基层常见疾病诊疗指南
ENGLISH ABSTRACT
中国药物性肝损伤基层诊疗与管理指南(2024年)
中华医学会
中华医学会杂志社
中华医学会肝病分会药物性肝病学组
中华医学会全科医学分会
中华医学会《中华全科医师杂志》编辑委员会
中国医药生物技术协会药物性肝损伤防治技术专业委员会
中国初级卫生保健基金会药物肝脏安全性专业委员会
中国药物性肝损伤基层诊疗与管理指南制定专家组
作者及单位信息
·
DOI: 10.3760/cma.j.cn114798-20240408-00225
Chinese guideline for diagnosis and management of drug-induced liver injury in primary care (2024)
Chinese Medical Association
Chinese Medical Association Publishing House
Study Group of Drug-Induced Liver Disease, Chinese Society of Hepatology
Chinese Society of General Practice
Editorial Board of Chinese Journal of General Practitioners of Chinese Medical Association
Committee on Prevention and Management of Drug-Induced Liver Injury, Chinese Medical Biotechnology Association
Committee on Drug Safety of Liver, China Primary Health Care Foundation
Expert Group of Chinese Guideline for Diagnosis and Management of Drug-Induced Liver Injury in Primary Care
Mao Yimin
Authors Info & Affiliations
Chinese Medical Association
Chinese Medical Association Publishing House
Study Group of Drug-Induced Liver Disease, Chinese Society of Hepatology
Chinese Society of General Practice
Editorial Board of Chinese Journal of General Practitioners of Chinese Medical Association
Committee on Prevention and Management of Drug-Induced Liver Injury, Chinese Medical Biotechnology Association
Committee on Drug Safety of Liver, China Primary Health Care Foundation
Expert Group of Chinese Guideline for Diagnosis and Management of Drug-Induced Liver Injury in Primary Care
Mao Yimin
Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Research Center of Fatty Liver Disease, Shanghai 200001, China
·
DOI: 10.3760/cma.j.cn114798-20240408-00225
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摘要

药物性肝损伤(drug-induced liver injury,DILI)是指由化学药品、生物制品、中成药等药品,以及中药材、天然药物、保健品、膳食补充剂等产品,或其代谢产物乃至其辅料、污染物、杂质等所导致的肝损伤。基层医疗机构所管理的患者中,普遍存在老年患者较多、多种疾病并存、多药联合治疗的现状,都可能增加DILI的发生风险。而且,对肝损伤机制、风险因素和临床表型等认识的局限,以及缺乏特异性诊断生物标志物和有效干预措施,使DILI的及时识别、建立诊断、预后预测、临床管理和风险防范面临巨大挑战。

药物性肝损伤;诊断;治疗;疾病管理;指南;基层
引用本文

中华医学会,中华医学会杂志社,中华医学会肝病分会药物性肝病学组,等. 中国药物性肝损伤基层诊疗与管理指南(2024年)[J]. 中华全科医师杂志,2024,23(08):813-830.

DOI:10.3760/cma.j.cn114798-20240408-00225

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药物性肝损伤(drug-induced liver injury,DILI)是指由化学药品、生物制品、中成药等药品,以及中药材、天然药物、保健品、膳食补充剂等产品,或其代谢产物乃至其辅料、污染物、杂质等所导致的肝损伤。基层医疗机构所管理的患者中,普遍存在老年患者较多、多种疾病并存、多药联合治疗的现状,都可能增加DILI的发生风险。而且,对肝损伤机制、风险因素和临床表型等认识的局限,以及缺乏特异性诊断生物标志物和有效干预措施,使DILI的及时识别、建立诊断、预后预测、临床管理和风险防范面临巨大挑战。
2018年,中华医学会受国家卫生健康委员会基层卫生健康司委托组织制定系列基层常见疾病诊疗指南,其中《药物性肝损伤基层诊疗指南(2019年)》刊载于《中华全科医师杂志》 1 , 2,是第一部由全科医学专家参与制定的面向基层的药物性肝损伤诊疗指南。5年来,关于DILI诊治的内容有了更多的循证医学证据。为进一步加强基层医疗机构医务人员对DILI的认识,帮助其及时识别、规范诊治和管理DILI并更新其对DILI的认识,我们开展了指南的更新修订工作。制定组专家根据最新研究进展提供的循证医学证据,并以《中国药物性肝损伤诊治指南(2023年版)》 3和《药物性肝损伤基层诊疗指南(2019年)》 1 , 2为指导编写了本部《中国药物性肝损伤基层诊疗与管理指南(2024年)》(以下简称“本指南”)。
鉴于DILI诊断和鉴别诊断的复杂性和困难性,DILI的特殊表型、慢性肝病基础上的DILI和药物导致的病毒性肝炎再激活等问题,不在本指南中阐述,可参考《中国药物性肝损伤诊治指南(2023年版)》 3的管理建议。本指南无法涵盖或解决临床实践中DILI诊疗的所有问题,也非强制性标准。因此,基层医疗机构的医务人员应充分了解相关研究证据,做出合理诊疗决策。本指南适用于基层医疗机构全科、消化内科、感染科、肝病科等医务人员使用,且将根据研究进展适时更新。
本指南的制定遵循国内外权威学术组织制定指南的基本流程和程序,所有执笔专家均签署了利益冲突声明。采用英国牛津大学循证医学中心证据分级和推荐标准(2011年版) 4进行证据评估( 表1 )。在指南各部分前列出了相应推荐意见。此外,为帮助基层医师阅读学习,在附录部分列出了相关名词解释(附录1)。
级别 描述
证据级别
1 基于RCTs的系统评价、全或无研究、效应量大的观察性研究
2 单个RCT、效应量大的观察性研究
3 非随机对照的队列研究,随访研究
4 病例系列、病例对照研究、回顾性对照研究
5 机制研究
推荐级别
A 证据级别为1的一致研究
B 证据级别为2、3的一致研究;证据级别为1的间接研究
C 证据级别为4的一致研究;证据级别为2、3的间接研究
D 证据级别为4的研究或任何级别的不一致或不确定的研究
英国牛津大学循证医学中心证据分级和推荐标准(2011年版) 4

注:分级可根据证据质量、不精确性、间接性(所引用研究的 PICO 与指南推荐意见所涉及的 PICO 不匹配)、效应量小而降级;也可以根据效应量大进行升级;推荐强度以2011版牛津分级为原则,但在部分推荐强度的形成过程中考虑了临床实践的具体情况并参考了欧美药物性肝损伤诊疗指南得出最终分级;RCT 随机对照试验;PICO:participants,interventions,comparisons,outcomes(对象,干预,对照,预后)

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附录
附录1 药物性肝损伤相关名词解释
名词 解释
固有型DILI 由药物或其代谢产物对肝脏的直接毒性造成,与剂量相关,达到一定剂量阈值或暴露水平的个体可发生肝损伤,具有可预测的特点
特异质型DILI 仅在暴露该药物的少数人群发生,通常被认为与药物剂量无关,且无法根据已知的药理作用预测,其发生主要与独特的宿主特征相关,如代谢特异质和免疫特异质
间接型DILI 因为某些药物通过改变或加剧先前存在的肝脏疾病(如慢性病毒性肝炎或脂肪肝),或通过改变患者的免疫系统状态而间接导致的肝损伤。例如大剂量激素或某些单抗导致的病毒性肝炎再激活,激发免疫导致的免疫介导的肝损伤,如免疫检查点抑制剂(ICIs)导致的肝损伤、药物诱导的自身免疫性肝炎(DI-ALH)等
海氏法则 符合海氏法则的案例被定义为肝细胞损伤型DILI,其血清ALT或AST≥3×ULN,同时血清总胆红素升高≥2×ULN;起病时无胆汁淤积表现(ALP≥2×ULN);排除ALT、AST和TBil同时升高的其他原因(如病毒性肝炎、大量酒精摄入等)
乙型肝炎病毒再激活 是指乙型肝炎表面抗原(HBsAg)阳性/乙型肝炎核心抗体(抗-HBc)阳性,或HBsAg 阴性/抗-HBc 阳性患者在接受免疫抑制剂或其他相关风险药物治疗时,HBV DNA 较基线升高≥2 log IU/ml,或基线HBV DNA 阴性者转为阳性,或 HBsAg 由阴性转为阳性
附录2 可能导致肝损伤的中草药
中药学功效 中草药
发散风寒 麻黄、苍耳子、细辛、紫菀
清热泻火 天花粉
清热燥湿 黄芩、白鲜皮、苦参
清热解毒 千里光、青黛、金果榄、山豆根、土茯苓、贯众、鸦胆子、板蓝根、白花蛇舌草、穿心莲、相思子、大白顶草、望江南子
清热凉血 牡丹皮、紫草
祛风寒湿 川乌、昆明山海棠、丁公藤、草乌
祛风湿热 雷公藤、防己、黑骨藤
补血 何首乌
活血止痛 延胡索、乳香、没药
清热化痰 黄药子
化湿 苍术、佩兰
补阳 补骨脂、淫羊藿
止咳平喘 白屈菜、款冬花
温化寒痰 八角莲、半夏
温里 吴茱萸
峻下逐水 京大戟、芫花、商陆
利尿通淋 木通
展开表格
中药学功效 中草药
凉血止血 羊蹄、地榆
收敛止血 白及
温经止血 艾叶
活血调经 番红花、益母草、泽兰
活血疗伤 马钱子、及己
破血消癥 莪术、水蛭、斑蝥、喜树
理气 川楝子、香附、乌药
开窍 石菖蒲
平抑肝阳 刺蒺藜
息风止痉 全蝎、蜈蚣、牛黄
重镇安神 朱砂
养心安神 缬草、合欢皮
敛肺涩肠 五味子、五倍子、罂粟壳、石榴皮
驱虫 苦楝皮
涌吐 常山、石蒜
攻毒杀虫止痒 雄黄、蟾酥、木鳖子、土荆皮、大风子
拔毒化腐生肌 黄丹、钩吻
其他 土三七
展开表格
附录3 常用肝脏生物化学检查指标及可能的临床意义
指标 异常可能的临床意义 对肝脏疾病的特异性
丙氨酸转氨酶 肝细胞损伤 >3×ULN具有一定肝脏特异性,肝外组织受损常为低水平升高,如骨骼肌
天冬氨酸转氨酶 肝细胞损伤 非肝脏特异性(骨骼肌、心脏、胰腺、血液)
总胆红素 胆汁淤积,摄取受损,结合或排泄受损,胆道梗阻,溶血 非肝脏特异性
碱性磷酸酶 胆汁淤积,浸润性疾病,胆道梗阻 非特异性(骨骼、唾液腺、肠、胆)
γ-谷氨酰转移酶 胆汁淤积,胆道梗阻 非特异性(肾、肝、胰腺、胃肠道、肺)
谷氨酸脱氢酶 肝细胞(线粒体)损伤 肝脏特异性,有助于区分肌肉损伤和肝损伤
白蛋白 肝细胞功能受损 营养不良、肾病综合征、肝硬化(任何原因)
国际标准化比值 肝细胞功能受损 维生素K缺乏症;抗凝剂
肌酸激酶 肌肉损伤 对区分肌肉损伤和肝损伤至关重要
附录4 RUCAM因果关系评估量表

药物:_______________初始ALT:_____________初始ALP:____________R值=[ALT/ULN]÷[ALP/ULN]=__________

肝损伤类型:肝细胞型(R≥5.0),胆汁淤积型(R≤2.0),混合型(2.0<R<5.0)

肝细胞损伤型 胆汁淤积型或混合型 评价
1.用药至发病的时间 初次用药 再次用药 初次用药 再次用药 计分
○从用药开始
●提示 5~90 d 1~15 d 5~90 d 1~90 d +2
●可疑 <5 d或>90 d >15 d <5 d或>90 d >90 d +1
○从停药开始
●可疑 ≤15 d ≤15 d ≤30 d ≤30 d +1
注:若肝损伤反应出现在开始服药前,或停药后>15 d(肝细胞损伤型)或>30 d(胆汁淤积型),则应考虑肝损伤与药物无关,不应继续进行RUCAM评分
2.病程 ALT在峰值和ULN之间的变化 ALP(或TBil)在峰值和ULN之间的变化
○停药后
●高度提示 8 d内下降≥50% 不适用 +3
●提示 30 d内下降≥50% 180 d内下降≥50% +2
●可疑 不适用 180 d内下降<50% +1
●无结论 无资料或30 d后下降≥50% 不变、上升或无资料 0
●与药作用相反 30 d后下降<50%或再次升高 不适用此指标评价 -2
○若继续用药
●无结论 出现以上任何情况 出现以上任何情况 0
3.危险因素
○饮酒或妊娠 饮酒 饮酒或妊娠(任意1种)
+1
0
○年龄 ≥55岁 ≥55岁 +1
<55岁 <55岁 0
4.伴随用药
○无伴随用药,或无资料,或伴随用药至发病时间不相符 0
○伴随用药至发病时间相符 -1
○伴随用药已知有肝毒性,且至发病时间提示或相符 -2
○伴随用药的肝损伤证据明确(再刺激反应呈阳性,或与肝损伤明确相关并有典型的警示标志) -3
5.除外其他肝损伤原因
第Ⅰ组(6种病因)
○急性甲型肝炎[抗-HAV(-)IgM(+)]或HBV感染[HBsAg和/或抗-HBc(-)]IgM(+)或HCV感染[抗-HCV(+)和/或HCV RNA(+),伴有相应的临床病史]
○胆道梗阻(影像检查证实)
○酒精中毒(有过量饮酒史且AST/ALT≥2)
○近期有低血压、休克或肝脏缺血史(发作2周以内)
第Ⅱ组(2类病因)
○合并自身免疫性肝炎、脓毒症、慢性乙型或丙型肝炎、原发性胆汁性胆管炎(PBC)或原发性硬化性胆管炎(PSC)等基础疾病
○临床特征或血清学和病毒学检测提示急性CMV、EBV或HSV感染
●排除组Ⅰ和组Ⅱ中的所有病因 +2
●排除组Ⅰ中的所有病因 +1
●排除组Ⅰ中的5或4种病因 0
●排除组Ⅰ中的少于4种病因 -2
●非药物性因素高度可能 -3
6.药物既往肝损伤信息
○肝损伤反应已在说明书中标明 +2
○肝损伤反应未在说明书中标明,但曾有报道 +1
○肝损伤反应未知 0
7.再用药反应
○阳性 再次单用该药后ALT升高2倍 再次单用该药后ALP(或TBil)升高2倍 +3
○可疑 再次和首次发生肝损伤时使用的另一药物联合应用,ALT升高2倍 再次和首次发生肝损伤时使用的另一药物联合应用,ALP(或TBil)升高2倍 +1
○阴性 再次单用该药后ALT升高,但低于ULN 再次单用该药后ALP(或TBil)升高,但低于ULN -2
○未再用药或无法判断 其他情况 其他情况 0
总分意义判定:>8分为极可能;6~8分为很可能;3~5分为可能;1~2分为不太可能;≤0分可排除
展开表格
参考文献
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备注信息
A
茅益民,上海交通大学医学院附属仁济医院消化内科 上海市消化疾病研究所 上海市脂肪性肝病诊治研究中心,上海 200001,Email: mocdef.3ab6186911myoam
B
中华医学会, 中华医学会杂志社, 中华医学会肝病分会药物性肝病学组, 等. 中国药物性肝损伤基层诊疗与管理指南(2024年)[J]. 中华全科医师杂志, 2024, 23(8): 813-830. DOI: 10.3760/cma.j.cn114798-20240408-00225.
C
上海交通大学医学院附属仁济医院支阳、李晓芸、董一诺等在指南编写过程中的协助工作
D
所有作者声明不存在利益冲突
E
国家重点研发计划 (2022YFC35022101)
国家科技部“十三五”科技重大专项 (2017ZX09304016)
国家自然科学基金 (81970513,82270619)
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