李氏人工肝系统治疗乙肝慢加急性肝衰竭的疗效和预后评价
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摘要
乙肝病毒慢性感染过程中可能发生急性发作引起重型肝炎(慢加急性肝衰竭)、肝硬化、肝癌等情况,造成了巨大的社会负担和经济负担。乙肝肝衰竭病情危重,进展迅速,预后极差,目前内科综合治疗仍缺乏特效的治疗药物,病死率高达70%。李氏人工肝系统(Li's artificial liver system, Li-ALS)治疗重型肝炎肝衰竭获得重大突破,显著降低了患者病死率。早在2005年,李兰娟院士领导的人工肝团队就提出血浆置换联合血液滤过治疗中、晚期慢性乙型重型肝炎的疗效优于血浆置换的观点。本文进行了李氏人工肝系统血浆置换滤过方法治疗乙肝慢加急性肝衰竭35例的病例分析。
本文以浙大一院人工肝中心2011.6.1到2012.1.30期间采用李氏人工肝系统血浆置换滤过方法治疗的乙肝慢加急性肝衰竭患者为研究对象,通过回顾性研究,分析了李氏人工肝系统治疗前后各种指标的变化,并建立了Cox比例风险回归模型,分析了影响慢加急性肝衰竭预后的因素。
李氏人工肝系统血浆置换滤过方法治疗前后血三系都发生了显著的降低,并引起了治疗后血生化及凝血指标的极大改善。治疗后谷氨酸、甲硫氨酸、半胱氨酸、酪氨酸、组氨酸显著降低,其余氨基酸治疗后数值低于治疗前,但差异在统计学上不显著。1月和1年总体生存率分别为51.4%和40.0%。根据肝衰竭不同分期分层,早期1月和1年总体生存率分别为75.0%和50.0%；中期1月和1年总体生存率分别为63.2%和47.4%；晚期1月和1年总体生存率分别为25.0%和25.0%。用Cox比例风险回归模型进行回归分析,得到四个显著的变量：MELD评分(RR=1.379)、白细胞(RR=1.296).HBeAg(RR=0.083).胆碱酯酶/1000(RR=0.552)。
血浆置换既可以除去血液中的中小分子物质和与血浆蛋白结合的大分子毒性物质,同时还可补充肝衰竭患者缺乏的凝血因子、白蛋白等。但其对水电解质平衡以及酸碱失衡等内环境紊乱的调节作用较小,对中小分子物质的清除能力不如血液滤过和透析,对水负荷过重的情况无改善作用,而血液滤过正好弥补了这些不足。晚期患者体内蓄积的毒素高于早、中期,李氏人工肝系统血浆置换滤过方法经过持续性的血液滤过,更大程度上清除了血液中的毒素从而进一步提高了晚期患者生存率。
In the progress of chronic HBV infection, severe hepatitis (acute on chronic liver failure, ACLF), cirrhosis, hepatic carcinoma can occure and cause substantial social and economical burden. Hepatitis B liver failure is a critical condition with rapid progress and poor prognosis, currently there is still a lack of the effective medical treatment, mortality rate is as high as70%. Li's artificial liver system, short for Li-ALS, achieved a major breakthrough in treatment of severe hepatits liver failure, and significantly reduced the mortality of patients. As early as2005, Academician Li Lanjuan and her team pointed out that combination of plasma exchange and continuous veno-venous hemofiltration is superior in treatment of mid-stage and late-stage chronic HBV-induced severe hepatits. This thesis is a case analysis of35hepatitis B ACLF patients treated with Li-ALS plasma exchange hemofiltration method.
The study object is hepatitis B ACLF patients who was admitted in the first affiliated hospital, Zhejiang Univ. and treated with Li-ALS in the artificial liver center during2011.6.1and2012.1.30. By retrospective study, different index pre-and post Li-ALS treatment were analyzed, besides, a Cox proportional hazards regression model was established to analyze the impacting factors of prognosis.
After the treatment of Li-ALS plasma exchange hemofiltration method, blood cells declined significantly, while biochemical index and coagulation fuction were vastly improved. Glutamic acid, methionine, cysteine, tyrosine, histidine decreased after Li-ALS treatment. The survival rate of1month and1year was51.4%and40.0%, respectively. When stratified according to different stage of liver failure, the survival rate of1month and1year was75.0%and50.0%for early stage,63.2%and47.4%for mid-stage,25.0%and25.0%for late stage. Four factors, MELD score (RR=1.379), white blood cell (RR=1.296), HBeAg (RR=0.083) and cholinesterase/1000(RR=0.552), were significant in the Cox proportional hazards regression model.
Plasma Exchange could exclude middle and small molecular weight substance and more importatly large molecular weight toxins binding to plasma proteins, at the same time, coagulation factors and albumin were suplymented. While hemofiltration could maintain the balance of water, electrolytes and PH, and have better clear rate of middle molecular weight substances, which perfectly maked up the deficiencies of plasma exchange. So Li-ALS using plasma exchange hemofiltration method could remove blood toxins in a greater extent and thus further improve the survival rate of late stage patients compared to using Li-ALS plasma exchange method only.
本文以浙大一院人工肝中心2011.6.1到2012.1.30期间采用李氏人工肝系统血浆置换滤过方法治疗的乙肝慢加急性肝衰竭患者为研究对象,通过回顾性研究,分析了李氏人工肝系统治疗前后各种指标的变化,并建立了Cox比例风险回归模型,分析了影响慢加急性肝衰竭预后的因素。
李氏人工肝系统血浆置换滤过方法治疗前后血三系都发生了显著的降低,并引起了治疗后血生化及凝血指标的极大改善。治疗后谷氨酸、甲硫氨酸、半胱氨酸、酪氨酸、组氨酸显著降低,其余氨基酸治疗后数值低于治疗前,但差异在统计学上不显著。1月和1年总体生存率分别为51.4%和40.0%。根据肝衰竭不同分期分层,早期1月和1年总体生存率分别为75.0%和50.0%；中期1月和1年总体生存率分别为63.2%和47.4%；晚期1月和1年总体生存率分别为25.0%和25.0%。用Cox比例风险回归模型进行回归分析,得到四个显著的变量：MELD评分(RR=1.379)、白细胞(RR=1.296).HBeAg(RR=0.083).胆碱酯酶/1000(RR=0.552)。
血浆置换既可以除去血液中的中小分子物质和与血浆蛋白结合的大分子毒性物质,同时还可补充肝衰竭患者缺乏的凝血因子、白蛋白等。但其对水电解质平衡以及酸碱失衡等内环境紊乱的调节作用较小,对中小分子物质的清除能力不如血液滤过和透析,对水负荷过重的情况无改善作用,而血液滤过正好弥补了这些不足。晚期患者体内蓄积的毒素高于早、中期,李氏人工肝系统血浆置换滤过方法经过持续性的血液滤过,更大程度上清除了血液中的毒素从而进一步提高了晚期患者生存率。
In the progress of chronic HBV infection, severe hepatitis (acute on chronic liver failure, ACLF), cirrhosis, hepatic carcinoma can occure and cause substantial social and economical burden. Hepatitis B liver failure is a critical condition with rapid progress and poor prognosis, currently there is still a lack of the effective medical treatment, mortality rate is as high as70%. Li's artificial liver system, short for Li-ALS, achieved a major breakthrough in treatment of severe hepatits liver failure, and significantly reduced the mortality of patients. As early as2005, Academician Li Lanjuan and her team pointed out that combination of plasma exchange and continuous veno-venous hemofiltration is superior in treatment of mid-stage and late-stage chronic HBV-induced severe hepatits. This thesis is a case analysis of35hepatitis B ACLF patients treated with Li-ALS plasma exchange hemofiltration method.
The study object is hepatitis B ACLF patients who was admitted in the first affiliated hospital, Zhejiang Univ. and treated with Li-ALS in the artificial liver center during2011.6.1and2012.1.30. By retrospective study, different index pre-and post Li-ALS treatment were analyzed, besides, a Cox proportional hazards regression model was established to analyze the impacting factors of prognosis.
After the treatment of Li-ALS plasma exchange hemofiltration method, blood cells declined significantly, while biochemical index and coagulation fuction were vastly improved. Glutamic acid, methionine, cysteine, tyrosine, histidine decreased after Li-ALS treatment. The survival rate of1month and1year was51.4%and40.0%, respectively. When stratified according to different stage of liver failure, the survival rate of1month and1year was75.0%and50.0%for early stage,63.2%and47.4%for mid-stage,25.0%and25.0%for late stage. Four factors, MELD score (RR=1.379), white blood cell (RR=1.296), HBeAg (RR=0.083) and cholinesterase/1000(RR=0.552), were significant in the Cox proportional hazards regression model.
Plasma Exchange could exclude middle and small molecular weight substance and more importatly large molecular weight toxins binding to plasma proteins, at the same time, coagulation factors and albumin were suplymented. While hemofiltration could maintain the balance of water, electrolytes and PH, and have better clear rate of middle molecular weight substances, which perfectly maked up the deficiencies of plasma exchange. So Li-ALS using plasma exchange hemofiltration method could remove blood toxins in a greater extent and thus further improve the survival rate of late stage patients compared to using Li-ALS plasma exchange method only.
引文
Biancofiore, G., L. M. Bindi, et al. (2003). "Combined twice-daily plasma exchange and continuous veno-venous hemodiafiltration for bridging severe acute liver failure." Transplant Proc 35(8):3011-3014.
Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ, Lawrence Erlbaum Associates.
Jin, J., W. J. Ye, et al. (2009). "[Combined slower plasma exchange and continuous veno-venous hemofiltration with a parallel circuit in the treatment of chronic severe viral hepatitis B patients.]." Zhonghua Gan Zang Bing Za Zhi 17(2):95-98.
Li, J., J. Xin, et al. (2012). "Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure." J Proteome Res.
Li, L. J., Q. Yang, et al. (2004). "Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases." World J Gastroenterol 10(20): 2984-2988.
Lou, Y. F., W. Dong, et al. (2012). "Changes in peripheral T-lymphocyte subsets in acute-on-chronic liver failure patients with artificial liver support system." Hepatogastroenterology 59(115):814-817.
Nakae, H., C. Yonekawa, et al. (2001). "Effectiveness of combining plasma exchange and continuous hemodiafiltration (combined modality therapy in a parallel circuit) in the treatment of patients with acute hepatic failure." Ther Apher 5(6):471-475.
Sadamori, H., T. Yagi, et al. (2002). "High-flow-rate haemodiafiltration as a brain-support therapy proceeding to liver transplantation for hyperacute fulminant hepatic failure." Eur J Gastroenterol Hepatol 14(4):435-439.
Xu, X., X. Liu, et al. (2013). "Artificial Liver Support System Combined with Liver Transplantation in the Treatment of Patients with Acute-on-Chronic Liver Failure." PLoS One 8(3):e58738.
Zhai, S., L. Zhang, et al. (2011). "The ratio of Th-17 to Treg cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure." Viral Immunol 24(4):303-310.
Zheng, M. H., K. Q. Shi, et al. (2013). "A model to predict 3-month mortality risk of acute-on-chronic hepatitis B liver failure using artificial neural network." J Viral Hepat 20(4):248-255.
叶卫江,李兰娟,et al. (2005).“血浆置换联合血液滤过治疗慢性乙型重型肝炎的临床研究.”中华肝脏病杂志13(5)：370-373.
中华医学会肝病学分会and中华医学会感染病学分会(2011).“慢性乙型肝炎防治指南(2010年版).”中华传染病杂志29(2)：65-80.
中华医学会感染病学分会肝衰竭与人工肝学组and中华医学会肝病学分会重型肝病与人工肝学组(2012).”肝衰竭诊治指南(2012年版).”中华临床感染病杂志5(6)：321-327.
Amer, M. E., S. Z. El-Sayed, et al. (2011). "Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells." Eur J Gastroenterol Hepatol 23(10):936-941.
Aupet, S., G. Simone, et al. (2013). "Isolation of Viable Human Hepatic Progenitors from Adult Livers Is Possible Even After 48 Hours of Cold Ischemia." Tissue Eng Part C Methods.
Baharvand, H., S. M. Hashemi, et al. (2008). "Differentiation of human embryonic stem cells into functional hepatocyte-like cells in a serum-free adherent culture condition." Differentiation 76(5):465-477.
Banas. A., T. Teratani, et al. (2007). "Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes." Hepatologv 46(1):219-228.
Bin, W. T., L. M. Ma, et al. (2012). "Embryonic hepatocyte transplantation for hepatic cirrhosis:efficacy and mechanism of action." World J Gastroenterol 18(4): 309-322.
Cao, H., J. Yang, et al. (2012). "Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure." BMC Med 10:56.
Chen, Y. F., C. Y. Tseng, et al. (2012). "Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol." Hepatologv 55(4):1193-1203.
Christ, B. and P. Stock (2012). "Mesenchymal stem cell-derived hepatocytes for functional liver replacement." Front Immunol 3:168.
Ezzat, T., D. K. Dhar, et al. (2012). "Dynamic tracking of stem cells in an acute liver failure model." World J Gastroenterol 18(6):507-516.
Gasbarrini, A., G L. Rapaccini, et al. (2007). "Rescue therapy by portal infusion of autologous stem cells in a case of drug-induced hepatitis." Dig Liver Dis 39(9): 878-882.
Gridelli, B., G. Vizzini, et al. (2012). "Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell-based therapy and case report on cell transplantation." Liver Transpl 18(2):226-237.
Hong, S. H., E. J. Gang, et al. (2005). "In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells." Biochem Biophys Res Commun 330(4):1153-1161.
Jiang, Y, B. N. Jahagirdar, et al. (2002). "Pluripotency of mesenchymal stem cells derived from adult marrow." Nature 418(6893):41-49.
Jones, E. A., D. Tosh, et al. (2002). "Hepatic differentiation of murine embryonic stem cells." Exp Cell Res 272(1):15-22.
Kamimura, R., T. Ishii, et al. (2012). "Comparative study of transplantation of hepatocytes at various differentiation stages into mice with lethal liver damage." Cell Transplant.
Khan, A. A., N. Parveen, et al. (2008). "Safety and efficacy of autologous bone marrow stem cell transplantation through hepatic artery for the treatment of chronic liver failure:a preliminary study." Transplant Proc 40(4):1140-1144.
Kim, M. Y., S. K. Baik, et al. (2012). "THE EVALUATION OF EFFECTIVENESS AND SAFETY FOR NEW THERAPY WITH BONE MARROW DERIVED AUTOLOGOUS MESENCHYMAL STEM CELL FOR HEPATIC FAILURE CAUSED BY ALCOHOLIC LIVER CIRRHOSIS; PHASE II STUDY." Journal of Hepatology 56:S151-S151.
Kuai, X. L., X. Q. Cong, et al. (2006). "Treatment of surgically induced acute liver failure by transplantation of HNF4-overexpressing embryonic stem cells." Chin J Dig Dis 7(2):109-116.
Li, J., J. Xin, et al. (2012). "Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure." J Proteome Res.
Lin, H., Z. Zhang, et al. (2012). "[Prospective controlled trial of safety of human umbilical cord derived-mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis]." Zhonghua Gan Zang Bing Za Zhi 20(7):487-491.
Miryounesi, M., A. Piryaei, et al. (2013). "Repeated versus single transplantation of mesenchymal stem cells in carbon tetrachloride-induced liver injury in mice." Cell Biol Int.
Mohamadnejad, M., K. Alimoghaddam, et al. (2012). "Prospective randomized placebpo-controlled trial of bone marrow mesenchymal stem cell transplantation in decompensated cirrhosis." Hepatology 56:920A-920A.
Moslem. M., M. R. Valojerdi, et al. (2013). "Therapeutic Potential of Human-induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells in Mice with Lethal Fulminant Hepatic Failure." Cell Transplant.
Parekkadan, B., D. van Poll, et al. (2007). "Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure." PLoS One 2(9):e941.
Peng, L., D. Y. Xie, et al. (2011). "Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B:short-term and long-term outcomes." Hepatology 54(3):820-828.
Petersen, B. E., W. C. Bowen, et al. (1999). "Bone marrow as a potential source of hepatic oval cells." Science 284(5417):1168-1170.
Rastogi, A., C. Bihari, et al. (2012). "Hepatic stellate cells are involved in the pathogenesis of acute-on-chronic liver failure (ACLF)." Virchows Arch 461(4): 393-398.
Salama, H., A. R. Zekri, et al. (2010). "Autologous CD34+ and CD 133+ stem cells transplantation in patients with end stage liver disease." World J Gastroenterol 16(42):5297-5305.
Schwartz, R. E., M. Reyes, et al. (2002). "Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells." J Clin Invest 109(10): 1291-1302.
Seo, M. J., S. Y. Suh, et al. (2005). "Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo." Biochem Biophys Res Commun 328(1): 258-264.
Shi, M., Z. Zhang, et al. (2012). "Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients." Stem Cells Transl Med 1(10):725-731.
Spahr, L., Y. Chalandon, et al. (2013). "Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease:a randomized controlled trial." PLoS One 8(1):e53719.
Thomson, J. A., J. Itskovitz-Eldor, et al. (1998). "Embryonic stem cell lines derived from human blastocysts." Science 282(5391):1145-1147.
Turner, R. A., E. Wauthier, et al. (2013). "Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts." Hepatology 57(2):775-784.
Watt, A. J. and L. M. Forrester (2006). "Deriving and identifying hepatocytes from embryonic stem cells." Stem Cell Rev 2(1):19-22.
Wesson, R. N. and A. M. Cameron (2011). "Stem cells in acute liver failure." Adv Surg 45:117-130.
Yukawa, H., M. Watanabe, et al. (2012). "Monitoring transplanted adipose tissue-derived stem cells combined with heparin in the liver by fluorescence imaging using quantum dots." Biomaterials 33(7):2177-2186.
Zagoura, D. S., M. G. Roubelakis, et al. (2012). "Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure." Gut 61(6):894-906.
Zhang, F. T., H. J. Wan, et al. (2011). "Transplantation of microencapsulated umbilical-cord-blood-derived hepatic-like cells for treatment of hepatic failure." World J Gastroenterol 17(7):938-945.
Zhang, Z., H. Lin, et al. (2012). "Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients." J Gastroenterol Hepatol 27 Suppl 2:112-120.
Zhu, W., X. L. Shi, et al. (2013). "Effects of xenogeneic adipose-derived stem cell transplantation on acute-on-chronic liver failure." Hepatobiliary Pancreat Dis Int 12(1):60-67.
李兰娟(2012).“肝衰竭临床治疗中的难点和热点.”中华肝脏病杂志20(6).
于颖彦,计骏,et al.(2007).“肝衰竭肝脏的组织病理学变化及其干细胞活化情况.”中华病理学杂志36(11)：4.
Cohen, J. (1988). Statistical Power Analysis for the Behavioral Sciences. Hillsdale, NJ, Lawrence Erlbaum Associates.
Jin, J., W. J. Ye, et al. (2009). "[Combined slower plasma exchange and continuous veno-venous hemofiltration with a parallel circuit in the treatment of chronic severe viral hepatitis B patients.]." Zhonghua Gan Zang Bing Za Zhi 17(2):95-98.
Li, J., J. Xin, et al. (2012). "Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure." J Proteome Res.
Li, L. J., Q. Yang, et al. (2004). "Effect of artificial liver support system on patients with severe viral hepatitis:a study of four hundred cases." World J Gastroenterol 10(20): 2984-2988.
Lou, Y. F., W. Dong, et al. (2012). "Changes in peripheral T-lymphocyte subsets in acute-on-chronic liver failure patients with artificial liver support system." Hepatogastroenterology 59(115):814-817.
Nakae, H., C. Yonekawa, et al. (2001). "Effectiveness of combining plasma exchange and continuous hemodiafiltration (combined modality therapy in a parallel circuit) in the treatment of patients with acute hepatic failure." Ther Apher 5(6):471-475.
Sadamori, H., T. Yagi, et al. (2002). "High-flow-rate haemodiafiltration as a brain-support therapy proceeding to liver transplantation for hyperacute fulminant hepatic failure." Eur J Gastroenterol Hepatol 14(4):435-439.
Xu, X., X. Liu, et al. (2013). "Artificial Liver Support System Combined with Liver Transplantation in the Treatment of Patients with Acute-on-Chronic Liver Failure." PLoS One 8(3):e58738.
Zhai, S., L. Zhang, et al. (2011). "The ratio of Th-17 to Treg cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure." Viral Immunol 24(4):303-310.
Zheng, M. H., K. Q. Shi, et al. (2013). "A model to predict 3-month mortality risk of acute-on-chronic hepatitis B liver failure using artificial neural network." J Viral Hepat 20(4):248-255.
叶卫江,李兰娟,et al. (2005).“血浆置换联合血液滤过治疗慢性乙型重型肝炎的临床研究.”中华肝脏病杂志13(5)：370-373.
中华医学会肝病学分会and中华医学会感染病学分会(2011).“慢性乙型肝炎防治指南(2010年版).”中华传染病杂志29(2)：65-80.
中华医学会感染病学分会肝衰竭与人工肝学组and中华医学会肝病学分会重型肝病与人工肝学组(2012).”肝衰竭诊治指南(2012年版).”中华临床感染病杂志5(6)：321-327.
Amer, M. E., S. Z. El-Sayed, et al. (2011). "Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells." Eur J Gastroenterol Hepatol 23(10):936-941.
Aupet, S., G. Simone, et al. (2013). "Isolation of Viable Human Hepatic Progenitors from Adult Livers Is Possible Even After 48 Hours of Cold Ischemia." Tissue Eng Part C Methods.
Baharvand, H., S. M. Hashemi, et al. (2008). "Differentiation of human embryonic stem cells into functional hepatocyte-like cells in a serum-free adherent culture condition." Differentiation 76(5):465-477.
Banas. A., T. Teratani, et al. (2007). "Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes." Hepatologv 46(1):219-228.
Bin, W. T., L. M. Ma, et al. (2012). "Embryonic hepatocyte transplantation for hepatic cirrhosis:efficacy and mechanism of action." World J Gastroenterol 18(4): 309-322.
Cao, H., J. Yang, et al. (2012). "Therapeutic potential of transplanted placental mesenchymal stem cells in treating Chinese miniature pigs with acute liver failure." BMC Med 10:56.
Chen, Y. F., C. Y. Tseng, et al. (2012). "Rapid generation of mature hepatocyte-like cells from human induced pluripotent stem cells by an efficient three-step protocol." Hepatologv 55(4):1193-1203.
Christ, B. and P. Stock (2012). "Mesenchymal stem cell-derived hepatocytes for functional liver replacement." Front Immunol 3:168.
Ezzat, T., D. K. Dhar, et al. (2012). "Dynamic tracking of stem cells in an acute liver failure model." World J Gastroenterol 18(6):507-516.
Gasbarrini, A., G L. Rapaccini, et al. (2007). "Rescue therapy by portal infusion of autologous stem cells in a case of drug-induced hepatitis." Dig Liver Dis 39(9): 878-882.
Gridelli, B., G. Vizzini, et al. (2012). "Efficient human fetal liver cell isolation protocol based on vascular perfusion for liver cell-based therapy and case report on cell transplantation." Liver Transpl 18(2):226-237.
Hong, S. H., E. J. Gang, et al. (2005). "In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells." Biochem Biophys Res Commun 330(4):1153-1161.
Jiang, Y, B. N. Jahagirdar, et al. (2002). "Pluripotency of mesenchymal stem cells derived from adult marrow." Nature 418(6893):41-49.
Jones, E. A., D. Tosh, et al. (2002). "Hepatic differentiation of murine embryonic stem cells." Exp Cell Res 272(1):15-22.
Kamimura, R., T. Ishii, et al. (2012). "Comparative study of transplantation of hepatocytes at various differentiation stages into mice with lethal liver damage." Cell Transplant.
Khan, A. A., N. Parveen, et al. (2008). "Safety and efficacy of autologous bone marrow stem cell transplantation through hepatic artery for the treatment of chronic liver failure:a preliminary study." Transplant Proc 40(4):1140-1144.
Kim, M. Y., S. K. Baik, et al. (2012). "THE EVALUATION OF EFFECTIVENESS AND SAFETY FOR NEW THERAPY WITH BONE MARROW DERIVED AUTOLOGOUS MESENCHYMAL STEM CELL FOR HEPATIC FAILURE CAUSED BY ALCOHOLIC LIVER CIRRHOSIS; PHASE II STUDY." Journal of Hepatology 56:S151-S151.
Kuai, X. L., X. Q. Cong, et al. (2006). "Treatment of surgically induced acute liver failure by transplantation of HNF4-overexpressing embryonic stem cells." Chin J Dig Dis 7(2):109-116.
Li, J., J. Xin, et al. (2012). "Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure." J Proteome Res.
Lin, H., Z. Zhang, et al. (2012). "[Prospective controlled trial of safety of human umbilical cord derived-mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis]." Zhonghua Gan Zang Bing Za Zhi 20(7):487-491.
Miryounesi, M., A. Piryaei, et al. (2013). "Repeated versus single transplantation of mesenchymal stem cells in carbon tetrachloride-induced liver injury in mice." Cell Biol Int.
Mohamadnejad, M., K. Alimoghaddam, et al. (2012). "Prospective randomized placebpo-controlled trial of bone marrow mesenchymal stem cell transplantation in decompensated cirrhosis." Hepatology 56:920A-920A.
Moslem. M., M. R. Valojerdi, et al. (2013). "Therapeutic Potential of Human-induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells in Mice with Lethal Fulminant Hepatic Failure." Cell Transplant.
Parekkadan, B., D. van Poll, et al. (2007). "Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure." PLoS One 2(9):e941.
Peng, L., D. Y. Xie, et al. (2011). "Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B:short-term and long-term outcomes." Hepatology 54(3):820-828.
Petersen, B. E., W. C. Bowen, et al. (1999). "Bone marrow as a potential source of hepatic oval cells." Science 284(5417):1168-1170.
Rastogi, A., C. Bihari, et al. (2012). "Hepatic stellate cells are involved in the pathogenesis of acute-on-chronic liver failure (ACLF)." Virchows Arch 461(4): 393-398.
Salama, H., A. R. Zekri, et al. (2010). "Autologous CD34+ and CD 133+ stem cells transplantation in patients with end stage liver disease." World J Gastroenterol 16(42):5297-5305.
Schwartz, R. E., M. Reyes, et al. (2002). "Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells." J Clin Invest 109(10): 1291-1302.
Seo, M. J., S. Y. Suh, et al. (2005). "Differentiation of human adipose stromal cells into hepatic lineage in vitro and in vivo." Biochem Biophys Res Commun 328(1): 258-264.
Shi, M., Z. Zhang, et al. (2012). "Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients." Stem Cells Transl Med 1(10):725-731.
Spahr, L., Y. Chalandon, et al. (2013). "Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease:a randomized controlled trial." PLoS One 8(1):e53719.
Thomson, J. A., J. Itskovitz-Eldor, et al. (1998). "Embryonic stem cell lines derived from human blastocysts." Science 282(5391):1145-1147.
Turner, R. A., E. Wauthier, et al. (2013). "Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts." Hepatology 57(2):775-784.
Watt, A. J. and L. M. Forrester (2006). "Deriving and identifying hepatocytes from embryonic stem cells." Stem Cell Rev 2(1):19-22.
Wesson, R. N. and A. M. Cameron (2011). "Stem cells in acute liver failure." Adv Surg 45:117-130.
Yukawa, H., M. Watanabe, et al. (2012). "Monitoring transplanted adipose tissue-derived stem cells combined with heparin in the liver by fluorescence imaging using quantum dots." Biomaterials 33(7):2177-2186.
Zagoura, D. S., M. G. Roubelakis, et al. (2012). "Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure." Gut 61(6):894-906.
Zhang, F. T., H. J. Wan, et al. (2011). "Transplantation of microencapsulated umbilical-cord-blood-derived hepatic-like cells for treatment of hepatic failure." World J Gastroenterol 17(7):938-945.
Zhang, Z., H. Lin, et al. (2012). "Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients." J Gastroenterol Hepatol 27 Suppl 2:112-120.
Zhu, W., X. L. Shi, et al. (2013). "Effects of xenogeneic adipose-derived stem cell transplantation on acute-on-chronic liver failure." Hepatobiliary Pancreat Dis Int 12(1):60-67.
李兰娟(2012).“肝衰竭临床治疗中的难点和热点.”中华肝脏病杂志20(6).
于颖彦,计骏,et al.(2007).“肝衰竭肝脏的组织病理学变化及其干细胞活化情况.”中华病理学杂志36(11)：4.