原发性胆汁性肝硬化的临床与基础研究及对治疗的反应

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英文题名：Clinical, Basic Research and the Effects of Drug Therapy for Primary Biliary Cirrhosis 作者：史旭华 论文级别：博士 学科专业名称：风湿病学 中文关键词：肝硬化 ; 胆汁性 ; 熊去氧胆酸 ; 泼尼松龙 ; 硫唑嘌呤 ; 前瞻性研究 ; 肝硬化 ; 胆汁性 ; 淋巴细胞亚群 ; 细胞因子 ; 肝硬化 ; 胆汁性 ; 抗线粒体抗体 ; 抗GP210抗体 ; 抗SP100抗体 ; 肝硬化 ; 胆汁性 ; 病理 ; 免疫组化 ; 淋巴细胞亚群 英文关键词：Liver cirrhosis ; biliary ; Ursodeoxycholic acid ; Prednisonlone ; Azatharaprine ; Prospective study ; Liver cirrhosis ; biliary ; lymphocytic subsets ; cytokine ; Liver cirrhosis ; biliary ; Anti-mitochondrial antibodies ; anti GP210 antibody ; anti SP100 antibody ; Liver cirrhosis ; biliary ; pathology ; immunohistochemical ; lymphocytic subsets 学位年度：2006 导师：张奉春 ; 张烜 ; 唐福林 学科代码：100201 学位授予单位：中国协和医科大学 论文提交日期：2006-05-01

摘要

第一部分药物治疗原发性胆汁性肝硬化的临床疗效观察
     目的前瞻性研究熊去氧胆酸(UDCA)、UDC联合泼尼松龙、UDCA联合硫唑嘌呤(Azp)三种治疗方案对原发性胆汁性肝硬化(PBC)的疗效并评价影响疗效的危险因素。材料与方法82例初诊PBC患者随机分为UDCA(U组，28人)、UDCA联合泼尼松龙(UP组，27人)、UDCA联合Azp(UA组，27人)三个治疗组，在治疗第0、3、6、12月采集详细的临床及实验室资料。记录肝硬化失代偿、死亡、肝移植等事件以及药物副作用。入选标准符合2000年美国肝脏病协会制定的PBC诊疗指南；排除标准为合并其他肝病，年龄＞70岁，肝功失代偿(Child分级B／C)，预计存活期不超过1年，合并其他自身免疫病。药物剂量为UDCA 13-15mg·d-1·kg-1；泼尼松龙起始剂量0.5mg·d-1·kg-1，4周开始减量，减至7.5mg·d-1时维持；Azp 1mg·d-1·kg-1。疾病进展规定为：观察期内肝硬化失代偿、肝移植或肝脏相关的死亡、胆红素升高到原水平两倍以上。生化缓解定义为：治疗后总胆红素(TBIL)正常同时碱性磷酸酶(ALP)和谷氨酰转肽酶(GGT)水平降至正常值高限1.5倍以下。结果UP组患者乏力和瘙痒程度改善(分别为P=0.015和P=0.037)，U组、UA组症状无改善。三组患者谷氨酸氨基转移酶(ALT)、天门冬酸氨基转移酶(AST)、ALP、GGT、总胆红素(TBIL)、直接胆红素(DBIL)、IgM均下降，组内效应分别为P=0.000、0.000、0.000、0.000、0.009、0.001、0.000，在3个月内下降最明显；三种治疗方案相比无差异。疾病进展分别为U组中2人，UP组3人(其中1人因食道静脉曲张破裂大出血死亡)，UA组1人。发生疾病进展的患者Mayo危险性评分(MRS)(4.4±0.15 vs 5.7±0.55，P=0.018)高、凝血酶原时间(PT)(11.6±0.12 vs 12.4±0.32，P=0.042)延长。U组未出现药物副作用；UP组血糖升高2例、满月脸5例、多毛1例；UA组白细胞下降2例，胆绞痛1例(UDCA相关)。基线ALP、GGT、总胆固醇(CHO)水平是生化缓解的危险因素(β=-2.095，P=0.015，Exp(β)=0.123，95％CI 0.023-0.663)，DBIL、TBIL、总胆汁酸(TBA)、PT也不利于生化缓解(β=-1.162，P=0.075，Exp(B)=0.313，95％CI 0.083-1.124)；联合泼尼松龙(β=-0.747，P=0.350，Exp(B)=0.474，95％CI 0.099-2.266)或Azp(β=-1.479，P=0.223，Exp(B)=0.228，95％CI 0.021-2.453)不能使生化缓解率提高。结论三种方案对PBC患者的肝脏生化指标、IgM的改善作用相同，UP方案可减轻乏力瘙痒症状：生化缓解多发生在治疗3月内，高水平的基线ALP、GGT、CHO是生化缓解的危险因素，高水平的TBIL、DBIL、TBA、PT不利于生化缓解，两种联合治疗方案不增加生化缓解率。MRS高、PT延长的患者易疾病进展。U方案副作用发生率低。
     第二部分原发性胆汁性肝硬化外周血淋巴亚群、细胞因子特点及药物治疗后的变化
     目的原发性胆汁性肝硬化(PBC)患者外周血淋巴细胞亚群及细胞因子的特点及其对治疗的反应。材料与方法全部病例来自论文第一部分熊去氧胆酸(UDCA)(U组)、UDCA联合泼尼松龙(UP组)、UDCA联合硫哗嘌呤(Azp)(UA组)治疗PBC的前瞻性、随机、对照研究中的82例PBC患者。参加者在治疗前和治疗3、6月时检测外周血淋巴细胞亚群(溶血法)和细胞因子(酶联免疫吸附分析，ELISA)水平。设未治疗的慢性乙型肝炎患者(CHB)29例和干燥综合征(PSS)21例，健康对照组(HS)20例与药物治疗前PBC患者相应的指标对比。结果与PSS患者相比，PBC患者B细胞比例低(P=0.010)、CD4+T细胞比例升高(P=0.003)、记忆细胞(CD4+CD45RO+)增多(P=0.051)、IFN-γ、TNF-α、IL-2均升高(分别为P=0.004、P=0.003、P=0.000)。与健康对照者比，PBC患者B细胞比例升高(P=0.366)但未达到统计学意义上的差异，CD4+T细胞比例升高(P=0.044)而CD8+T细胞比例降低(P=0.277)、CD4／CD8+比例升高(P=0.042)，记忆T细胞比例升高(P=0.049)，IFN-γ(P=0.001)、TNF-α(P=0.000)、IL-2(P=0.000)、IL-4(P=0.010)、IL-6(P=0.029)升高，IL-10低但未达到统计学意义上的差异(P=0.453)。外周血CD8+T细胞数与MRS(P=0.001)、胆红素水平(TBIL为P=0.010，DBIL为P=0.013)呈负相关而与白蛋白水平(P=0.008)正相关。外周血TNF-α水平与血ALT(p=0.005)、AST(p=0.002)、TBIL(p=0.001)、DBIL(p=0.002)、MRS(p=0.020)正相关。治疗后PBC患者B细胞比例下降(U组治疗6个月时P＜0.05)。三组CD8+T细胞升高(UP组6月时P=0.002)，U组和UP组CD4+T细胞比例(U组3、6月时为P=0.047，P=0.025)和CD4／CD8下降(UP组6个月时P=0.020)。治疗后三组患者记忆细胞比例减少、纯真细胞增多但尚未达统计学意义上的差异。三组治疗后CD4+CD28+T细胞比例的变化无统计学上差异；治疗后U组CD8+CD28+T细胞比例继续降低(6个月时P=0.032)，UP、UA组变化无统计学差异。治疗3月时U组IFN-Y、IL-2、IL-4、IL-6水平均降低，其中IFN-Y、IL-4、IL-6在6个月时再次升高，而UP组和UA组患者在治疗后均低于基线水平。三组TNF-α水平均较治疗前低(UP、UA组6月时分别为P=0.042和P=0.043)。结论CD4+T细胞比例的增加伴随CD8+T细胞比例的下降及CD8+T细胞与病情的相关性提示其在PBC发病机制中的重要作用。外周血同时存在Thl型和Th2型细胞因子的异常且以Th1细胞占主导地位，提示PBC以细胞免疫为主。TNF-α是参与PBC免疫损伤的重要因子并与病情相关。三种治疗方案对免疫系统的影响不完全相同。
     第三部分原发性胆汁性肝硬化自身抗体特征及其对药物治疗的反应
     目的研究PBC患者抗线粒体抗体(AMA)、抗线粒体抗体M2亚型(AMA-M2)、抗GP210抗体和抗SP100抗体的临床相关性及对药物治疗的反应。材料与方法82例初诊未治疗的PBC患者随机分为熊去氧胆酸(U组，28人)、熊去氧胆酸联合泼尼松龙(UP组，27人)、熊去氧胆酸联合硫唑嘌呤组(UA组，27人)三组，治疗前检测AMA(间接免疫荧光法，IIF)、AMA-M2(酶联免疫吸附分析法，ELISA)、抗GP210抗体和抗SP100抗体(免疫印迹法，IBT)，治疗第3、6月复查AMA、AMA-M2。结果PBC患者的AMA滴度、AMA-M2浓度与临床表现(乏力、瘙痒、黄疸)、肝生化指标(ALT、AST、ALP、GGT、TBIL、DBIL、ALB、TBA、CHO)、肝组织学病变程度(纤维化、汇管区炎症、汇周碎屑坏死、肝细胞坏死性损害、胆管增生或减少)间无相关性，AMA与IgM正相关(P=0.046)；AMA与外周血IL-6、IL-1β正相关(P=0.002，P=0.024)，AMA-M2与IL-6正相关(0.024)。三种治疗方案对AMA、AMA-M2水平无影响(分别为组内效应P=0.270，组间效应P=0.648和组内效应P=0.613，组间效应P=0.764)。疾病进展和疾病未进展的患者间、生化缓解和生化未缓解的患者间基线AMA、AMA-M2水平无差异。抗GP210抗体阳性患者比阴性患者黄疸发生率高(P=0.003)且程度重(P=0.005)、食道静脉曲张发生率高(P=0.005)、Mayo危险性评分高(P=0.005)、DBIL(P=0.035)和TBA水平(P=0.002)高而ALB水平(P=0.002)低、肝组织学分期晚(P=0.013)、纤维化重(P=0.002)；抗GP210抗体阳性者治疗6月时的生化缓解率低(16.7％vs 52.0％，P=0.012)，按胆红素水平将抗GP210抗体阴性与阳性患者1∶1匹配后两组生化缓解率无统计学意义上的差异(16.7 vs 33.3％，P=0.266)。抗SP100抗体阳性与阴性患者的症状、肝脏生化指标、IgM、肝组织学病变程度无差异。结论AMA、AMA-M2对PBC患者有诊断意义，但其水平与病情无关，既不受药物治疗影响，也不影响药物疗效。抗GP210抗体阳性的PBC患者病情重，生化缓解率低，但尚无证据表明抗GP210抗体本身对药物治疗有抵抗作用。抗SP100抗体可作为一项辅助诊断的手段，但与PBC患者的病情无关。
     第四部分原发性胆汁性肝硬化的肝脏病理与淋巴细胞浸润特征及其临床相关性
     目的研究PBC患者肝脏病理、淋巴细胞浸润特征及其临床相关性。材料与方法24例初诊未经治疗的PBC患者的肝脏穿刺标本常规进行HE染色，记录病理分期(LudwigⅠ-Ⅳ期，Ⅰ-Ⅱ为早期、Ⅲ-Ⅳ为晚期)、纤维化(0-3级，0.1级为轻度、2-3级为重度)、汇管区炎症(0-3级，0.1级为轻度、2-3级为重度)、汇管区周围碎屑坏死(0-2级，0级为轻度，1-2级为重度)、肝细胞坏死性损害(0-2级，0级为轻度，1-2级为重度)、胆管增生及胆管减少(0-2级，0级为轻度，1-2级为重度)；其中10例标本连续切片，进行免疫组化染色(CD20、CD45RO、CD8)，计数每个汇管区每种淋巴细胞亚型的平均数，分析前述指标的临床相关性。结果病理分期、纤维化程度与黄疸程度、总胆红素(TBIL)、直接胆红素(DBIL)、总胆汁酸(TBA)、总胆固醇(CHO)、IgG均呈正相关，与白蛋白(ALB)、血嗜酸细胞(EOS)比例负相关，纤维化程度还与Mayo危险性评分(MRS)正相关。汇周碎屑坏死与黄疸和瘙痒程度、MRS、碱性磷酸酶(ALP)、TBIL、DBIL、TBA正相关，还与血TNF-α水平正相关(相关系数0.617，P=0.006)。胆管减少程度与黄疸、MRS、天门冬酸氨基转移酶(AST)、TBIL、DBIL、TBA、IgG正相关而与ALB呈负相关。不同病理分期及不同严重程度的各种肝组织病变形态的PBC患者临床指标间的差异与前述相关分析中的结果一致。汇管区及汇管区周围CD20+淋巴细胞数与肝脏生化指标间无相关性，CD45RO+、CD8+淋巴细胞浸润程度与ALT、AST、GGT、TBA正相关，CD8+淋巴细胞还与ALP正相关(相关系数=0.775，P=0.041)，也与血IFN-γ水平正相关(相关系数0.901，P=0.006)。结论肝脏病理分期、纤维化程度、汇管区周围碎屑坏死、胆管减少程度是与PBC患者病情轻重及病程有关的指标。TNF-α是反映汇管区周围碎屑坏死程度的有用指标，二者反映了疾病处在进展期。PBC的组织学损害以细胞免疫为主，CD8+T细胞起重要作用，升高的IFN-γ水平增强CD8+T细胞对胆管的破坏。
Part one Prospective, randomized, controlled study ofursodeoxycholic acid, ursodeoxycholic acid combined withprednisonlone or azatharaprine therapy for primary biliary cirrhosis
     Object The aim of this study was to evaluate the effects of thecombination therapy with prednisonlone/azatharaprine and ursodeoxycholic acid(UDCA) for primary biliary cirrhosis (PBC), compared to UDCA monotherapy.Materials and methods Eighty two patients with untreated PBC were dividedrandomly into three groups. Group U (28 patients) received UDCA alone for 12months, group UP (27 patients) received UDCA and prednisonlone, while group UA(27 patients) received UDCA and Azp. The clinical and laboratory data was followedafter 3, 6 and 12 months. Inclusion criteria was the guideline for management of PBCwhich AASLD presented in 2000. The dose of these dugs were defined as UDCA13-15mg·d-1·kg-1, prednisonlone started with 0.5mg·d-1·kg-1, and tapered to7.5mg·d-1 from the fifth week, Azp 1mgod-1·kg-1. Disease progression wasdescriptived as liver decompensation, liver transplantation, two times elevation ofTBIL. Biochemical remission was defined as the normalization of serum bilirubinwith gamma-glutamyl transferase (GGT) with alkaline phosphatase (ALP)＜1.5×ULN (upper limit of normalization). Result Fatigue and pruritus were improvedonly in group UP. ALT, aspartate aminotransferase (AST), ALP, GGT, total bilirubin(TBIL), direct bilirubin (DBIL), IgM all decreased below or reached the ULN values(within-subject effects, P=0.000、0.000、0.000、0.000、0.009、0.001、0.000,respectively), and there had no ststistic significance between three groups(between-subject effects, P＞0.05 for all). The number of patients with diseaseprogression were two in group U, three in group UP, and one in group UA. Thepatients with disease progression had higher Mayo risk score(P=0.018) and prolongedProthrombin time (PT) (P=0.042). No side-effects occurred in group U. In group UP, side-effect related with Glucocorticosteroids occurred in eight patients. In group UA,two patients had side-effects related with Azp and one had side-effect related toUDCA. The level of ALP、GGT、CHO in baseline were risk factor for biochemicalremission (β=-2.095, P=0.015, Exp(β)=0.123, 95%CI 0.023-0.663), high level ofDBIL、TBIL、total bile acid (TBA)、PT of baseline were not beneficial forbiochemical remission. (β=-1.162, P=0.075, Exp(B)=0.313, 95%CI0.083-1.124),wether combined with prednisonlone (β=-0.747, P=0.350, Exp(B)= 0.474, 95%CI0.099-2.266) orAzp (β=-1.479, P=0.223, Exp(B)=0.228, 95%CI0.021-2.453)with UDCA were not related with biochemical remission. CONCLUSIONS Thereare no difference between three groups for improve biochemical data of liver and IgM.High level of ALP, GGT, CHO in baseline are risk factor for biochemical remission.High level of TBIL、DBIL、TBA、PT are also not beneficial for biochemical remission.The combination with prednisonlone or Azp are not related with the ratio ofbiochemical remission. The disease of patients with higher Mayo risk score andprolonged PT tend to progress.
     Part two Character of peripheral lymphocytic subsets and cytokinesin patients with primary biliary cirrhosis and their change aftertherapy
     Object The aim of this study was to describe the Character ofperipheral lymphocytic subsets and cytokines in patients with primary biliary cirrhosisand their change after therapy. Materials and methods Eighty two patients withuntreated PBC were divided randomly into three groups. Group U (28 patients)received UDCA for 12 months, group UP (27 patients) received UDCA andprednisonlone, while group UA (27 patients) received UDCA and azatharaprine (Azp).Peripheral lymphocytic subsets and cytokines were detected at 0, 3, 6 months aftertherapy using tricolour flowcytometry analysis and ELISA respectively. Twenty ninepatients with chronic hepatitis B (CHB), twenty one patients with pimary Sj(?)gren'ssyndrome (PSS) and twenty healthy people were also included as controls. ResultCompared with PSS, the percent of B cells were decreased (P=0.010), the percent of CD4+T cells (P=0.003) and memory cells (CD4+CD45RO+) (P=0.051) wereincreased, and the level of IFN-γ, TNF-α, IL-2 were all increased (P=0.004, P=0.003P=0.000 respectively) in PBC. Compared with healthy control (HC), the percent ofCD8+T cells (P=0.277) decreased companied with the increase of percent of CD4+Tcell (P=0.044) and the ratio of CD4/CD8 (P=0.042) in PBC. And the patients withPBC also had higher percent of memory cells (P=0.049) than HC. The level of IFN-γ(P=0.001), TNF-α(P=0.000), IL-2 (P=0.000), IL-4 (P=0.010), IL-6 (P=0.029)were increased in PBC comparing with HC. The lower level of IL-10 was observed inPBC than in HC but didn't reach the statistic significance. The number of CD8+Tcells in peripheral were correlated with lower Mayi risk score (MRS) (P=0.001), TBIL(P=0.010), DBIL (P=0.013), and higher albumin (P=0.008). The level of TNF-αinperipheral were correlated with higher ALT (p=0.005) , AST (P=0.002) , TBIL(P=0.001) , DBIL (P=0.002) , MRS (P=0.020) . The percent of B cells decreasedin patients with PBC after therapy and reached the statistic significance in group U atsixth month. The percent of CD8+T cells increased in the three groups(P=0.002 ingroup UP at the sixth month). The percent of CD4+T cell (P=0.047, P=0.025 in groupU at the third and sixth months) and the ratio of CD4/CD8 (P=0.020 in group UP atthe sixth month) were decreased in group U and UP. Though didn't reach the statisticsignificance, the percent of memory cells decreased in the three groups. The percentof CD8+CD28+T cells in CD8+T cells was dereased in group U after UDCA therapy.The level of IFN-γ, IL-2, IL-4, IL-6 all decreased after therapy at the third month ingroup U, and rebounded thereafter. In group of UP and UA, all these cytokines weresurpressed below the level of baseline. TNF-αdecreased in all the three group aftertherapy (P=0.042 and P=0.043 in group UP and UA at the sixth month).
     CONCLUSIONS The reduction of CD8+T cells and the correlations with diseaseactivity revealve it's important role in the pathogenesis of PBC. PBC is a disease withpredominant cellular immunity as described with the pattern of peripheral cytokines.TNF-αis an important cytokine in the pathogenesis of patients with PBC, andcorrelated with the severity of the disease. The effects on the peripheral lymphocyticsubsets and cytokines of these three regime for the therapy of PBC are not identical.But the increase of CD8+T and the suppression of cytokines after therapy wereresponsive for the clinical amelioration of the disease.
     Part three Character of self antibody in patients with primary biliarycirrhosis and their change after therapy
     Object The aim of this study was to describe the character ofAnti-mitochondrial antibodies (AMA), Anti-mitochondrial M2 antibodies (AMA-M2),anti GP210 antibody (anti-GP210 Ab) and anti SP100 antibody (anti-SP100 Ab) inpatients with primary biliary cirrhosis (PBC) and their correlation with therapy.Materials and methods Eighty two patients with untreated PBC were dividedrandomly into three groups. Group U (28 patients) received UDCA, group UP (27patients) received UDCA and prednisonlone, while group UA (27 patients) receivedUDCA and azatharaprine (Azp). AMA (IIF), AMA-M2 (ELISA), anti-GP210antibody and anti-SP 100 antibody (IBT) were detected in these patients before therapy.AMA and AMA-M2 were repeated after therapy at the third and sixth months. ResultThere had no correlations between the titer of AMA, concentration of AMA-M2 andsymptoms, biochemical data of liver, histopathologie character in liver. AMA wascorrelated with peripheral IL-6 and IL-1β. The three protocol of therapy had noimpact on the level of AMA or AMA-M2 (within-subjects effects, P=0.270,between-subjects effects, P=0.648 for AMA; within-subjects effects, P=0.613,between-subjects effects P=0.764 for AMA-M2) . Whether the patient had diseaseprogression or biochemical remission, the difference of AMA or AMA-M2 didn'treach the statistic significance. The patients with anti-GP210 antibody had moresevere icterus(P=0.005), more frequent incident of esophageal varices (P=0.005),higher Mayo risk score (P=0.005). DBIL (P=0.035 ), TBA (P=0.002) in patients withthe antibody were higher and ALB was lower than those without. The patients withanti-GP210 antibody had later pathologic stage (P=0.013) and severe fibrosis(P=0.002). The biochemical remission was lower in patient with anti-GP210 antibodythan those without (16.7% vs 52.0%, respectively, P=0.012) . Being matched withBIL and MRS, the ratio of biochemical remission in two groups didn't reach thestatistic significance (16.7 vs 33.3%, P=0.266). There had no difference betweenpatients with anti-SP100 and those withought in symptoms, biochemical data of liver,histopathologic character in liver. CONCLUSIONS AMA, AMA-M2, anti-SP100 antibody were valuble in the diagnosis of PBC, but they are not related with theseverity of the disease. Patients with anti-GP210 antibody had more severe diseaseand this antibody correlate with lower ratio of biochemical remission. But it's notanti-GP210 antibody itself resist the role of drugs for PBC but because there are morerelatively severe cases in patients with positive anti-GP210 antibody.
     Part four Clinicopathological features of primary biliary cirrhosis
     Object The aim of this study was to describe the clinicopathologicalfeatures and character of lymphocytic subsets in portal tract of primary biliarycirrhosis (PBC). Materials and methods The liver biopsy speciments were obtainedfrom twenty four patients with PBC who participate in a prospective, randomized,controlled trial (Part one) through percutaneously needle puncture. These sampleswere fixed in formaldehyde and embedded in paraffin for routine histologicalexamination. Pathologic stage according to Ludwig (stage 1-4), fibsosis (grade 0-3),portal and periportal inflammation (grad 0-3), lymphocytic periportal piecemealnecrosis (grade 0-2), ductular proliferation (grade 0-2), intralobular hepatocytenecrosis (grade 0-2) and the degree of ductopenia (0-2) were record. Serial sections,4um-thick, were prepared for immunohistochemistry (CD20, CD45RO, CD8). Theaverage numbers of every lymphocytic subsets per portal area were computed. ResultThe pathologic stages, degree of fibrosis were positively correlated with ictetus, totalbilirubin (TBIL), total bile acid (TBA)、Cholesterol (CHO)、IgG, and negtivelycorrelated with albumin (ALB)、percent of eosinophilic cell ( EOS ). Fibrosis was alsopositively correlated with Mayo risk score (MRS). Lymphocytic periportal piecemealnecrosis was positively correlated with the degree of icterus and pruritus, MRS,alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirunbin (DBIL), total bileacid (TBA), and also TNF-α(correlations 0.617, P=0.006). the degree ofductopeniawas positively correlated with the extent of icterus, MRS, aspartate aminotransferase(AST), TBIL, DBIL, TBA, IgG, and negtively correlated with ALB. No correlationswere observed between the numbers of CD20+T cells in portal area and biochemicaldata of liver. But the numbers of CD45RO+, CD8+ T cell were positively with ALT、 AST、gamma-glutamyl transferase (GGT)、TBA, and CD8+T cells also positivelycorrelated with ALP (correlations 0.775, P=0.041 ) and IFN-Γ(correlations 0.901,P=0.006). CONCLUSIONS The pathologic stage and the degree of fibsosis,lymphocytic periportal piecemeal necrosis, ductopenia are correlated with the diseaseseverity and reflect the process of the disease. TNF-αis a usful cytokine which canreflect the degree of lymphocytic periportal piecemeal necrosis, and they all reflectthe progression of the disease. Cellular immunity is important in the process of PBC.Acompanied with elevated IFN-γ, CD8+T cells destroy the interlobular bile duct.

引文

1. Neuberger J. Primary biliary cirrhosis. Lancet JT - Lancet 1997; 350(9081): 875-9.
    2. Poupon RE, Eschwege E, Poupon R. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Interim analysis of a double-blind multicentre randomized trial. The UDCA-PBC Study Group. J Hepatol JT- Journal of hepatology 1990; 11(1): 16-21.
    3. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol JT- Journal of hepatology 2000; 32(4): 561-6.
    4. Leuschner M, Dietrich CF, You T, Seidl C, Raedle J, Herrmann G, et al. Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment. Gut JT - Gut 2000;46(1): 121-6.
    5. Chan CW, Gunsar F, Feudjo M, Rigamonti C, Vlachogiannakos J, Carpenter JR, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 2005:21(3):217-26.
    6. Jorgensen R, Angulo P, Dickson ER, Lindor KD. Results of long-term ursodiol treatment for patients with primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2002:97(10):2647-50.
    7. Combes B, Luketic VA, Peters MG, Zetterman RK, Garcia-Tsao G, Munoz SJ, et al. Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2004:99(2) :264-8.
    8. Levy C, Angulo P. Ursodeoxycholic acid and long-term survival in primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2004;99(2):269-70.
    9. Poupon RE, Lindor KD, Pares A, Chazouilleres O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 2003:39(1):12-6.
    10. Paumgartner G. Ursodeoxycholic acid for primary biliary cirrhosis: treat early to slow progression. J Hepatol JT - Journal of hepatology 2003:39(1):112-4.
    11. Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology JT - Gastroenterology 2002;122(3):652-8.
    12. Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology JT - Hepatology (Baltimore, Md.) 1989; 10(4): 420-9.
    13. Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 1996:25(1):49-57.
    14. Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1976;70(5 PT. 1):656-60.
    15. Christensen E, Neuberger J, Crowe J, Altman DG, Popper H, Portmann B, et al. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology JT - Gastroenterology 1985;89(5):1084-91.
    16. Bjorkland A, Festin R, Mendel-Hartvig I, Nyberg A, Loof L, Totterman TH. Blood and liver-infiltrating lymphocytes in primary biliary cirrhosis: increase in activated T and natural killer cells and recruitment of primed memory T cells. Hepatology JT - Hepatology (Baltimore, Md.) 1991:13(6) :1106-11.
    17. Spengler U, Pape GR, Hoffmann RM, Johnson JP, Eisenburg J, Paumgartner G, et al. Differential expression of MHC class II subregion products on bile duct epithelial cells and hepatocytes in patients with primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1988:8(3): 459-62.
    18. Shimoda S, Van de Water J, Ansari A, NakamuraM, Ishibashi H, Coppel RL, et al. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest JT - The Journal of clinical investigation 1998;102(10):1831-40.
    19. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest JT - The Journal of clinical investigation 2002; 109 (9): 1231-40.
    20. Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, et al. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med JT - The Journal of experimental medicine 2002;195 (1):113-23.
    21. Bjorkland A, Loof L, Mendel-Hartvig I, Totterman TH. Primary biliary cirrhosis. High proportions of B cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes. J Immunol JT - Journal of immunology (Baltimore, Md: 1950) 1994:153(6): 2750-7.
    22. Nagano T, Yamamoto K, Matsumoto S, Okamoto R, Tagashira M, Ibuki N, et al. Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol JT - Journal of clinical immunology 1999:19(6): 422-7.
    23. Shindo M, MullinGE, Braun-Elwert L, Bergasa NV, Jones EA, James SP. Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB). Clin Exp Immunol JT - Clinical and experimental immunology 1996;105(2):254-9.
    24. Berg PA, Klein R, Rocken M. Cytokines in primary biliary cirrhosis. Semin Liver Dis JT -Seminars in liver disease 1997;17(2):115-23.
    25. Krams SM, Cao S, Hayashi M, Villanueva JC, Martinez 0M. Elevations in IFN-gamma, IL-5, and IL-10 in patients with the autoimmune disease primary biliary cirrhosis: association with autoantibodies and soluble CD30. Clin Immunol Immunopathol JT - Clinical immunology and immunopathology 1996;80(3 Pt 1):311-20.
    26. Musialik J, Michalkiewicz J, Petelenz M, Mazurek U, Mazur W, Madalinski K, et al. Reduction of CD45RA isoform expression and decrease in CD4 and CD8 receptor density in lymphocytes of patients with primary biliary cirrhosis. Scand J Gastroenterol JT - Scandinavian journal of gastroenterology 2003:38(4):421-6.
    27. Kaplan MM. Primary biliary cirrhosis. N Engl J Med JT - The New England journal of medicine 1996:335(21): 1570-80.
    28. Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OF. Natural history of early primary biliary cirrhosis. Lancet JT - Lancet 1996:348(9039):1399-402.
    29. Flisiak R, Pelszynska M, Prokopowicz D, Rogalska M, Grygoruk U. High concentration of antimitochondrial antibodies predicts progressive primary biliary cirrhosis. World J Gastroenterol JT - World journal of gastroenterology : WJG 2005;11(36):5706-9.
    30. Floreani A, Baragiotta A, Pizzuti D, Martines D, Cecchetto A, Chiarelli S. Mucosal IgA defect in primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2002:97(2):508-10.
    31. Masuda J, Omagari K, Ohba K, Hazama H, Kadokawa Y, Kinoshita H, et al. Correlation between histopathological findings of the liver and IgA class antibodies to 2-oxo-acid dehydrogenase complex in primary biliary cirrhosis. Dig Dis Sci JT - Digestive diseases and sciences 2003:48(5): 932-8.
    32. Matsumura S, Van De Water J, Leung P, Odin JA, Yamamoto K, Gores GJ, et al. Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 2004:39(5): 1415-22.
    33. Van Norstrand MD, Malinchoc M, Lindor KD, Therneau TM, Gershwin ME, Leung PS, et al. Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology JT -Hepatology (Baltimore, Md.) 1997:25(1) :6-11.
    34. Lassoued K, Brenard R, Degos F, Courvalin JC, Andre C, Danon F, et al. Antinuclear antibodies directed to a 200-kilodalton polypeptide of the nuclear envelope in primary biliary cirrhosis. A clinical and immunological study of a series of 150 patients with primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1990:99(1):181-6.
    35. Szostecki C, KrippnerH, PennerE, Bautz FA. Autoimmune sera recognize a 100 kD nuclear protein antigen (sp-100). Clin Exp Immunol JT - Clinical and experimental immunology 1987:68(1): 108-16.
    36. Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology JT Gastroenterology 1996:110(3):840-7.
    37. Lin F, Noyer CM, Ye Q, Courvalin JC, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR. Hepatology JT -Hepatology (Baltimore, Md.) 1996:23(1):57-61.
    38. Nickowitz RE, Wozniak RW, Schaffner F, Worman HJ. Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis. Gastroenterology JT -Gastroenterology 1994:106(1):193-9.
    39. Leuschner U., Broome U., Stiehl A.. Cholestatic liver diseases: therapeutic options and perspectives. Kluwer academic publishers. 2003,94-109.
    40. Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol JT - Virchows Archiv. A, Pathological anatomy and histology 1978;379(2):103-12.
    41. Poupon R, Chazouilleres O, Balkau B, Poupon RE. Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group. J Hepatol JT - Journal of hepatology 1999; 30(3): 408-12.
    42. Li XM, Jeffers LJ, Reddy KR, de Medina M, Silva M, Villanueva S, et al. Immunophenotyping of lymphocytes in liver tissue of patients with chronic liver diseases by flow cytometry. Hepatology JT- Hepatology (Baltimore, Md.) 1991; 14(1): 121-7.
    43. Krams SM, Van de Water J, Coppel RL, Esquivel C, Roberts J, Ansari A, et al. Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis. Hepatology JT-Hepatology (Baltimore, Md.) 1990; 12(2): 306-13.
    44. Meuer SC, Moebius U, Manns, MM. Dienes HP, Ramadori G, Hess G, et al. Clonal analysis of human T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis. Eur J Immunol JT - European journal of immunology 1988; 18(9): 1447-52.
    45. Leon MP, Spickett G, Jones DE, Bassendine MF. CD4+ T cell subsets defined by isoforms of CD45 in primary biliary cirrhosis. Clin Exp Immunol JT - Clinical and experimental immunology 1995; 99(2): 233-9.
    46. Hoffmann RM, Pape GR, Spengler U, Rieber EP, Eisenburg J, Dohrmann J, et al. Clonal analysis of liver-derived T cells of patients with primary biliary cirrhosis. Clin Exp Immonol JT-Clinical and experimental imunology 1989; 76(2): 210-5.
    47. Ahmed AF, Ohtani H, Nio M, Funaki N, Shimaoka S, Nagura H, et al. CD8+ T cells infiltrating into bile ducts in biliary atresia do not appear to function as cytotoxic T cells: a clinicopathological analysis. J Pathol JT- The Journal of pathology 2001; 193(3): 383-9.
    48. Kita H, Imawari M, Gershwin ME. Cellular immune response in primary biliary cirrhosis. Hepatol Res 2004; 28(1): 12-17.
    1. Heathcote EJ. Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology JT - Hepatology (Baltimore, Md.) 2000;31(4): 1005-13.
    2. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis JT - Annals of the rheumatic diseases 2002:61(6):554-8.
    3. Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol JT - Virchows Archiv. A, Pathological anatomy and histology 1978:379(2):103-12.
    4. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med JT - The New England journal of medicine 1991;324(22):1548-54.
    5. Vuoristo M, Farkkila M, Karvonen AL, LeinoR, Lehtola J, Makinen J, et al. A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid. Gastroenterology JT - Gastroenterology 1995;108(5):1470-8.
    6. Hwang SJ, Chan CY, Lee SD, Wu JC, Tsay SH, Lo KJ. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a short-term, randomized, double-blind controlled, cross-over study with long-term follow up. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1993:8(3): 217-23.
    7. Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology JT - Hepatology (Baltimore, Md.) 1989; 10(4) :420-9.
    8. Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1976;70(5 PT. 1):656-60.
    9. Talwalkar JA, Souto E, Jorgensen RA, LindorKD. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol JT - Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2003; 1(4):297-302.
    10. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology JT -Hepatology (Baltimore, Md.) 1994; 19(5): 1149-56.
    11. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med JT - The New England journal of medicine 2005:353(12) :1261-73.
    12. Poupon RE, Eschwege E, Poupon R. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Interim analysis of a double-blind multicentre randomized trial. The UDCA-PBC Study Group. J Hepatol JT - Journal of hepatology 1990;11(1):16-21.
    13. Battezzati PM, PoddaM, Bianchi FB, NaccaratoR, Orlandi F, Surrenti C, et al. Ursodeoxycholic acid for symptomatic primary biliary cirrhosis. Preliminary analysis of a double-blind multicenter trial. Italian Multicenter Group for the Study of UDCA in PBC. J Hepatol JT -Journal of hepatology 1993;17(3):332-8.
    14. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol JT - Journal of hepatology 2000;32(4):561-6.
    15. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology JT - Gastroenterology 1999;117(4):918-25.
    16. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, NuutinenH, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology JT - Hepatology (Baltimore, Md.) 2005;41(4):747-52.
    17. Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology JT -Hepatology (Baltimore, Md.) 2000;31(2):318-23.
    18. Wolfhagen FH, van Hoogstraten HJ, van Buuren HR, van Berge-Henegouwen GP, ten Kate FJ, Hop WC, et al. Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study. J Hepatol JT - Journal of hepatology 1998;29(5):736-42.
    19. Lim AG, Wolfhagen HJ, Verma A, van Buuren HR, Jazrawi RP, Levy JH, et al. Soluble intercellular adhesion molecule-1 in primary biliary cirrhosis: effect of ursodeoxycholic acid and immunosuppressive therapy. Eur J Gastroenterol Hepatol JT - European journal of gastroenterology & hepatology 1997;9(2):155-61.
    20. Leuschner M, Guldutuna S, You T, Hubner K, Bhatti S, Leuschner U. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 1996;25(1):49-57.
    21. Leuschner M, Dietrich CF, You T, Seidl C, Raedle J, Herrmann G, et al. Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment. Gut JT - Gut 2000;46(1): 121-6.
    22. van Hoogstraten HJ, Hansen BE, van Buuren HR, ten Kate FJ, van Berge-Henegouwen GP, Schalm SW. Prognostic factors and long-term effects of ursodeoxycholic acid on liver biochemical parameters in patients with primary biliary cirrhosis. Dutch Multi-Centre PBC Study Group. J Hepatol JT - Journal of hepatology 1999;31(2):256-62.
    23. Balan V, Dickson ER, Jorgensen RA, Lindor KD. Effect of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis. Mayo Clin Proc JT - Mayo Clinic proceedings. Mayo Clinic 1994;69(10):923-9.
    24. Poupon RE, Ouguerram K, Chretien Y, Verneau C, Eschwege E, Magot T, et al. Cholesterol-lowering effect of ursodeoxycholic acid in patients with primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1993; 17 (4):577-82.
    25. Turner IB, Myszor M, Mitchison HC, Bennett MK, Burt AD, James OF. A two year controlled trial examining the effectiveness of ursodeoxycholic acid in primary biliary cirrhosis. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1994;9(2):162-8.
    26. Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol JT - Journal of hepatology 1992;15 (3):336-44.
    27. Crowe J, Christensen E, Smith M, Cochrane M, Ranek L, Watkinson G, et al. Azathioprine in primary biliary cirrhosis: a preliminary report of an international trial. Gastroenterology JT - Gastroenterology 1980;78(5 Pt 1): 1005-10.
    28. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis JT - Clinics in liver disease 2004; 8(1): 67-81, vi.
    29. Trauner M, Graziadei IW. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 1999;13(8):979-96.
    30. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med JT - The New England journal of medicine 1994:330(19): 1342-7.
    31. Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1994; 106 (5): 1284-90.
    32. Papatheodoridis GV, Hadziyannis ES, Deutsch M, Hadziyannis SJ. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial. Am J Gastroenterol JT - The American journal of gastroenterology 2002:97(8): 2063-70.
    33. Chan CW, Gunsar F, Feudjo M, Rigamonti C, Vlachogiannakos J, Carpenter JR, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 2005:21(3):217-26.
    34. Prince M, Christensen E, Gluud C. Glucocorticosteroids for primary biliary cirrhosis. Cochrane Database Syst Rev JT - Cochrane database of systematic reviews (Online) 2005:(2):CD003778.
    35. Christensen E, Neuberger J, Crowe J, Altman DG, Popper H, Portmann B, et al. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology JT - Gastroenterology 1985:89(5):1084-91.
    36. Yela C, Manzano L, Castellano G, Garfia C, Solis JA. Primary biliary cirrhosis treated with azathioprine and liver transplantation. J Hepatol JT - Journal of hepatology 1997;27(3): 599.
    1. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjogren' s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis JT - Annals of the rheumatic diseases 2002;61(6):554-8.
    2. Dienes HP, Lohse AW, Gerken G, Schirmacher P, Gallati H, Lohr HF, et al. Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis. Virchows Arch JT - Virchows Archiv : an international journal of pathology 1997;431(2):119-24.
    3. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest JT - The Journal of clinical investigation 2002; 109(9): 1231-40.
    4. Moreno-Otero R, Civeira MP, Suou T, Kanof ME, James SP, Jones EA. Reduced numbers of CD8+ T cells and B cell-expression of Leu-8 antigen in peripheral blood of patients with primary biliary cirrhosis. Hepatogastroenterology JT - Hepato-gastroenterology 1994:41(3):239-43.
    5. Musialik J, Michalkiewicz J, Petelenz M, Mazurek U, Mazur W, Madalinski K, et al. Reduction of CD45RA isoform expression and decrease in CD4 and CD8 receptor density in lymphocytes of patients with primary biliary cirrhosis. Scand J Gastroenterol JT - Scandinavian journal of gastroenterology 2003:38(4):421-6.
    6. Krams SM, Van de Water J, Coppel RL, Esquivel C, Roberts J, Ansari A, et al. Analysis of hepatic T lymphocyte and immunoglobulin deposits in patients with primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1990:12(2):306-13.
    7. Shimizu M, Yuh K, Aoyama S, Ichihara I, Watanabe H, Shijo H, et al. Immunohistochemical characterization of inflammatory infiltrates at the site of bile duct injury in primary biliary cirrhosis. Liver JT - Liver 1986:6(1): 1-6.
    8. Ahmed AF, Ohtani H, Nio M, Funaki N, Shimaoka S, Nagura H, et al. CD8+ T cells infiltrating into bile ducts in biliary atresia do not appear to function as cytotoxic T cells: a clinicopathological analysis. J Pathol JT - The Journal of pathology 2001;193(3):383-9.
    9. Koshino Y, Kida H, Takasawa K, Goshima S, Takeda S, Yoshimura M, et al. [Glomerular lesions in primary biliary cirrhosis]. Nippon Jinzo Gakkai Shi JT - Nippon Jinzo Gakkai shi 1986:28(10): 1385-91.
    10. van den Oord JJ, Fevery J, de Groote J, Desmet VJ. Immunohistochemical characterization of inflammatory infiltrates in primary biliary cirrhosis. Liver JT - Liver 1984;4(4):264-74.
    11. Kamihira T, Shimoda S, Harada K, Kawano A, Handa M, Baba E, et al. Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 2003:125(5):1379-87.
    12. Isse K, Harada K, Sato Y, Nakanuma Y. Characterization of biliary intra-epithelial lymphocytes at different anatomical levels of intrahepatic bile ducts under normal and pathological conditions: numbers of CD4+CD28- intra-epithelial lymphocytes are increased in primary biliary cirrhosis. Pathol Int JT- Pathology international 2006; 56(1): 17-24.
    13. Spengler U, Leifeld L, Braunschweiger I, Dumoulin FL, Lechmann M, Sauerbruch T. Anomalous expression of costimulatory molecules B7-1, B7-2 and CD28 in primary biliary cirrhosis. J Hepatol JT- Journal of hepatology 1997; 26(1): 31-6.
    14. Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology JT- Hepatology (Baltimore, Md.) 2006; 43(4): 729-37.
    15. Menendez-Caro JL, Alvarez-Mon M, Giron JA, Manzano L, Garrido A, Abreu L, et al. Increased IgM B cell differentiation lymphokineproduction by T lymphocytes from patients with primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 1994; 20(4): 446-53.
    16. Kita H, Imawari M, Gershwin ME. Cellular immune response in primary biliarycirrhosis. Hepatol Res 2004; 28(1): 12-17.
    17. Kikuchi K, Lian ZX, Yang GX, Ansari AA, Ikehara S, Kaplan M, et al. Bacterial CpG induces hyper-IgM production in CD27(+) memory B cells in primary biliary cirrhosis. Gastroenterology JT- Gastroenterology 2005; 128(2): 304-12.
    18. Beuers U, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology JT - Hepatology (Baltimore, Md.) 1998; 28(6): 1449-53.
    19. Trauner M, Graziadei IW. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 1999; 13(8): 979-96.
    20. Kaplan MM. Novosphingobium aromaticivorans: a potential initiator of primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2004; 99(11): 2147-9.
    21. Selmi C, Gershwin ME. Bacteria and human autoimmunity: the case of primary biliary cirrhosis. CUrT Opin Rheumatol JT - Current opinion in rheumatology 2004; 16(4): 406-10.
    22. Wang AP, Migita K, Ito M, Takii Y, Daikoku M, YokoyamaT, et al. Hepatic expression of toll-like receptor 4 in primary biliary cirrhosis. J Autoimmun JT - Journal of autoimmunity 2005; 25(1): 85-91.
    23. Ljungh A, Nilsson HO, Wadstrom T, Stenram U, Willen R. Microbes as trigger for primary biliary cirrhosis and primary sclerosing cholangitis. Dig Liver Dis JT - Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2005; 37(10): 803-4.
    24. Bjorkland A, Festin R, Mendel-Hartvig I, Nyberg A, Loof L, Totterman TH. Blood and liver-infiltrating lymphocytes in primary biliary cirrhosis: increase in activated T and natural killer cells and recruitment of primed memory T cells. Hepatology JT - Hepatology (Baltimore, Md.) 1991; 13(6): 1106-11.
    25. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol JT - Journal of immunology (Baltimore, Md: 1950) 1986; 136(7): 2348-57.
    26. Romagnani P, Annunziato F, Piccinni MP, Maggi E, Romagnani S. Cytokines and chemokines in T lymphopoiesis and T-cell effector function. Immunol Today JT - Immunology today 2000; 21(9): 416-8.
    27. Liew FY. T(H)1 and T(H)2 cells: a historical perspective. Nat Rev Immunol JT - Nature reviews. Immunology 2002; 2(1): 55-60.
    28. Berg PA, Klein R, Rocken M. Cytokines in primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 1997; 17(2): 115-23.
    29. Itoh S, Matsuzaki Y, Kimura T, Ikegami T, Shoda J, Fujiwara M, et al. Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliarycirrhosis-like hepatic lesions induced by graft-versus-host reaction. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 2000; 15(4): 443-51.
    30. Harada K, Van de Water J, Leung PS, Coppel RL, Ansari A, Nakanuma Y, et al. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset. nepatology JT - Hepatology (Baltimore, Md.) 1997; 25(4): 791-6.
    31. Harada K, Isse K, Kamihira T, Shimoda S, Nakanuma Y. Thl eytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 2005; 41(6): 1329-38.
    32. Shindo M, Mullin GE, Braun-Elwert L, BergasaNV, Jones EA, James SP. Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB). Clin Exp Immunol JT - Clinical and experimental immunology 1996; 105(2): 254-9.
    33. Hanada S, Harada M, Koga H, Kawaguchi T, Taniguchi E, Kumashiro R, et al. Tumor necrosis factor-alpha and interferon-gamm directly impair epithelial barrier function in cultured mouse cholangiocytes. Liver Int JT - Liver international: official journal of the International Association for the Study of the Liver 2003; 23(1): 3-11.
    34. Miller LC, Kaplan MM. Serum interleukin-2 and tumor necrosis factor-alpha in primary biliary cirrhosis: decrease by colchicine and relationship to HLA-DR4. Am J Gastroenterol JT - The American journal of gastroenterology 1992; 87(4): 465-70.
    35. Nagano T, Yamamoto K, Matsumoto S, Okamoto R, Tagashira M, Ibuki N, et al. Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol JT - Journal of clinical immunology 1999; 19(6): 422-7.
    36. Kakumu S, Yoshioka K, Tsutsumi Y, Wakita T, Arao M. Production of tumor necrosis factor, interleukin 1, and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis. Clin Immunol Immunopathol JT - Clinical immunology and immunopathology 1990; 56(1): 54-65.
    37. Nishio A, Keeffe EB, Gershwin ME. Immunopathogenesis of primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 2002; 22(3): 291-302.
    38. Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology JT - Gastroenterology 1992; 103(1): 264-74.
    39. Neuman M, Angulo P, Malkiewicz I, Jorgensen R, Shear N, Dickson ER, et al. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 2002; 17(2): 196-202.
    40. Lin SY, Chen WY, Lee FY, Huang CJ, Sheu WH. Activation of ubiquitin-proteasome pathway is involved in skeletal muscle wasting in a rat model with biliary cirrhosis: potential role of TNF-alpha. Am J Physiol Endocrinol Metab JT - American journal of physiology. Endocrinology and metabolism 2005; 288(3): E493-501.
    41. Broome U, Eriksson LS, Sundin U, Sundqvist KG. Decreased in vitro production of tumor necrosis factor in primary biliary cirrhosis patients. Scand J Gastroenterol JT - Scandinavian journal of gastroenterology 1992; 27(2): 124-8.
    42. Wells RG. Fibrogenesis. V. TGF-beta signaling pathways. Am J Physiol Gastrointest Liver Physiol JT - American journal of physiology. Gastrointestinal and liver physiology 2000; 279(5): G845-50.
    1. Walker JG, Doniach D, Roitt IM, Sherlock S. Serological tests in diagnosis of primary bleary cirrhosis. Lancet JT - Lancet 1965; 39: 827-31.
    2. Floreani A, Baragiotta A, Pizzuti D, Martines D, Cecchetto A, Chiarelli S. Mucosal IgAdefect in primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2002; 97(2): 508-10.
    3. Ichiki Y, Leung PS, Ishibashi H, Coppel RL, Ansari AA, Gershwin ME. Mitochondria and autoimmunity in primary biliary cirrhosis. Mitochondrion JT - Mitochondrion 2004; 4(5-6): 743-53.
    4. Masuda J, Omagari K, Ohba K, Hazama H, Kadokawa Y, Kinoshita H, et al. Correlation between histopathological findings of the liver and IgA class antibodies to 2-oxo-acid dehydrogenase complex in primary biliary cirrhosis. Dig Dis Sci JT - Digestive diseases and sciences 2003; 48(5): 932-8.
    5. Flisiak R, Pelszynska M, Prokopowicz D, Rogalska M, Grygoruk U. High concentration of antimitochondrial antibodies predicts progressive primary biliary cirrhosis. World J Gastroenterol JT - World journal of gastroenterology: WJG 2005; 11(36): 5706-9.
    6. Van Norstrand MD, Malinchoc M, Lindor KD, Therneau TM, Gershwin ME, Leung PS, et al. Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology JT - Hepatology (Baltimore, Md.) 1997; 25(1): 6-11.
    7. Benson GD, Kikuchi K, Miyakawa H, Tanaka A, Watnik MR, Gershwin ME. Serial analysis of antimitochondrial antibody in patients with primary biliary cirrhosis. Clin Dev Immunol JT-Clinical & developmental immunology 2004; 11(2): 129-33.
    8. Neuberger J. Antibodies and primary biliary cirrhosis - piecing together the jigsaw. J Hepatol JT - Journal of hepatology 2002; 36(1): 126-9.
    9. Shibata M, Onozuka Y, Morizane T, Koizumi H, Kawagnchi N, Miyakawa H, et al. Prevalence of antimitochondrial antibody in Japanese corporate workers in Kanagawa prefecture. J Gastroenterol JT - Journal of gastroenterology 2004; 39(3): 255-9.
    10. Courvalin JC, Lassoued K, Bartnik E, Blobel G, Wozniak RW. The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest JT - The Journal of clinical investigation 1990; 86(1): 279-85.
    11. Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Autoantibodies from patients with primary biliary cirrhosis preferentially react with the amino-terminal domain of nuclear pore complex glycoprotein gp210. J Exp Med JT - The Journal of experimental medicine 1995; 182(4): 1159-62.
    12. Nickowitz RE, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein Gp210. J Exp Med JT - The Journal of experimental medicine 1993; 178(6) :2237-42.
    13. Bandin O, Courvalin JC, Poupon R, Dubel L, Homberg JC, Johanet C. Specif icity and sensitivity of gp210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1996;23 (5): 1020-4.
    14. Worman HJ, Courvalin JC. Antinuclear antibodies specific for primary biliary cirrhosis. Autoimmun Rev JT - Autoimmunity reviews 2003;2(4):211-7.
    15. Lassoued K, Brenard R, Degos F, Courvalin JC, Andre C, Danon F, et al. Antinuclear antibodies directed to a 200-kilodalton polypeptide of the nuclear envelope in primary biliary cirrhosis. A clinical and immunological study of a series of 150 patients with primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1990;99(1):181-6.
    16. Nickowitz RE, Wozniak RW, Schaffner F, Worman HJ. Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis. Gastroenterology JT -Gastroenterology 1994;106(1):193-9.
    17. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2003;98(2):431-7.
    18. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology JT - Hepatology (Baltimore, Md.) 1989; 10(1): 1-7.
    19. Itoh S, Ichida T, Yoshida T, Hayakawa A, Uchida M, Tashiro-Itoh T, et al. Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1998:13(3): 257-65.
    20. Vergani D, Bogdanos DP. Positive markers in AMA-negative PBC. Am J Gastroenterol JT - The American journal of gastroenterology 2003;98(2):241-3.
    21. Invernizzi P, Podda M, Battezzati PM, Crosignani A, ZuinM, Hitchman E, et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 2001;34(3):366-72.
    22. Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, et al. Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 2005;42(3):386-92.
    23. Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, et al. Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun JT - Journal of autoimmunity 2006;26(2):138-45.
    24. Szostecki C, Guldner HH, Will H. Autoantibodies against "nuclear dots" in primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 1997;17(1):71-8.
    25. Zuchner D, Sternsdorf T, Szostecki C, Heathcote EJ, Cauch-Dudek K, Will H. Prevalence, kinetics, and therapeutic modulation of autoantibodies against Sp100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis. Hepatology JT -Hepatology (Baltimore, Md.) 1997:26(5): 1123-30.
    
    26. Bogdanos DP, Vergani D, Muratori P, Muratori L, Bianchi FB. Specificity of anti-sp100 antibody for primary biliary cirrhosis. Scand J Gastroenterol JT - Scandinavian journal of gastroenterology 2004;39 (4):405-6; author reply 407.
    
    27. Bogdanos DP, Pares A, Rodes J, Vergani D. Primary biliary cirrhosis specific antinuclear antibodies in patients from Spain. Am J Gastroenterol JT - The American journal of gastroenterology 2004;99(4):763-4; author reply 765.
    1. Poupon R, Chazouilleres O, Balkau B, Poupon RE. Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis. UDCA-PBC Group. J Hepatol JT - Journal of hepatology 1999; 30 (3):408-12.
    2. Desmet V, Roskams T, Van Eyken P. Ductular reaction in the liver. Pathol Res Pract JT - Pathology, research and practice 1995;191(6):513-24.
    3. Ludwig J. The pathology of primary biliary cirrhosis and autoimmune cholangitis. Baillieres Best Pract Res Clin Gastroenterol JT - Bailliere's best practice & research. Clinical gastroenterology 2000:14(4): 601-13.
    4. Ludwig J, Dickson ER, McDonald GS. Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol JT - Virchows Archiv. A, Pathological anatomy and histology 1978;379(2):103-12.
    5. Zachou K, Rigopoulou E, Liaskos C, PatsiaouraK, Makri E, Stathakis N, et al. Primary biliary cirrhosis presented as peripheral eosinophilia in asymptomatic women with or without elevated alkaline phosphatase. Eur J Gastroenterol Hepatol JT - European journal of gastroenterology & hepatology 2004;16(4): 425-8.
    6. Yamazaki K, Nakadate I, Suzuki K, Sato S, Masuda T. Eosinophilia in primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 1996:91(3):516-22.
    7. Papatheodoridis GV, Hadziyannis ES, Deutsch M, Hadziyannis SJ. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial. Am J Gastroenterol JT - The American journal of gastroenterology 2002;97(8):2063-70.
    8. Corpechot C, Poujol-Robert A, Wendum D, Calotte M, Chretien Y, Poupon RE, et al. Biochemical markers of liver fibrosis and lymphocytic piecemeal necrosis in UDCA-treated patients with primary biliary cirrhosis. Liver Int JT - Liver international : official journal of the International Association for the Study of the Liver 2004:24(3):187-93.
    9. Locke GR 3rd, Therneau TM, Ludwig J, Dickson ER, Lindor KD. Time course of histological progression in primary biliary cirrhosis. Hepatology JT -Hepatology (Baltimore, Md.) 1996:23(1):52-6.
    10. Kakumu S, Yoshioka K, Tsutsumi Y, Wakita T, Arao M. Production of tumor necrosis factor, interleukin 1, and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis. Clin Immunol Immunopathol JT-Clinical immunology and immunopathology 1990;56(1):54-65.
    11. Jones A, Selby PJ, Viner C, Hobbs S, Gore ME, McElwain TJ. Tumour necrosis factor, cholestatic jaundice, and chronic liver disease. Gut JT-Gut 1990;31(8):938-9.
    12. Nisbio A, Keeffe EB, Gershwin ME. Immunopathogenesis of primary biliary cirrhosis. Semin Liver Dis JT-Seminars in liver disease 2002;22(3):291-302.
    13. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest JT-The Journal of clinical investigation 2002;109(9):1231-40.
    14. Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CDld tetramer. Gastroenterology JT-Gastroenterology 2002;123(4):1031-43.
    15. Medina J, Sanz-Cameno P, Garcia-Buey L, Martin-Vilchez S, Lopez-Cabrera M, Moreno-Otero R. Evidence of angiogenesis in primary biliary cirrhosis: an immunohistochemical descriptive study. J Hepatol JT-Journal of hepatology 2005;42(1):124-31.
    1. Neuberger J. Primary biliary cirrhosis. Lancet JT - Lancet 1997;350(9081):875-9.
    
    2. Levy C, Lindor KD. Current management of primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol JT - Journal of hepatology 2003;38 Suppl 1:S24-37.
    3. Hagey LR, Crombie DL, Espinosa E, Carey MC, Igimi H, Hofmann AF. Ursodeoxycholic acid in the Ursidae: biliary bile acids of bears, pandas, and related carnivores. J Lipid Res JT - Journal of lipid research 1993:34(11): 1911-7.
    4. BeuersU, Boyer JL, Paumgartner G. Ursodeoxycholic acid in cholestasis: potential mechanisms of action and therapeutic applications. Hepatology JT -Hepatology (Baltimore, Md.) 1998;28(6):1449-53.
    5. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology JT - Hepatology (Baltimore, Md.) 2002;36(3):525-31.
    6. van de Meeberg PC, Wolfhagen FH, Van Berge-Henegouwen GP, Salemans JM, Tangerman A, van Buuren HR, et al. Single or multiple dose ursodeoxycholic acid for cholestatic liver disease: biliary enrichment and biochemical response. J Hepatol JT - Journal of hepatology 1996;25(6):887-94.
    7. Alpini G, Baiocchi L, Glaser S, Ueno Y, Marzioni M, Francis H, et al. Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha. Hepatology JT -Hepatology (Baltimore, Md.) 2002; 35 (5): 1041-52.
    8. Trauner M, Graziadei IW. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 1999;13(8):979-96.
    9. Rodrigues CM, Steer CJ. The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent. Expert Opin Investig Drugs JT - Expert opinion on investigational drugs 2001;10(7):1243-53.
    10. Benz C, Angermuller S, Tox U, Kloters-Plachky P, Riedel HD, Sauer P, et al. Effect of tauroursodeoxycholic acid on bile-acid-induced apoptosis and cytolysis in rat hepatocytes. J Hepatol JT - Journal of hepatology 1998;28(1):99-106.
    11. Rolo AP, Palmeira CM, Wallace KB. Mitochondrially mediated synergistic cell killing by bile acids. Biochim Biophys Acta JT - Biochimica et biophysica acta 2003:1637(1):127-32.
    12. Van Hoogstraten HJ, De Smet MB, Renooi j W, Breed JG, Engels LG, Den Ouden-Muller JW, et al. A randomized trial in primary biliary cirrhosis comparing ursodeoxycholic acid in daily doses of either 10 mg/kg or 20 mg/kg. Dutch Multicentre PBC Study Group. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 1998; 12(10) :965-71.
    13. Verma A, Jazrawi RP, Ahmed HA, Davis T, Bland JM, Benson M, et al. Optimum dose of ursodeoxycholic acid in primary biliary cirrhosis. Eur J Gastroenterol Hepatol JT - European journal of gastroenterology & hepatology 1999;11(10):1069-76.
    14. Angulo P, Dickson ER, Therneau TM, Jorgensen RA, Smith C, DeSotel CK, et al. Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. J Hepatol JT - Journal of hepatology 1999:30(5):830-5.
    15. Angulo P, Jorgensen RA, Lindor KD. Incomplete response to ursodeoxycholic acid in primary biliary cirrhosis: is a double dosage worthwhile?. Am J Gastroenterol JT - The American journal of gastroenterology 2001:96(11):3152-7.
    16. Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group. N Engl J Med JT - The New England journal of medicine 1991;324(22):1548-54.
    17. Vuoristo M, Farkkila M, Karvonen AL, Leino R, Lehtola J, Makinen J, et al. A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid. Gastroenterology JT - Gastroenterology 1995;108(5):1470-8.
    18. Hwang SJ, Chan CY, Lee SD, Wu JC, Tsay SH, Lo KJ. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a short-term, randomized, double-blind controlled, cross-over study with long-term follow up. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1993; 8 (3): 217-23.
    19. Talwalkar JA, Souto E, Jorgensen RA, Lindor KD. Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol JT - Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2003;1(4):297-302.
    20. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology JT -Hepatology (Baltimore, Md.) 1994;19(5):1149-56.
    21. Poupon RE, Eschwege E, Poupon R. Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. Interim analysis of a double-blind multicentre randomized trial. The UDCA-PBC Study Group. J Hepatol JT - Journal of hepatology 1990;11(1):16-21.
    22. Battezzati PM, Podda M, Bianchi FB, Naccarato R, Orlandi F, Surrenti C, et al. Ursodeoxycholic acid for symptomatic primary biliary cirrhosis. Preliminary analysis of a double-blind multicenter trial. Italian Multicenter Group for the Study of UDCA in PBC. J Hepatol JT - Journal of hepatology 1993; 17(3): 332-8.
    23. Pares A, Caballeria L, Rodes J, Bruguera M, Rodrigo L, Garcia-Plaza A, et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol JT - Journal of hepatology 2000;32(4):561-6.
    24. Combes B, Carithers RL Jr, Maddrey WC, Lin D, McDonald MF, Wheeler DE, et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology JT -Hepatology (Baltimore, Md.) 1995;22 (3):759-66.
    25. Leuschner M, Dietrich CF, You T, Seidl C, Raedle J, Herrmann G, et al. Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment. Gut JT -Gut 2000;46(1): 121-6.
    26. Balan V, Dickson ER, Jorgensen RA, Lindor KD. Effect of ursodeoxycholic acid on serum lipids of patients with primary biliary cirrhosis. Mayo Clin Proc JT - Mayo Clinic proceedings. Mayo Clinic 1994:69(10): 923-9.
    27. Poupon RE, OuguerramK, Chretien Y, Verneau C, Eschwege E, Magot T, et al. Cholesterol-lowering effect of ursodeoxycholic acid in patients with primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1993; 17(4):577-82.
    28. Turner IB, Myszor M, Mitchison HC, Bennett MK, Burt AD, James OF. A two year controlled trial examining the effectiveness of ursodeoxycholic acid in primary biliary cirrhosis. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1994;9(2):162-8.
    29. van Hoogstraten HJ, Hansen BE, van Buuren HR, ten Kate FJ, van Berge-Henegouwen GP, Schalm SW. Prognostic factors and long-term effects of ursodeoxycholic acid on liver biochemical parameters in patients with primary biliary cirrhosis. Dutch Multi-Centre PBC Study Group. J Hepatol JT -Journal of hepatology 1999;31(2):256-62.
    30. Leuschner U, Fischer H, Kurtz W, Guldutuna S, Hubner K, Hellstern A, et al. Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology JT -Gastroenterology 1989;97(5):1268-74.
    31. Angulo P, Batts KP, Therneau TM, Jorgensen RA, Dickson ER, Lindor KD. Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1999; 29 (3): 644-7.
    32. Batts KP, Jorgensen RA, Dickson ER, Lindor KD. Effects of ursodeoxycholic acid on hepatic inflammation and histological stage in patients with primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 1996:91(11):2314-7.
    33. Leuschner U, Guldutuna S, Imhof M, Hubner K, Benjaminov A, Leuschner M. Effects of ursodeoxycholic acid after 4 to 12 years of therapy in early and late stages of primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 1994;21(4):624-33.
    34. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology JT -Hepatology (Baltimore, Md.) 1999;29(4):1007-12.
    35. Combes B, Markin RS, Wheeler DE, Rubin R, West AB, Mills AS, et al. The effect of ursodeoxycholic acid on the florid duct lesion of primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1999:30(3): 602-5.
    36. Neuman MG, Cameron RG, Haber JA, Katz GG, Blendis LM. An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cirrhosis. Liver JT - Liver 2002:22(3):235-44.
    37. Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 2000:32(6): 1196-9.
    38. Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology JT Gastroenterology 2002:122(3):652-8.
    39. Poupon RE, Lindor KD, Pares A, Chazouilleres O, Poupon R, Heathcote EJ. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 2003:39(1):12-6.
    40. Paumgartner G. Ursodeoxycholic acid for primary biliary cirrhosis: treat early to slow progression. J Hepatol JT - Journal of hepatology 2003:39(1):112-4.
    41. Chan CW, Papatheodoridis GV, Goulis J, Burroughs AK. Ursodeoxycholic acid and histological progression in primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 2003:39(6): 1094-5.
    42. Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet JT - Lancet 1999:354(9184):1053-60.
    43. Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, Murtaugh PA, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1994:106 (5): 1284-90.
    44. Lindor KD, Therneau TM, Jorgensen RA, Malinchoc M, Dickson ER. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1996:110(5): 1515-8.
    45. Lindor KD, Jorgensen RA, Therneau TM, Malinchoc M, Dickson ER. Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis. Mayo Clin Proc JT - Mayo Clinic proceedings. Mayo Clinic 1997:72(12):1137-40.
    46. Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med JT - The New England journal of medicine 1994:330(19): 1342-7.
    47. Poupon RE, Bonnand AM, Chretien Y, Poupon R. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology JT - Hepatology (Baltimore, Md.) 1999:29(6): 1668-71.
    48. Papatheodoridis GV, Hadziyannis ES, Deutsch M, Hadziyannis SJ. Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial. Am J Gastroenterol JT - The American journal of gastroenterology 2002;97(8):2063-70.
    49. Combes B, Luketic VA, Peters MG, Zetterman RK, Garcia-Tsao G, Munoz SJ, et al. Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2004:99(2):264-8.
    50. Heathcote EJ, Stone J, Cauch-Dudek K, Poupon R, Chazouilleres O, Lindor KD, et al. Effect of pretransplantation ursodeoxycholic acid therapy on the outcome of liver transplantation in patients with primary biliary cirrhosis. Liver Transpl Surg JT - Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 1999;5(4):269-74.
    51. Chan CW, Gunsar F, Feudjo M, Rigamonti C, Vlachogiannakos J, Carpenter JR, et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 2005:21(3):217-26.
    52. Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev JT - Cochrane database of systematic reviews (Online) 2002;(1):CD000551.
    53. Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote EJ. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology JT -Gastroenterology 1997:113(3):884-90.
    54. Combes B. Ursodeoxycholic acid in primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 1997:17(2):125-8.
    55. Simko V, Michael S, Prego V. Ursodeoxycholic therapy in chronic liver disease: a meta-analysis in primary biliary cirrhosis and in chronic hepatitis. Am J Gastroenterol JT - The American journal of gastroenterology 1994:89(3):392-8.
    56. Neuberger J. URSO-panacea or placebo?. Hepatology JT - Hepatology (Baltimore, Md.) 2000:31(4): 1027-8.
    57. Holtmeier J, Leuschner U. Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis. Digestion JT - Digestion 2001:64(3):137-50.
    58. Mitchison HC, Bassendine MF, Malcolm AJ, Watson AJ, Record CO, James OF. A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss. Hepatology JT - Hepatology (Baltimore, Md.) 1989:10(4):420-9.
    59. Mitchison HC, Palmer JM, Bassendine MF, Watson AJ, Record CO, James OF. A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol JT - Journal of hepatology 1992:15(3):336-44.
    60. Leuschner M, Guldutuna S, You T, HubnerK, Bhatti S, Leuschner U. Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 1996:25(1):49-57.
    61. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology JT - Gastroenterology 1999:117(4):918-25.
    62. Angulo P, Jorgensen RA, Reach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology JT - Hepatology (Baltimore, Md.) 2000:31(2):318-23.
    63. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, NuutinenH, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology JT - Hepatology (Baltimore, Md.) 2005:41(4):747-52.
    64. Prince M, Christensen E, Gluud C. Glucocorticosteroids for primary biliary cirrhosis. Cochrane Database Syst Rev JT - Cochrane database of systematic reviews (Online) 2005;(2):CD003778.
    65. Gong Y, Frederiksen SL, Gluud C. D-penicillamine for primary biliary cirrhosis. Cochrane Database Syst Rev JT - Cochrane database of systematic reviews (Online) 2004;(4):CD004789.
    66. Lindor KD, Dickson ER, Jorgensen RA, Anderson ML, Wiesner RH, Gores GJ, et al. The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology JT - Hepatology (Baltimore, Md.) 1995:22(4 Pt 1):1158-62.
    67. Van Steenbergen W, Sciot R, Van Eyken P, Desmet V, Fevery J. Combined treatment with methotrexate and ursodeoxycholic acid in non-cirrhotic primary biliary cirrhosis. Acta Clin Belg JT - Acta clinica Belgica 1996:51(1):8-18.
    68. Gonzalez-Koch A, Brahm J, Antezana C, Smok G, Cumsille MA. The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone. J Hepatol JT - Journal of hepatology 1997:27(1):143-9.
    69. Bach N, Odin JA. Primary biliary cirrhosis: a Mount Sinai perspective. Mt Sinai J Med JT - The Mount Sinai journal of medicine, New York 2003:70(4):242-50.
    70. Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, et al. Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology JT Hepatology (Baltimore, Md.) 2005;42 (5): 1184-93.
    71. Gong Y, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev JT -Cochrane database of systematic reviews (Online) 2005;(3):CD004385.
    72. Ikeda T, Tozuka S, Noguchi O, Kobayashi F, Sakamoto S, Marumo F, et al. Effects of additional administration of colchicine in ursodeoxycholic acid-treated patients with primary biliary cirrhosis: a prospective randomized study. J Hepatol JT - Journal of hepatology 1996:24(1):88-94.
    73. Poupon RE, Huet PM, Poupon R, Bonnand AM, Nhieu JT, Zafrani ES. A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. UDCA-PBC Study Group. Hepatology JT -Hepatology (Baltimore, Md.) 1996:24(5): 1098-103.
    74. Battezzati PM, Zuin M, Crosignani A, Allocca M, Invernizzi P, Selmi C, et al. Ten-year combination treatment with colchicine and ursodeoxycholic acid for primary biliary cirrhosis: a double-blind, placebo-controlled trial on symptomatic patients. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 2001:15(9):1427-34.
    75. Almasio PL, Floreani A, Chiaramonte M, Provenzano G, Battezzati P, Crosignani A, et al. Multicentre randomized placebo-controlled trial of ursodeoxycholic acid with or without colchicine in symptomatic primary biliary cirrhosis. Aliment Pharmacol Ther JT - Alimentary pharmacology & therapeutics 2000; 14(12): 1645-52.
    76. Kaplan MM, Cheng S, Price LL, Bonis PA. A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results. Hepatology JT -Hepatology (Baltimore, Md.) 2004:39(4) :915-23.
    77. Ross A, Sherlock S. A trial of azathiorrine in primary biliary cirrhosis. Gut JT - Gut 1970:11(12): 1058.
    78. Heathcote J, Ross A, Sherlock S. A prospective controlled trial of azathioprine in primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1976;70(5 PT. 1):656-60.
    79. Crowe J, Christensen E, Smith M, Cochrane M, Ranek L, Watkinson G, et al. Azathioprine in primary biliary cirrhosis: a preliminary report of an international trial. Gastroenterology JT Gastroenterology 1980:78(5 Pt 1): 1005-10.
    80. Christensen E, Neuberger J, Crowe J, Altman DG, Popper H, Portmann B, et al. Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial. Gastroenterology JT -Gastroenterology 1985:89(5):1084-91.
    81. Christensen E, Neuberger J, Crowe J, Portmann B, Williams R, Altman DG, et al. Azathioprine and prognosis in primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1986;90(2):508-9.
    82. Wolfhagen FH, van Hoogstraten HJ, van Buuren HR, van Berge-Henegouwen GP, ten Kate FJ, Hop WC, et al. Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study. J Hepatol JT - Journal of hepatology 1998:29(5): 736-42.
    83. Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients?. J Gastroenterol JT - Journal of gastroenterology 2003;38(6):573-8.
    84. Rust C, Beuers U. Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis. Clin Rev Allergy Immunol JT - Clinical reviews in allergy & immunology 2005;28(2):135-45.
    85. Oo YH, Neuberger J. Options for treatment of primary biliary cirrhosis. Drugs JT - Drugs 2004:64(20): 2261-71.
    86. Heathcote EJ. Evidence-based therapy of primary biliary cirrhosis. Eur J Gastroenterol Hepatol JT - European journal of gastroenterology & hepatology 1999:11(6):607-15.
    87. MacQuillan GC, Neuberger J. Liver transplantation for primary biliary cirrhosis. Clin Liver Dis JT- Clinics in liver disease 2003;7(4):941-56, ix.
    88. Liermann Garcia RF, Evangelista Garcia C, McMaster P, Neuberger J. Transplantation for primary biliary cirrhosis: retrospective analysis of 400 patients in a single center. Hepatology JT - Hepatology (Baltimore, Md.) 2001:33(1):22-7.
    89. Neuberger J. Transplantation for primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 1997:17(2): 137-46.
    90. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology JT - Hepatology (Baltimore, Md.) 1989:10(1): 1-7.
    91. Gilroy RK, Lynch SV, Strong RW, Kerlin P, Balderson GA, Stuart KA, et al. Confirmation of the role of the Mayo Risk Score as a predictor of resource utilization after orthotopic liver transplantation for primary biliary cirrhosis. Liver Transpl JT - Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2000;6(6):749-52.
    92. Neuberger J. Recurrent primary biliary cirrhosis. Liver Transpl JT - Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 2003;9(6):539-46.
    93. Wolfhagen FH, van Buuren HR, den Ouden JW, Hop WC, van Leeuwen JP, Schalm SW, et al. Cyclical etidronate in the prevention of bone loss in corticosteroid-treated primary biliary cirrhosis. A prospective, controlled pilot study. J Hepatol JT - Journal of hepatology 1997:26(2):325-30.
    1. Neuberger J. Primary biliary cirrhosis. Lancet JT - Lancet 1997:350(9081):875-9.
    2. Dienes HP, Lohse AW, Gerken G, Schirmacher P, Gallati H, Lohr HF, et al. Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis. Virchows Arch JT - Virchows Archiv : an international journal of pathology 1997;431(2):119-24.
    3. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest JT - The Journal of clinical investigation 2002;109(9):1231-40.
    4. Kita H, Imawari M, Gershwin ME. Cellular immune response in primary biliary cirrhosis. Hepatol Res 2004:28(1) -.12-17.
    5. Moreno-Otero R, Civeira MP, Suou T, Kanof ME, James SP, Jones EA. Reduced numbers of CD8+ T cells and B cell-expression of Leu-8 antigen in peripheral blood of patients with primary biliary cirrhosis. Hepatogastroenterology JT - Hepato-gastroenterology 1994;41(3):239-43.
    6. Musialik J, Michalkiewicz J, Petelenz M, Mazurek U, Mazur W, Madalinski K, et al. Reduction of CD45RA isoform expression and decrease in CD4 and CD8 receptor density in lymphocytes of patients with primary biliary cirrhosis. Scand J Gastroenterol JT - Scandinavian journal of gastroenterology 2003:38(4): 421-6.
    7. Bjorkland A, Festin R, Mendel-Hartvig I, Nyberg A, Loof L, Totterman TH. Blood and liver-infiltrating lymphocytes in primary biliary cirrhosis: increase in activated T and natural killer cells and recruitment of primed memory T cells. Hepatology JT - Hepatology (Baltimore, Md.) 1991:13(6): 1106-11.
    8. Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y. HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases. J Exp Med JT - The Journal of experimental medicine 1995; 181 (5): 1835-45.
    9. Shimoda S, Van de Water J, Ansari A, Nakamura M, Ishibashi H, Coppel RL, et al. Identification and precursor frequency analysis of a common T cell epitope motif in mitochondrial autoantigens in primary biliary cirrhosis. J Clin Invest JT - The Journal of clinical investigation 1998:102(10): 1831-40.
    10. Kita H, Lian ZX, Van de Water J, He XS, Matsumura S, Kaplan M, et al. Identification of HLA-A2-restricted CD8(+) cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J Exp Med JT - The Journal of experimental medicine 2002;195(1):113-23.
    11. Itoh S, Matsuzaki Y, Kimura T, Ikegami T, Shoda J, Fujiwara M, et al. Cytokine profile of liver-infiltrating CD4+ T cells separated from murine primary biliary cirrhosis-like hepatic lesions induced by graft-versus-host reaction. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 2000; 15 (4): 443-51.
    12. Tsuneyama K, Harada K, Yasoshima M, Kaji K, Gershwin ME, Nakanuma Y. Expression of co-stimulatory factor B7-2 on the intrahepatic bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis: an immunohistochemical study. J Pathol JT - The Journal of pathology 1998; 186 (2): 126-30.
    13. Spengler U, Leifeld L, Braunschweiger I, Dumoulin FL, Lechmann M, Sauerbruch T. Anomalous expression of costimulatory molecules B7-1, B7-2 and CD28 in primary biliary cirrhosis. J Hepatol JT -Journal of hepatology 1997;26(1):31-6.
    14. Kamihira T, Shimoda S, Harada K, Kawano A, Handa M, Baba E, et al. Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis. Gastroenterology JT -Gastroenterology 2003;125(5):1379-87.
    15. Panasiuk A, Prokopowicz D, Zak J. Peripheral blood T, B lymphocytes and NK cells in primary biliary cirrhosis. Rocz Akad Med Bialymst JT - Roczniki Akademii Medycznej w Bialymstoku (1995) 2001:46:231-9.
    16. Isse K, Harada K, Sato Y, Nakanuma Y. Characterization of biliary intra-epithelial lymphocytes at different anatomical levels of intrahepatic bile ducts under normal and pathological conditions: numbers of CD4+CD28- intra-epithelial lymphocytes are increased in primary biliary cirrhosis. Pathol Int JT - Pathology international 2006;56(1):17-24.
    17. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol JT - Journal of immunology (Baltimore, Md: 1950) 1986:136(7):2348-57.
    18. Romagnani P, Annunziato F, Piccinni MP, Maggi E, Romagnani S. Cytokines and chemokines in T lymphopoiesis and T-cell effector function. Immunol Today JT - Immunology today 2000;21(9):416-8.
    19. Harada K, Van de Water J, Leung PS, Coppel RL, Ansari A, Nakanuma Y, et al. In situ nucleic acid hybridization of cytokines in primary biliary cirrhosis: predominance of the Th1 subset. Hepatology JT -Hepatology (Baltimore, Md.) 1997; 25 (4): 791-6.
    20. Berg PA, Klein R, Rocken M. Cytokines in primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 1997; 17(2):115-23.
    21. Shindo M, Mullin GE, Braun-Elwert L, Bergasa NV, Jones EA, James SP. Cytokine mRNA expression in the liver of patients with primary biliary cirrhosis (PBC) and chronic hepatitis B (CHB). Clin Exp Immunol JT - Clinical and experimental immunology 1996;105(2):254-9.
    22. Hanada S, Harada M, Koga H, Kawaguchi T, Taniguchi E, Kumashiro R, et al. Tumor necrosis factor-alpha and interferon-gamma directly impair epithelial barrier function in cultured mouse cholangiocytes. Liver Int JT - Liver international : official journal of the International Association for the Study of the Liver 2003;23(1):3-11.
    23. Miller LC, Kaplan MM. Serum interleukin-2 and tumor necrosis factor-alpha in primary biliary cirrhosis: decrease by colchicine and relationship to HLA-DR4. Am J Gastroenterol JT - The American journal of gastroenterology 1992;87(4):465-70.
    24. Nagano T, Yamamoto K, Matsumoto S, Okamoto R, Tagashira M, Ibuki N, et al. Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol JT - Journal of clinical immunology 1999; 19 (6): 422-7.
    25. Kakumu S, Yoshioka K, Tsutsumi Y, Wakita T, Arao M. Production of tumor necrosis factor, interleukin 1, and interferon-gamma by peripheral blood mononuclear cells from patients with primary biliary cirrhosis. Clin Immunol Immunopathol JT -Clinical immunology and immunopathology 1990;56(1) :54-65.
    26. Nishio A, Keeffe EB, Gershwin ME. Immunopathogenesis of primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 2002;22(3):291-302.
    27. Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, et al. Serum levels of cytokines in chronic liver diseases. Gastroenterology JT - Gastroenterology 1992;103(1):264-74.
    28. Neuman M, Angulo P, Malkiewicz I, Jorgensen R, Shear N, Dickson ER, et al. Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 2002;17(2):196-202.
    29. Liu Y, Wenger RH, Zhao M, Nielsen PJ. Distinct costimulatory molecules are required for the induction of effector and memory cytotoxic T lymphocytes. J Exp Med JT - The Journal of experimental medicine 1997; 185 (2): 251-62.
    
    30. Yasoshima M, Kono N, Sugawara H, Katayanagi K, Harada K, Nakanuma Y. Increased expression of interleukin-6 and tumor necrosis factor-alpha in pathologic biliary epithelial cells: in situ and culture study. Lab Invest JT - Laboratory investigation; a journal of technical methods and pathology 1998:78(1) :89-100.
    1. ChouMJ, Lee SL, Chen TY, Tsay GJ. Specificity of antinuclear antibodies in primary biliary cirrhosis. Ann Rheum Dis JT - Annals of the rheumatic diseases 1995;54(2):148-51.
    2. Worman HJ, Courvalin JC. Antinuclear antibodies specific for primary biliary cirrhosis. Autoimmun Rev JT - Autoimmunity reviews 2003;2(4):211-7.
    3. Enarson P, Rattner JB, Ou Y, Miyachi K, Horigome T, Fritzler MJ. Autoantigens of the nuclear pore complex. J Mol Med JT - Journal of molecular medicine (Berlin, Germany) 2004;82(7):423-33.
    4. Shimoda S, Nakamura M, Ishibashi H, Kawano A, Kamihira T, Sakamoto N, et al. Molecular mimicry of mitochondrial and nuclear autoantigens in primary biliary cirrhosis. Gastroenterology JT Gastroenterology 2003;124(7):1915-25.
    5. Ruffatti A, Arslan P, Floreani A, De Silvestro G, Calligaro A, Naccarato R, et al. Nuclear membrane-staining antinuclear antibody in patients with primary biliary cirrhosis. J Clin Immunol JT - Journal of clinical immunology 1985;5 (5):357-61.
    6. Lozano F, Pares A, Borche L, Plana M, Gallart T, Rodes J, et al. Autoantibodies against nuclear envelope-associated proteins in primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1988; 8 (4): 930-8.
    7. Lassoued K, Guilly MN, Andre C, Paintrand M, Dhumeaux D, Danon F, et al. Autoantibodies to 200 kD polypeptide(s) of the nuclear envelope: a new serologic marker of primary biliary cirrhosis. Clin Exp Immunol JT - Clinical and experimental immunology 1988;74(2):283-8.
    8. Courvalin JC, Lassoued K, Bartnik E, Blobel G, Wozniak RW. The 210-kD nuclear envelope polypeptide recognized by human autoantibodies in primary biliary cirrhosis is the major glycoprotein of the nuclear pore. J Clin Invest JT - The Journal of clinical investigation 1990;86(1):279-85.
    9. Wesierska-Gadek J, Hohenauer H, Hitchman E, Penner E. Autoantibodies from patients with primary biliary cirrhosis preferentially react with the amino-terminal domain of nuclear pore complex glycoprotein GP210. J Exp Med JT - The Journal of experimental medicine 1995;182(4):1159-62.
    10. Nickowitz RE, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a restricted region within the cytoplasmic tail of nuclear pore membrane glycoprotein GP210. J Exp Med JT - The Journal of experimental medicine 1993;178(6):2237-42.
    11. Bandin O, Courvalin JC, Poupon R, Dubel L, Homberg JC, Johanet C. Specificity and sensitivity of GP210 autoantibodies detected using an enzyme-linked immunosorbent assay and a synthetic polypeptide in the diagnosis of primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1996:23(5): 1020-4.
    12. Lassoued K, Brenard R, Degos F, Courvalin JC, Andre C, Danon F, et al. Antinuclear antibodies directed to a 200-kilodalton polypeptide of the nuclear envelope in primary biliary cirrhosis. A clinical and immunological study of a series of 150 patients with primary biliary cirrhosis. Gastroenterology JT -Gastroenterology 1990;99(1):181-6.
    13. Nickowitz RE, Wozniak RW, Schaffner F, Worman HJ. Autoantibodies against integral membrane proteins of the nuclear envelope in patients with primary biliary cirrhosis. Gastroenterology JT Gastroenterology 1994;106(1):193-9.
    14. Itoh S, Ichida T, Yoshida T, Hayakawa A, Uchida M, Tashiro-Itoh T, et al. Autoantibodies against a 210 kDa glycoprotein of the nuclear pore complex as a prognostic marker in patients with primary biliary cirrhosis. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1998; 13 (3): 257-65.
    15. Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, et al. Antibody titer to GP210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol JT -Journal of hepatology 2005;42 (3):386-92.
    16. Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, et al. Increased expression of nuclear envelope GP210 antigen in small bile ducts in primary biliary cirrhosis. J Autoimmun JT - Journal of autoimmunity 2006;26 (2):138-45.
    17. Miyachi K, Shibata M, Onozuka Y, Kikuchi F, Imai N, Horigome T. Primary biliary cirrhosis sera recognize not only GP210 but also proteins of the p62 complex bearing N-acetylglucosamine residues from rat liver nuclear envelope. Anti-p62 complex antibody in PBC. Mol Biol Rep JT - Molecular biology reports 1996;23 (3-4):227-34.
    18. Wesierska-Gadek J, Hohenuer H, Hitchman E, Penner E. Autoantibodies against nucleoporin p62 constitute a novel marker of primary biliary cirrhosis. Gastroenterology JT - Gastroenterology 1996; 110(3): 840-7.
    19. Miyachi K, Hankins RW, Matsushima H, Kikuchi F, Inomata T, Horigome T, et al. Profile and clinical significance of anti-nuclear envelope antibodies found in patients with primary biliary cirrhosis: a multicenter study. J Autoimmun JT - Journal of autoimmunity 2003;20(3):247-54.
    
    20. Invernizzi P, Podda M, Battezzati PM, Crosignani A, Zuin M, Hitchman E, et al. Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 2001;34 (3):366-72.
    21. Courvalin JC, Lassoued K, Worman HJ, Blobel G. Identification and characterization of autoantibodies against the nuclear envelope lamin B receptor from patients with primary biliary cirrhosis. J Exp Med JT - The Journal of experimental medicine 1990;172(3):961-7.
    22. Lin F, Noyer CM, Ye Q, Courvalin JC, Worman HJ. Autoantibodies from patients with primary biliary cirrhosis recognize a region within the nucleoplasmic domain of inner nuclear membrane protein LBR. Hepatology JT -Hepatology (Baltimore, Md.) 1996;23(1) :57-61.
    23. Szostecki C, Guldner HH, Will H. Autoantibodies against "nuclear dots" in primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 1997;17(1):71-8.
    24. Muratori P, Muratori L, Ferrari R, Cassani F, Bianchi G, Lenzi M, et al. Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol JT - The American journal of gastroenterology 2003;98(2):431-7.
    25. Zuchner D, Sternsdorf T, Szostecki C, Heathcote EJ, Cauch-Dudek K, Will H. Prevalence, kinetics, and therapeutic modulation of autoantibodies against SP100 and promyelocytic leukemia protein in a large cohort of patients with primary biliary cirrhosis. Hepatology JT - Hepatology (Baltimore, Md.) 1997:26(5): 1123-30.
    26. Bogdanos DP, Baum H, Butler P, Rigopoulou EI, Davies ET, Ma Y, et al. Association between the primary biliary cirrhosis specific anti-SP100 antibodies and recurrent urinary tract infection. Dig Liver Dis JT - Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 2003:35(11):801-5.
    27. Bogdanos DP, Pares A, Rodes J, Vergani D. Primary biliary cirrhosis specific antinuclear antibodies in patients from Spain. Am J Gastroenterol JT - The American journal of gastroenterology 2004:99(4):763-4; author reply 765.
    28. LuettigB, Boeker KH, Schoessler W, Will H, Loges S, Schmidt E, et al. The antinuclear autoantibodies SP100 and GP210 persist after orthotopic liver transplantation in patients with primary biliary cirrhosis. J Hepatol JT - Journal of hepatology 1998:28(5):824-8.
    29. Dubel L, Farges O, Courvalin JC, Sebagh M, Johanet C. Persistence of GP210 and multiple nuclear dots antibodies does not correlate with recurrence of primary biliary cirrhosis 6 years after liver transplantation. J Hepatol JT - Journal of hepatology 1998;28(1):169-70.
    30. Tan EM. Antinuclear antibodies in scleroderma. Int J Dermatol JT - International journal of dermatology 1981;20(9):569-73.
    31. Earnshaw W, Bordwell B, Marino C, Rothfield N. Three human chromosomal autoantigens are recognized by sera from patients with anti-centromere antibodies. J Clin Invest JT - The Journal of clinical investigation 1986;77 (2):426-30.
    32. Parveen S, Morshed SA, Nishioka M. High prevalence of antibodies to recombinant CENP-B in primary biliary cirrhosis: nuclear immunofluorescence patterns and ELISA reactivities. J Gastroenterol Hepatol JT - Journal of gastroenterology and hepatology 1995;10(4):438-45.
    33. Onozuka Y, Shibata M, Yonezawa H, Terauti K, Miyachi K, Ueno Y. [Clinical significance of anti-centromere antibody and anti-CENP-B antibody in sera of patients with primary biliary cirrhosis]. Rinsho Byori JT - Rinsho byori. The Japanese journal of clinical pathology 1996;44(9):877-82.
    34. Marasini B, Gagetta M, Rossi V, Ferrari P. Rheumatic disorders and primary biliary cirrhosis: an appraisal of 170 Italian patients. Ann Rheum Dis JT - Annals of the rheumatic diseases 2001:60(11) :1046-9.
    35. Whyte J, Hough D, Maddison PJ, McHugh NJ. The association of primary biliary cirrhosis and systemic sclerosis is not accounted for by cross reactivity between mitochondrial and centromere antigens. J Autoimmun JT - Journal of autoimmunity 1994;7(3):413-24.
    36. Invernizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J. Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis JT - Seminars in liver disease 2005:25(3):298-310.