药物性肝损伤诊断相关生化指标阈值制定的研究现状及思考

doi:10.19803/j.1672-8629.2022.03.03

中国药物警戒 ›› 2022, Vol. 19 ›› Issue (3): 244-247.
DOI: 10.19803/j.1672-8629.2022.03.03

• 真实世界数据支持药械监测与评价专栏 • 上一篇下一篇

药物性肝损伤诊断相关生化指标阈值制定的研究现状及思考

聂晓璐^1,2, 彭亚光¹, 孙子墨¹, 彭晓霞^1,*

¹国家儿童医学中心,首都医科大学附属北京儿童医院临床流行病学与循证医学中心,北京 100045;
²北京大学公共卫生学院流行病与卫生统计学系,北京 100191

收稿日期:2021-10-20 出版日期:2022-03-15 发布日期:2022-03-16
通讯作者: ^*彭晓霞,女,博士,研究员,临床流行病学与循证医学。E-mail：pengxiaoxia@bch.com.cn
作者简介:聂晓璐,女,硕士,助理研究员,药物流行病学与循证医学。
基金资助:
国家自然科学基金面上项目（72174128）,首都医科大学附属北京儿童医院国家自然科学基金培育基金（GPQN202005）

Threshold setting of biochemical indexes related to diagnosis of drug-induced liver injury

NIE Xiaolu^1,2, PENG Yaguang¹, SUN Zimo¹, PENG Xiaoxia^1,*

¹Center for Clinical Epidemiology and Evidence-based Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China;
²Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China

Received:2021-10-20 Online:2022-03-15 Published:2022-03-16

摘要/Abstract

摘要： 目的了解药物性肝损伤（DILI）诊断相关生化指标阈值制定现状,为开展药品不良反应监测工作提供参考。方法结合最新发布的国内外DILI临床诊疗指南、专家共识和卫生行业标准,对DILI最新发病机制分类、诊断相关生化指标阈值制定进展进行梳理。结果明确目前国际DILI生化诊断标准为满足任一血清生化检验实验室标准之一可定义为DILI,相关标准有：①丙氨酸氨基转移酶（ALT）≥5倍正常值上限（ULN）;②ALT≥3×ULN,同时总胆红素（TBL）>2ULN,不伴有碱性磷酸酶（ALP）升高;③ALP≥2×ULN,特别是伴有5'-核苷酸酶升高,但没有骨病者（即ALP升高原因由肝脏引起）。DILI诊断相关生化检验指标参考区间在儿童阶段呈现年龄依赖趋势。结论在开展DILI相关研究时,特别是针对儿童人群开展研究时,DILI相关生化指标阈值应选取各年龄相对应的参考区间加以确定,提高结局判断准确性。

关键词: 药物性肝损伤, 生化指标, 诊断阈值, 指南, 参考区间, 监测

Abstract: Objective To investigate the currently-used biochemical thresholds related to the diagnosis of drug-induced liver injury (DILI) in order to provide reference for monitoring of adverse drug reactions. Methods Based on the newly released guidelines for clinical diagnosis and treatment, expert consensus and health industry standards of DILI at home and abroad, the latest classification of pathogenesis of DILI and the establishment of thresholds of biochemical indicators related to diagnosis were summarized. Results The current international biochemical diagnostic criteria for DILI were determined as follows: ①ALT≥5×ULN; ②ALT≥3×ULN, TBL > 2×ULN, without ALP elevation; ③ALP≥2×ULN, especially with 5'- nucleotide enzyme elevation, but without any bone disease (ALP elevation is caused by the liver). The reference intervals of biochemical test indexes related to the diagnosis of DILI were age-dependent in children. Conclusion In DILI-related studies, especially those for children, the thresholds of DILI-related biochemical indicators should be determined by the reference interval corresponding to each age group in order to make outcome judgment more accurate.

Key words: drug-induced liver injury, biochemical indices, diagnostic threshold, guidelines, reference interval, monitoring

中图分类号:

R944.1

聂晓璐, 彭亚光, 孙子墨, 彭晓霞. 药物性肝损伤诊断相关生化指标阈值制定的研究现状及思考[J]. 中国药物警戒, 2022, 19(3): 244-247.

NIE Xiaolu, PENG Yaguang, SUN Zimo, PENG Xiaoxia. Threshold setting of biochemical indexes related to diagnosis of drug-induced liver injury[J]. Chinese Journal of Pharmacovigilance, 2022, 19(3): 244-247.

参考文献

[1] Durg-induced Liver Disease Group, Chinese Society of Hepatology, Chinese Medical Association. Guidelines of diagnosis and treatment for drug-induced liver injury: a 2015 update[J]. J Clin Hepatol(临床肝胆病杂志), 2015, 31(11): 1752-1768.
[2] CHALASANI NP, MADDUR H, RUSSO MW, et al.ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2021, 116(5): 878-898.
[3] KOIDO M, KAWAKAMI E, FUKUMURA J, et al.Polygenic architecture informs potential vulnerability to drug-induced liver injury[J]. Nature Medicine, 2020, 26(10): 1541-1548.
[4] MAO YM.Strengthening transformation research and promoting scientific supervision of drug induced liver injury[J]. Adverse Drug Reactions Journal(药物不良反应杂志), 2020, 22(2): 58-61.
[5] HOOFNAGLE JH, BJÖRNSSON ES. Drug-induced liver injury - types and phenotypes[J]. N Engl J Med, 2019, 381(3): 264-273.
[6] YU LC, CHEN CW.Pathogenesis of drug-induced liver injury: current understanding and future needs[J]. J Clin Hepatol(临床肝胆病杂志), 2021, 37(11): 2515-2524.
[7] SHI YP, WANG SB, LI D, et al.Research progress of drug-induced liver injury[J]. Journal of Pediatric Pharmacy(儿科药学杂志), 2018, 24(7): 58-61.
[8] ROSENZWEIG P, BROHIER S, ZIPFEL A.The placebo effect in healthy volunteers: influence of experimental conditions on the adverse events profile during phase I studies[J]. Clin Pharmacol Ther, 1993, 54(5): 578-583.
[9] ROSENZWEIG P, BROHIER S, ZIPFEL A.Data on placebo in healthy volunteers: impact of experimental conditions on safety, and on laboratory and physiological variables during phase I trials[J]. Therapie, 1996, 51(4): 356-357.
[10] SIBILLE M, DEIGAT N, DURIEU I, et al.Laboratory data in healthy volunteers: reference values, reference changes, screening and laboratory adverse event limits in Phase I clinical trials[J]. Eur J Clin Pharmacol, 1999, 55(1): 13-19.
[11] PURKINS L, LOVE ER, EVE MD, et al.The influence of diet upon liver function tests and serum lipids in healthy male volunteers resident in a phase I unit[J]. Br J Clin Pharmacol, 2004, 57(2): 199-208.
[12] TEMPLE R.Hy's law: predicting serious hepatotoxicity[J]. Pharmacoepidemiol Drug Saf, 2006, 15(4): 241-243.
[13] BÉNICHOU C. Criteria of drug-induced liver disorders. Report of an international consensus meeting[J]. J Hepatol, 1990, 11(2): 272-276.
[14] NEUSCHWANDER-TETRI BA, CALDWELL SH.Nonalcoholic steatohepatitis: summary of an AASLD single topic conference[J]. Hepatology, 2003, 37(5): 1202-1219.
[15] MAKAR GA, WEINER MG, KIMMEL SE, et al.Incidence and prevalence of abnormal liver associated enzymes in patients with atrial fibrillation in a routine clinical care population[J]. Pharmacoepidemiol Drug Saf, 2008, 17(1): 43-51.
[16] WEIL JG, BAINS C, LINKE A, et al.Background incidence of liver chemistry abnormalities in a clinical trial population without underlying liver disease[J]. Regul Toxicol Pharmacol, 2008, 52(2): 85-88.
[17] SAUKKONEN JJ, COHN DL, JASMER RM, et al.An official ATS statement: hepatotoxicity of antituberculosis therapy[J]. Am J Respir Crit Care Med, 2006, 174(8): 935-952.
[18] AITHAL GP, WATKINS PB, ANDRADE RJ, et al.Case definition and phenotype standardization in drug-induced liver injury[J]. Clin Pharmacol Ther, 2011,89(6): 806-815.
[19] CHALASANI NP, HAYASHI PH, BONKOVSKY HL, et al.ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2014, 109(7): 950-966, 967.
[20] EASL clinical practice guidelines: drug-induced liver injury[J]. J Hepatol, 2019, 70(6): 1222-1261.
[21] Group AcbaCW. Drug-induced liver injury (DILI): current status and future directions for drug development and the post-market setting[R/OL]. Geneva, Switzerland: Council for International Organizations of Medical Sciences (CIOMS), 2020. https://cioms.ch/wp-content/uploads/2020/06/CIOMS_DILI_Web_16Jun2020.pdf.
[22] 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.
[23] ZHANG HL, XU LL, XIE YJ, et al.201 Cases of drug-induced liver injury in children[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2020, 17(10): 715-719.
[24] LI J, HE LM, ZHANG HX, et al.Analysis of 70 cases of children with drug-induced liver injury[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2020, 17(7): 431-436.
[25] Professional Committee of clinical examination standards of the Ministry of health. WS/T 404.1-2012. Reference intervals of clinical biochemistry tests commonly used[S]. Ministry of Health of the People's Republic of China, 2021.
[26] Beijing Children's Hospital Affiliated to Capital Medical University, the First Affiliated Hospital of China Medical University, Clinical laboratory center of National Health Commission, et al. WS/T 780-2021. Reference intervals of clinical biochemistry tests commonly used for children[S]. State Health Commission of the People's Republic of China, 2021.
[27] NI X, SONG W, PENG X, et al.Pediatric reference intervals in China (PRINCE): design and rationale for a large, multicenter collaborative cross-sectional study[J]. Science Bulletin, 2018, 63(24): 1626-1634.

药物性肝损伤诊断相关生化指标阈值制定的研究现状及思考

Threshold setting of biochemical indexes related to diagnosis of drug-induced liver injury

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