熊去氧胆酸降低肝移植术后胆道并发症发生风险的随机对照研究

Ursodeoxycholic acid decreases risk of biliary complications after liver transplantation: a randomized controlled trial

目的评估熊去氧胆酸（UDCA）降低肝移植受者术后胆道并发症（BC）的临床疗效。方法选取2011年7月至2013年12月于中山大学附属第一医院行肝移植术的215例受者作为本次研究的评估对象。采用随机对照研究方法。入组病例按2∶1随机分为用药组和空白组,用药组受者于肝移植术后第1天起每天服用UDCA 250 mg,2次/d;空白组不服用UDCA或其他安慰剂,治疗时间为6个月,停药后继续随访6个月。研究观察终点为复合观察终点,包括非外科因素引起的缺血性胆道病变（ITBL）、术后1个月后由非外科及排斥反应引起的总胆红素（TBIL）〉51.3μmol/L、移植物失功、受者死亡。比较两组受者术前一般情况、手术相关情况、术后各项生化指标、术后转归情况、复合观察终点累积发生率、受者生存比例及移植物累积存活率。采用两独立样本t检验或基于秩次的两独立样本Wilcoxon检验比较年龄、Child-Pugh评分和冷缺血时间等定量资料。用卡方检验或Fisher确切概率法比较开腹手术史、激素诱导等定性资料。采用Kaplan-Meier法绘制生存曲线,利用log-rank检验比较两组复合观察终点累计发生率。P〈0.05为差异有统计学意义。结果 60例受者纳入研究：空白组20例,用药组40例。两组受者术前基线情况可比。手术相关情况（冷缺血时间、手术时间、无肝期、热缺血时间、术中出血量、红细胞输注量、ICU住院时间及激素诱导情况）差异均无统计学意义（t=1.12,U=298,U=331,U=359,U=344,U=398,U=329,χ2=.01,P均〉0.05）。空白组受者肝移植术后第1、2、3周血清γ-谷氨酰转肽酶,第2、3、4周血清碱性磷酸酶及第2、3、6个月血清总胆汁酸水平均高于用药组,差异均有统计学意义（U=206、160、148、222、211、219、144、140和94,P均〈0.05）。空白组受者术后第1、6、12个月复合观察终点累计发生率分别为15%、15%、28%,用药组分别为3%、18%、18%,两组差异均无统计学意义（χ2=.66,P〉0.05）。空白组受者术后第1、6、12个月生存比例分别为90%、90%、84%,用药组均为97.5%。两组差异均无统计学意义（χ2=.28,P〉0.05）。空白组受者术后第1、6、12个月移植物累积存活率分别为90.0%、84.4%、77.9%,用药组均为97.5%,两组差异均有统计学意义（χ2=.13,P〈0.05）。结论 UDCA对移植肝具有保护作用,可有效减轻由缺血再灌注及疏水性胆汁酸造成的移植肝损伤,促进移植肝酶学指标恢复正常。用药组移植物存活率优于空白组,但在复合观察终点比较中未能显示出降低胆道并发症的临床效果。

Objective This study was designed to investigate the effects of ursodeoxycholic acid（ UDCA） administration on the incidence of biliary complication（ BC） and the possible side effects after liver transplantation. Methods Two hundred and fifteen recipients who got liver transplantation in First Affiliated Hospital of Sun Yat-Sen University between July 2011 and December2013 were selected as evaluation objects. Randomized controlled study method was used. The recipients who met the inclusion criterias were randomly divided into two groups by the ratio of 2 to 1. Time of drug treatment was 6 months and all the recipients were still followed up for 6 months after drug treatment. General preoperative,operation related indexes,prognosis,composite observation endpoints incidence,survival rate,graft cumulative survival rate of recipients were compared. The composite observation endpoints included ischemia-type biliary lesions（ ITBL） by non-surgical factor,TBIL 51. 3 μmol/L 1 month after surgery without surgical and rejection factors,graft loss and death.Quantitative data like age,Child-Pugh score,cold ischemia time between the two groups was compared by two independent sample t-test or Wilcoxon rank testing. Qualitative data like the history of open operation and hormone induction between the two groups was compared by Chi-squared test or Fisher＇s exact test. Survivorship curve was diagramed by Kaplan-Meier. The cumulative incidence of composite observation endpoints between the two groups was compared by log rank test. Results 60 cases were enrolled eventually,including 20 cases of the control group,40 cases of UDCA treatment group. There was no statistical difference on general preoperative and operation related indexes（ cold ischemia time,operation time,anhepatic phase,warm ischemic time,blood loss during operation,blood red cell transfusion,ICU stay time and hormone induction） between two groups（ t = 1. 12,U = 298,U = 331,U = 359,U = 344,U = 398,U = 329,χ2=0. 01,P all 〉0. 05）. For UDCA treatment group,serum GGT levels at post-transplant week 1,2,3,ALP levels on post-transplant week 2,3,4 and TBA levels on post-transplant month 2,3,6 were all significantly lower than those of control group（ U =206、160、148、222、211、219、144、140 and 94,P all 〈0. 05）. There was no statistical difference on composite endpoint cumulative incidence and survival rate of recipients during 1th,6th,12 th month between the two groups（ χ2=0. 66 and 3. 28,P all 〉0. 05）. Statistical significance was found when compared the graft cumulative survival rate of the two groups on post-transplant month 1,6,12（ χ2=. 13,P 〈0. 05）. Conclusions This study demonstrated that it was safe for UDCA using in liver transplant recipients. UDCA improves serum liver tests in the early postoperative period,which was consistent with the hypothesis that UDCA may protect the hepatobiliary system against hydrophobic bile acids and ischemical reperfusion injury early after liver transplantation. The graft survival rate of UDCA treatment group was better than the control group, but the clinical effect of reducing bile duct complications could not be shown in the comparison of the composite observation endpoints.