非诺贝特联合熊去氧胆酸治疗生化应答不佳原发性胆汁性胆管炎的疗效与安全性

Efficacy and safety of fenofibrate combined with ursodeoxycholic acid in the treatment of primary biliary cholangitis with poor biochemical response

目的探讨非诺贝特联合熊去氧胆酸(UDCA)治疗生化应答不佳原发性胆汁性胆管炎(PBC)的疗效与安全性。方法收集2010年1月至2018年1月在首都医科大学附属北京友谊医院肝病中心门诊诊断为UDCA生化应答不佳、加用非诺贝特治疗的早期PBC患者的病历资料进行回顾性分析,评价联合治疗的疗效和安全性。联合治疗方案为非诺贝特+UDCA,疗效指标为有效率和生化应答率。联合治疗12个月时血清碱性磷酸酶(ALP)降至治疗前基线值以下为有效,降至<1.5×参考值上限为实现生化应答。安全性指标为非诺贝特相关不良反应(肝损伤、肾损伤等)发生率。结果纳入分析的患者共42例,男性12例,女性30例;加用非诺贝特时年龄为(53±10)岁;联合治疗时间为5 d~34个月。对34例联合治疗患者的疗效分析结果显示,治疗12个月时ALP平均水平较基线值下降,其中10例(29.4%)降至参考值范围,有效率为100%;治疗前ALP为235(210,326)U/L,治疗12个月时降至134(104,190)U/L,差异有统计学意义(P=0.001)。34例患者中25例(73.5%)患者实现生化应答,治疗前ALP为221(198,256)U/L,治疗12个月时降至125(99,143)U/L,差异有统计学意义(P=0.010)。42例患者中16例(38.1%)发生非诺贝特相关不良反应,包括肝损伤8例(19.0%,其中1例合并烧心),肾损伤4例(9.5%),肌痛、颜面部水肿、烧心、头痛、皮肤瘙痒伴皮疹各1例(各2.3%)。8例肝损伤患者4例为轻度、1例为中度、3例为重度;轻度者未予干预,2个月后丙氨酸转氨酶(ALT)恢复至基线水平;中、重度者,停用非诺贝特并予保肝治疗后ALT和总胆红素均恢复至基线水平。4例肾损伤患者中2例停用非诺贝特后血清肌酐(Scr)恢复至基线水平;2例未停药,Scr自行恢复至参考值范围。结论非诺贝特联合UDCA治疗生化应答不佳的早期PBC患者有效,有73.5%的患者实现生化应答。非诺贝特常见不良反应为肝损伤及肾损伤,用药期间需密切监测患者的肝、肾功能。

Objective To explore the efficacy and safety of fenofibrate combined with ursodeoxy⁃cholic acid(UDCA)in the treatment of primary biliary cholangitis(PBC)with poor biochemical response.Methods The medical records of early PBC patients who were diagnosed with poor biochemical response to UDCA and treated with fenofibrate in Outpatient Department of the Liver Research Center of Beijing Friendship Hospital,Capital Medical University from January 2010 to January 2018 were collected and analyzed retrospectively,so as to evaluate the efficacy and safety of combination treatment.The combination treatment regimen consisted of fenofibrate and UDCA.The efficacy indicators were the efficacy rate and biochemical response rate.When the serum alkaline phosphatase(ALP)decreased to below the baseline value before treatment after 12 months of combination therapy,it was defined as effectiveness,and when it decreased to<1.5 times of upper limit of normal(ULN),the biochemical response was achieved.The safety indicator was the incidence of adverse reactions(liver injury,kidney injury,etc.)related to fenofibrate.Results A total of 42 patients were enrolled in the analysis,including 12 males and 30 females.The age was(53±10)years when fenofibrate was added and the duration of combination therapy was from 5 days to 34 months.The efficacy analysis of 34 patients with combined treatment showed that the average level of ALP decreased from the baseline value after 12 months of treatment,of which 10 patients(29.4%)fell to the reference value range,and the effective rate was 100%.The ALP was 235(210,326)U/L before treatment and decreased to 134(104,190)U/L after 12 months of treatment,with a statistically significant difference(P=0.001).Of the 34 patients,25(73.5%)achieved biochemical response.The ALP before treatment was 221(198,256)U/L and decreased to 125(99,143)U/L after 12 months of treatment,with a statistically significant difference(P=0.010).Of the 42 patients,16(38.1%)developed adverse reactions related to fenofibrate,including liver injury in 8 patients(19.0%,one case was complicated with hearthurn),kidney injury in 4 patients(9.5%),myalgia,facial edema,heartburn,headache,and skin itch with rash in 1 patient each(each 2.3%).Of the 8 patients with liver injury,4 were mild,1 was moderate,and 3 were severe;the mild cases were not inter⁃vened,and the alanine aminotransferase(ALT)returned to the baseline level after 2 months;in moderate and severe cases,ALT and total bilirubin returned to the baseline level after stopping fenofibrate and receiving liver protection treatment.Of the 4 patients with renal injury,the serum creatinine(Scr)in 2 patients returned to the baseline level after withdrawal of fenofibrate,in the other 2 patients it recovered to the reference value range spontaneously without drug withdrawal.Conclusions Fenofibrate combination with UDCA is effective in the treatment of early PBC patients with poor biochemical response,the rate of biochemical response is 73.5%.The common adverse reactions of fenofibrate are liver injury and kidney injury.During the medication,the patients′liver and kidney function should be closely monitored.