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.     

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.     

国产熊去氧胆酸治疗原发性胆汁性肝硬化患者的随访

目的 观察国产熊去氧胆酸对原发性胆汁性肝硬化患者肝功生化指标的影响.方法 选择北京友谊医院经肝穿活检病理学或AMA-M2阳性而确诊的原发性胆汁性肝硬化患者,应用国产熊去氧胆酸(13-15)mg/ks day,分三次口服,定期(每隔3个月)复查肝功.结果 从用药第三个月起,γ-GT、ALP、ALT、AST水平开始明显下降(P＜0.05).结论 国产熊去氧胆酸可以改善原发性胆汁性肝硬化患者胆汁淤积相关指标(GGT、ALP),降低转氨酶(ALT、AST)水平.     

Fatigue measurements in patients with primary biliary cirrhosis and the risk of mortality during follow‐up

Background: Fatigue was recently suggested to predict an increased risk of mortality in a primary biliary cirrhosis (PBC) cohort during follow‐up. Aims: To analyse the impact of fatigue on prognosis in PBC. Methods: Patients with PBC who had earlier completed the fatigue impact scale (FIS) were identified. Prognosis in terms of death and liver transplantation (Tx) was determined. Results: FIS values at baseline were analysed from 208 patients (192 females; median age 59 years (interquartile range 51–67), median follow‐up of 5 years. Overall, 181 patients were alive at follow‐up, 22 (12%) died and five (2.4%) underwent transplantation. FIS at baseline was 28 (12–47) and FIS at follow‐up was 25 (8–64) (P<0.001; r=0.69). Among survivors, FIS at baseline was 27 (12–43), 36 (12–72) in those who died (P=0.059) and 99 (41–102) in those who underwent transplantation (P=0.0008). FIS at baseline was 44 (12–88) in patients with death and/or Tx vs. 27 (12–43) in survivors (P=0.003). Age [hazard ratio (HR) 1.1 (confidence interval (CI) 1.0–1.2)] and aspartate aminotransferase [HR 2.0 (CI 1.3–3.0)] were independently associated with decreased survival on multivariate analysis. FIS scores over 40 [HR 9.6 (CI 2.3–39.7)] and bilirubin [HR 4.8 (CI 2.8–8.2)] were independently associated with a poor outcome in patients who underwent Tx or had a liver‐related death. Conclusions: Fatigue seems to change little over time in PBC. Fatigue levels were higher at baseline in those who died or underwent Tx. High fatigue levels seem to be a predictor of risk of liver‐related mortality and need for transplantation over time but not a predictor of non‐liver‐related mortality.     

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。     

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.     

原发性胆汁性肝硬化患者临床与病理学特点

目的:探讨不同程度的原发性胆汁性肝硬化(PBC)患者临床与病理特点.方法:根据PBC患者是否已进展至肝硬化将患者分为慢性胆管炎组(CC)和肝硬化组(LC),比较两组患者生化指标、肝脏组织学变化及临床并发症的差异,所有患者均给予熊去氧胆酸(UDCA)治疗,观察患者1年转归情况.结果:CC组患者病理损伤轻,对治疗敏感,LC组患者病理损伤重,治疗效果差,易出现进行性升高性黄疸、慢性肝功能衰竭.结论:PBC患者早期使用UDCA治疗有助于控制病情进展,当本病进展至肝硬化期则预后不良.     

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.     

Combination therapy of bezafibrate and ursodeoxycholic acid for primary biliary cirrhosis: A meta‐analysis

The aim of this study was to assess the efficiency and safety of combination therapy of ursodeoxycholic acid (UDCA) and bezafibrate for primary biliary cirrhosis. A meta‐analysis of all long‐term randomized controlled trials comparing the combination of UDCA and bezafibrate with UDCA monotherapy was performed via electronic searches. Seven trials, which included 177 patients, were assessed. Combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy in improving liver biochemistry, alkaline phosphatase (mean difference [MD], ?146.15 IU/L; 95% confidence interval [CI], ?193.58 to ?98.72; P < 0.00001), γ‐glutamyltransferase (MD, ?20.64 IU/L; 95% CI, ?30.86 to ?10.43; P < 0.0001), immunoglobulin M (MD, ?90.96 mg/dL; 95% CI, ?137.36 to ?44.56; P = 0.0001) and triglycerides (MD, ?15.49 mg/dL; 95% CI, ?30.25 to ?0.74; P = 0.04). However, their effects on pruritus (odds ratio [OR], 0.82; 95% CI, 0.30–2.24; P = 0.70) and alanine aminotransferase (MD, ?8.41 IU/L; 95% CI, ?22.57 to 5.75; P = 0.24) did not differ significantly. This meta‐analysis revealed no significant differences in the incidence of all‐cause mortality (OR, 0.72; 95% CI, 0.10–5.49; P = 0.75) and adverse events (OR, 0.35; 95% CI, 0.07–1.84; P = 0.22) between patients treated with combination therapy and those treated with monotherapy. In this meta‐analysis, combination therapy with UDCA and bezafibrate was more effective than UDCA monotherapy. Combination therapy improved liver biochemistry, but did not improve clinical symptoms, incidence of death or adverse events more effectively than monotherapy.     

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis: A short-term, randomized, double-blind controlled, cross-over study with long-term follow up

Abstract In order to evaluate the efficacy of ursodeoxycholic acid (UDCA) in the treatment of Chinese patients with primary biliary cirrhosis, a short-term, randomized, double-blind controlled, cross-over study was done with long-term follow up. In the first part of the study, 12 patients were randomly chosen to receive either UDCA 600 mg/day for 3 months followed by a placebo for 3 months or a placebo for 3 months followed by UDCA for 3 months. The clinical symptoms of pruritus improved when the patients were receiving UDCA but became worse when receiving a placebo. Mean serum levels of alkaline phosphatase (ALPase), γ-glutamyl transferase (γ-GT), total bilirubin, cholesterol, alanine aminotransferase (ALT) and aspartate aminotransferase all decreased below the baseline values when receiving UDCA treatment and all increased above the baseline values when receiving the placebo. The difference was statistically significant. In the second part of the study, 19 patients received long-term UDCA treatment (mean 20 months). The clinical symptoms of pruritus improved in 90% of the pruritic patients. Serum levels of ALPase, γ-GT and ALT fell significantly from the pretreatment values 6, 12 and from the mean 20 months after UDCA treatment. Serum levels of total bilirubin fell significantly 6 and 12 months after UDCA treatment but did not reach statistical significance at the last follow up. No patient lost antimitochondrial antibody and elevated immunoglobulin levels did not improve significantly, but the Mayo clinical risk score improved significantly after long-term UDCA treatment. Treatment failure was noted in three patients: two patients in the histologic stage IV with clinical overt jaundice died of complications 4 and 5 months after UDCA treatment, respectively; another patient underwent a liver transplantation 1 year after the UDCA treatment due to progressive jaundice. No severe adverse reaction was noted during UDCA treatment, only one patient suffered from a mild allergic reaction. In conclusion, UDCA is safe and effective in the treatment of Chinese PBC patients in stages I—III.     

Primary biliary cirrhosis: survival of a cohort followed for 10 years

OBJECTIVES: To study the natural course of primary biliary cirrhosis (PBC) in order to be able to design accurate clinical pharmacological studies and evaluate the need for liver transplantation. DESIGN: A cohort of 86 patients with PBC living in northern Sweden was followed for a 10-year period during 1983-93. No patients received therapy with ursodeoxy cholic acid or other drugs during the follow-up period. METHOD: At start all patients were investigated personally by the authors. At follow-up medical notes were scrutinized and special questionnaires to the current responsible physician were applied. Endpoints were the time of dropout, liver transplantation, death or end of the study period. RESULTS: At follow-up data were available for 84 patients (97%). During the study period 34 patients died, of whom 28 were symptomatic; 15 deaths had no direct connection to PBC. Nineteen deaths were related to PBC of whom two were asymptomatic, the most common cause being end-stage liver disease with liver coma. During the study period in all eight patients were subjected to liver transplantation. CONCLUSIONS: The survival rate of the 32 asymptomatic PBC patients at the start of the study was the same as a sex- and age-matched standard background population. Those patients with symptomatic PBC from the beginning of study had a survival rate at 10 years of 50%, and the most ominous sign was a bilirubin greater than 35 micromol L(-1) . Liver transplantation was performed in almost 10% in this cohort until 1993. Since then, the indications and referral practice for liver transplantation has changed and is now higher.     

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.     

Natural history and prognostic factors of primary biliary cirrhosis in Taiwan: a follow‐up study up to 18 years

Purpose: The natural history of primary biliary cirrhosis (PBC) has been little studied in Asia. We conducted a Taiwanese cohort study on the natural history of PBC and analysed the prognostic factors. Methods: This study enrolled 96 consecutive PBC patients between 1985 and 2006 to evaluate the baseline characteristics and outcomes. Results: There were 74 females and 22 males. Eighty‐five were positive for antimitochondrial antibodies in sera, and 11 were negative. The clinical manifestations and prognosis were similar between these two groups. In a median follow‐up of 47.5±55.8 months, 27 patients died. Multivariate analysis indicated that the independent prognostic factors were serum albumin (P=0.021), creatinine (P=0.033) and ursodeoxycholic acid treatment (P=0.008). Besides, 42 patients developed adverse outcomes. Albumin (P<0.001), bilirubin (P=0.019) and prothrombin time (PT) (P=0.010) were significant factors. Moreover, a Mayo risk score <5, a Model for End‐Stage Liver Disease (MELD) score <6, a Child–Pugh stage A and early liver histology were associated with favourable outcomes. Conclusion: Serum albumin, bilirubin and PT were independent prognostic factors of adverse outcomes for Taiwanese PBC patients. Besides, the Mayo risk score, the MELD score, the Child–Pugh stage and liver histology were also validated to predict survival.     

Antimitochondrial antibody‐negative primary biliary cirrhosis: a subset of primary biliary cirrhosis

Objective: Antimitochondrial antibodies (AMA) are the hallmark in primary biliary cirrhosis (PBC); nevertheless, it has long been recognized that 5–10% patients with typical features compatible with PBC do not have detectable AMA, and they were referred to as ‘AMA‐negative PBC’. This study aimed to evaluate whether AMA‐negative/positive PBC represents different clinical entities. Methods: We compared the clinical, laboratory, percentage of regulatory T cells (Tregs) in peripheral blood, liver biopsy features and response to treatment of the two groups of patients. The first group was comprised of 12 patients with ‘AMA‐negative PBC’. The second was made up of another 12 PBC patients with positive AMA. Results: Antimitochondrial antibodies‐negative/positive patients were remarkably similar in terms of clinical manifestations, liver biochemistries and histological findings. The frequency of anti‐nuclear antibodies, anti‐smooth‐muscle antibody, anti‐gp210 and anti‐sp100 antibody showed no significant difference between the two groups. A significantly lower mean percentage of CD4⁺CD25^high T cells was observed in peripheral blood mononuclear cells of AMA‐negative/positive PBC patients compared with that of the 12 control subjects (5.8±1.8 and 5.4±1.4% vs. 7.6±1.7% respectively; P=0.014 and 0.004). However, no difference could be found between AMA‐negative and AMA‐positive PBC patients (P=0.599). After 1 year treatment with ursodeoxycholic acid, the two groups showed similar response. Conclusion: Antimitochondrial antibody‐negative/positive PBC patients are similar in clinical, laboratory, percentage of Treg in peripheral blood, liver biopsy features and response to treatment. This suggests that AMA‐negative PBC may be a variant of AMA‐positive PBC rather than a separate clinical entity.     

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.     

Fibrate for treatment of primary biliary cirrhosis

Recent studies of the effectiveness of ursodeoxycholic acid (UDCA) therapy in patients with primary biliary cirrhosis (PBC) reported that UDCA therapy did not necessarily stop the progression of liver fibrosis in all patients, even those with early stage PBC. Thus, there is a need for more effective treatments that could prevent asymptomatic PBC from progressing to the icteric stage. Bezafibrate is effective in approximately two-thirds of non-icteric patients who have not shown a complete response to UDCA. Serum bilirubin, aspartate aminotransferase and γ-guanosine 5'-triphosphate levelswere significantly lower in patients who responded to additional bezafibrate on univariate analysis. The putative mechanism by which bezafibrate acts in cholestasis is by increasing phospholipid output into bile, which forms micelles with the hydrophobic bile acid that reduces its toxicity.     

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。     

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).     

The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study.

Aim: Treatment with ursodeoxycholic acid (UDCA) improves the survival of stage I and II primary biliary cirrhosis (PBC) patients. However, new therapeutic options are needed for patients who are refractory to UDCA and for those whose disease is at an advanced stage. Bezafibrate could be useful in PBC treatment, since it increases phospholipid output into the bile and reduces the cytotoxicity of hydrophobic bile acids, which are increased with cholestasis. Methods: We conducted two prospective, multicenter randomized open studies in non-cirrhotic patients with PBC to evaluate the efficacy of bezafibrate. One study compared UDCA and bezafibrate monotherapy (study 1: 45 patients [37 females], mean age 55.9 years), and the other evaluated the addition of bezafibrate to patients who were refractory to UDCA (study 2: 21 patients [18 females], mean age 54.1 years). Results: Study 1 demonstrated that bezafibrate monotherapy was as effective as UDCA and study 2 revealed that bezafibrate combined with UDCA was effective in improving and maintaining biliary enzymes where the ineffectiveness of long-term treatment with UDCA was confirmed. Conclusion: This multicenter, randomized, open study revealed that combination therapy of bezafibrate and UDCA improved biliary enzymes in non-cirrhotic Japanese patients with PBC refractory to UDCA. Further studies are needed to evaluate whether combination therapy improves histological staging and prognosis.