熊去氧胆酸及其联合激素和免疫抑制剂治疗原发性胆汁性肝硬化的临床观察

目的 观察熊去氧胆酸(UDCA)、UDCA联合泼尼松龙、UDCA联合硫唑嘌呤3种方案治疗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.方法 82例初诊PBC患者随机分为单用UDCA(U组,28例)、UDCA联合泼尼松龙(UP组,27例)、UDCA联合硫唑嘌呤(UA组,27例)3个治疗组,在治疗第0、3、6、12个月采集临床、实验室资料及药物不良反应.主要采用重复测量的方差分析和COX回归进行统计学处理.结果 UP组患者较U组及UA组在乏力和瘙痒程度上有明显改善(P=0.015和P=0.037),U组、UA组无改善.3组患者治疗后丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、谷氨酰转肽酶(GGT)、总胆红素、直接胆红素(DBIL)和IgM均下降,组内比较差异有统计学意义(P＜0.05),3组间比较差异无统计学意义(P＞0.05).发生疾病进展的患者Mayo危险性评分高(P=0.018)、凝血酶原时间(PT)延长(P=0.042).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,U组未出现药物不良反应.ALP、GGT、总胆固醇基线水平高是生化缓解的危险因素(P=0.015).总胆红素、DBIL、总胆汁酸增高、PT延长不利于肝生化缓解(P=0.075).结论 3种方案对PBC患者肝脏生化指标、IgM的改善作用相近,UDCA联合泼尼松龙方案可减轻乏力、瘙痒症状,单用UDCA方案不良反应发生率最低.Mayo危险性评分高、PT延长的患者疾病易进展;高水平的ALP、GGT、总胆固醇是生化缓解的危险因素;高水平的总胆红素、DBIL、总胆汁酸、PT不利于生化缓解.

Abstract：

Objective The aims of this study were to compare the clinical and laboratory responses to ursodeoxycholic acid (UDCA) monotherapy with the combination therapy of UDCA plus prednisolone/azathioprine in primary biliary cirrhosis(PBC),and to investigate the risk factors affecting the therapeutic responses.Methods Eighty-two patients with untreated PBC were divided randomly into three groups.Group U (28 patients) received UDCA alone,group UP(27 patients) received UDCA and pr ednisolone,while group UA (27 patients ) received UDCA and azathioprine.The clinical and laboratory data were recorded after treated for 3,6 and 12 months.Repeated measures ANOVA and COX regression model were used for statistical analysis.Results Fatigue and pruritus were improved only in group UP(P=0.015 and P=0.037 respectively).Alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),gamma-glutamyl transferase (GGT),total bilirubin (TBIL),direct bilirubin (DBIL) and IgM in the 3 groups were decreased (P＜0.05),while there was no statistical significant difference between the three groups (P＞0.05).The patients with disease progression had higher Mayo risk score (MRS) (P=0.018) and prolonged prothrombin time (PT)(P=0.042).In group UP,side-effect associated with glucocorticosteroids occurred in eight patients while there was no side-effect in group U.High baseline levels of ALP、GGT and CHO were risk factors for biochemical remission(P=0.015).The increase of DBIL,TBIL,total bile acid(TBA) and PT did not contribute to the prediction of biochemical remission ( P=0.075 ).Conclusion There are no differences among the three groups in the improvement of hepatic biochemical data and IgM.The combination therapy of UDCA with prednisolone could relieve fatigue and itching.The disease of patients with higher Mayo risk score and prolonged PT tend to progress.High baseline levels of ALP,GGT and CHO are risk factors for biochemical remission.High baseline levels of TBIL,DBIL,TBA and PT could not predict biochemical remission.The incidence of adverse effect is lowest when treated with UDCA alone.     

熊去氧胆酸治疗无重叠和有重叠特征原发性胆汁性肝硬化的疗效及生存分析

目的观察熊去氧胆酸（ursodeoxyeholicacid,UDCA）对具有自身免疫性肝炎（autoimmunehepatitis,AIH）重叠特征的原发性胆汁性肝硬化（Drimarybiliarycirrhosis．PBC）和单纯PBC患者的疗效以及对生存期的影响。方法回顾性分析20例因PBC死亡的患者,以患者死亡为研究终点,采用简化评分标准进行分组。其中12例诊断可能为AIH,将此12例具重叠特征和8例无重叠特征的PBC患者分别进行研究,分析2组在UDCA初治及研究终点时的临床特征、UDCA治疗的生化学应答及生存期情况。结果2组在UDCA治疗基线的PLT、ALP、GGT、ALT、AST、ALB、TBIL、TBA、CRE、PT、INR水平及梅奥风险评分差异均无统计学意义,而抗核抗体或抗平滑肌抗体≥1：80的阳性率、血清球蛋白或IgG／〉1．1倍正常值上限的百分比及AIH治疗前的简化评分差异均有统计学意义。UDCA治疗后有重叠特征组的生存时间为（24．4＋16．5）个月,中位生存时间为22．0个月;无重叠特征组生存时间为（60．6＋43-3）个月,中位生存时间为50．5个月。采用Kaplan-Meier生存分析显示,重叠特征组经过UDCA治疗后预后较差,Log-rank检验结果显示2组生存时间差异有统计学意义。在导致死亡的原因中,2组发病率差异均无统计学意义,但数据显示上消化道出血仍为主要死亡原因。结论对于巴黎标准不能确诊而简化评分标准可确诊的AIH—PBC患者,单纯UDCA治疗预后差,生存时间较无重叠特征的PBC患者短。     

原发性胆汁性肝硬化的熊去氧胆酸治疗

原发性胆汁性肝硬化 (ｐｒｉｍａｒｙｂｉｌｉａｒｙｃｉｒｒｈｏｓｉｓ ,ＰＢＣ)是一种好发于中年女性的自身免疫性病变 ,其病理特征是慢性进行性肝内小叶间胆管和中隔胆管的非化脓性炎性破坏及淋巴肉芽肿。其自然进程约 2 0年 ,自出现症状至死于肝功能衰竭或食管静脉曲张破裂约 10年。治疗原则包括对症处理、免疫调节、消炎利胆和抗纤维化及肝移植。其中熊去氧胆酸 (ＵＤＣＡ)是当今公认的治疗ＰＢＣ的主要药物。一、ＵＤＣＡ对ＰＢＣ的组织学改善(一 )门静脉周围组织学改善　在ＰＢＣ肝内小胆管 (外径小于 10 0 μｍ的小叶间胆管 )是主要…     

熊去氧胆酸治疗原发性胆汁性肝硬化疗效观察

原发性胆汁性肝硬化(PBC)是一种原因不明的自身免疫性疾病，迄今尚无特效药物治疗。1996年4月至2003年10月，我们采用熊去氧胆酸(UDCA)治疗PBC患者41例，取得较满意疗效。现报告如下。     

熊去氧胆酸治疗原发性胆汁性肝硬化疗效观察

目的采用熊去氧胆酸单独用药,以及与强的松或思美泰联合用药方法,观察三种治疗方案临床效果。方法29例分①熊去氧胆酸(尤思弗)组10例,给予尤思弗250mg,3/d,口服;②尤思弗+泼尼松组9例,上述剂量尤思弗加泼尼松,30mg/d,逐渐减量至10mg/d维持治疗;③尤思弗+思美泰组10例,上述剂量尤思弗加思美泰1.5g/d,静滴。4周为1个疗程,观察治疗后患者临床症状及肝功改善情况。结果治疗后三组患者乏力、纳差、皮肤瘙痒、尿黄、腹胀症状均有一定程度的缓解。泼尼松治疗组消化道症状及皮肤瘙痒症状缓解疗效较佳。三组退黄效果比较尤思弗与其他药物联合治疗组疗效相近,差异无统计学意义。结论单独使用尤思弗与联合药物治疗原发性胆汁性肝硬化疗效相近,且副作用少。而思美泰相对价格昂贵,限制了长期用药治疗。     

熊去氧胆酸治疗原发性胆汁性肝硬化的疗效分析

目的评价熊去氧胆酸治疗原发性胆汁性肝硬化的疗效。方法18例原发性胆汁性肝硬化患者口服UDCA 10~15mg.kg-1.d-1,服药时间均2年以上。于服药后1、3、6、12、18、24个月时分别复查肝功能。服药前及服药后12个月和24个月时行快速肝穿刺法取肝组织常规行病理检查。结果18例患者主要表现为GGT及ALP的升高,AST、ALT均轻至中度升高。UDCA治疗PBC所有患者的生化指标均有明显改善,其中以ALT和AST下降迅速,在3个月后明显下降,6个月时基本恢复正常,而GGT和ALP则下降缓慢,ALP于12个月后恢复正常,24个月后仍有大部分病人GGT仍未恢复正常。12例肝活检患者12个月后共有5例肝组织学病理变化得到改善。结论UDCA能显著改善PBC患者的肝功能变化,长期应用UDCA治疗可延缓肝脏组织学进展。     

熊去氧胆酸治疗不同临床分期原发性胆汁性肝硬化的2年随访观察

目的 观察熊去氧胆酸(UDCA)对不同临床分期原发性胆汁性肝硬化(PBC)患者的长期疗效.方法 91例PBC患者通过自身对照的方法随访观察2年,观察应用UDCA治疗的2年内不同阶段症状、生化学指标及肝组织学病理变化.计数资料以例数或百分比描述,用配对计数资料的x2检验及重复测量数据的方差分析等方法进行统计学分析.结果 Ⅱ期患者完成治疗后6个月,碱性磷酸酶(ALP)及γ-谷氨酰转肽酶(GGT)水平下降51.9%和67.3%;治疗1年,其生化学应答率为81.25%(巴黎标准)和93.75%(巴塞罗那标准);治疗2年,ALP及GGT下降65.33%和86.75%,IgM水平于治疗1年后由62.5%降至正常;Ⅲ期患者治疗后6个月,ALP及GGT水平下降48.8%和46.6%,治疗1年生化学应答率为36.84%(巴黎标准)和57.89%(巴塞罗那标准),治疗2年ALP及GGT下降76.16%和78.63%,IgM水平于治疗1年后由28.9%降至正常,乏力、黄疸及瘙痒症状有所好转;Ⅳ期患者治疗后6个月,ALP及GGT下降43.65%和33.39%,治疗1年,生化学应答率为30.43%(巴黎标准)和56.52%(巴塞罗那标准),治疗2年,ALP及GGT下降56.84%和53.06%;IgM水平于治疗1年后,17.4%降至正常,黄疸及瘙痒症状也有所好转.11例不同分期PBC患者于治疗前后行肝活组织检查,其中Ⅰ期和Ⅱ期PBC肝脏组织学基本恢复,Ⅲ期及Ⅳ期PBC可见病理学进展,但炎症细胞浸润减轻.结论 UDCA治疗临床Ⅱ期～Ⅳ期的PBC均出现良好的生化学应答,以Ⅱ期应答率最高,并且可改善PBC患者临床症状.对于Ⅰ～Ⅱ期的患者,UDCA治疗可使肝脏组织学恢复,Ⅲ～Ⅳ期患者治疗后虽可见病理学进展,但其炎症细胞浸润明显减轻.提示早期诊断、早期治疗,应用UDCA长期治疗是治疗该病的关键.     

熊去氧胆酸治疗原发性胆汁性肝硬化研究进展

原发性胆汁性肝硬化（PBC）是一种慢性肝内胆汁淤积性疾病．好发于中年女性。PBC最常见的死因为肝功能衰竭，这曾是肝移植的首要指征，但有效的治疗已减少了这类患者对肝移植的需求，并使其预期寿命得以延长.熊去氧胆酸（UDCA）是目前较为公认的治疗PBC的药物．但仍存在很大争议。本文就UDCA治疗PBC的作用机制、临床疗效依据、临床应用等方面的研究进展作一综述。     

Autoimmune hemolysis associated with primary biliary cirrhosis responding to ursodeoxycholic acid as sole treatment

Coombs' positive autoimmune hemolytic anemia (AIHA) has been rarely described in association with primary biliary cirrhosis (PBC). The previously reported cases have responded to treatment with a combination of corticosteroids and ursodeoxycholic acid (UDCA). We report a case of AIHA occurring in association with PBC, which has responded to treatment with UDCA alone. Possible mechanisms of autoimmune hemolysis in this patient include bile salt induced immune dysregulation and direct damage to red cell membranes by bile salts leading to exposure of neoantigens and development of red cell autoantibodies. A trial of UDCA as a single agent should be considered as initial treatment in this rare disorder.     

原发性胆汁性肝硬化的治疗进展

原发性胆汁性肝硬化（PBC）是一种原因不明的慢性进行性肝内胆汁淤积性疾病,其发病率有逐年上升趋势。其治疗主要包括针对胆汁淤积的熊去氧胆酸、针对免疫异常发病机制的糖皮质激素或免疫抑制剂以及并发症的对症治疗,终末期患者适合肝移植。随着新药的不断研发和临床应用,对最新的治疗研究进展作一简要综述。结合近5年国内外PBC治疗的最新研究进展,观察哪一种方法可以根治PBC,不良反应最小,还须要进一步研究。     

Combination therapy with ursodeoxycholic acid and colchicine for primary biliary cirrhosis

Twelve patients with primary biliary cirrhosis (PBC), stages I to III, received long-term therapy with a combination of 600 mg ursodeoxycholic acid (UDCA) and 1 mg colchicine given daily for more than 2 years. Drug toxicity was mild; one patient experienced diarrhoea that was probably due to colchicine. Serum levels of bilirubin, alkaline phosphatase (ALPase), gamma-glutamyl transpeptidase and alanine aminotransferase decreased by more than 50% of the initial values. Serum albumin and cholesterol levels also improved, but immunoglobulins and anti-mitochondrial antibody titre did not change. Histologic features in the eight patients who received serial liver biopsies before and 2 years after the beginning of treatment were evaluated. Piecemeal necrosis and portal inflammation were improved, but there was no change in portal fibrosis. Patients were divided into two groups; the first received both drugs from the outset, and the second group were started on UDCA for 3 months followed by the addition of colchicine. After 3 months, the improvement in serum bilirubin and ALPase in the first group was greater than in the second. However, in the second group, the ALPase levels had decreased significantly when measured at 6 and 9 months after the treatment compared with the levels at 3 months. These findings suggest that UDCA and colchicine may have a synergistic effect. This combination therapy appears to be safe and effective, both clinically and histologically, for treating PBC.     

Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid

Background and Aim: Ursodeoxycholic acid (UDCA) has been widely used in the treatment of patients with primary biliary cirrhosis (PBC). However, some patients are refractory to UDCA. The aim of this study is to clarify the additive improvement induced by bezafibrate in patients refractory to UDCA. Methods: This study was a prospective analysis of 37 consecutive PBC patients. All patients were treated first for 6 months with UDCA, and then with bezafibrate, if their alkaline phosphatase (ALP) levels did not decrease more than 40% or within the normal range after 6 months' treatment with UDCA. Clinical parameters were monitored for the subsequent 24 months. Result: Twenty‐two patients (59%) achieved improvement of ALP levels after the treatment with UDCA. Those patients (Group A) had significantly lower levels of ALP at diagnosis than those with abnormal ALP levels after 6 months' treatment with UDCA (Group B; P = 0.020). They continued UDCA monotherapy, and maintained normal ALP levels at subsequent follow ups. However, immunoglobulin M (IgM) levels remained abnormal in eight patients, whose IgM levels at the time of diagnosis were significantly higher than those whose IgM were normalized after 6 months' treatment with UDCA (P = 0.026). Those in Group B were treated additionally with bezafibrate, and 12 patients (80%) achieved normal ALP and IgM levels within 12 months of commencement of therapy. Conclusion: Higher ALP level at diagnosis is one of the predictors for UDCA failure. Combination treatment of bezafibrate in addition to UDCA may be an effective treatment for PBC patients refractory to UDCA.     

愈肝方联合熊去氧胆酸治疗原发性胆汁性肝硬化临床疗效分析

目的：观察中药愈肝方联合熊去氧胆酸（UDCA）治疗原发性胆汁性肝硬化（PBC）的临床疗效。方法：回顾性分析2007年1月-2010年12月在我院住院且符合纳入标准的PBC患者共66人,根据治疗方案不同,分为愈肝方与UDCA治疗组及UDCA治疗组,比较两组的临床疗效。结果：治疗4周后,愈肝方与UDCA组的好转率优于UDCA组,且在总胆红素、碱性磷酸酶两项主要生化指标方面均较UDCA组有显著下降。结论：愈肝方联合UDCA治疗原发性胆汁性肝硬化,较单用UDCA能更有效。     

Biochemical response to ursodeoxycholic acid predicts long‐term outcome in Japanese patients with primary biliary cirrhosis

Aim: There is an ongoing need for predictors of long‐term outcomes for patients with primary biliary cirrhosis (PBC). Biochemical response to ursodeoxycholic acid (UDCA) has been introduced to predict development of symptoms by our group (Ehime criteria) and to predict long‐term outcomes in Western countries (Paris, Barcelona and Rotterdam criteria). The aim of this study was to evaluate whether these criteria are also useful to predict long‐term outcomes in Japanese patients with PBC. Methods: A retrospective chart review was conducted for 227 Japanese patients with PBC. Patients taking UDCA with an observation period of more than 6 months were included in the study. Data collection included demographics, biochemical and serological markers, and histological stage. Four different criteria regarding biochemical response to UDCA were compared and evaluated. Results: In total, 138 patients met the inclusion criteria and underwent analysis. Using the Ehime criteria, the transplant‐free survival rate was significantly higher in responders than in non‐responders (P = 0.010). The Paris criteria also predicted long‐term outcomes in our population (P = 0.003), whereas the Barcelona and Rotterdam criteria showed no such association (P = 0.282 and P = 0.553, respectively). Conclusion: Good biochemical response to UDCA according to the Ehime and Paris criteria is associated with long‐term outcome in Japanese patients with PBC and allows identification of non‐responders who may benefit from further trials. Finally, Ehime criteria should be validated in a different patient cohort.     

Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis

BACKGROUND: Ursodeoxycholic acid is currently used for the treatment of primary biliary cirrhosis at 13-15 mg/kg/day, but liver tests of some patients do not return to normal at this dose. Studies reported here were designed to test whether a higher dose of ursodeoxycholic acid than is currently used would induce still greater biliary enrichment of ursodeoxycholic acid and whether such enrichment would lead to still further improvement in liver tests in patients with early primary biliary cirrhosis. METHODS: A total of 20 patients with histologically proven primary biliary cirrhosis were enrolled. Patients had early stage primary biliary cirrhosis as serum bilirubin levels were normal and the Mayo risk score 4.2 +/- 0.5. Group 1 received 600, 1200 and 1800 mg/day of ursodeoxycholic acid; group 2 received 900, 1500 and 2100 mg/day. The order of periods was randomized. Each treatment period lasted 3 months followed by a further 3 months during which a standard dose of ursodeoxycholic acid was given. At the end of each treatment period, liver tests were evaluated, and biliary bile acid pattern of duodenal bile was determined using high pressure liquid chromatography. RESULTS: Biliary bile acid became enriched in ursodeoxycholic acid in direct relationship to dosage [r = 0.84, p < 0.001). At doses of 1800 mg/day (25-35 mg/kg/day), biliary ursodeoxycholic acid averaged 69 +/- 6.6%. A progressive decrease of alanine aminotransferase [p < 0.0001), aspartate aminotransferase [p < 0.001) and alkaline phosphatase [p < 0.02) was observed with increasing concentrations of ursodeoxycholic acid in bile. Biochemical liver tests showed a stronger correlation with biliary concentrations of ursodeoxycholic acid than with the administered dose. CONCLUSIONS: In early primary biliary cirrhosis, higher dose ursodeoxycholic acid appears to be more effective than doses currently recommended.     

A multi-center double-blind controlled trial of ursodeoxycholic acid for primary biliary cirrhosis

A multi-center double-blind controlled trial of ursodeoxycholic acid (UDCA) for treatment of primary biliary cirrhosis (PBC) was carried out. Twenty two and 23 patients were treated with 600mg/day UDCA and placebo, respectively, for 24 weeks. In UDCA - treated patients, fall of serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyltranspeptidase activities started within 4 weeks after start of the trial and continued throughout the trial period. The serum IgM level fell in 7 UDCA-treated patients examined but not in 10 placebo-treated patients examined. Serum bilirubin concentration showed no significant change at the end of the study in either of UDCA- and placebotreated group of patients. There was no significant difference between these two groups with respect to the frequency of improvement of pruritus. In UDCA-treated patients, serum bile acid composition changed markedly, though its concentation showed no significant change. The percentage of total bile acid which ursodeoxycholic acid took up increased, whereas those which cholic acid, chenodeoxycholic acid and deoxycholic acid took up were decreased. This work was supported in part by a grant from the Japanese Ministry of Public Health and Welfare. We express thanks to the following physicians for referring their patients for inclusion in this study: Mamoru Hohzumi (Tokyo Koseinenkin Hospital, Tokyo), Toshihiro Azuma (First Department of Internal Medicine, Okayama University Medical School, Okayama), Takafumi Ichida (Third Department of Internal Medicine, Niigata University School of Medicine, Niigata), Tadao Unuma (Mitsui Memorial Hospital, Tokyo), Masashi Unoura (First Department of Internal Medicine, Kanazawa University School of Medicine, Kanazawa) and others. We are also indebted to a moderator, Prof. Fujio Nakagawa (Department of Pharmacy, Faculty of Medicine, University of Tokyo, Tokyo).     

A two year controlled trial examining the effectiveness of ursodeoxycholic acid in primary biliary cirrhosis

Abstract Forty-six patients with primary biliary cirrhosis from a single centre were studied in a randomized placebo-controlled trial to determine the effectiveness of ursodeoxycholic acid (UDCA) over a 2 year period. The two groups were well-matched at baseline. For each parameter, by calculating the difference between the median changes with time between the UDCA group and the placebo group, it was found that from entry, with respect to placebo, there were differences between median changes (MCD) favouring the UDCA group in bilirubin {MCD 5 μmol/L [95% confidence interval (CI) 1 to 12] at 1 year and 5 μmol/L (95% CI 1 to 9) at 2 years}, alkaline phosphatase MCD 242 iu/L (95% CI 107 to 360) at 1 year and 268 iu/L (95% CI 146 to 424) at 2 years and aspartate aminotransferase MCD 26 iu/L (95% CI 12 to 41) at 1 year and 37 iu/L (95% CI 16 to 64) at 2 years. Within the UDCA group, there was long-term fall in alkaline phosphatase [median fall 116 iu/L (95% CI 93 to 378) at 2 years and aspartate aminotransferase [median fall 18 iu/L (95% CI 6 to 47) at 2 years; however, the major change in bilirubin was a modest rise over 2 years in the placebo group [median rise 2 μmol/L (95% CI 1 to 9)]. Changes in albumin, prothrombin ratio and immunoglobulins were generally minor and not significant.
Ursodeoxycholic acid did not generally influence stage progression or histological features, although a smaller percentage of non-cirrhotic patients were documented as having developed cirrhosis on UDCA compared to placebo (14 vs 57%) over the 2 years. There appeared to be no consistent effect on pruritus and general well-being. The medication was well-tolerated and safe. In conclusion, UDCA appears to have beneficial effects on some serum biochemical markers in primary biliary cirrhosis and so may have a role in retarding disease progression. It could be useful in combination with an immunosuppressive or an anti-fibrotic agent.