药物性肝损伤外周血清免疫学特点的初步探析

王宇; 罗琼; 李书; 沈晓萍; 李爽; 陶艳艳; 刘成海

doi:10.3969/j.issn.1001-5256.2022.05.023

药物性肝损伤外周血清免疫学特点的初步探析

DOI: 10.3969/j.issn.1001-5256.2022.05.023

王宇^{1, 2a, 2b},
罗琼^{2a, 2b},
李书¹,
沈晓萍¹,
李爽^1, , ,,
陶艳艳^{2a, 2b},
刘成海^{2a, 2b, 3, , ,}

1.
上海市宝山中西医结合医院消化科，上海 201999
2a.
上海中医药大学附属曙光医院肝病二科，上海 201203
2b.
海中医药大学附属曙光医院肝病研究所，上海 201203
3.
上海中医健康服务协同创新中心，上海 201203

基金项目:

上海市卫生健康委员会科研项目 (20214Y0236);

上海市中医药事业发展三年行动计划 (ZY〔2018-2020〕-CCCX-5001);

上海市科学技术委员会科技计划项目 (20Z21900100)

伦理学声明：本研究方案于2018年3月7日经由上海中医药大学附属曙光医院伦理委员会审核批准，批号：2017-560-43。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：王宇负责课题设计，资料分析，撰写论文；沈晓萍、罗琼参与收集数据，修改论文；李书、李爽、陶艳艳、刘成海负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
李爽, 15800647366@163.com

刘成海, chenghailiu@hotmail.com

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出版历程
- 收稿日期: 2021-09-22
- 录用日期: 2021-10-25
- 出版日期: 2022-05-20

A preliminary study on the peripheral seroimmunological characteristics of drug-induced liver injury

Yu WANG^{1, 2a, 2b},
Qiong LUO^{2a, 2b},
Shu LI¹,
Xiaoping SHEN¹,
Shuang LI^{1
, ,
,},
Yanyan TAO^{2a, 2b},
Chenghai LIU^{2a, 2b, 3
, ,
,}

1.
Department of Gastroenterology, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai 201999, China
2a.
Second Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2b.
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3.
Shanghai Innovation Center of TCM Health Service, Shanghai 201203, China

Research funding:

Scientific Research Project of Shanghai Municipal Health Commission (20214Y0236);

Three-year Action Plan for the Development of Traditional Chinese Medicine in Shanghai (ZY〔2018-2020〕-CCCX-5001);

Science and Technology Planning Project of Shanghai Science and Technology Commission (20Z21900100)

More Information

Corresponding author: LI Shuang, 15800647366@163.com(ORCID: 0000-0001-6220-6408); LIU Chenghai, chenghailiu@hotmail.com(ORCID: 0000-0002-1696-6008)

摘要

摘要: 目的探讨细胞免疫、细胞因子等外周血清免疫学指标在药物性肝损伤(DILI)中的特征性表现。方法回顾性分析2019年1月—2021年8月于曙光医院及宝山分院收集的219例DILI患者病历资料，按照药物损伤类别及损伤程度进行分组，就其临床特征、生化及外周血清免疫学特点进行分析。从健康体检者中选取29例作为肝功能正常组，从DILI病例中复核确认42例急性起病治疗前1周内做过细胞因子及细胞免疫评价的作为DILI对照组。符合正态分布的计量资料采用独立样本t检验，不符合正态分布的计量资料组间比较采用Mann-Whitney U检验；计数资料组间比较采用Fisher检验。结果 219例DILI患者中女性122例(56%)，男性97例(44%)。由中药、中成药或者保健品导致损伤89例(40%)，由抗结核、抗肿瘤等西药导致损伤130例(60%)。其中临床分型肝细胞损伤型82例(37%)，胆汁淤积型17例(8%)，混合损伤型120例(55%)。潜伏期最长为180 d，最短为1 d，中位数天数为15 d。其主要症状表现中乏力占49%。细胞毒性T淋巴细胞(%) 及CD4/CD8比值在中药、中成药或保健品组与西药组之间差异均具有统计学意义(Z值分别为2.55、3.08，P值分别为0.011、0.002)。肝功能正常与DILI对照组比较，IL-6、IL-10在DILI的外周免疫血清分布中均具有统计学意义(Z值分别为3.828、2.695，P值分别为＜0.001、0.007)。结论细胞毒性T淋巴细胞在中草药、中成药制剂或保健品和西药类两者的致病机制中或扮演不同角色；药物或药物-蛋白复合物或可影响炎症及免疫通路，释放相关的细胞因子如IL-6、IL-10参与DILI发病进程。
- 化学性与药物性肝损伤 /
- 中草药 /
- 免疫
Abstract: Objective To investigate the characteristic manifestation of the peripheral seroimmunological indicators such as cellular immunity and cytokines in drug-induced liver injury (DILI). Methods The medical records of 219 patients with DILI collected in Shuguang Hospital and Baoshan Branch from January 2019 to August 2021 were retrospectively analyzed, grouped according to the type of drug injury and the degree of injury, and their clinical characteristics, biochemical and peripheral serum immunological characteristics were analyzed. analyze.Twenty-nine cases were selected from the healthy subjects as the normal liver function group, and 42 cases of DILI cases who had undergone cytokine and cellular immune evaluation within 1 week before the acute onset treatment were confirmed as the DILI control group. The t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the Fisher test was used to compare the count data between groups. Results Among the 219 DILI patients, 122 (56%) were female and 97 (44 %) were male. 89 cases (40%) of injuries were caused by traditional Chinese medicines, proprietary Chinese medicines or health products, and 130 cases (60%) were caused by western medicines such as anti-tuberculosis and anti-tumor. Among them, 82 cases (37%) were classified as hepatocyte injury type, 17 cases (8%) of cholestatic type, and 120 cases (55%) of mixed injury type. The longest incubation period was 180 days, the shortest was 1 day, and the median was 15 days. Fatigue accounted for 49% of the main symptoms. There were statistically significant differences in cytotoxic T lymphocytes (%) and CD4/CD8 ratio between the traditional Chinese medicine, Chinese patent medicine or health product group and the western medicine group (Z=2.55 and 3.08, P=0.011 and 0.002, ). From 219 DILI patients, it was confirmed that 42 patients who had detected peripheral immune indicators were compared with 29 patients with normal liver function physical examination. The statistical analysis showed that IL-6 and IL-10 were statistically significant in the peripheral immune serum distribution of DILI. Significance (Z=3.828 and 2.695, P < 0.001 and 0.007). Conclusion Cytotoxic T lymphocytes may play different roles in the pathogenic mechanisms of Chinese herbal medicines, Chinese patent medicine preparations or health products and western medicines; drugs or drug-protein complexes may affect inflammatory and immune pathways and release related cytokines For example, IL-6 and IL-10 are involved in the pathogenesis of DILI.
- Chemical and Drug Induced Liver Injury /
- Drugs, Chinese Herbal /
- Immunity

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表 1 所有DILI患者临床症状分布

Table 1. Distribution of clinical symptoms in all DILI patients

临床症状	病例数	所占构成比
乏力	108	49%
纳差	59	27%
恶心	35	16%
小便色黄	31	14%
腹胀	22	10%
腹痛	16	7%
皮肤瘙痒或皮疹	8	4%
胁痛	4	2%

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表 2 中草药、中成药制剂或保健品和西药两组的外周血指标比较

Table 2. Peripheral blood indexes of Chinese herbal medicine, Chinese patent medicine preparation or health care products and Western medicine

生化指标	中草药、中成药制剂或保健品(n=89)	西药(n=130)	Z值	P值
ALT(U/L)	246.000(98.850~716.000)	273.500(118.750~711.00)	0.609	0.542
TBil(μmou/L)	23.200(14.400~80.750)	37.450(15.225~111.175)	1.300	0.194
GGT(U/L)	134.000(67.00~275.000)	137.000(78.500~284.000)	0.287	0.774
ALP(U/L)	134.000(93.500~211.500)	141.500(92.000~193.000)	0.092	0.926
Alb(U/L)	39.200(35.650~42.800)	38.000(35.000~41.000)	1.571	0.116
INR	1.010(0.970~1.097)	1.040(0.950~1.452)	0.359	0.719
淋巴细胞(×10⁹/L)	1.640(1.240~2.110)	1.670(1.235~2.040)	0.193	0.847
补体C3(g/L)	1.010(0.892~1.100)	1.010(0.880~1.110)	0.087	0.931
补体C4(g/L)	0.241(0.182~0.250)	0.242(0.190~0.250)	0.147	0.883
细胞毒性T淋巴细胞(%)	28.082(20.245~30.000)	28.082(24.942~33.002)	2.554	0.011
辅助性T淋巴细胞(%)	44.040(39.000~46.168)	44.010(36.000~45.637)	1.499	0.134
自然杀伤细胞(%)	14.778(10.810~14.778)	14.778(10.847~14.778)	0.217	0.828
总T淋巴细胞(%)	70.109(67.420~75.835)	70.109(69.907~75.140)	0.457	0.648
CD4/CD8比值	1.694(1.335~2.210)	1.694(1.115~1.694)	3.081	0.002

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表 3 中草药、中成药制剂或保健品和西药DILI患者肝损伤程度分级

Table 3. Classification of liver injury in DILI patients with Chinese herbal medicine, Chinese patent medicine or health care products and Western medicine

造成肝损伤药物分类	肝损伤程度分级
造成肝损伤药物分类	1级	2级	3级	4级
中草药、中成药制剂或保健品	62	8	8	11
西药	77	12	21	20

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表 4 肝功能正常组与DILI组的细胞免疫及细胞因子比较

Table 4. Comparison of cellular immunity and cytokines between Normal liver function group and DILI Group

指标	肝功能正常组(n=29)	DILI对照组(n=42)	统计值	P值
IL-6(pg/mL)	1.820(1.200~3.650)	4.302(2.512~4.735)	Z=3.828	＜0.001
IL-10(pg/mL)	1.440(0.800~3.844)	3.745(1.497~4.000)	Z=2.695	0.007
TNFα(pg/mL)	1.480(0.590~4.435)	2.885(0.902~4.435)	Z=0.808	0.419
自然杀伤细胞(%)	13.200(7.000~18.600)	13.050(9.550~17.500)	Z=0.129	0.898
细胞毒性T淋巴细胞(%)	22.600(19.900~28.000)	21.270(16.985~28.575)	Z=0.760	0.447
辅助性T淋巴细胞(%)	44.334±7.367	42.892±9.806	t=3.196	0.482
T淋巴细胞(%)	65.589±14.205	69.093±9.806	t=0.584	0.869
CD4/CD8比值	2.065±0.842	2.099±0.966	t=1.673	0.878

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