间接型药物性肝损伤:新类型与新挑战

间接型药物性肝损伤是由药物的治疗作用所引起的肝损伤,而不是因为药物固有的肝毒性或免疫原性所导致的一类新型药物性肝损伤(DILI)。目前临床常见的间接型DILI主要有3种临床表型,即免疫检测点抑制剂相关肝损伤、药物引起肝炎病毒再激活和药物影响肝细胞代谢所致的脂肪肝或原有脂肪肝加重。由于间接型DILI是一类新型DILI,临床对其认识不足,诊治经验缺乏。尤其是随着免疫检测点抑制剂在临床快速推广应用,间接型DILI迅速增加,给临床诊断和治疗带来更大的挑战。因此,对间接型DILI常见类型的临床特点、发病机制及诊断治疗等研究进展等进行综述,具有重要的临床意义。     

抗菌药物致急性肝损伤防治探讨

目的探讨抗菌药物致急性肝损伤的防治方法。方法对有关文献资料进行综合分析。结果抗菌药物致急性肝损害一般预后较好,个别重型可致肝功能严重损害,乃至昏迷死亡。结论药物性肝损伤属医源性疾病,临床医生在选择时要慎重,治疗过程中要严密监测血常规、肝功能,及时发现,及时治疗一般预后良好,个别重症可危及生命;只要医生认真对待,是可以预防肝损害的发生。     

32例闭合性肝损伤的诊断和治疗体会

目的探讨损伤程度不同的闭合性肝损伤的诊断和治疗方法。方法 32例闭合性肝损伤临床资料回顾性分析。结果 32例闭合性肝外伤治愈30例,2例死亡。1例死于探查术中;1例死于术后2 d脑挫伤并脑疝形成。结论 1血液动力学稳定,病情稳定Ⅰ-Ⅱ级肝外伤可试行腹腔下探查和缝合止血。2严重肝外伤在积极补充血容量的同时应立即手术止血。3术中腹腔积血自血回输对抢救患者生命是一种良好措施。4腹腔穿刺在闭合性肝损伤的诊断中是一项简单、便利、有效、可靠方法。     

不规则肝叶切除治疗严重肝损伤临床观察

目的探讨不规则肝叶切除对严重肝损伤患者的治疗价值,为临床救治肝损伤患者提供参考。方法将我院2008年7月至2011年10月收治的58例严重肝损伤患者按入院时间先后分为观察组和对照组。对照组患者给予解剖性肝叶切除,观察组患者给予不规则肝叶切除,比较两组治疗效果、并发症发生率、手术时间及术中出血情况。结果与对照组比较,观察组手术时间短,术中出血量少,差异均有统计学意义;观察组治愈率高,并发症发生率低,但差异均无统计学意义。结论采用不规则肝叶切除治疗严重肝损伤具有较好的效果,且手术时间短,术中出血量少。     

药物性肝损伤的临床药学监护

摘 要 目的： 探讨临床药师对药物性肝损伤患者开展临床药学监护的方法。方法: 详细介绍临床药师参与3例典型药物性肝损伤病例的治疗过程及分析。结果: 病例1提示在临床用药过程中应警惕新的可能导致药物性肝损的药物并及时发现并采取合理诊治;病例2提示发生药物性肝损伤时,临床药师可利用TDM判断致肝损害的药物;病例3提示应关注特殊患者的肝功能,对于肝功能异常的患者,应避免使用肝毒性的药物或选用肝毒性较小的药物。结论:临床药师应多途径、多环节参与药物性肝损伤的药学实践,关注新的可能导致药物性肝损伤的药物;提供TDM监测,为诊断药物性肝损伤提供客观依据;关注患者的肝肾功能,为患者提供更佳的用药方案。     

肝损伤动物模型研究进展

已知多种致病原因可导致肝损伤 ,如病毒性肝炎、酒精性肝炎和药物性肝炎等。各种有害因素所致的肝损伤可表现为肝坏死、脂肪肝、胆汁郁积、肝纤维化、肝硬化及肝癌等。对肝损伤的防治目前仍是一个全球性的严峻课题。通过建立实验性肝损伤动物模型 ,研究肝病的发生机制 ,筛选保肝药物 ,探索保肝作用原理 ,具有十分重要的现实意义。现将近几年来国内外对实验性肝损伤动物模型分类、造模方法、检测指标及造模剂作用原理等有关方面的研究进展情况作一综述。1　化学性肝损伤动物模型1 1　四氯化碳性肝损伤　四氯化碳 (ＣＣｌ4)溶于精制植物油。急…     

玉屏风多糖对小鼠免疫性肝损伤的影响

目的 观察玉屏风多糖(YPF-P)对卡介苗(BCG)和脂多糖(LPS)致小鼠免疫性肝损伤模型的影响.方法 BCG尾静脉注射致敏小鼠10 d后,静脉给LPS激发小鼠产生急性免疫性肝损伤,16 h后取肝和脾,计算肝脏、脾脏指数并观察肝脏病理变化,分光光度法测血清AST和ALT浓度,肝匀浆中SOD、MDA、NO含量,RT-PCR 法检测肝匀浆TNF-αmRNA表达水平.结果 YPF-P(100,200 mg·kg-1)能降低免疫性肝损伤小鼠的肝脏、脾脏指数;减少免疫性肝损伤小鼠血清中升高的ALT、AST含量;降低肝匀浆中升高的MDA、NO水平,升高其降低的SOD水平;使肝匀浆中TNF-αmRNA表达水平下降.结论 YPF-P对小鼠急性免疫性肝损伤具有一定的保护作用,这可能与它清除自由基,增强机体抗脂质过氧化能力及降低炎性细胞因子的表达有关.     

肝损伤25例手术治疗体会

<正> 肝损伤病情较严重,其主要病变是大出血、休克及胆汁漏所致的胆汁性腹膜炎及其它器官的合并伤。死亡率较高。1977年以来,我们共手术治疗肝损伤25例,现总结如下。临床资料男性17例,女性8例,最大年龄52岁,最小年龄5岁。损伤原因:压砸伤7例,车辆挤压伤13例,高处跌伤5例。损伤部位:右半肝16例,左半肝5例,肝门区3例,肝尾叶1例。主要合并伤:脾破裂2例,肠破裂1例,肠系膜血肿3例,肋骨骨折5例,脑挫伤1例。     

抗结核药物肝损伤中患者治疗中的临床干预

目的:探讨抗结核药物肝损伤中患者治疗中的临床干预.方法:以我院住院的抗结核药物所致肝功能异常患者为例,对患者的临床资料进行回顾性分析,探讨肝损害患者的临床干预措施以及干预的效果.结果:我院2015年6月～2016年6月期间共有95例肝损伤患者,其中有45为轻度肝功能异常,50例患者重度的肝功能异常,轻度肝功能异常患者予以密切观察病情并变化,并继续原方案抗结核治疗,重度功能异常患者予以保肝、解毒治疗后有50例患者均好转,3例患者死亡.结论:在对结核病患者进行抗结核治疗时,要密切监测患者的症状及肝功能指标变化,根据监测结果采取相应的措施,防止患者发生严重的肝损害.     

静脉注射胺碘酮继发急性肝损伤16例诊疗分析

目的分析静脉注射胺碘酮继发急性肝损伤的临床特点及发病机制。方法2005年3月—2013年3月两院发生的静脉注射胺碘酮继发急性肝损伤病例16例患者的基本情况、基础疾病、合并用药情况、静脉应用胺碘酮的指征、发现急性肝损伤时累积使用胺碘酮的剂量、静脉注射胺碘酮至发现急性肝损伤的时间、肝功能变化特点以及转归进行临床分析。结果多数患者肝损伤发生在静脉注射胺碘酮后的3日内，仅有少数患者肝损伤在静脉注射胺碘酮3日以后发生。大多数病例仅为无症状的肝损害，表现为肝脏转氨酶水平的快速升高，甚至超过正常值上限10倍以上，及时停药后，肝功能可恢复正常。有症状的严重急性肝损伤病例罕见，可发生肝衰竭甚至死亡。结论静脉注射胺碘酮后的急性肝损伤是一种潜在的致命的不良反应，且不可预知，虽然死亡病例罕见，但仍应引起临床医师的注意。     

Animal models of idiosyncratic drug-induced liver injury—Current status

The infrequent occurrence of idiosyncratic reactions and their dependence on individual sensitivity factors allow them to go undetected in current preclinical safety evaluation using conventional animal tests. Better predictive models for idiosyncratic, drug-induced liver injury (IDILI) would enable the preclinical elimination of drug candidates with idiosyncrasy liability and could provide evidence for a mode of action for these responses, suggest early biomarkers of IDILI, and lead to the development of mechanism-based, in vitro screens. Desirable characteristics of an animal model include the production of liver injury in a large fraction of animals of relatively inexpensive species/strains and the ability to distinguish drugs that cause IDILI in humans from ones that do not. The mechanistic basis for idiosyncratic reactions remains poorly understood. However, attempts at animal model development have been made based on several hypothesized modes of action of IDILI. These hypotheses have centered on drug disposition polymorphisms, adaptive immunity, mitochondrial dysfunction, failure to adapt to modest injury, inflammatory stress, and multiple determinants, and the success in achieving animal models of liver injury for each of these is discussed. Despite numerous challenges associated with animal models of IDILI, some models have emerged and are proving useful in exploring potential mechanisms. Current animal models are not perfect, but they hold promise for increasing the prediction and understanding of human idiosyncratic drug reactions.     

Mitochondrial abnormalities--a link to idiosyncratic drug hepatotoxicity?

Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem and poses a considerable challenge for drug development as an increasing number of successfully launched drugs or new potential drugs have been implicated in causing DILI in susceptible patient subsets. Although the incidence for a particular drug is very low (yet grossly underestimated), the outcome of DILI can be serious. Unfortunately, prediction has remained poor (both for patients at risk and for new chemical entities). The underlying mechanisms and the determinants of susceptibility have largely remained ill-defined. The aim of this review is to provide both clinical and experimental evidence for a major role of mitochondria both as a target of drugs causing idiosyncratic DILI and as mediators of delayed liver injury. We develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2(+/-) mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept.     

Zebrafish as model organisms for studying drug-induced liver injury

Drug-induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high-throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de-ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers.     

肝损状态下尿苷二磷酸葡萄糖醛酸转移酶研究进展

肝脏是人体内最重要的代谢器官,包含绝大部分的Ⅰ相和Ⅱ相代谢酶,在内源性和外源性物质的代谢解毒方面起着重要的作用.参与葡萄糖醛酸代谢的尿苷二磷酸葡萄糖醛酸转移酶(UGT)是Ⅱ相代谢中最重要的酶,与常见的CYP450酶相比,研究相对滞后,尤其在肝损伤状态下UGT的相关研究仍处于探索阶段.本文参考最新UGT的研究成果,综述了UGT分子生物学目前研究的概况、肝脏分布及其与肝脏疾病的关系;总结了几种不同诱因的肝损伤病理状态UGT表达和葡萄糖醛酸代谢的变化情况并且深入探讨了相关机制,旨在为药物的肝脏代谢尤其是在肝损状态下葡萄糖醛酸结合消除研究提供一定的参考依据,为肝脏疾病患者的临床合理用药提供指导.     

脂质组学在肝脏疾病中的研究进展

肝脏疾病是一类常见病、多发病,严重威胁人类的生命健康,肝脏疾病的研究已成为当今器质性疾病领域研究的热点与难点,近年来,学者们通过研究发现肝脏疾病与机体的脂质化合物代谢密切相关。脂质组学是代谢组学的重要分支,能通过分析机体的脂质变化水平来评价肝脏疾病、寻找表征肝脏疾病的生物标志物、研究肝脏疾病发生的可能机制,在肝脏疾病的研究中发挥着巨大的作用。该文在对脂质组学研究方法进行综述的同时,还以不同类型的肝脏疾病为出发点,重点对近年来脂质组学在肝脏疾病中的应用进行了归纳与分析,以期为肝脏疾病的深入研究和肝脏疾病的临床治疗提供参考。     

芒果苷滴丸对小鼠实验性肝损伤的保护作用

目的：研究芒果苷滴丸（MDP）对小鼠实验性肝损伤的保护作用及其机制。方法：以MDP对小鼠灌胃给药,对MDP进行最大耐受量（MTD）测定;采用四氯化碳（CCl4）、D-氨基半乳糖盐酸盐（D—GaIN）诱导小鼠急性肝损伤模型;卡介苗（BCG）加脂多糖（LPS）联合诱导小鼠免疫性肝损伤模型。分光光度法检测血清中丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）含量和肝组织匀浆中超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽过氧化物酶（GSH—Px）含量,苏木精-伊红（HE）染色法对肝脏组织作病理切片法检查。结果：①以MDP对小鼠灌胃给药,其MTD为180g·kg^-1,相当于原药材36g·kg^-1。②MDP能显著降低急性、免疫性肝损伤小鼠血清中ALT、AST含量（P〈0．01）,能降低急性肝损伤小鼠肝匀浆MDA含量（P〈0．01）,升高肝匀浆SOD、GSH—PX活性（P〈0．01）,病理结果表明MDP能减轻免疫性小鼠肝损伤的肝损伤程度。结论：MDP对急性、免疫性肝损伤小鼠具有显著保护作用,其作用机制可能与抗脂质过氧化有关。     

老年药物性肝损害的临床特点

药物引起的肝毒性是老年人肝脏疾病的重要原因,发生率是年轻人的4倍多,且类型几乎包括了所有已知的肝脏疾病。因为大多数的临床试验排除了大于75~80岁年龄组患者,有关药物副作用的报告在大于60岁年龄组中相当罕见。为此,需要进一步的临床研究,以探讨老年患者肝脏的药物副作用。本文主要综述了老年药物性肝损害的主要临床表现和诊断以及近年来常见药物(心血管药物和抗微生物药物)引起肝损伤的临床情况。     

甲氨蝶呤治疗异位妊娠致肝损伤的临床特点和影响因素分析

目的分析甲氨蝶呤治疗异位妊娠致肝损伤的临床特点和影响因素,为临床安全用药提供参考。方法收集2018年1月1日—2020年5月31日使用甲氨蝶呤治疗的异位妊娠患者病历资料,回顾性分析患者肝损伤的临床特点,以及患者特征和药物因素对肝损伤的影响。结果共纳入320例患者,其中49例发生肝损伤,发生率为15.31%。临床分型均为肝细胞损伤型,RUCAM量表评分均在3分以上,38例(77.55%)≥6分。肝损伤多发生在停药后3 d内,严重程度主要为2级和3级。28例经保肝治疗后痊愈或好转,12例未经治疗自行痊愈或好转,9例未复查。分析显示,患者年龄(P=0.98)、体质量指数(P=0.19)、乙型肝炎表面抗原(HBsAg)是否阳性(P=0.13)和异位妊娠类型(P=0.78)均与肝损伤无关。不同治疗方案(P0.01)和合并使用致肝功能异常药物(P0.05)与肝损伤有关,预防性使用保肝药物未见对肝损伤有影响(P=0.92)。结论甲氨蝶呤引起的肝损伤发生较早,具有可逆性。5 d连续给药方案和合并使用致肝功能异常药物的患者更易引发肝损伤,建议加强监测肝功能,个体化选择治疗方案,避免不合理的联合用药。     

生物标志物在药物性肝损伤中应用的研究进展

摘 要药物性肝损伤是伴随着药物使用而出现的最常见不良反应之一,也是药物研发失败及药物撤市或限制使用的主要原因。生物标志物检测是临床前药物肝毒性评价和临床患者潜在肝损伤诊断的重要技术手段,而传统的肝损伤指标因缺乏特异性和灵敏性等因素,限制了其在早期评价中的应用。因此,寻求及验证新的生物标志物势在必行。本文主要对结合现代组学等技术探索出具有科研及临床价值的新型生物标志物研究现状予以概述。以期为科研人员、临床医师、新药研发机构等预测药物的肝毒性及可能的发展趋势,判断药物引起的肝损伤程度等提供参考。     

Cell based approaches for evaluation of drug-induced liver injury

An improved understanding of mechanisms that underlie drug-induced liver injury (DILI) is required to enable design of drugs that have minimal potential to cause this adverse reaction in man. Available evidence suggests DILI arises in susceptible patients because of an imbalance between chemical insults (which are an inherent property of certain drugs and/or their metabolites) and the ability of the liver to mount compensatory/adaptive responses. In vivo safety testing in pre-clinical species ensures that drugs which enter clinical trials do not cause reproducible and dose-dependent liver injury in man, but is of limited value for exploration of underlying mechanisms and does not assess potential to cause rare idiosyncratic DILI. This review highlights the value that can be gained from in vitro studies using cultured hepatocytes and also hepatocyte-derived cell lines transfected with individual human cytochrome P450 (CYP450) isoforms. We have evaluated a range of mechanisms and endpoints (cell necrosis, mitochondrial injury, inhibition of biliary transporters and metabolite-mediated toxicity) using these model systems. Our data indicate that multiple mechanisms are likely to be involved in development of idiosyncratic DILI in man caused by numerous drugs, e.g. the anticonvulsant chlorpromazine.