099-1106.
15. Rifai K, Ernst T, Kretschmer U, Bahr MJ, Schneider A, Hafer C,et al. Prometheus-a new extracorporeal system for the treatmentof liver failure. J Hepatol 2003;39:984-990.
16. Evenepoel P, Laleman W, Wilmer A, et al. Detoxifying capacity and kinetics of Prometheus:a new extracorporeal system for the treatment of liver failure.Blood Purif 2005; 23:349-358.
17. Rifai K, Ernst T, Kretschmer U, et al. Prometheus:a new extracorporeal system for the treatment of liver failure. J Hepatol 2003; 39:984-990.
18. Krisper P, Haditsch B, Stauber R, et al. In vivo quantification of liver dialysis:comparison of albumin dialysis and fractionated plasma separation. J Hepatol2005; 43:451-457.
19. Laleman W, Wilmer A, Evenepoel P, et al. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure.Crit Care 2006; 10:R108.
20. Sauer IM, Goetz M, Steffen I, et al. In vitro comparison of the molecular adsorbent
recirculation system (MARS) and single-pass albumin dialysis(SPAD). Hepatology 2004; 39:1408-1414.
21. Rozga J. Liver support technology-an update. Xenotransplantation 2006; 13: 380-389.
22. Clemmesen JO, Kondrup J, Nielsen LB, Larsen FS, Ott P. Effects of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure. Am J Gastroenterol.2001;96:1217-1223.
23. Hisamitsu Shinohara et al. New Type of Artificial Liver Support System (ALSS) Using the Photocatalytic Effect of Titanium Oxide. Dig Dis Sci.2007, 52:2271-2275.
1 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.肝衰竭诊疗指南.中华临床感染病杂志.2008,4,1(1)：47-53.
2 Li LJ, Yang Q, Huang JR. et al. Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases. World J Gastroenterol, 2004,10:2984-2988.
3 Bernal W, Wendon J. Liver transplantation in adults with acute liver failure. J Hepatol 2004;40:192-197.
4 Rolando N, Wade J, Davalos M, et al. The systemic inflammatoryresponse syndrome in acute liver failure. Hepatology,2000; 32:734-739.
5 Vaquero J, Polson J, Chung C, et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology,2003; 125:755-764.
6 Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infection in acute liver failure. Semin Liver Dis 1996;16:389-402.
7 重型肝炎继发医院感染临床分析.王占军,柳忠生.现代中西医结合杂志,2008,17(5)：676-677.
8 程风英.抗病毒治疗慢性重型乙型肝炎165例临床分析.临床内科杂志,2008,25(7)：484-486.
9 肖光明,何凯茵,雷春亮等.慢性重型乙型肝炎抗病毒治疗的生存分析.中华传染病杂志,2009,27(7)：423-425.
10 Yu JW, Sun LJ, Zhao YH, et al. The Study of Efficacy of Lamivudine in Patients with Severe Acute Hepatitis B. Dig Dis Sci.2009 Dec 3. [Epub ahead of print].
11 Wong VW, Chan HL. Severe acute exacerbation of chronic hepatitis B:a unique presentation of a common disease.J Gastroenterol Hepatol.2009 Jul;24(7):1179-86.
12 Wang YM, Tang YZ.Antiviral therapy for hepatitis B virus associated hepatic failure. Hepatobiliary Pancreat Dis Int.2009,8:17.
13 Fujiwara K, Yasui S, Yonemitsu Y, et al.Efficacy of combination therapy of antiviral and immunosuppressive drugs for the treatment of severe acute exacerbation of chronic hepatitis B. J Gastroenterol.2008;43(9):711-9. Epub 2008 Sep 20.
14 李丽军,李铭,李卫等.使用激素治疗重型肝炎价值的再探讨.实用肝脏病杂志,2006,9(3)：163-164.
15 朱喜增,翟玉峰,张怀宏.拉米夫定联合胸腺素α1治疗慢性重型乙型肝炎疗效观察.医学信息,2007,20(12)：2093-2095.
16 高明宏,刘百坤.胸腺素α1治疗慢性重型乙型肝炎的临床观察.中国厂矿医学,2007,20(5)：481-482.
17 于强,席启辉,高世定.高压氧治疗亚急性重型肝炎的临床疗效分析.实用肝脏病杂志,2009,12(4)：283-284.
18 KIMURA M,OSUMI S,OGIHARA M. Prostaglandin E(EP1) receptor agonist-induced synthesis and proliferation in primary cultures of adult rat hepatocytes:the involvement of TGF-α J. Endocrinology,2001,142(10):4428-4440.
19 杨景毅,倪辉,冼永超等.前列地尔治疗慢性重型肝炎65例临床疗效观察.中国现代药物应用,2009,3(16)：101-103.
20 黄砚青,陈辉,王鲁文等.乙酰半胱氨酸治疗慢性重型乙型肝炎的临床疗效观察.中西医结合肝病杂志,2009,19(3)：140-142.
21 戴锴,杨丽华.N-乙酰半胱氨酸和还原型谷胱甘肽治疗重型肝炎的临床对比观察.临床内科杂志,2009,26(8)：535-537.
22 Song HY, Jiang CH, Yang JR. et al. The change of intestinal mucosa barrier in chronic severe hepatitis B patients and clinical intervention. Zhonghua Gan Zang Bing Za Zhi.2009 Oct;17(10):754-8.
23 Shawcross D,Jalan R.The pathophysiologic basis of hepatic encephaiopathy:entral role for ammonia and inflammation.Cellular and Molecular Life Sciences,2005,62:2295.
24 Alba L,Hay JE,Angulo P,et al.Lactulose therapy in acute liver failure.Journal of Hepatology,2002,36:33A.
25 Ahmad I, Khan AA, Alam A,et al.L-ornithine-L-aspartate infusion efficacy in hepatic encephalopathy. J Coll Physicians Surg Pak.2008,18(11):684-7.
26 Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora:effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology. 2004,39(5):1441-9.
27 Al Sibae MR, McGuire BM.Current trends in the treatment of hepatic encephalopathy.Ther Clin Risk Manag.2009,5(3):617-26.
28 Jalan R,Wright G,Davies NA,et al.L-ornithine phenylacetate (OP):a novel treatment for hyperammonemia and hepatic encephalopathy.Medical Hypotheses,2007,69:1064.
29 Gentile S, Guarino G, Romano M,et al.A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol.2005,3(2):184-91.
30 Malaguarnera M, Gargante MP, Cristaldi E, et al.Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci.2008,53(11):3018-25.
31 de Soarez PC, Oliveira AC, Padovan J, et al.A critical analysis of studies assessing L-ornithine-L-aspartate (LOLA) in hepatic encephalopathy treatment. Arq Gastroenterol.2009,46(3):241-7.
32 Stravitz RT,Kramer AH,D avern T.et al.Acute intensive care of patients with acute liver failure..Recommendations of the US.Acute Liver Failure Study Group.Critical Care Medicine,2007,35:2498.
33 MasA.Hepaticencephalopathy:from pathophysiology to treatment. Digestion 2006,73(Suppl 1):S86-S93.
34 Vaquero J,Polson J.Chung C,et al.Infection and the progression of encephalopathy in acute liver failure. Gastroenterology,2003,125:755.
35 Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in acute liver failure:an analysis of fifty patients. Hepatology 1990; 11:49-53.
36 吕晓峰,李保义,安凤霞等.重型肝炎并发医院内真菌感染168例临床分析.中西医结合肝病杂志,2009,19(2)：83-84.
37 重型肝炎并医院内真菌感染临床分析张岸平,佘长建,李超群.中国现代医药杂志,2008,10(3)：42-44.
38 Shami V,Caldwell SH,Hespenheide EE,et al. Recombinant activated factor Ⅶ for coagulopattthy in fulminant hepatic failure compared with conventional therapy.Liver Transplantation,2003,9:138.
39 中医药治疗重型肝炎疗效的Meta分析.刘国旺,曹武奎,唐克诚.天津医药,2009,37(3)：218-220.
40 曾岳祥,谭兰香,周泳昕等.重肝合剂保留灌肠阻抑重型肝炎内毒素血症的临床研究.中西医结合肝病杂志,2009,19(3)：134-136.
41 谭善忠,徐乾,杨觉民等.足三里穴位注射小剂量地塞米松小剂量地塞米松治疗肝衰竭早期疗效分析.中西医结合肝病杂志,2009,19(4)：241-243.
42 Dernertriou AA,Brown RS Jr,Busuttil RW,et al.Prospective randomized multicenter controlled trial of a bioartificial liver in treating acute liver failure.Ann surg,2004,239:660.
43 Sauer IM,Kardassis D,Zeillinger K,ea al.Clinical extracorporeal hybrid liver support-phase I study with primary porcine liver cells. Xenotransplantation, 2003,10:460.
44 李兰娟,杨芊,黄建荣等.混合型人工肝支持系统治疗慢性重型肝炎疗效研究.透析与人工器官,2004,1：21.
45 De Bartolo L,Morelli S,Piscioneri A,et al.Novel membranes and surface modification able to activate specific cellular responses.Biomo lecular Engineering,2007,24:23.
46陈志,王英杰,张世昌等.聚砜膜生物反应器实验系统构建及对重型肝炎患者血浆的影响.中国组织工程研究与临床康复,2008,12(6)：1175-1178.
47 Huang JR, Du WB.A brief regarding the Fourth International Symposium on Hepatic Failure and Artificial Liver. CHINESE JOURNAL OF HEPATOLOGY.2007,15(7):551.
48.黄建荣,杜维波.第四届国际暨全国肝衰竭与人工肝学术会议纪要.中华肝脏病杂志,2007,15(7)：551.
49.Tong YL, Huang JR, Chen YM. Effect observation of selective plasma exchange in treating chronic sever hepatitis. Zhonghua Chuanranbing Zazhi,2006,24:124-126.童娅玲,黄建荣,陈月美.选择性血浆置换治疗慢性重型肝炎临床疗效观察.中华传染病杂志,2006,24：124-126.
50.喻成波,杨京,曹红翠等.慢性重型乙型肝炎人工肝血浆置换疗法的临床研究2008,35(1)：4-6.
51.袁雯霞,黄建荣.非生物型人工肝治疗肝衰竭的现状.内科急危重症杂志,2009,15(3)：122-124.
52. Adham M. Extracorporeal liver support:waiting for the deciding vote J. ASAIO Journal,2003,621-632.
53.中华医学会感染病学分会肝衰竭与人工肝学组.非生物型人工肝支持系统治疗肝衰竭指南(2009年版).中华临床感染病杂志,2009,2(6)：321-325.
54.金洁,叶卫江,俞海燕等.缓慢性血浆置换同步并联血液滤过治疗慢性乙型重型肝炎.中华肝脏病杂志,2009,17(2)：95-98.
55.胡肖兵,高洪波,廖明儿等.不同物理型人工肝治疗模式早期救治慢性重型肝炎疗效比较.中国中西医结合急救杂志,2008,15(2)：117-119.
56. Singer AL, Olthoff KM, Kim H, Rand E, Zamir G, Shaked A. Role of plasmapheresis in the management of acute hepatic failure in children. Ann Surg 2001;234:418-24.
57. Heemann U, Treichel U, Loock J, et al. Albumin dialysis in cirrhosis with superimposed acute liver injury:a prospective, controlled study. Hepatology.2002; 36:949-958.
58.刘国旺,曹武奎,唐克诚.改良Port配方在重型肝炎血液滤过治疗中的应用.天津医药,2009,37(3)：228-229.
59.郑树森.我国肝移植的现状和展望.中华外科杂志,2009,47(1)：27-29.
60. Xi ZF, Xia Q, Zhang JJ, et al.The role of entecavir in preventing hepatitis B recurrence after liver transplantation. J Dig Dis.2009,10(4):321-7.
61. Wu LM, Xu X, Zheng SS.Hepatitis B virus reinfection after liver transplantation: related risk factors and perspective. Hepatobiliary Pancreat Dis Int. 2005,4(4):502-8.
1 Li LJ, Yang Q, Huang JR, et al. Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases. World J Gastroenterol, 2004,10:2984-2988.
2 Tong YL, Huang JR, Chen YM. Effect observation of selective plasma exchange in treating chronic sever hepatitis. Zhonghua Chuanranbing Zazhi,2006,24:124-126.童娅玲,黄建荣,陈月美.选择性血浆置换治疗慢性重型肝炎临床疗效观察.中华传染病杂志,2006,24：124-126.
3 Yang YF, Wei LL, Zhang N, et al. The efficacy of artificial liver support system treatment on hepatic failure in China:a meta-analysis. Chin J Hepatol,2006, 14(10):732-734.
4.杨永峰,魏林玲,张宁等.国内人工肝支持系统治疗重型肝炎疗效的Meta分析.中华肝脏病杂志,2006,14(10)：732-734.
5. Splendiani G, Tancredi M, Daniele M, et al. Treatment of acute liver failure with hemodetoxification techniques J. Int J Artif Organs,1990-06,13(6):370-374.
6. Li LJ, Progress in clinical application of artificial liver support systems. Chin J Hepatol,2005,13(11):844-855.
7.李兰娟,人工肝临床应用若干进展.中华肝脏病杂志,2005,13(11)：844-855.
8.黄建荣.非生物型人工肝支持系统新技术.药品评价,2007,4(1)：17-19.
9. Adham M. Extracorporeal liver support:waiting for the deciding vote J. ASAIO Journal,2003,621-632.
10 中华传染病与寄生虫病学会人工肝学组.人工肝支持系统治疗的操作指南J中华肝脏病杂志,2002,10(5)：329-333.
11 Biancofiore G, Bindi LM, Urbani L, et al. Combined twice-dailv plasma exchange and continuous veno-venous hemodialiltration for bridsing severe acute liver failure. Transplant Proc,2003,35(8):3011-3014.
12. Xu B, Jiang JJ, Lin Z, et al. Easy method for separation and recovery of albumin and clearance of bilirubin from plasma. Chin J Clini Hepatol,2002,18(6):340-341.
13.徐兵,江家骥,林灼等.简便法分离回收血浆白蛋白并清除胆红素.临床肝胆病杂志,2002,18(6)：340-341.