熊去氧胆酸联合中药治疗原发性胆汁性肝硬化临床研究
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摘要
目的
原发性胆汁性肝硬化(primary biliary cirrhosis, PBC)是一种病因未明的慢性进行性胆汁淤积性自身免疫性肝脏疾病,多见于中年女性。病理改变主要是由自身免疫介导的,以肝内细小胆管的慢性非化脓性炎症、慢性胆汁淤积、肝纤维化为特征,最终可发展为肝硬化。近年来,随着国内外对该病研究的深入及对其认识的加深,此病的检出率也明显上升。但是目前对于此病的病因尚未完全查明,因此尚无特异的治疗措施,主要是对症和支持治疗。由于熊去氧胆酸(UDCA)可通过免疫调节、增加内源性胆汁酸的分泌和保护肝细胞膜等机制而发挥其改善患者肝功能和延缓疾病进程的作用,对于早期病变有一定的疗效。是目前被公认的具有确实疗效的首选药物。而激素、硫唑嘌呤和甲氨蝶呤等西药疗效不肯定,且有较严重的不良反应,临床上常与UDCA联合使用。中医药在治疗自身免疫性疾病及抗肝纤维化方面已得到了广泛的肯定。为进一步提高治疗本病的疗效,对本病患者采用UDCA联合中医药辨证治疗,并与单纯服用UDCA及单纯服用中药的患者进行对比,从而观察并研究中西医联合治疗对原发性胆汁性肝硬化的临床疗效。
方法
所有病例均为2007年12月至2010年2月就诊于本院门诊及住院的病人,共有56例,且都符合PBC的临床诊断标准。对这些患者随机分为单用中药治疗组20例(A组)、单用UDCA治疗组15例(B组)和联合中药及UDCA治疗组21例(C组)。对于A组及C组病人,按照中医辨证施治的原则,分为瘀血内停型、湿热中阻型、肝郁脾虚型及肝肾阴虚型四型,分别以膈下逐瘀汤、茵陈蒿汤、柴胡疏肝散及一贯煎为主方,随症加减相应药物；B组病人单用UDCA 250mg/次,口服,日3次；C组则在服用UDCA的同时,配合中医辨证施治,服用相应中药方剂。分别观察治疗4、12、24周后,主要临床症状体征及主要生化、免疫指标的改变。并对治疗后的有效率及按Child-Pugh标准分级的变化等相关指标进行对比。对治疗后各项相关指标的变化使用SPSS13.0软件进行相应的统计学分析。
结果
(1)症状体征改善方面有瘙痒、乏力及黄疸等症状的患者,三组病人在4、12及24周时症状及体征均有所改善,但在12及24周时,A组和C组病人症状及体征的改善好转较B组病人明显,具有显著性差异(P<0.05)；B组部分病人症状改善不明显；(2)主要生化指标的改变24周时,三组病人的主要生化指标均较前有所改善,尤以C组改善较为明显。且在24周时C组病人主要生化指标的改善较A、B两组病人的改善具有显著性差异(P<0.05)；同时B组大部分病人的主要生化指标较治疗前也有明显改善(P<0.05)。但A组对主要生化指标的改善均不及B组及C组明显。且B组在降低TBIL及GGT方面较A组更为明显(P<0.05)；(3)主要免疫指标的改变单纯服用UDCA的B组病人经治疗后,主要免疫指标IgG、IgM、IgA的改善较单纯服用中药的A组更为明显,但无显著性差异(P>0.05)。C组病人经治疗后,主要免疫指标较治疗前均有明显改善(P<0.05)。与A组相比,也有较明显差异(P<0.05)；(4)按Child-Pugh标准评分分级对比对所有病人按照Child-Pugh标准进行评估分级,并对处于不同等级的病人数及在本组病人总数中所占百分比进行统计和对比,三组病人在治疗前各级病人数及所占比例无显著性差异(P>0.05),在12周及24周时对A级的病例数及所占比例进行比较,C组A级病人数较治疗前有明显增多,但与治疗前相比无显著性差异(P>0.05)。
结论
(1)单用UDCA在治疗PBC时,对早中期病例效果较为显著,尤其是在改善患者的主要生化及免疫指标方面。但是对于晚期患者,则效果欠佳；(2)中药在改善PBC患者的主要生化及免疫指标方面,虽不及UDCA明显,但中药可有效改善患者的症状及体征。(3) UDCA联合中药辨症治疗PBC可发挥各自的优势,较单用UDCA治疗效果更好,值得临床进一步推广应用。
Objective
Primary biliary cirrhosis (PBC) is an unexplained and chronic progressive cholestatic autoimmune liver disease, it's more common in middle-aged women.The main pathological changes are mediated by its own immune ,and its characteristics are chronic non-suppurative inflammation in intrahepatic small bile ducts, chronic cholestasis and liver fibrosis,in the end it can develop cirrhosis. In recent years, international and domestic research on the disease are more deeper and knowledge about the disease are followed to enhance, detection rate about the disease is significantly increased. But now the causes about the disease has not yet fully identified, so there is no specific treatment measures, mainly symptomatic and supportive treatment. As ursodeoxycholic acid (UDCA) can improver liver function of patients and delay disease progression by regulating the immune、increasing secretion of endogenous bile acid、protect the liver cell membrane and other mechanism. It have a certain effect in early lesions of the disease. It is currently recognized as a really effective drug of choice. But efficacy of western medicines such as the hormone, azathioprine and methotrexate etc. is not sure, and there are more severe adverse reactions, it often used with UDCA. Chinese medicine has been widely affirmed in treating autoimmune diseases and hepatic fibrosis. To further enhance the efficacy in treating the disease, let the patients of it take UDCA combined with TCM Differential Treatment, and compare with the patients simply taking UDCA patients and simply taking traditional Chinese medicine, to observe and study clinical efficacy of the treatment of primary biliary cirrhosis through integrative medicine of Western Medicine and TCM.
Methods
All cases are outpatient and hospitalized patients from December 2007 to February 2010 in the hospital, a total of 56 cases, and are consistent with the clinical diagnostic criteria of PBC. These patients were randomly divided into three groups,one group of 20 patients treated with traditional Chinese medicine (A group),one group of 15 cases treated with UDCA (B group),and one group of 21 cases combined with TCM and UDCA (C group). The patients in A group and C group, in accordance with the Chinese medicine's principles of observing symptom and giving treatment, are divide into blood stasis type, damp heat resistance type, the liver and liver-kidney deficiency type IV, respectively unliquefaction, tarragon soup, fried CHAIHUSUGAN scattered along the main square and, with the disease by adding or reducing appropriate drugs; patients in B group only take UDCA 250mg/time,3 times a day, po.; patients in C group, while taking UDCA, taking the appropriate prescription of Chinese medicine by following the Chinese medicine's principles of observing symptom and giving treatment. Observe the changes of main clinical symptoms and signs、the major biochemical and immune parameters in 4,12,24 weeks after treatment. And compare the efficient after treatment and the changes of relevant indicators according to Child-Pugh classification standards. And analyses the changes of relevant indicators after treatment by using SPSS13.0 statistical analysis software.
Results
(1) improvement of symptoms and signs the patients that feeling itching, fatigue ,jaundice and other symptoms, there are effective on improvements symptoms and signs in patients of three groups after 4,12 and 24 weeks ,however, in 12 and 24 weeks, the improvement of symptoms and signs in patients of A group and C group are significant through comparing with patients of B group; there are significant difference (P<0.05); but there are no obvious improvement of symptoms in some patients of B group. (2) The changes of major biochemical targets the main biochemical parameters of three groups patients at 24 weeks were improved by comparing with previous parameters, especially in C group, it's more significant. And the improvement of main biochemical targets in C group' patients at 24 weeks are significantly different (P<0.05) in compared with improvement of A, B groups' patients; The major biochemical indicators of most of patients in Group B are significantly improved (P<0.05) by comparing with it before. But the improvements of major biochemical indexes in patients of A group are not significantly by comparing with patients of group B and C. And in lower TBIL and GGT, the group B is more obvious than the group A (P <0.05);(3) The changes of major immune parameters The improvement of main immune targets IgG, IgM, IgA of B group's patients simply taking UDCA after treatment is more obvious than the improvement of patients in group A, but no significant difference (P> 0.05). The major immune parameters of patients of group C after treatment were significantly improved compared with them before treatment (P<0.05). Compared with A group, there is a more significant difference (P<0.05);(4) compare grades according to Child-Pugh scores Assess and classify all the patients in accordance with the Child-Pugh classification assessment criteria, and compare the number of patients at different levels and statistic the percentage, patients of three groups before treatment there is no significant difference (P> 0.05) in the number of different levels and percentage, at 12 weeks and 24 weeks compare the number of A-level and percentage of cases,patients of A-level in C Group increased significantly though comparing with the number of them before treatment, but there was no significant difference (P> 0.05) by comparing with them before treatment.
Conclusion
(1) Only take UDCA in treating PBC, the results were more significant in early and medium-term patients,but the results of advanced cases is ineffective; (2) Compared with single treatment group with TCM, in the improvement of the main biochemical and immunological indices after taking UDCA in some patients were obvious; (3) The effect of treatment by combined traditional Chinese medicine Bianzhenzhiliao with UDCA in treating PBC were better than only take UDCA, and it is worthy of further promotion.
原发性胆汁性肝硬化(primary biliary cirrhosis, PBC)是一种病因未明的慢性进行性胆汁淤积性自身免疫性肝脏疾病,多见于中年女性。病理改变主要是由自身免疫介导的,以肝内细小胆管的慢性非化脓性炎症、慢性胆汁淤积、肝纤维化为特征,最终可发展为肝硬化。近年来,随着国内外对该病研究的深入及对其认识的加深,此病的检出率也明显上升。但是目前对于此病的病因尚未完全查明,因此尚无特异的治疗措施,主要是对症和支持治疗。由于熊去氧胆酸(UDCA)可通过免疫调节、增加内源性胆汁酸的分泌和保护肝细胞膜等机制而发挥其改善患者肝功能和延缓疾病进程的作用,对于早期病变有一定的疗效。是目前被公认的具有确实疗效的首选药物。而激素、硫唑嘌呤和甲氨蝶呤等西药疗效不肯定,且有较严重的不良反应,临床上常与UDCA联合使用。中医药在治疗自身免疫性疾病及抗肝纤维化方面已得到了广泛的肯定。为进一步提高治疗本病的疗效,对本病患者采用UDCA联合中医药辨证治疗,并与单纯服用UDCA及单纯服用中药的患者进行对比,从而观察并研究中西医联合治疗对原发性胆汁性肝硬化的临床疗效。
方法
所有病例均为2007年12月至2010年2月就诊于本院门诊及住院的病人,共有56例,且都符合PBC的临床诊断标准。对这些患者随机分为单用中药治疗组20例(A组)、单用UDCA治疗组15例(B组)和联合中药及UDCA治疗组21例(C组)。对于A组及C组病人,按照中医辨证施治的原则,分为瘀血内停型、湿热中阻型、肝郁脾虚型及肝肾阴虚型四型,分别以膈下逐瘀汤、茵陈蒿汤、柴胡疏肝散及一贯煎为主方,随症加减相应药物；B组病人单用UDCA 250mg/次,口服,日3次；C组则在服用UDCA的同时,配合中医辨证施治,服用相应中药方剂。分别观察治疗4、12、24周后,主要临床症状体征及主要生化、免疫指标的改变。并对治疗后的有效率及按Child-Pugh标准分级的变化等相关指标进行对比。对治疗后各项相关指标的变化使用SPSS13.0软件进行相应的统计学分析。
结果
(1)症状体征改善方面有瘙痒、乏力及黄疸等症状的患者,三组病人在4、12及24周时症状及体征均有所改善,但在12及24周时,A组和C组病人症状及体征的改善好转较B组病人明显,具有显著性差异(P<0.05)；B组部分病人症状改善不明显；(2)主要生化指标的改变24周时,三组病人的主要生化指标均较前有所改善,尤以C组改善较为明显。且在24周时C组病人主要生化指标的改善较A、B两组病人的改善具有显著性差异(P<0.05)；同时B组大部分病人的主要生化指标较治疗前也有明显改善(P<0.05)。但A组对主要生化指标的改善均不及B组及C组明显。且B组在降低TBIL及GGT方面较A组更为明显(P<0.05)；(3)主要免疫指标的改变单纯服用UDCA的B组病人经治疗后,主要免疫指标IgG、IgM、IgA的改善较单纯服用中药的A组更为明显,但无显著性差异(P>0.05)。C组病人经治疗后,主要免疫指标较治疗前均有明显改善(P<0.05)。与A组相比,也有较明显差异(P<0.05)；(4)按Child-Pugh标准评分分级对比对所有病人按照Child-Pugh标准进行评估分级,并对处于不同等级的病人数及在本组病人总数中所占百分比进行统计和对比,三组病人在治疗前各级病人数及所占比例无显著性差异(P>0.05),在12周及24周时对A级的病例数及所占比例进行比较,C组A级病人数较治疗前有明显增多,但与治疗前相比无显著性差异(P>0.05)。
结论
(1)单用UDCA在治疗PBC时,对早中期病例效果较为显著,尤其是在改善患者的主要生化及免疫指标方面。但是对于晚期患者,则效果欠佳；(2)中药在改善PBC患者的主要生化及免疫指标方面,虽不及UDCA明显,但中药可有效改善患者的症状及体征。(3) UDCA联合中药辨症治疗PBC可发挥各自的优势,较单用UDCA治疗效果更好,值得临床进一步推广应用。
Objective
Primary biliary cirrhosis (PBC) is an unexplained and chronic progressive cholestatic autoimmune liver disease, it's more common in middle-aged women.The main pathological changes are mediated by its own immune ,and its characteristics are chronic non-suppurative inflammation in intrahepatic small bile ducts, chronic cholestasis and liver fibrosis,in the end it can develop cirrhosis. In recent years, international and domestic research on the disease are more deeper and knowledge about the disease are followed to enhance, detection rate about the disease is significantly increased. But now the causes about the disease has not yet fully identified, so there is no specific treatment measures, mainly symptomatic and supportive treatment. As ursodeoxycholic acid (UDCA) can improver liver function of patients and delay disease progression by regulating the immune、increasing secretion of endogenous bile acid、protect the liver cell membrane and other mechanism. It have a certain effect in early lesions of the disease. It is currently recognized as a really effective drug of choice. But efficacy of western medicines such as the hormone, azathioprine and methotrexate etc. is not sure, and there are more severe adverse reactions, it often used with UDCA. Chinese medicine has been widely affirmed in treating autoimmune diseases and hepatic fibrosis. To further enhance the efficacy in treating the disease, let the patients of it take UDCA combined with TCM Differential Treatment, and compare with the patients simply taking UDCA patients and simply taking traditional Chinese medicine, to observe and study clinical efficacy of the treatment of primary biliary cirrhosis through integrative medicine of Western Medicine and TCM.
Methods
All cases are outpatient and hospitalized patients from December 2007 to February 2010 in the hospital, a total of 56 cases, and are consistent with the clinical diagnostic criteria of PBC. These patients were randomly divided into three groups,one group of 20 patients treated with traditional Chinese medicine (A group),one group of 15 cases treated with UDCA (B group),and one group of 21 cases combined with TCM and UDCA (C group). The patients in A group and C group, in accordance with the Chinese medicine's principles of observing symptom and giving treatment, are divide into blood stasis type, damp heat resistance type, the liver and liver-kidney deficiency type IV, respectively unliquefaction, tarragon soup, fried CHAIHUSUGAN scattered along the main square and, with the disease by adding or reducing appropriate drugs; patients in B group only take UDCA 250mg/time,3 times a day, po.; patients in C group, while taking UDCA, taking the appropriate prescription of Chinese medicine by following the Chinese medicine's principles of observing symptom and giving treatment. Observe the changes of main clinical symptoms and signs、the major biochemical and immune parameters in 4,12,24 weeks after treatment. And compare the efficient after treatment and the changes of relevant indicators according to Child-Pugh classification standards. And analyses the changes of relevant indicators after treatment by using SPSS13.0 statistical analysis software.
Results
(1) improvement of symptoms and signs the patients that feeling itching, fatigue ,jaundice and other symptoms, there are effective on improvements symptoms and signs in patients of three groups after 4,12 and 24 weeks ,however, in 12 and 24 weeks, the improvement of symptoms and signs in patients of A group and C group are significant through comparing with patients of B group; there are significant difference (P<0.05); but there are no obvious improvement of symptoms in some patients of B group. (2) The changes of major biochemical targets the main biochemical parameters of three groups patients at 24 weeks were improved by comparing with previous parameters, especially in C group, it's more significant. And the improvement of main biochemical targets in C group' patients at 24 weeks are significantly different (P<0.05) in compared with improvement of A, B groups' patients; The major biochemical indicators of most of patients in Group B are significantly improved (P<0.05) by comparing with it before. But the improvements of major biochemical indexes in patients of A group are not significantly by comparing with patients of group B and C. And in lower TBIL and GGT, the group B is more obvious than the group A (P <0.05);(3) The changes of major immune parameters The improvement of main immune targets IgG, IgM, IgA of B group's patients simply taking UDCA after treatment is more obvious than the improvement of patients in group A, but no significant difference (P> 0.05). The major immune parameters of patients of group C after treatment were significantly improved compared with them before treatment (P<0.05). Compared with A group, there is a more significant difference (P<0.05);(4) compare grades according to Child-Pugh scores Assess and classify all the patients in accordance with the Child-Pugh classification assessment criteria, and compare the number of patients at different levels and statistic the percentage, patients of three groups before treatment there is no significant difference (P> 0.05) in the number of different levels and percentage, at 12 weeks and 24 weeks compare the number of A-level and percentage of cases,patients of A-level in C Group increased significantly though comparing with the number of them before treatment, but there was no significant difference (P> 0.05) by comparing with them before treatment.
Conclusion
(1) Only take UDCA in treating PBC, the results were more significant in early and medium-term patients,but the results of advanced cases is ineffective; (2) Compared with single treatment group with TCM, in the improvement of the main biochemical and immunological indices after taking UDCA in some patients were obvious; (3) The effect of treatment by combined traditional Chinese medicine Bianzhenzhiliao with UDCA in treating PBC were better than only take UDCA, and it is worthy of further promotion.
引文
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[3]井上恭一.原发性胆汁性肝硬化的诊疗研究进展[J].日本医学介绍,1997,18(10)：454-455.
[4]姚光弼.重视原发性胆汁性肝硬化的临床研究[J].中华肝脏病杂志,2002,10(5)：325-326.
[5]房静远.原发性胆汁性肝硬化的熊去氧胆酸治疗.肝脏2002；7：116-117.
[6]施健,刘苏,陈伟忠等.中等剂量熊去氧胆酸治疗原发性胆汁性肝硬化的系统评价.中华消化杂志2005：25：355-358·
[7]Pares A, Rodes J.Treatment of primary biliary cirrhosis.Minerva Gastroenterol Dietol 2000;46:165-174.
[8]Fickert P, Zollner G, Fuchsbichler A, et al. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology,2001,121 (1):170-183.)
[9]Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems:clinical implications for understanding and treating cholestasis.J Clin Gastroenterol 2005;39:S111-124)
[10]Van Nieuwkerk CM, Elferink RP,Groen AK, et al. Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology,1996,111(1):165-171.
[11]Lazaridis KN Gores GJ Lindor KD Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders,. J Hepatol 2001; 35:134-146;
[12]Kowdley KV. Ursodeoxycholic acid therapy in hepatobiliary disease. Am J Med 2000; 108:481-486)
[13]Pusl T, Beuers U. Ursodeoxycholic acid treatment of vanishing bile duct syndromes. World J Gastroenterol 2006;12:3487-3495
[14]Paumgartner G. Medical treatment of Cholestatic liver diseases:From pathobiology to pharmacological targets. World J Gastroenterol 2006;12:4445-4451
[15]Qiao L, Yacoub A, Studer E, et al. Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes. Hepatology,2002,35 (4):779-789.
[16]Beuers U, Boyer JL,Paumgartner G. Ursodeoxycholic acid in cholestasis:potential mechanism of action and therapeutic applications. Hepatolpgy,1998,28(5):1449-1453.
[17]TraunerM, Craziadei W. Mechanisms of action and therapeutic applications of ursodeoycholic acid in chronic liver disease. Aliment Pharmacol Ther,1999,13(8):979-996.
[18]Miyachi K, Shibata M, Hasegawa C, Onozuka Y, Fritzler MJ. Case of primary biliary cirrhosis patient with anti-p97/VCP antibodies presenting a mild clinical course. Rinsho Byori 2005; 53:19-23.
[19]Correia L, Podevin P, Borderie D, Verthier N, Montet JC, Feldmann G, Poupon R, Weill B, Calmus Y. Effects of bile acids on the humoral immune response: a mechanistic approach. Life Sci 2001;69:2337- 2348
[20]端木潜何峰王智胜吴志春刘皖生.熊去氧胆酸治疗原发性胆汁性肝硬化1年总结报告[J].实用肝脏病杂志,2009,12(1)：50-52.
[21]Dimoulios P, Kolios G, Notas G, et al. Ursodeoxycholic acid reduces increased circulating endothelin2in primary biliary cirrhosis. Aliment Pharmacol Ther,2005,21:227-234.
[22]Chan CW, Gunsar F, Feud jo M, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis:a follow-up to 12years. Aliment Pharmacol Ther,2005,21:217-226.
[23].Poupon RE, Lindor KD, Pares A, et al. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003:39:12-16.
[24]. Ter Borg PC, Sehalm SW, Hansen BE, et al.Prognosis of ursodeoxycholic Acid-treated
Patients with primary biliary cirrhosis. Results of a10-yr cohort study involving 297patients. Am J Gastroenterol 2006;101:2044-2050.
[25].Ludwig J, Dickson ER, MeDonald GS.Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol 1978; 379:103-112.
[26].邱德凯,马雄主编.自身免疫性肝病基础与临床.上海：上海科学技术出版社,第1版.2006：212.
[27]EASL发布《胆汁淤积性肝病处理指南》.胃肠病学和肝病学杂志2009；18(9)：874.
[28]Heurgue A, Vitry F, Diebold MD, Yaziji N, Bernard-Chabert B, Pennaforte JL, Picot R, Louvet H, Fremond L, Geoffroy P, Schmit JL, Cadiot G, Thief in G.OverlaP syndrome of primary biliary cirrhosis and autoimmune hepatitis:a retrospective study of 115 cases of autoimmune liver disease. Gastroenterol Cli Biol 2007; 31:17-25
[29]Houdi jk AP, Oosterling SJ, Siroen MP, de Jong S, Rihir M, Rijssenbeek AL, Teerlink T, van Leeuwen PA. Hypertaurinemia in bile duct-ligated rats after surgery:the effect of gut endotoxin restriction on organ fluxes and oxidative status. JPEN J Parenter Enteral Nutr 2006; 30:186-193
[30]Chen JZ, Raymond K. Treatment Effect of Rifampicin on Cholestasis. Internet J Pharm2006;4:2
[31]Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, Schmitt JM,Walker EC, Jones EA. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med 1995; 123:161-167.
[32]Kiani S, Ebrahimkhani MR, Shariftabrizi A, Doratotaj B, Payabvash S, Riazi K, Dehghani M, Honar H, Karoon A, Amanlou M, Tavangar SM, Dehpour AR. Opioid system blockade decreases collagenase activity and improves liver injury in a rat model of cholestasis.J Gastroenterol Hepatol 2007; 22:406-413
[33]Jones EA, Neuberger J, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis; the avoidance of opioid withdrawal-like reactions. QJM 2002;95:547-552
[34].苏经格原发性胆汁肝硬化30例中医临床分析[J].中国医药学报,2003,18(7)：444-446.
[35]董振华徐慧媛齐贺彬 中西医结合治疗原发性胆汁性肝硬化25例临床观察[J].世界中西医结合杂志,2009,4(3)：185-188.
[36]杨静波,赵长普,李学慧以中药为主辨证治疗原发性胆汁性肝硬 化14例[J].中医研究,2007,20(3)：39-41.
[37]宗 岩中西医结合治疗原发性胆汁性肝硬化22例临床体会[J].时珍国医国药,2008,19,(10)：2553.
[38]卢晶莹中西医结合治疗原发性胆汁性肝硬化[J].中国实用医药,2009,4(1)：56-57.
[39]苏春芝.中西医结合治疗原发性胆汁性肝硬化疗效观察[J].辽宁中医杂志,2008,35.
[40]刘晋河,董振华.原发性胆汁性肝硬化合并干燥综合征的中医证候特点[J].中华中医药杂志,2008,23(2)：174-176.
[41]黄峰,戴侃记,孙晓洁 补阳还五汤加味治疗原发性胆汁性肝硬化30例[J].陕西中医学院学报,2006,29(5)：39-41.
[42]唐海鸿,陈英杰,童光东,周大桥,贺劲松,周小舟,郑颖俊熊去氧胆酸联合通胆汤对原发性胆汁性肝硬化的治疗作用[J].世界华人消化杂志；16(13)：1417-1424.
[43]苏经格.中药治疗原发性胆汁性肝硬化20例[J].中医杂志,2004,45(7)：528-529.
[44]杨静波1,赵长普,李学慧。以中药为主辨证治疗原发性胆汁性肝硬化14例[J].中医研究,2007,20(3)：39-41.
[45]顾杰,薛惠明.中药治疗原发性胆汁性肝硬化引起的皮肤痉痒2例.上海中医药杂志,2004,38(10)：34-35.
[46]董振华徐慧媛齐贺彬。中西医结合治疗原发性胆汁性肝硬化25例临床观察[J].世界中西医结合杂志,2009,4(3)：185-188.
[47]陈国凤,成军,李莉,等.110例原发性胆汁性肝硬化的治疗研究.中西医结合肝病杂志,2004,14(2)：70-73.
[48]蒋健,何淼.原发性胆汁性肝硬化的临床特征及中西医结合治疗探讨[J].中西医结合学报,2003,1(2)：99-102.
[49]苏春芝.中西医结合治疗原发性胆汁性肝硬化疗效观察[J].辽宁中医杂志,2008,35(3)：416-417.
[50]黄峰,戴侃记,孙晓洁.补阳还五汤加味治疗原发性胆汁性肝硬化30例[J].陕西中医学院学报,2006,29(5)：39-41.
[51]徐荣亮.中药方剂治疗原发性胆汁性肝硬化32例疗效观察[J].江西医药,2006,41(5)：297-299.
[52]周 兵, 蔡光先, 柏正平, 曾松林, 付曙华柔肝健脾活血利胆法联合熊去氧胆酸治疗原发性胆汁性肝硬化疗效观察[J].中国中西医结合消化杂志,2009,17(4)：252-255.
[2]中国中西医结合学会肝病专业委员会肝纤维化中西医结合诊疗指南中西医结合肝病杂志,2006,16(5)：316-320。
[3]熊文生.中西医结合治疗肝肾阴虚型难治性腹水30例[J].陕西中医,2006,27(1)：8.。
[4]姚光弼,范上达,廖家杰等.原发性胆汁性肝硬化.临床肝脏病学,2004,3：483-490
[5]Talw alkar JA, Lindor KD. Primary cirrhosis[J]. Lancet,2003, 362:53-61
[6]Rbour L, Rupps R, Field L, et al. Characteristics of primary biliary cirrhosis in British Columbia. s First Nations population [J]. Can J Gastroenterol,2005,19:305-310
[7]Fan LY, Zhong RQ, XQ, et al. Genetic association of tumornecrosis factor (TNF)-Alpha polymorphisms with primary biliary cirrhosis and autoimmune liver disease in a Chinese population [J]. Zhonghua Ganzangbing Zazhi,2004,12:160-162
[8]Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems:clinical implications for understanding and treating cholestasis. J Clin Gastroenterol 2005;39:S111-124)
[9]V an Nieuwkerk CM, Elferink RP,Groen AK,et al.Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology, 1996,111(1):165-171.
[10]Lazaridis KN Gores GJ Lindor KD Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders,. J Hepatol 2001; 35:134-146;
[11]Kowdley KV. Ursodeoxycholic acid therapy in hepatobiliary disease. Am J Med 2000; 108:481-486)
[12]Pusl T, Beuers U. Ursodeoxycholic acid treatment of vanishing bile duct syndromes. World J Gastroenterol 2006;12:3487-3495
[13]Paumgartner G. Medical treatment of Cholestatic liver diseases:From pathobiology to pharmacological targets. World J Gastroenterol 2006;12:4445-4451
[14]Qiao L, Yacoub A, Studer E, et al. Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes. Hepatology,2002,35 (4):779-789.
[15]Beuers U,Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis:potential mechanism of action and therapeutic applications. Hepatolpgy,1998,28(5):1449-1453.
[16]TraunerM, Craziadei W. Mechanisms of action and therapeutic applications of ursodeoycholic acid in chronic liver disease. Aliment Pharmacol Ther,1999,13(8):979-996.
[17]Miyachi K, Shibata M, Hasegawa C, Onozuka Y, Fritzler MJ. Case of primary biliary cirrhosis patient with anti-p97/VCP antibodies presenting a mild clinical course. Rinsho Byori 2005; 53:19-23.
[18]Correia L, Podevin P, Borderie D, Verthier N, Montet JC, Feldmann G, Poupon R, Weill B, Calmus Y. Effects of bile acids on the humoral immune response:a mechanistic approach. Life Sci 2001; 69:2337-2348
[19]Dimoulios P, Kolios G,Notas G, et al. Ursodeoxycholic acid reduces increased circulating endothelin2in primary biliary cirrhosis. Aliment Pharmacol Ther,2005,21:227-234.
[20]Chan CW, Gunsar F, Feudjo M, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis:a follow-up to 12years. Aliment Pharmacol Ther,2005,21:217-226.
[21]EASL发布《胆汁淤积性肝病处理指南》.胃肠病学和肝病学杂志2009; 18(9)：874.
[1]魏嘉,高静,徐肇敏.原发性胆汁性肝硬化研究进展[J].中华消化杂志,2003,23(10)：623-624.
[2]任可,徐灿,金震东.熊去氧胆酸治疗胆汁性淤积性肝病研究进展[J].临床肝胆病杂志,2002,18(4)：199-200.
[3]井上恭一.原发性胆汁性肝硬化的诊疗研究进展[J].日本医学介绍,1997,18(10)：454-455.
[4]姚光弼.重视原发性胆汁性肝硬化的临床研究[J].中华肝脏病杂志,2002,10(5)：325-326.
[5]房静远.原发性胆汁性肝硬化的熊去氧胆酸治疗.肝脏2002；7：116-117.
[6]施健,刘苏,陈伟忠等.中等剂量熊去氧胆酸治疗原发性胆汁性肝硬化的系统评价.中华消化杂志2005：25：355-358·
[7]Pares A, Rodes J.Treatment of primary biliary cirrhosis.Minerva Gastroenterol Dietol 2000;46:165-174.
[8]Fickert P, Zollner G, Fuchsbichler A, et al. Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver. Gastroenterology,2001,121 (1):170-183.)
[9]Trauner M, Wagner M, Fickert P, Zollner G. Molecular regulation of hepatobiliary transport systems:clinical implications for understanding and treating cholestasis.J Clin Gastroenterol 2005;39:S111-124)
[10]Van Nieuwkerk CM, Elferink RP,Groen AK, et al. Effects of Ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene. Gastroenterology,1996,111(1):165-171.
[11]Lazaridis KN Gores GJ Lindor KD Ursodeoxycholic acid mechanisms of action and clinical use in hepatobiliary disorders,. J Hepatol 2001; 35:134-146;
[12]Kowdley KV. Ursodeoxycholic acid therapy in hepatobiliary disease. Am J Med 2000; 108:481-486)
[13]Pusl T, Beuers U. Ursodeoxycholic acid treatment of vanishing bile duct syndromes. World J Gastroenterol 2006;12:3487-3495
[14]Paumgartner G. Medical treatment of Cholestatic liver diseases:From pathobiology to pharmacological targets. World J Gastroenterol 2006;12:4445-4451
[15]Qiao L, Yacoub A, Studer E, et al. Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes. Hepatology,2002,35 (4):779-789.
[16]Beuers U, Boyer JL,Paumgartner G. Ursodeoxycholic acid in cholestasis:potential mechanism of action and therapeutic applications. Hepatolpgy,1998,28(5):1449-1453.
[17]TraunerM, Craziadei W. Mechanisms of action and therapeutic applications of ursodeoycholic acid in chronic liver disease. Aliment Pharmacol Ther,1999,13(8):979-996.
[18]Miyachi K, Shibata M, Hasegawa C, Onozuka Y, Fritzler MJ. Case of primary biliary cirrhosis patient with anti-p97/VCP antibodies presenting a mild clinical course. Rinsho Byori 2005; 53:19-23.
[19]Correia L, Podevin P, Borderie D, Verthier N, Montet JC, Feldmann G, Poupon R, Weill B, Calmus Y. Effects of bile acids on the humoral immune response: a mechanistic approach. Life Sci 2001;69:2337- 2348
[20]端木潜何峰王智胜吴志春刘皖生.熊去氧胆酸治疗原发性胆汁性肝硬化1年总结报告[J].实用肝脏病杂志,2009,12(1)：50-52.
[21]Dimoulios P, Kolios G, Notas G, et al. Ursodeoxycholic acid reduces increased circulating endothelin2in primary biliary cirrhosis. Aliment Pharmacol Ther,2005,21:227-234.
[22]Chan CW, Gunsar F, Feud jo M, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis:a follow-up to 12years. Aliment Pharmacol Ther,2005,21:217-226.
[23].Poupon RE, Lindor KD, Pares A, et al. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003:39:12-16.
[24]. Ter Borg PC, Sehalm SW, Hansen BE, et al.Prognosis of ursodeoxycholic Acid-treated
Patients with primary biliary cirrhosis. Results of a10-yr cohort study involving 297patients. Am J Gastroenterol 2006;101:2044-2050.
[25].Ludwig J, Dickson ER, MeDonald GS.Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol 1978; 379:103-112.
[26].邱德凯,马雄主编.自身免疫性肝病基础与临床.上海：上海科学技术出版社,第1版.2006：212.
[27]EASL发布《胆汁淤积性肝病处理指南》.胃肠病学和肝病学杂志2009；18(9)：874.
[28]Heurgue A, Vitry F, Diebold MD, Yaziji N, Bernard-Chabert B, Pennaforte JL, Picot R, Louvet H, Fremond L, Geoffroy P, Schmit JL, Cadiot G, Thief in G.OverlaP syndrome of primary biliary cirrhosis and autoimmune hepatitis:a retrospective study of 115 cases of autoimmune liver disease. Gastroenterol Cli Biol 2007; 31:17-25
[29]Houdi jk AP, Oosterling SJ, Siroen MP, de Jong S, Rihir M, Rijssenbeek AL, Teerlink T, van Leeuwen PA. Hypertaurinemia in bile duct-ligated rats after surgery:the effect of gut endotoxin restriction on organ fluxes and oxidative status. JPEN J Parenter Enteral Nutr 2006; 30:186-193
[30]Chen JZ, Raymond K. Treatment Effect of Rifampicin on Cholestasis. Internet J Pharm2006;4:2
[31]Bergasa NV, Alling DW, Talbot TL, Swain MG, Yurdaydin C, Turner ML, Schmitt JM,Walker EC, Jones EA. Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial. Ann Intern Med 1995; 123:161-167.
[32]Kiani S, Ebrahimkhani MR, Shariftabrizi A, Doratotaj B, Payabvash S, Riazi K, Dehghani M, Honar H, Karoon A, Amanlou M, Tavangar SM, Dehpour AR. Opioid system blockade decreases collagenase activity and improves liver injury in a rat model of cholestasis.J Gastroenterol Hepatol 2007; 22:406-413
[33]Jones EA, Neuberger J, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis; the avoidance of opioid withdrawal-like reactions. QJM 2002;95:547-552
[34].苏经格原发性胆汁肝硬化30例中医临床分析[J].中国医药学报,2003,18(7)：444-446.
[35]董振华徐慧媛齐贺彬 中西医结合治疗原发性胆汁性肝硬化25例临床观察[J].世界中西医结合杂志,2009,4(3)：185-188.
[36]杨静波,赵长普,李学慧以中药为主辨证治疗原发性胆汁性肝硬 化14例[J].中医研究,2007,20(3)：39-41.
[37]宗 岩中西医结合治疗原发性胆汁性肝硬化22例临床体会[J].时珍国医国药,2008,19,(10)：2553.
[38]卢晶莹中西医结合治疗原发性胆汁性肝硬化[J].中国实用医药,2009,4(1)：56-57.
[39]苏春芝.中西医结合治疗原发性胆汁性肝硬化疗效观察[J].辽宁中医杂志,2008,35.
[40]刘晋河,董振华.原发性胆汁性肝硬化合并干燥综合征的中医证候特点[J].中华中医药杂志,2008,23(2)：174-176.
[41]黄峰,戴侃记,孙晓洁 补阳还五汤加味治疗原发性胆汁性肝硬化30例[J].陕西中医学院学报,2006,29(5)：39-41.
[42]唐海鸿,陈英杰,童光东,周大桥,贺劲松,周小舟,郑颖俊熊去氧胆酸联合通胆汤对原发性胆汁性肝硬化的治疗作用[J].世界华人消化杂志；16(13)：1417-1424.
[43]苏经格.中药治疗原发性胆汁性肝硬化20例[J].中医杂志,2004,45(7)：528-529.
[44]杨静波1,赵长普,李学慧。以中药为主辨证治疗原发性胆汁性肝硬化14例[J].中医研究,2007,20(3)：39-41.
[45]顾杰,薛惠明.中药治疗原发性胆汁性肝硬化引起的皮肤痉痒2例.上海中医药杂志,2004,38(10)：34-35.
[46]董振华徐慧媛齐贺彬。中西医结合治疗原发性胆汁性肝硬化25例临床观察[J].世界中西医结合杂志,2009,4(3)：185-188.
[47]陈国凤,成军,李莉,等.110例原发性胆汁性肝硬化的治疗研究.中西医结合肝病杂志,2004,14(2)：70-73.
[48]蒋健,何淼.原发性胆汁性肝硬化的临床特征及中西医结合治疗探讨[J].中西医结合学报,2003,1(2)：99-102.
[49]苏春芝.中西医结合治疗原发性胆汁性肝硬化疗效观察[J].辽宁中医杂志,2008,35(3)：416-417.
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