药物性肝损伤常见药物发病机制的研究进展

药物性肝损伤(DILI)是临床上常见的药物不良反应,可进展为慢性肝损伤、肝纤维化,甚至导致肝衰竭或死亡[1,2]。据报道有1 100多种药物可引起不同程度的肝毒性[3]。在西方国家DILI的发病率估计为总人口的(1~20)/100 000[4-6]。在我国,中药和膳食补充剂(HDS)(26.81%)及抗结核药物(21.99%)是主要的两大类引起DILI的药物。前一类包括草药、藏药、蒙药、保健品和HDS;后一类包括异烟肼、利福平、吡嗪酰胺和乙胺丁醇。除药、HDS和抗结核药物外,其他常见的引起DILI的药物包括抗肿瘤药或免疫调节剂(8.34%),抗感染药(6.08%),精神药物(4.90%),非性激素(3.04%),心血管药物(2.98%),消化系统药物(2.04%),呼吸系统药物(1.47%)和肌肉骨骼药物(1.32%)切。目前DILI的发病机制未明,本文通过检索国内外最新发表文献,对常见的引起DILI药物的发病机制研究进展综述如下。     

中国药物性肝损伤诊治指南（2023年版）

药物性肝损伤（DILI）是重要的药物不良反应,严重者可导致急性肝衰竭甚至死亡。目前,DILI的诊断仍是排他性的策略,因此,详细的病史采集、全面仔细地排除肝损伤的其他潜在病因,是建立正确诊断的关键。本指南根据最新研究进展提供的循证医学证据制定,旨在为临床医师在实践中如何及时识别疑似DILI患者,规范诊断和管理提供专业的指导。根据我国的实际情况,指南也专门重点阐述了慢性肝病基础上的DILI、药物导致的肝炎病毒再激活、DILI的常见病因（草药和膳食补充剂、抗结核药物、抗肿瘤药物）,以及临床试验中DILI的信号和评估等内容。     

中国药物性肝损伤诊治指南（2023年版）撤回

药物性肝损伤（DILI）是重要的药物不良反应,严重者可导致急性肝衰竭甚至死亡。目前,DILI的诊断仍是排他性的策略,因此,详细的病史采集、全面仔细地排除肝损伤的其他潜在病因,是建立正确诊断的关键。本指南根据最新研究进展提供的循证医学证据制定,旨在为临床医师在实践中如何及时识别疑似DILI患者,规范诊断和管理提供专业的指导。根据我国的实际情况,指南也专门重点阐述了慢性肝病基础上的DILI、药物导致的肝炎病毒再激活、DILI的常见病因（草药和膳食补充剂、抗结核药物、抗肿瘤药物）,以及临床试验中DILI的信号和评估等内容。     

解读ACG临床指南:“特异质型药物性肝损伤的诊断和管理”

2014年6月美国胃肠病学会(ACG)发布了全球首个关于药物性肝损伤(DILI)的临床指南:"特异质型药物性肝损伤的诊断和管理",其内容涵盖了特异质型DILI(IDILI)的危险因素、诊断、鉴别诊断和治疗等各方面,同时对草药和膳食补充剂(HDS)引起的DILI和慢性肝病患者的DILI问题进行了专门的讨论。指南对规范DILI的临床诊断和治疗具有重要价值,为IDILI患者提供了最佳管理建议。但目前DILI领域研究的证据质量较弱,临床医师应在指南框架指导下,充分考虑患者可能的个体化差异,作出最佳临床决策。     

抗结核药所致药物性肝损伤诊断与处理专家建议

在结核病抗结核治疗过程中可能会出现各种不同程度的药物不良反应,其中以抗结核药所致药物性肝损伤(druginduced liver injury,DILI)最为多见,危害性最大,也是我国DILI的常见类型之一,轻者表现为一过性转氨酶升高,重者可致肝衰竭,甚至危及生命,部分患者因此不得不中止抗结核治疗,从而影响结核病的治疗效果,临床医生应高度重视这个问题.目前,国内外尚缺乏统一的抗结核药所致DILI诊断标准和处理指南,为提高广大临床医生对抗结核药所致DILI的认识及其处理水平,经多次召开专题研讨会,并邀请结核病、肝病和药物学等多学科专家进行反复讨论与修改,形成了本建议.     

《抗结核药物所致药物性肝损伤诊断与处理专家建议》解读

<正>中华医学会结核病学分会与《中华结核和呼吸杂志》编辑委员会制定了《抗结核药物所致药物性肝损伤诊断与处理专家建议》(以下简称专家建议)[1]。该专家建议对抗结核药物使用过程中导致肝损伤的诊断及治疗等多个方面的内容给出了明确的建议,对临床有较大的实用价值,现对该专家建议进行解读,以便更好地为临床处理抗结核药物所致药物性肝损伤(DILI)提供指导。1制定了抗结核药物所致DILI的定义     

药物性肝损伤的诊断和鉴别诊断:实践中的挑战

由于缺乏特异性的生物学标志物,且药物可导致目前已知的所有肝损伤类型,药物性肝损伤(DILI)的诊断和鉴别诊断成为临床上极具挑战性的课题。目前,DILI的诊断仍基于排除性策略。尽管RUCAM量表已被各大指南推荐为临床实践中评估肝损伤与可疑药物之间因果关系的标准方法,但其自身的局限性以及DILI复杂的临床表型使该量表尚无法完全满足复杂临床场景的需求。开发DILI诊断新的评估量表和特异性的生物学标志物,应是未来努力的方向。     

肝组织学在药物性肝损伤诊断中的价值

肝组织学检查对药物性肝损伤(DILI)的诊断、分型及预后判断临床意义重要, 并能够对RUCAM评分量表进行有效补充。DILI的临床表型复杂多样, 几乎涵盖已知的所有急性、慢性和重型肝损伤类型。DILI损伤的靶部位广泛, 包括肝细胞、胆管上皮细胞及血管内皮细胞等, 病理损伤模式与多种类型非DILI肝病表现酷似, 鉴别诊断难度较大。随着免疫检查点类抗肿瘤药物的临床广泛应用, 相关肝损伤的发生率呈增加趋势, 肝组织学检查能够有效评估其临床病理表型及病变程度, 从而指导治疗。特殊类型(如药物相关肝血管病变等)的DILI、多病因重叠DILI、慢性DILI及DILI诱发肝衰竭等情况下, 肝组织学检查有助于明确病因诊断, 指导临床及时合理治疗以及评估预后。目前DILI的组织学评价尚无国际统一标准, 加之高特异性和高灵敏度的血清学标志物缺乏, 因此肝组织学检查在DILI的诊断与鉴别诊断中作用尚不可替代。     

ACG临床指南简介：特异质型肝损伤的诊断和管理

由美国胃肠病学会（ACG）组织起草的全球首个关于药物性肝损伤（DILI）的指南,于近期正式发布。由于导致DILI的药品种类繁多,表型多样且缺乏客观诊断方法,造成DILI的临床诊断和管理尤为困难,因此,该指南的发布,对规范DILI的临床诊治具有重要意义。本文将介绍其主要内容。     

EASL临床实践指南简介:药物性肝损伤

<正>本指南讨论重点是特异质型药物性肝损伤(DILI)。特异质型DILI可影响包括个体患者的健康、药物监管决策和药物开发计划的多个方面。从临床角度,DILI可导致个体健康问题、住院甚至危及生命的肝衰竭、死亡或需要肝移植治疗。此外,由于相对较低的发病率、临床表型复杂,以及特异性生物标     

Adverse drug reactions and organ damage: The liver

Drug-induced liver injury (DILI) is among the most challenging acute or chronic liver conditions to be handled by physicians. Despite its low incidence in the general population, DILI is a frequent cause of acute liver failure. As such, the possibility of DILI should be considered in all patients who present with acute liver damage, independent of any known pre-existing liver disease. DILI can be classified as intrinsic/dose-dependent (e.g., acetaminophen toxicity) or idiosyncratic/dose-independent, with the latter form being relatively uncommon. Amoxicillin–clavulanate is the antimicrobial that is most frequently associated with idiosyncratic DILI. Large, ongoing, prospective studies in western countries have reported other drugs associated with DILI, including nonsteroidal anti-inflammatory drugs, statins, and herbal and dietary supplements. An important safety issue, DILI is one of the most frequently cited reasons for cessation of drug development during or after preclinical studies and for withdrawal of a drug from the market. This review summarizes the epidemiology, risk factors, commonly implicated drugs, clinical features, and diagnosis of DILI, with the aim of aiding physicians in the management of this debated problem. Old and new biomarkers for DILI and pharmacogenetic studies are also described.     

Drug-induced liver injury in Japan: An analysis of 1676 cases between 1997 and 2006

At the 44th Annual Meeting of the Japan Society of Hepatology, 1674 cases of drug-induced liver injury (DILI), occurring between January 1997 and December 2006, were reviewed. Data were obtained by questionnaires completed by the 29 presenters of the special DILI session during the meeting. This article presents the review's findings, including the role of dietary supplements and Chinese herbal medicines in DILI.     

Sex disparity and drug-induced liver injury

Drug-induced liver injury (DILI) is a potentially serious clinical condition that remains a major problem for patients, physicians and those involved in the development of new drugs. Population and hospital-based studies have reported incidences of DILI varying from 1.4 to 19.1/100.000. Overall, females have a 1.5- to 1.7-fold greater risk of developing adverse drug reactions and the female/male ratio increases after the age of 49 years, suggesting a clear susceptibility of DILI after menopause. Sex differences in pharmacokinetics and pharmacodynamic, sex-specific hormonal effects or interaction with signalling molecules that can influence drug efficacy and safety and differences in abnormal immune response following drug exposure are the main probable causes of the higher vulnerability observed among female patients. A novel phenotype of autoimmune-mediated DILI following the use of check-point inhibitors in oncology and haematology has been recently described. Finally, there have been increasing reports of DILI associated with use of herbal and dietary supplements that is more frequently reported in women.     

慢性药物性肝损伤的诊治研究进展

慢性药物性肝损伤(drug-induced liver injury,DILI)是药物不良反应中较为严重的一种疾病。随着新药的不断研发及临床应用,以及中药和食物补充剂的应用,慢性DILI的发生率不断增高。因此,充分了解其诊断及治疗对慢性DILI患者非常重要。本文对慢性DILI的最新研究进展作一概述,以期更加全面地了解该疾病。     

药物性肝损伤慢性化的研究近况

尽管药物性肝损伤(DILI)通常表现为急性过程,但仍有约20%患者会发生慢性化。慢性DILI病程反复且无有效﹑公认的治疗方法。随着新药的不断研发及其临床应用,以及中药和食物补充剂的应用,DILI慢性化的发生率不断增高。通过DILI流行病学﹑危险因素﹑临床表现﹑诊断及治疗等角度对DILI慢性化的最新研究近况进行概述,以期更加全面地了解认识慢性DILI。     

Mechanisms of isoniazid‐induced idiosyncratic liver injury: Emerging role of mitochondrial stress

Idiosyncratic drug‐induced liver injury (DILI) is a significant adverse effect of antitubercular therapy with isoniazid (INH). Although the drug has been used for many decades, the underlying mode of action (both patient‐specific and drug‐specific mechanisms) leading to DILI are poorly understood. Among the patient‐specific determinants of susceptibility to INH‐associated DILI, the importance of HLA genetic variants has been increasingly recognized, whereas the role of polymorphisms of drug‐metabolizing enzymes (NAT2 and CYP2E1) has become less important and remains controversial. However, these polymorphisms are merely correlative, and other molecular determinants of susceptibility have remained largely unknown. Regarding the drug‐specific mechanisms underlying INH‐induced liver injury, novel concepts have been emerging. Among these are covalent protein adduct formation via novel reactive intermediates, leading to hapten formation and a potential immune response, and interference with endogenous metabolism. Furthermore, INH and/or INH metabolites (e.g. hydrazine) can cause mitochondrial injury, which can lead to mitochondrial oxidant stress and impairment of energy homeostasis. Recent studies have revealed that underlying impairment of complex I function can trigger massive hepatocellular injury induced by otherwise nontoxic concentrations of INH superimposed on these mitochondrial deficiencies. This review discusses these emerging new paradigms of INH‐induced DILI and highlights recent insights into the mechanisms, as well as points to the existing large gaps in our understanding of the pathogenesis.