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ZHANG Yan, LI Yanjun, LIU Jiahui, DENG Jiao, YUAN Yuan, ZHANG Jingyi. Adverse reaction analysis of drug-induced liver injury[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404034
Citation: ZHANG Yan, LI Yanjun, LIU Jiahui, DENG Jiao, YUAN Yuan, ZHANG Jingyi. Adverse reaction analysis of drug-induced liver injury[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404034

Adverse reaction analysis of drug-induced liver injury

doi: 10.12206/j.issn.2097-2024.202404034
  • Received Date: 2024-04-09
  • Rev Recd Date: 2024-10-29
  •   Objective  To analyze the adverse reaction reports of drug-induced liver injury in recent ten years, explore the characteristics and related rules of drug-induced liver injury, and provide reference for clinical safe drug use.   Methods  ADRs in our hospital from 2011 to 2021 which belonged to drug-induced liver injuries were collected, and Pareto analysis was carried on.   Results  In 259 ADR reports, the most common type of drug-induced liver injury was hepatocellular injury (37.84%). The age of drug-induced liver injury was mainly over 46 years, totaling 195 (75.28%). Drugs were mainly distributed in cardiovascular system medicine (44.02%), anti-infective medicine (23.94%)and anti-tumor medicine (11.58%). Among the cardiovascular drugs, atorvastatin calcium 40mg and over 40mg were the highest proportion, with 53 cases (46.49%). The main anti-infectious drugs were cephalosporins (29.03%), carbapenem (19.35%), antifungal (17.74%)and quinolones (11.29%). Adverse reactions occurred within 6 days (69.88%), the duration of adverse reactions was 1-2 weeks(31.66%), and most patients improved (47.88%) or cured (37.07%).   Conclusion  For middle-aged and elderly patients, when the application of cardiovascular system drugs, anti-infective drugs or anti-tumor drugs, it is necessary to monitor the liver function changes of patients for at least 6 days. If there are abnormalities, the drugs should be stopped or given treatment in time, to avoid the progress of drug-induced liver injury.
  • [1] DEVARBHAVI H, AITHAL G, TREEPRASERTSUK S, et al. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines[J]. Hepatol Int, 2021, 15(2):258-282. doi:  10.1007/s12072-021-10144-3
    [2] 袁琳娜, 那恒彬译, 李武. 《2021年亚太肝病学会共识指南: 药物性肝损伤》摘译[J]. 临床肝胆病杂志, 2021, 7(6):1291-1294.
    [3] TESCHKE R, UETRECHT J. Mechanism of idiosyncratic drug induced liver injury(DILI): unresolved basic issues[J]. Ann Transl Med, 2021, 9(8):730. doi:  10.21037/atm-2020-ubih-05
    [4] TESCHKE R. Idiosyncratic DILI: Analysis of 46, 266 Cases Assessed for Causality by RUCAM and Published From 2014 to Early 2019[J]. Front Pharmacol, 2019, 10:730. doi:  10.3389/fphar.2019.00730
    [5] 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, 中华医学会肝病学分会药物性肝病学组, 茅益民. 中国药物性肝损伤诊治指南(2023年版)[J]. 胃肠病学, 2023, 28(7):397-431.
    [6] ANDRADE R J, CHALASANI N, BJORNSSON E S, et al. Drug-induced liver injury[J]. Nat Rev Dis Primers, 2019, 5:1-22. doi:  10.1038/s41572-018-0051-2
    [7] LUCENA M I, SANABRIA J, GARCÍA-CORTES M, et al. Drug-induced liver injury in older people[J]. Lancet Gastroenterol Hepatol, 2020, 5(9):862-874. [. doi:  10.1016/S2468-1253(20)30006-6
    [8] 李彩萍. 药物性肝损伤作用机制的研究进展[J]. 中国药物与临床, 2023, 23(6):405-408.
    [9] LICATA A, GIAMMANCO A, MINISSALE M G, et al. Liver and statins: a critical appraisal of the evidence[J]. Curr Med Chem, 2018, 25(42):5835-5846.
    [10] BJÖRNSSON E, JACOBSEN E I, KALAITZAKIS E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing[J]. J Hepatol, 2012, 56(2):374-380. doi:  10.1016/j.jhep.2011.07.023
    [11] ZAMOR P J, RUSSO M W. Liver function tests and statins[J]. Curr Opin Cardiol, 2011, 26(4):338-341. doi:  10.1097/HCO.0b013e328347036f
    [12] MEURER L, COHEN S M. Drug-induced liver injury from statins[J]. Clin Liver Dis, 2020, 24(1):107-119. doi:  10.1016/j.cld.2019.09.007
    [13] BJÖRNSSON E S. Drug-induced liver injury: an overview over the most critical compounds[J]. Arch Toxicol, 2015, 89(3):327-334. doi:  10.1007/s00204-015-1456-2
    [14] CHALASANI N P, MADDUR H, RUSSO M W, et al. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2021, 116(5):878-898. doi:  10.14309/ajg.0000000000001259
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Adverse reaction analysis of drug-induced liver injury

doi: 10.12206/j.issn.2097-2024.202404034

Abstract:   Objective  To analyze the adverse reaction reports of drug-induced liver injury in recent ten years, explore the characteristics and related rules of drug-induced liver injury, and provide reference for clinical safe drug use.   Methods  ADRs in our hospital from 2011 to 2021 which belonged to drug-induced liver injuries were collected, and Pareto analysis was carried on.   Results  In 259 ADR reports, the most common type of drug-induced liver injury was hepatocellular injury (37.84%). The age of drug-induced liver injury was mainly over 46 years, totaling 195 (75.28%). Drugs were mainly distributed in cardiovascular system medicine (44.02%), anti-infective medicine (23.94%)and anti-tumor medicine (11.58%). Among the cardiovascular drugs, atorvastatin calcium 40mg and over 40mg were the highest proportion, with 53 cases (46.49%). The main anti-infectious drugs were cephalosporins (29.03%), carbapenem (19.35%), antifungal (17.74%)and quinolones (11.29%). Adverse reactions occurred within 6 days (69.88%), the duration of adverse reactions was 1-2 weeks(31.66%), and most patients improved (47.88%) or cured (37.07%).   Conclusion  For middle-aged and elderly patients, when the application of cardiovascular system drugs, anti-infective drugs or anti-tumor drugs, it is necessary to monitor the liver function changes of patients for at least 6 days. If there are abnormalities, the drugs should be stopped or given treatment in time, to avoid the progress of drug-induced liver injury.

ZHANG Yan, LI Yanjun, LIU Jiahui, DENG Jiao, YUAN Yuan, ZHANG Jingyi. Adverse reaction analysis of drug-induced liver injury[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404034
Citation: ZHANG Yan, LI Yanjun, LIU Jiahui, DENG Jiao, YUAN Yuan, ZHANG Jingyi. Adverse reaction analysis of drug-induced liver injury[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202404034
  • 药物性肝损伤(DILI)是指由各类处方或非处方的化学药物、生物制剂、传统中药、天然药、保健品、膳食补充剂及其代谢产物或辅料所诱发的肝损伤[1]。药物性肝损伤是临床上不明原因肝损伤的重要病因。全面了解不同药物导致肝损伤的风险因素、临床特征和预后,有助于临床医生及药师及时识别、诊断和管理。国内公众对安全、合理用药的认知和意识普遍较薄弱,因此,药物性肝损伤的防治在中国已成为不容忽视的问题。由于我国人口基数庞大、临床用药种类繁杂,以及人群药物代谢酶的基因多态性,DILI的发病率有逐年上升的趋势[2]。其发病机制复杂,病理变化广泛,临床表现无特异性,且由于缺乏具有诊断意义的辅助检查手段及发病率低的原因,确诊药物性肝损伤比较困难[3]。本文旨在通过对259例DILI不良反应报告进行回顾性分析,从而为减少药物性肝损伤、提升临床用药安全提供依据。

    • 收集本院2011年至2021年药品不良反应报告,对其中发生药物性肝损伤的报告共259例进行统计分析。

    • 本研究对纳入的不良反应报告依据因果关系评分量表(RUCAM)进行病例评价。将药物与肝损伤的因果关系分为5级:﹥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分为可排除[4]

      肝损伤分类:根据丙氨酸氨基转移酶(ALT),碱性磷酸酶(ALP)上升的程度,以及两者比值(R)进行分类。①肝细胞损伤型:ALT≥3 ULN,且R≥5;②胆汁淤积型:ALP≥2 ULN,且 R≤2;③混合型:ALT≥3 ULN,ALP≥2 ULN,且 2<R<5。④肝脏生化学检查异常:若 ALT 和 ALP 达不到上述标准,则称为“肝脏生化学检查异常”。R=(ALT 实测值/ALT ULN)/(ALP 实测值/ALP ULN),ULN为正常值上限[5]

    • 对药物性肝损伤的ADR报告按照患者年龄、体重、DILI分型、给药途径、药物种类、他汀类药物及剂量、抗菌药分类、转归、不良反应发生时间等进行分类登记、汇总。

    • 应用Excel软件进行数据收集,SPSS 22进行统计分析。分析各分类病例数、构成比、累计构成比。依据帕累托分类原则,将影响因素分成3类:A类为主要因素,累计构成比0~<80%;B类为次要因素,累计构成比80%~<90%;C类为一般因素,累计构成比为90%~100%。

    • 共259例药物性肝损伤患者,评价为极可能的病例22例(8.49%)、评价为很可能的病例有144例(55.60%)、评价为可能的病例93例(35.91%),均有明确肝功能异常指征且无原发性肝脏疾病,符合药物性肝病指南的诊断标准。其中男性172人,女性87人;平均年龄(57±18.03)岁;患者平均体重(66.76±10.70)kg;合并疾病中脑血管疾病(36.29%)、心血管疾病(20.85%)、肿瘤(14.29%)较为常见。根据肝损伤分类标准,最常见的为肝细胞损伤型,共98例(37.84%);胆汁淤积型共63例(24.32%),混合型共54例(20.85%),肝脏生化学检查异常共44例(18.99%)。详见表1

      特征 例数 占比(%)
      性别
      172 66.41
      87 33.59
      合并疾病
      脑血管疾病 94 36.29
      心血管疾病 54 20.85
      肿瘤 37 14.29
      感染 36 13.9
      自身免疫相关疾病 11 4.25
      肾功能不全 7 2.7
      其他 19 7.34
      分型
      肝细胞损伤型 98 37.84
      胆汁淤积型 63 24.32
      混合型 54 20.85
      肝脏生化学检查异常 44 18.99

      将259例药物性肝损伤的患者按不同年龄段降序排列,并分别计算构成比和累计构成比,其中65岁以上老年人占比最高(30.50%),年龄﹥45岁者累计构成比为195例(75.29%),为主要因素,详见表2

      年龄(岁) 例数 构成比(%) 累计构成比(%) 因素类型
      >65 79 30.50 30.50 A
      56~65 68 26.25 56.75 A
      46~55 48 18.53 75.28 A
      36~45 30 11.58 86.87 B
      26~35 22 8.49 95.37 C
      15~25 11 4.25 99.61 C
      <15 1 0.39 100 C
      合计 259
    • 引起药物性肝损伤的主要药物、构成比及累计构成比情况详见表3,其中心血管系统用药物(44.02%)、抗感染药物(23.94%)和抗肿瘤药物(11.58%)为导致DILI的主要因素(A类);其他10类药品为次要因素或一般因素(B类和C类)。

      药物种类代表药物例数构成比
      (%)
      累计构成比
      (%)
      因素类型
      心血管疾病用药阿托伐他汀、瑞舒伐他汀、普伐他汀、非诺贝特、米力农、胺碘酮、托伐普坦11444.0244.02A
      抗感染药物头孢他啶、头孢曲松、头孢哌酮舒巴坦等6223.9467.95A
      抗肿瘤药物吉西他滨、环磷酰胺、甲氨蝶呤、卡培他滨、盐酸多柔比星脂质体、
      顺铂、多西他赛、奥沙利铂
      3011.5879.54A
      神经系统疾病用药卡马西平、普瑞巴林、丙戊酸钠、丙戊酰胺、依达拉奉186.9586.49B
      消化系统疾病用药美沙拉秦、柳氮磺吡啶、泮托拉唑、奥美拉唑83.0989.58B
      抗凝药依诺肝素钠、那曲肝素钙、低分子肝素钙72.7092.28C
      内分泌疾病用药苯溴马隆、二甲双胍、甲巯咪唑72.7094.98C
      镇痛药洛索洛芬、氨酚烷胺31.1696.14C
      营养支持药物中长链脂肪乳(C4-24)、脂肪乳氨基酸葡萄糖31.1697.30C
      免疫系统药物环孢素20.7798.07C
      造影剂碘克沙醇20.7798.84C
      中成药康莱特、血必净20.7799.61C
      生物制品重组人干扰素b10.39100.00C
      合计259
    • 心血管系统药物引起的肝损伤共114例,其中他汀类调脂药物占绝大部分,共105例。其中阿托伐他汀钙40 mg及以上占比最高,达到46.49%,共53例,与瑞舒伐他汀10 mg均为A类因素;阿托伐他汀钙20 mg或10 mg为B类次要因素;普伐他汀钠片40 mg以及其他药物如胺碘酮、托伐普坦、米力农、尼可地尔为一般因素(C类),详见表4

      药物及剂量 例数 构成比
      (%)
      累计构成比
      (%)
      因素
      类型
      阿托伐他汀钙40 mg及以上 53 46.49 46.49 A
      瑞舒伐他汀钙10 mg 25 21.92 68.41 A
      阿托伐他汀钙20 mg 20 17.54 85.95 B
      阿托伐他汀钙10 mg 6 5.26 91.21 B
      盐酸胺碘酮 3 2.63 93.84 C
      托伐普坦 3 2.63 96.47 C
      米力农 2 1.75 98.22 C
      尼可地尔 1 0.89 99.10 C
      普伐他汀钠片40 mg 1 0.89 100 C
      合计 114
    • 抗感染药物引起DILI的比例仅次于心血管系统用药,达到23.94%,共62例。按照抗感染药物分类进行统计发现,抗菌药物中头孢菌素类(29.03%)、碳青霉烯类(19.35%)、抗真菌类(17.74%)、喹诺酮类(11.29%)为主要因素(A类),利奈唑胺及万古霉素为次要因素(B类),其他如四环素类、抗病毒药物,阿奇霉素为一般因素(C类),见表5

      抗感染药物品种分类 代表药物 例数 构成比
      (%)
      累计构成比
      (%)
      因素类型
      头孢菌素 头孢他啶、头孢曲松、头孢哌酮舒巴坦、头孢呋辛、头孢唑林钠、头孢美唑 18 29.03 29.03 A
      碳青霉烯类 亚胺培南、美罗培南、比阿培南 12 19.35 48.38 A
      抗真菌类 伏立康唑 11 17.74 66.12 A
      喹诺酮类 左氧氟沙星、莫西沙星 7 11.29 77.41 A
      噁唑酮类 利奈唑胺 4 6.45 83.86 B
      糖肽类 万古霉素 4 3.23 87.09 B
      四环素类 米诺环素、替加环素 2 3.23 90.32 C
      抗病毒药 膦甲酸钠、更昔洛韦 2 1.61 91.93 C
      大环内酯类 阿奇霉素 1 1.62 100 C
      合计 62
    • 在259例药物性肝损伤ADR报告中,出现不良反应的平均时间为6.84 d;1~3 d(41.31%)及4~6 d(28.57%),为主要因素(A类);1~2周为次要因素(B类),其余天数为一般因素(C类),见表6

      发生不良反应时间 例数 构成比(%) 累计构成比(%) 因素类型
      1~3 d 107 41.31 41.31 A
      4~6 d 74 28.57 69.88 A
      1~2周 53 20.46 90.35 B
      2~4周 16 6.18 96.53 C
      >1个月 9 3.47 100.00 C
      总计 259

      DILI病程多在1周左右,停药或经治疗后多数可缓解。其中,持续1~2周的有82例(31.66%),4~6 d的69例(26.64%),为主要因素;持续1~3 d为次要因素,其他为一般因素。详见表7

      持续时间例数构成比(%)累计构成比(%)因素类型
      1~2周8231.6631.66A
      4~6 d6926.6458.30A
      1~3 d5822.3980.69B
      2~4周259.6590.35C
      持续238.8899.23C
      >1个月20.77100.00C
      总计259
    • 259例患者经停药或及时治疗后好转124例(47.88%),治愈96例(37.07%),持续37例(14.29%),死亡1例,不详1例。

    • 本研究发现中老年患者应用心血管系统药物、抗感染药物或抗肿瘤药物时发生药物性肝损伤风险较大,主要影响因素如下:

      一是年龄因素。中国正快速进入老龄化社会,老年人群是慢性疾病的主要群体,其需要长期服用多种药物,从而大大增加了药物性肝损伤的风险。本研究结果提示45~75岁是发生药物性肝损伤的主要年龄段,其中,65岁以上老年人占比最高。究其原因,一方面因老年患者的肝功能减弱,药物清除功能减弱,对毒性应激、免疫反应和组织修复过程迟缓[6];另一方面,老年患者通常合并疾病较多,联合用药情况普遍,故而发生药物性肝损伤的几率大,且多与剂量相关[7]

      二是药物种类因素。药物引起DILI主要与药物剂量、肝脏药物代谢、药物亲脂性、药物相互作用、特殊化学成分、线粒体危害、肝胆转运抑制等机制相关[8]。本研究的患者主要为住院患者,通过统计分析发现住院期间容易导致肝损伤的药物主要为心血管疾病常用药物、抗感染药物及抗肿瘤药物等。该类药物在医院患者中使用人群基数较大,部分药物使用疗程较长。

      心血管系统药物引起的DILI中他汀类的占比最高。有研究发现,他汀类使用期间经常会发生轻度至中度无症状血清转氨酶水平升高,其中多为胆汁淤积性肝损伤,且DILI发生率与剂量正相关[9]。也有一些文献指出与他汀类相关的DILI占3.4%,少见但有可能很严重[1011]。一般患者停药后会自行恢复,再次暴露容易出现类似肝损伤情况,对该类人群医护人员对该类患者严密监测[12]

      引起肝损伤的抗感染药物占比为23.94%,其中头孢菌素类、碳青霉烯类、抗真菌类是引起肝损伤的主要因素。已有文献证明抗生素是最常引起DILI的一类药物[13]。究其原因,主要是目前我国抗菌药的使用比例较高,且存在使用目的盲目、剂量较大及疗程长等药物滥用问题。因此,一方面要加强对抗菌药物的管理,实现临床合理用药;另一方面要增强抗菌药物不良反应监测,对药物性肝损伤早发现早干预[14]

    • 本研究中可见大多数DILI预后良好,因此临床一旦发生疑似药物肝损伤的情况时应尽早停药,给予无肝损害不良反应的替代药物,严重者应给予保肝药物治疗。医生在处方药物前应评估患者药物性肝损伤的风险水平,对于药物性肝损伤高风险的患者,需充分权衡获益及风险,尽可能避免肝毒性药物,同时叮嘱患者注意服药习惯。患者应严遵照医嘱用药,避免超剂量、超疗程用药和混合、重复用药。此外,临床药师应加入治疗决策团队,以确保符合药物配伍原则避免配伍禁忌,避免药物间相互作用导致药物性肝损伤风险增加。对于安全窗口较窄或特定的高风险药物,必要时可开展血药浓度监测,规范化的血药浓度监测可减少不合理用药造成的毒性。

      综上所述,药物性肝损伤是一种可以预防、可以控制的疾病。中老年患者应用心血管系统药物、抗感染药物或抗肿瘤药物时,需要在6 d内监测患者肝功能变化,如有异常应及时停药或给予治疗,从而避免药物性肝损伤的进展。

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