波生坦致肝损伤文献病例分析

Literature case analysis of liver injury caused by bosentan

目的了解波生坦致肝损伤的临床特点。方法检索PubMed、Ovid、Web of Science、Embase、Springer⁃link、Wiley Oline Library和中国知网、万方、维普数据库(截至2020年4月),收集波生坦致肝损伤的病例报告类文献,提取患者相关信息(一般情况、原发病、合并疾病、波生坦应用情况、合并用药情况以及肝损伤发生情况、处置及转归等),进行描述性统计分析。结果共检索到波生坦致肝损伤的病例报告类文献10篇,涉及12例患者(中国、日本各3例,意大利2例,澳大利亚、巴西、加拿大、瑞典各1例)。12例患者均为女性;年龄29~79岁,平均55岁;原发疾病为系统性硬化症相关肺动脉高压(PAH)5例,结缔组织病相关PAH 2例,特发性、继发性、慢性血栓栓塞性、胆汁肝硬化相关、非肝硬化门静脉高压相关PAH各1例;合并其他疾病者4例。12例患者均存在联合用药情况,联用药物1~9种。肝损伤发生在服用波生坦20 d^57个月(<1个月3例,1~3个月4例,>12个月5例);均表现为转氨酶升高,伴有胆红素升高者5例;6例有临床表现描述,包括皮肤巩膜黄染4例,食欲不振4例,恶心3例,乏力3例,呕吐、体重减轻和嗜睡各1例;1例行肝穿刺活检术,结果显示为自身免疫性肝炎。发生肝损伤后波生坦停用或剂量减半,视肝损伤情况给予对症治疗,12例患者中9例肝功能恢复正常,2例好转,1例因多器官衰竭死亡。结论波生坦相关肝损伤可发生在用药20 d^57个月,多发生在用药3个月内;临床表现与其他药物性肝损伤类似,部分患者可无临床症状,仅表现为肝功能异常,少数患者可出现严重肝损伤;停用波生坦后肝功能多可恢复正常或好转。

Objective To understand the clinical characteristics of bosentan⁃related liver injury.Methods PubMed,Ovid,Web of Science,Embase,Springer⁃link,Wiley Oline Library,CNKI,Wanfang and VIP databases were searched as of April 2020 and case reports on bosentan⁃related liver injury were collected.General information,primary diseases,comorbidities,bosentan use,combined medication,and occurrence,treatment and outcome of liver injury in patients were extracted and analyzed by descriptive statistical method.Results A total of 10 case reports on bosentan⁃related liver injury were included,involving 12 patients(3 from China,3 from Japan,2 from Italy,and 4 from Australia,Brazil,Canada,and Sweden respectively).The 12 patients were all female,aged from 29 to 79 years with an average age of 55 years.The primary diseases were systemic sclerosis⁃associated pulmonary hypertension(PAH)in 5 patients,connective tissue disease⁃associated PAH in 2 patients,idiopathic,secondary,chronic thromboembolic,biliary cirrhosis⁃associated,and non⁃hepatic portal hypertension⁃associated PAH in 5 patients,respectively.Four patients had comorbidities.All the 12 patients had combined medications,which included 1-9 kinds of drug.Liver injury occurred in patients 20 days to 57 months after bosentan administration(<1 month in 3 patients,1⁃3 months in 4 patients,and>12 monthsin 5 patients)and was manifested as elevated transaminases,accompanied by elevated bilirubin in 5 patients;the clinical manifestations in 6 patients were described,including yellow staining of skin and sclera in 4 cases,anorexia in 4 patients,nausea in 3 patients,fatigue in 3 patients,and vomiting,weight loss,and drowsiness in 3 patients,respectively;liver biopsy was performed in 1 patient,showing autoimmune hepatitis.After liver injury,bosentan was discontinued or continued with a halved dose;symptomatic treatments were given depending on the specific situation of liver injury;among the 12 patients,9 had normal liver function,2 had improved liver function,and 1 died of multiple organ failure.Conclusions Bosentan⁃related liver injury may occur within 20 days to 57 months of medication and often within 3 months,with similar clinical manifestations to those induced by other drugs.Some patients may have no clinical symptoms but only abnormal liver function while severe liver injury may occur in a small number of patients.Liver function can usually return to normal or be improved after discontinuation of bosentan.