药物性肝损伤的肝细胞死亡方式及治疗药物研究进展

药物性肝损伤（DILI）是临床常见的肝损伤类型,是严重的药物不良反应之一。细胞死亡是DILI的重要特征,药物可通过诱导内质网应激和激活死亡受体等方式激活凋亡通路,诱导肝细胞凋亡或坏死,诱发肝损伤。除凋亡和坏死外,DILI过程中还伴随着自噬、焦亡和铁死亡。自噬可以清除受损的蛋白质以及细胞器,是肝细胞存活的重要机制,但也可能诱导肝细胞死亡。焦亡和铁死亡是最近发现的细胞死亡方式,其在DILI中的作用尚未完全阐明。阻断肝细胞死亡通路,是治疗DILI的重要手段。水飞蓟素、柚皮素、人参皂苷等可以抑制肝细胞死亡通路,是DILI的潜在治疗药。针对不同细胞死亡方式的机制和特点,研究改善肝细胞死亡的药物对治疗DILI具有重要意义。总结了DILI中肝细胞死亡的机制,并论述了潜在的药物治疗,旨在为DILI的治疗提供参考。     

抗菌药物致肝损伤的研究进展

近年来,药物引起的肝损伤报道逐年增加。其中,抗菌药物是引起药物性肝损伤的最常见药物之一。抗菌药物临床应用非常广泛,如果应用不当会增加肝损伤的发生率和严重程度。本文按照抗菌药物的分类,从研究现状、流行病学、发病机制、病例报道等方面,综述了近期各类抗菌药物所致肝损伤的研究进展,旨在为抗菌药物的合理应用提供参考。     

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.     

106例药物性肝损伤患者用药回顾性调查

目的：了解某院药物性肝损伤（DILI）住院患者药物使用情况,为合理用药提供依据。方法：查阅某院 2014年1月-2017年12月因DILI住院的患者病历,对其用药史及药物治疗的适应证、剂量、溶媒等信息进行回顾性调查分析。结果：DILI41~60岁是高发阶段,占52.83%;引起DILI的药物以中药占60.69%比例最高,其次为抗感染药物和解热镇痛药;临床保肝药物使用基本合理,不合理应用主要是无适应征使用PPI和中药注射剂等。结论：关注中药、抗感染药物引起肝损伤的不良反应,DILI药物治疗应避免使用引起肝脏损伤的药物,减轻肝脏负担,保证合理用药。     

抗甲状腺药物所致肝损伤的研究进展

药物治疗是甲状腺功能亢进的主要治疗方法,常用的抗甲状腺药物包括丙基硫氧嘧啶、甲巯咪唑及其前体药物卡比马唑。这些抗甲状腺药物可引起不同程度的肝损伤。虽然对抗甲状腺药物导致肝毒性的认识已超过70年,但是近年来仍有一些新的报道和阐述。对常见抗甲状腺药物导致肝损伤的发生率、临床病理特点、作用机制以及预防等方面的研究进展进行综述和分析,为临床安全、合理用药提供参考。     

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。     

不同乳腺癌化疗方案致药物性肝损伤的比较

目的：探讨3种不同乳腺癌化疗方案致药物性肝损伤的特点,为后续保肝治疗提供参考。方法：回顾性分析某院2010年1月-2014年12月纳入临床路径病种行首次化疗的乳腺癌病历,收集病例信息,统计不同化疗方案致药物性肝损伤的发生率、严重程度、临床类型以及患者特点和预后情况。结果：该院3种乳腺癌化疗方案的肝损伤发生率分别为：5.7%（CEF方案：环磷酰胺+表柔比星+5-氟尿嘧啶）、14.9%（TC方案：多西他赛+环磷酰胺）、4.0%（AC方案：环磷酰胺+吡柔比星）,其中TC方案的肝损伤发生率与CEF方案和AC方案比较差异有显著性（P<0.05）;3种方案致肝损伤的严重程度主要集中在1级和2级肝损伤,但TC方案还导致了3级肝损伤;而在肝损伤类型方面,CEF方案所致肝损伤多表现为胆汁淤积型肝损伤（77.8%）,TC方案多表现为混合型肝损伤（60.0%）,AC方案多表现为肝细胞损伤型肝损伤（66.7%）,3种化疗方案所致的肝损伤均能很好地治愈或转归。结论：在3种乳腺癌化疗方案所致的肝损伤中TC方案所致肝损伤的发生率和严重程度均较高,各个方案所致肝损伤的类型各有特点,临床可根据其特点进行肝损伤的针对性防治。     

他汀类药物引起的肝损害

他汀类药物是3-羟基3-甲基戊二酰辅酶A还原酶抑制剂,是目前临床上广泛应用的降脂药物。他汀类药物所致肝损害(SILI)无特殊临床特征,与其他药物所致肝损害类似。SILI以肝细胞型多见,胆汁淤积型不常见,混合型少见。SILI的发生机制可能与药物本身的毒性、继发性效应及免疫机制等有关。高剂量、联合用药、肝病史等是SILI的危险因素。应用他汀类药物期间发生轻度肝损害者可减小药物剂量继续使用;发生中度肝损害者应在减量的同时使用保肝药物;发生严重肝损害者则需停药并采取相应的对症治疗措施。临床医师处方他汀类药物要注意严格掌握用药剂量,加强用药期间的实验室监测,尽量避免联合用药,并应嘱咐患者加强营养、注意休息。肝病患者慎用他汀类药物。大部分患者的SILI是可逆的。     

药物性肝损害的临床分析

目的：指导临床医生合理用药和及时、正确诊治药物性肝损害。方法：对2002年我院住院病人住院期间肝功能指标发生异常的205例病例进行回顾性调查分析。结果：205例中药物性肝损害48例，涉及药物10类、28种，依次为抗肿瘤药、抗生素、降血脂药、降糖药及激素类药，肝损害类型呈多样性。结论：药物性肝损害是临床上较常见和易被忽视的疾病，应引起临床医务工作者的重视。     

药物性肝损伤的基因多态性研究进展

药物性肝损伤是常见药源性疾病之一，其临床诊治极为困难，且易发展成急性肝功能衰竭。相关药物基因组学研究已经发现包括CYP450、UGT、GST、NAT等药物代谢酶类，ABCB1、ABCC2等药物转运体以及人类白细胞抗原的基因多态性与药物性肝损伤具相关性。本文将综述药物性肝损伤的基因多态性研究进展，以期为药物性肝损伤的临床及时诊治和科学研究提供参考。     

硫普罗宁治疗抗结核药物性肝损害的临床观察

目的:探讨硫普罗宁治疗抗结核药物性肝损害的疗效。方法:121例抗结核药物性肝损害患者,随机分为治疗组61例,对照组60例,治疗组给予硫普罗宁注射液0.2 g加入5%葡萄糖注射液250 mL中静脉滴注,每日1次,对照组给予一般护肝药治疗。结果:两组治疗前比较差异无显著性(P>0.05),治疗组与对照组治疗4周后比较差异有显著性(P<0.05);治疗组治疗7,15,30 d,丙氨酸转移酶(ALT)、总胆红素(TBIL)复常率为78.69%,91.8%和100%,对照组治疗7,15,30 d,ALT、TBIL复常率分别为31.67%,71.67%,90%,治疗组ALT、TBIL复常率优于对照组(P<0.01)。结论:硫普罗宁治疗抗结核药物性肝损害效果明显。     

自噬在药物性肝损伤中的作用研究进展

药物性肝损伤(DILI)是临床上最为常见的一类药源性病变,可导致急性肝衰竭,严重时可造成肝硬化、肝癌甚至死亡.近年来,DILI的发生率呈逐年增加的趋势,成为药物研发失败和已上市药物被撤市的重要原因.自噬是细胞内蛋白质和受损细胞器进行清除的过程,对细胞稳态、质量与数量乃至存活与死亡等调控有着十分重要的意义.越来越多研究表...     

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。     

异甘草酸镁治疗抗结核药物所致肝损伤疗效的Meta分析

目的 用Meta分析评价异甘草酸镁治疗抗结核药物所致肝损伤的疗效。方法 检索中国期刊全文数据库（CNKI）、维普网（VIP）、万方数据库、PubMed、EMbase与Cochrane Library,并辅以其他检索方法,纳入异甘草酸镁治疗抗结核药物所致肝损伤患者的随机对照试验（RCTs）,检索截至日期为2019年4月。按照纳入和排除的标准由2名研究人员分别独立筛选文献、处理资料与评价所纳入文献的质量。Meta分析结果采用RevMan 5.2软件处理。结果 本研究全部纳入了10个RCTs,一共有823名患者。Meta分析结果表明：①异甘草酸镁可以有效治疗结核药物所致的肝损伤患者,具有统计学差异;②异甘草酸镁治疗结核药物性肝损伤时可有效改善患者的丙氨酸氨基转移酶（ALT）水平、总胆红素（TBil）水平,与对照组比较,差异有统计学意义。结论 异甘草酸镁可以有效地治疗抗结核药物所致的肝损伤患者,并促进肝功能快速恢复,但仍需更多高质量的临床研究来进一步证明。     

二硫代氨基甲酸吡咯烷对小鼠免疫性肝损伤的抑制作用

目的探讨二硫代氨基甲酸吡咯烷(PDTC)对免疫性肝损伤的抑制作用及其机制。方法设正常对照、脂多糖(LPS)、卡介苗(BCG)、BCG+LPS、PDTC和BCG+PDTC+LPS组。除正常对照、LPS和PDTC组外,其余各组小鼠经尾静脉注射BCG(每只2.5mg)。10d后,LPS和BCG+LPS组分别给予LPS(0.2mg·kg-1,ip),PDTC和BCG+PDTC+LPS组在给予LPS前24和2h分别给予PDTC(100mg·kg-1,ip),对照组给予等体积生理盐水。每组15只小鼠用于观察LPS处理后72h的死亡率;每组6只小鼠于LPS处理后1.5h处死,取肝脏,用RT-PCR检测肝脏组织肿瘤坏死因子α(TNF-α)和白细胞介素1β(IL-1β)mRNA表达水平,用凝胶电泳迁移率分析法测定肝脏核因子κB(NF-κB)结合活性;每组12只小鼠于LPS处理后6h取血,处死,留取肝脏,测定血清谷丙转氨酶(GPT)活性、一氧化氮(NO)水平和肝组织还原型谷胱甘肽(GSH)含量,制备肝组织切片进行HE染色,观察组织病理变化。结果与正常对照组比较,BCG和LPS组小鼠肝脏炎症细胞明显增加,血清GPT活性升高,肝脏GSH含量显著下降,肝脏TNF-α与IL-1β mRNA表达增强,各组均未见小鼠死亡;PDTC组除血清GPT活性升高外,上述其他指标均未发生明显改变。与BCG和LPS组比较,BCG+LPS组血清GPT活性进一步升高,并伴有大面积肝脏坏死和大量炎症细胞浸润,肝脏NF-κB结合活性显著升高,TNF-α和IL-1β表达进一步增强,GSH水平下降,血清NO水平增加,小鼠死亡率40%。与BCG+LPS组比较,PDTC预处理明显抑制BCG+LPS引起的肝脏NF-κB活性、TNF-α及IL-1β mRNA表达增强,升高肝脏GSH含量,降低血清GPT活性和NO水平,减轻BCG+LPS引起的肝脏炎症和坏死,未见小鼠死亡。结论PDTC可抑制BCG+LPS引起的小鼠免疫性肝损伤,其机制可能与其抗炎和抗氧化作用有关。     

Tissue influx of neutrophils and monocytes is delayed during development of trovafloxacin‐induced tumor necrosis factor‐dependent liver injury in mice

Idiosyncratic drug‐induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)‐induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX‐induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX‐treated mice, but even more so in control mice treated with the non‐DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2 hours after TNF administration, but at 4 hours, the relative neutrophil amounts were reduced again in Veh‐ and LVX‐treated mice whereas the amounts in TVX‐treated mice remained at the same increased level as at 2 hours. The influx of monocytes/macrophages, which was unaffected in Veh‐ and LVX‐treated mice was markedly reduced or even absent in TVX‐treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti‐inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development.     

常见肝损伤动物模型构建和应用的研究状况

肝是机体生物转化的最主要器官,对于维持机体的生命活动发挥着重要作用.因此肝损伤会对机体造成严重伤害,轻则引发脂肪肝,持续性加重将诱导肝纤维化和肝硬化,最终导致肝衰竭或肝癌,严重危及人体生命健康.对此,建立与临床肝损伤的病理生理过程及发病程度相似的动物模型对于更好地探究肝损伤患者的发病机制及临床治疗方法就具有十分重要的意...     

Risk of oral antifungal agent-induced liver injury in Taiwanese

Aim

Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients'' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations.

Methods

A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort.

Results

Of the 90 847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10 000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration ≥ 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10 000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI.

Conclusions

Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole.     

肠道菌群介导药物性肝损伤的研究进展

药物性肝损伤是临床上最常见、最严重的不良反应之一,既增加患者的医疗负担,也给新药研发及上市带来挑战。目前,药物性肝损伤的发生机制仍不十分明确。近年来,研究发现肠道菌群与药物性肝损伤密切相关,但对肠道菌群参与药物性肝损伤的具体作用机制仍尚无统一结论。肠道菌群可能通过增加肠道通透性致使内毒素外漏、破坏肠道代谢物平衡、直接影响药物代谢及促进炎症和氧化应激等途径参与药物性肝损伤。本文将对肠道菌群参与药物性肝损伤的可能机制,及基于机制的防治措施等研究进展进行综述,以期为药物性肝损伤研究及临床安全合理用药提供科学参考。