IL-4 mediates dicloxacillin-induced liver injury in mice

Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2).     

Estradiol and progesterone modulate halothane-induced liver injury in mice

Drug-induced liver injury (DILI) is one of the major problems in drug development and clinical drug therapy. In general, it is believed that women exhibit worse outcomes from DILI than men. It is known that halothane (HAL), an inhaled anesthetic, rarely induces severe liver injury. The risk factors for severe HAL-induced liver injury (HILI) are female sex, genetics and adult age. To investigate the underlying mechanism by which women are more susceptible to HILI, we focused on two major female sex hormones, estradiol (E2) and progesterone (Prog). In this study, we first found that pretreatment of mice with E2 attenuated HILI, whereas pretreatment with Prog exacerbated HILI. E2 and Prog had no effects on the degree of metabolic activation, the ratio of GSH/GSSG or oxidative stress in the liver. We observed higher numbers of neutrophils infiltrated into the liver and increased hepatic mRNA levels of proinflammatory cytokines, tumor necrosis factor (TNF) α, interleukin (IL)-1β and IL-6 and chemokines, CXCL1 and CXCL2 by pretreatment with Prog, whereas E2 pretreatment resulted in the opposite effects. These results suggest that E2 and Prog play a critical role in HILI via immune-related responses and female sex hormone balance might represent a risk factor for HILI.     

美索巴莫致急性肝损伤

1例61岁男性患者因腰椎间盘突出症口服美索巴莫0.5 g,1次/d。6 d后,腰痛缓解,自行停药。6d后,因腰痛加重再次服用相同剂量美索巴莫。再次用药后第7天,患者出现皮肤黄染、尿色加深,伴有食欲减退。6 d后,因厌食而自行停药。实验室检查：丙氨酸转氨酶（ ALT）1369 U/L,天冬氨酸转氨酶（ AST）1198 U/L,直接胆红素（ DBil）87.1μmol/L,间接胆红素（ IBil）75.4μmol/L。诊断为药物性肝损伤。给予谷胱甘肽（1.8 g,1次/d）和异甘草酸镁（0.1 g,1次/d）静脉滴注。1 d后复查：ALT 1331 U/L,AST 503 U/L,DBil 73.9μmol/L,IBil 68.9μmol/L。13 d后肝功能复查：ALT 131 U/L,AST 71 U/L,DBil 34.5μmol/L,IBil 45.0μmol/L。改为口服谷胱甘肽（0.4 g,3次/d）和甘草酸二铵（0.15 g,3次/d）。1个月后随访,患者黄染消退,ALT 19 U/L,AST 11 U/L,DBil 1.3μmol/L,IBil 11.4μmol/L。     

Flucloxacillin-induced liver injury

Flucloxacillin is a common cause of drug-induced liver injury in Europe, affecting in the region of 8.5 in every 100,000 first time users of the drug. The mechanism by which the drug causes the liver injury is currently unknown but it is believed to be influenced by a combination of genetic and environmental factors. This review summarises what is currently known about the disposition of flucloxacillin in the liver, considers potential mechanisms by which flucloxacillin may cause the liver injury, and suggests candidate genes which could determine individual susceptibility to flucloxacillin-induced liver injury.     

还原型谷胱甘肽与多烯磷脂酰胆碱对环磷酰胺诱导小鼠肝损伤的修复作用

目的：分析比较还原型谷胱甘肽与多烯磷脂酰胆碱对环磷酰胺诱导小鼠肝损伤的防护作用。方法采用简单随机抽样法将40只昆明小鼠分为肝损伤模型组、还原型谷胱甘肽组、多烯磷脂酰胆碱组和对照组,每组10只。前3组小鼠实验第1-4天均腹腔注射环磷酰胺（100 mg· kg-1·d-1）诱导肝损伤,第5-14天分别腹腔注射0.9%氯化钠注射液0.2 ml、还原型谷胱甘肽180 mg · kg-1· d-1、多烯磷脂酰胆碱90 mg·kg-1·d-1;对照组同期腹腔注射等体积0.9%氯化钠注射液。实验第1天给药前和第15天测定小鼠体重;实验第15天,小鼠处死前眼眶取血测定血清总胆红素和谷胱甘肽水平,处死小鼠后取肝脏称重并计算肝脏系数,取肝组织测定丙氨酸转氨酶（ ALT）、天冬氨酸转氨酶（AST）、超氧化物歧化酶（SOD）、过氧化氢酶（CAT）活性和丙二醛（MDA）水平,并进行肝组织形态学观察。结果实验第15天,应用环磷酰胺的3组小鼠体重均明显低于对照组（P 〈0.01或 P 〈0.05）,但还原型谷胱甘肽组体重高于肝损伤模型组（P 〈0.05）;肝损伤模型组小鼠肝脏系数（5.74%±0.11%）高于对照组（4.68%±0.37%）和还原型谷胱甘肽组（4.81%±0.19%）（均 P 〈0.01）,多烯磷脂酰胆碱组小鼠肝脏系数（5.25%±0.35%）]也高于对照组（P 〈0.05）。肝损伤模型组、还原型谷胱甘肽组、多烯磷脂酰胆碱组血清总胆红素水平[（129.8±1.9）、（110.9±1.3）、（125.7±2.6）μmol/ L]均高于对照组（100.8±3.0）μmol/ L（均 P 〈0.01）,但还原型谷胱甘肽组低于肝损伤模型组（P 〈0.01）。肝损伤模型组和多烯磷脂酰胆碱组血清谷胱甘肽水平[（50.5±1.9）、（55.9±2.4）g/ L]均低于对照组和还原型谷胱甘肽组[（73.8±4.3）、（71.3±3.7）g/ L]（均 P 〈0.01）。肝损伤模型组、还原型谷胱甘肽组、多烯磷脂酰胆碱组肝组织 AST、ALT、SOD 和 CAT ?     

双环醇治疗严重银屑病患者药物性肝损伤的临床研究

目的 评估双环醇片对严重银屑病患者服用药物所致肝损伤的疗效.方法 选取2015年2月至2016年7月在本院治疗的中重度银屑病并出现肝损害的患者共计243例.依据随机数字表法将患者随机分为两组,即双环醇组(n=122)与甘草酸二胺组(n=121).双环醇组患者口服双环醇片,甘草酸二铵组患者口服甘草酸二铵胶囊,治疗8周.对患者的临床症状与用药后不良反应进行观察记录,同时检测患者血尿常规与肝、肾功能.结果 两组患者肝功指标ALT、TBIL、AST、ALP在治疗4周后均显著降低,治疗前后比较差异均有统计学意义(均P＜ 0.05);双环醇组ALT[第4周:(65.34±29.51)U/L比(90.29±32.27) U/L,P＜0.05;第8周:(37.20±15.91) U/L比(55.5±21.93) U/L,P＜0.05]与AST[第4周:(71.42±35.92) U/L比(92.84±47.58) U/L,P＜0.05;第8周:(36.26±14.42)U/L比(56.30±28.35) U/L,P＜0.05)]指标在治疗第4周与第8周显著低于甘草酸二铵组,差异均有统计学意义;治疗8周后,双环醇组的有效率较甘草酸二铵组显著提高,差异有统计学意义(84.4％比66.1％,p＜0.001).结论 双环醇片对严重银屑病患者服用药物所致的肝损伤进行治疗,疗效好、安全性高,值得临床推广.     

白介素-17对急性肺损伤小鼠中性粒细胞凋亡的影响

目的白介素-17（IL-17）作为前炎症因子可以导致趋化性细胞因子的增高,从而促进中性粒细胞和单核细胞的募集。本实验通过建立急性肺损伤（ALI）小鼠模型观察IL-17在体内环境下对中性粒细胞凋亡的影响,探讨体内环境下IL-17的变化与血液中性粒细胞的凋亡的关系。方法雄性C57小鼠30只,体质量22～27g,随机分为正常对照组（对照组）,15只;ALI模型组（模型组）,15只,脂多糖（LPS）腹腔注射6mg/kg、10ml/kg致急性肺损伤。分别观察小鼠呼吸频率、活动情况及直接光镜观察肺组织血管及肺泡变化情况,中性粒细胞凋亡,淋巴细胞CD3＋/4＋/8＋分类检测,血清IL-17含量的检测。结果急性肺损伤时小鼠的IL-17的含量（0.10±0.002）pg/L,正常对照组（0.08±0.003）pg/L（P〈0.05）。CD4＋%模型组（21.99±1.83）,对照组（14.97±0.99）（P〈0.01）。中性粒细胞凋亡百分比（%）模型组（1.15±0.17）%,对照组（0.32±0.05）%（P〈0.01）。结论在ALI发病24h时,由于各种炎性细胞因子及其他炎性介质的作用,中性粒细胞表达了较高的凋亡率,而IL-17在其中起到了一定作用,中性粒细胞的凋亡与IL-17有一定的相关性。     

药物性肝损伤临床相关因素分析

目的探讨190例药物性肝损伤病例的病因、临床特点及预后相关因素,以指导临床诊断和治疗。方法对我院2006年1月～2010年12月190例药物性肝损伤住院病例进行回顾性研究,分析其用药、临床表现和预后转归情况。结果引起药物性肝损伤的药物品种繁多,其中抗肿瘤药占首位56例(29.4%),中药50例(26.3%);临床分型以肝细胞型为主152例(80.0%),胆汁淤积型24例(12.6%);临床表现无明显特异性,其中无任何临床表现者84例(44.2%),有明显黄疸者48例(25.3%);经治疗后治愈30例(15.8%),好转150例(78.9%),死亡0例,10例失访。结论近年来药物性肝损伤呈明显增加趋势,以抗肿瘤药及中药为主,一般预后较好。     

Systematic review on herb-induced liver injury in Korea

Herbal drugs are generally regarded as safe due to their extensive clinical use especially in East Asian countries. However, the potential toxicity of herbal drugs has become an important medical issue recently, resulting in numerous reports of drug-induced liver injury (DILI). Here, we performed a systematic review of herbal medicines with the potential to cause hepatotoxicity in Korea. A literature search of six databases, including PubMed and five Korean electronic databases, was performed to identify cases of herb-induced liver injury (HILI) in Korea, yielding 31 unique reports, including 21 single herb and 10 multi-herb preparations. From these reports, we identified 97 cases of HILI (47 males, 49 females, and 1 unknown sex) consisting of 74.7% hepatocellular-type injury, 10.8% cholestatic-type injury, and 14.5% mixed-type injury. Causative agents included 21 unique herbal preparations, including 11 single species and 10 multispecies, with Polygoni Multiflori (39.2%) and Dictamnus dasycarpus (37.1%) as the most frequent agents. These analyses presented a feature of HILI, and produced a comprehensive list of herbs with a higher risk of hepatotoxicity in Korea. Further studies will be necessary to ascertain the mechanisms by which these herbs induce HILI and to determine whether these effects are specific to the Korean population.     

药物性肝损伤临床诊断方法研究进展

药物性肝损伤(Drug-induced liver injury, DILI)是一种广泛的药物不良反应,最终可引发急性肝衰竭。目前,药物性肝损伤已逐渐成为一个全球不容忽视的公共医药问题,其发病率呈逐年上升趋势,是市场上撤回批准药物最常见的原因。及早确定药物性肝损伤,并尽快停止肝毒性药物的使用可防止进一步的损伤。因此,药物性肝损伤临床诊断是及时治疗药物性肝损伤的关键。本文就以目前临床上常用于药物性肝损伤的诊断方法予以总结评价,以期为防治药物性肝损伤提供新的见解与参考。     

胺碘酮引起的肝损伤

Ⅲ类抗心律失常药胺碘酮可引起肝损伤,发生率约为14%-82%。胺碘酮致肝损伤的临床表现差异较大,包括无症状性肝酶水平升高、暴发性肝衰竭甚至死亡。组织病理学表现类似于酒精性肝病,特点为溶酶体内磷脂沉积和颗粒细胞聚集。胺碘酮引起肝损伤的机制主要与药物及其代谢产物的毒性作用、免疫介导和遗传因素相关,静脉给药引起肝损伤主要考虑为助溶剂聚山梨醇酯80作用。男性、心功能不全、血药浓度〉2.5 mg/ L 可能为胺碘酮致肝损伤的危险因素。临床应用胺碘酮应严格掌握适应证,并应根据患者的身体状况选择恰当的用药方法。用药期间应严密监测患者肝功能和/或血药浓度。出现肝功能异常时,应仔细权衡治疗获益和风险而决定是否减量或停药。     

Nitroglycerin ameliorates liver injury and regulates adaptive immunity in mice

This study aimed to assess the protective effect of nitroglycerin, a commonly used drug in cardiovascular diseases, on mice with acute liver injury induced by carbon tetrachloride (CCl₄). The mice were randomly divided into three groups: control, CCl₄, and CCl₄ + nitroglycerin. They were killed at 0, 6, 12, 24, and 48 h after treatment. Blood and liver tissue samples were collected for analysis. Analysis of the amounts of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hepatic glutathione (GSH), and malondialdehyde (MDA) showed that nitroglycerin protected against CCl₄-induced acute liver injury. Liver histological analysis provided further evidence of the protective effect of nitroglycerin. Furthermore, we found that nitroglycerin suppressed the increase of T helper 17 (Th17) cells in CCl₄-induced acute liver injury mice. The results indicate that nitroglycerin is a potential candidate for hepatic disease.     

异甘草酸镁治疗抗结核药物性肝损害的效果分析

目的 探讨异甘草酸镁治疗抗结核药物性肝损害的临床效果.方法 选择本院2012年8月～2013年8月收治的45例抗结核药物性肝损害患者为研究对象,随机分为观察组（23例）和对照组（22例）,对照组给予常规对症支持治疗,观察组在对照组的基础上给予异甘草酸镁治疗,对比观察两组患者的临床治疗效果.结果 两组患者治疗后肝功能各项指标均优于治疗前,且观察组较对照组改善更明显,差异有统计学意义（P＜0.05）.观察组优良率为91.30％（21/23）,明显高于对照组的63.64％（14/22）,差异有统计学意义（P＜0.05）.观察组不良反应发生率为8.70％（2/23）,对照组不良反应发生率为9.09％（2/22）,两组差异无统计学意义（P＞0.05）.结论 异甘草酸镁治疗抗结核药物性肝损害的临床效果显著,且药物安全性高,值得临床广泛推广.     

Protection of mice against carbon tetrachloride-induced acute liver injury by endogenous and exogenous estrogens

Gender is a crucial factor determining susceptibility to drug-induced liver injury (DILI) in humans and experimental animals. However, no general concept of sex differences in DILI has been established, as metabolic events specific to one DILI model are difficult to apply to other DILI models. Herein, we examined sex differences in carbon tetrachloride (CCl₄)-induced hepatotoxicity, a widely employed DILI model. Male and female CD-1 mice were intraperitoneally administered CCl₄. Additionally, some male mice were administered genistein or another isoflavone to evaluate the effects of exogenous estrogens. Dose-dependent alanine aminotransferase leakage was observed at a CCl₄ range of 0.5–10 mmol/kg, with male-dominant sex differences mainly observed at lower doses. No sex differences in hepatic glutathione levels or thiobarbituric acid-reactive substance formation were detected. CCl₄ induced hepatic inflammatory genes, interleukin (IL)-6 and tumor necrosis factor (TNF)-α, predominantly in female mice, which might be involved in DILI resistance, observed in female mice. Treatment of male mice with phytoestrogens, especially genistein, attenuated CCl₄-induced hepatotoxicity. Moreover, genistein inhibited IL-6 and TNF-α expression, suggesting possible hepatoprotection via immunosuppression. In conclusion, female mice are resistant to CCl₄-induced hepatotoxicity, and male mice were afforded protection by genistein, probably via mechanisms based on anti-estrogenic, antioxidant and/or anti-inflammatory effects.     

双环醇片预防抗结核药物所致肝损害的疗效分析

目的观察双环醇片预防抗结核药物所致肝损害的临床疗效。方法将435例初治肺结核病人随机分为两组,均应用"2HRZS(E)/4HR"方案抗结核化疗,试验组218例,抗结核治疗同时每日口服双环醇片75mg治疗,对照组217例,抗结核治疗同时每日口服甘草酸二铵胶囊450mg治疗。结果试验组药物性肝损害发生率(4.1%)及HBsAg阳性病人肝损害发生率(8.0%)均较对照组(12.4%,33.3%)低(P<0.01,P<0.05)。试验组抗结核化疗中断率为2.3%,调整化疗方案率为1.4%;与对照组(6.9%,4.6%)比较,均有显著性差异(P<0.05)。两组均未发生与研究药物相关的其他不良事件。结论双环醇片75mg?d-1可显著降低初治肺结核患者抗结核药物所致肝损害的发生率,并可减少因抗结核药所致肝损害而造成的不规则化疗发生率。     

雷贝拉唑钠肠溶片致肝损伤

1例45岁男性患者因反酸给予雷贝拉唑钠肠溶片10 mg,1次/d。3周后因症状加重自行加倍服药。3 d后出现全身乏力、食欲减退、小便深黄。停用雷贝拉唑钠肠溶片。实验室检查：丙氨酸转氨酶401 U/L,天冬氨酸转氨酶314 U/L,碱性磷酸酶143 U/L,γ-L-谷氨酰转移酶359 U/L,总胆红素22.7μmol/L。给予保肝治疗。1周后复查,丙氨酸转氨酶40 U/L,天冬氨酸转氨酶15 U/L。     

不稳定心绞痛患者PCI术后出现肝损伤病例分析

目的探讨临床药师在合理用药中的作用。方法临床药师通过参与1例疑似药物性肝损伤(DILI)的病例分析,协助临床医师评价药物性肝损伤的可能性,根据病情变化及时调整用药方案,提供个体化的药学服务。结果 DILI虽然内涵清晰,概念明确,但由于患者及药物等因素的复杂多变,在很多情况下DILI难以准确判断;其临床诊断既需要考虑患者疾病状况、用药情况,甚至生活习惯,又要结合患者肝、肾功能相关指标,所用药物特性等多因素综合评判。结论临床药师应充分发挥在药物药理作用、代谢、不良反应等方面的专业优势,为保证患者药物治疗的安全性和有效性提供有力保障。在引发DILI药物难以准确判断的情况下,明确具体诱发药物并非第一要务;重要的是及时停用可疑药物及对症处理,改善患者预后;适时为患者提供DILI事前预防、事后合理的药学监护等个体化药学服务。     

静脉滴注莫西沙星致肝功能异常

1例64岁男性患者因肺部感染给予莫西沙星0．4g,1次／d静脉滴注,并口服肺力咳胶囊及西替利嗪。第2天,血生化检查示丙氨酸转氨酶（ALT）49U／L、天冬氨酸转氨酶（AST）30U／L。第5天ALT及AST分别升至166U／L、53U／L。第9天停用莫西沙星,改为左氧氟沙星0．5g,1次／d口服,并行保肝治疗,肺力咳胶囊及西替利嗪按原剂量继续服用。第10天ALT111U／L,AST28U／L;第13天ALT77U／L,AST23U／L。2个月后肝功能恢复正常（ALT28U／L,AST21U／L）。     

Circulating extracellular vesicles as a potential source of new biomarkers of drug-induced liver injury

Like most cell types, hepatocytes constantly produce extracellular vesicles (EVs) such as exosomes and microvesicles that are released into the circulation to transport signaling molecules and cellular waste. Circulating EVs are being vigorously explored as biomarkers of diseases and toxicities, including drug-induced liver injury (DILI). Emerging data suggest that (a) blood-borne EVs contain liver-specific mRNAs and microRNAs (miRNAs), (b) the levels can be remarkably elevated in response to DILI, and (c) the increases correlate well with classical measures of liver damage. The expression profile of mRNAs in EVs and the compartmentalization of miRNAs within EVs or other blood fractions were found to be indicative of the offending drug involved in DILI, thus providing more informative assessment of liver injury than using alanine aminotransferase alone. EVs in the urine and cell culture medium were also found to contain proteins or mRNAs that were indicative of DILI. However, major improvements in EV isolation methods are needed for the discovery, evaluation, and quantification of possible DILI biomarkers in circulating EVs.