抗结核药物导致肝损伤的临床特征及危险因素分析

黄德良; 戴炜; 陈军; 叶晓光

doi:10.3969/j.issn.1001-5256.2021.10.022

抗结核药物导致肝损伤的临床特征及危险因素分析

DOI: 10.3969/j.issn.1001-5256.2021.10.022

黄德良^{1, 2},
戴炜²,
陈军²,
叶晓光^1, ,

1.
广州医科大学附属第二医院感染科，广州 510000
2.
国家传染病临床研究中心，南方科技大学第二附属医院 (深圳市第三人民医院)肝病医学中心肝病四科，广东深圳 518100

基金项目:

深圳市医学重点学科，深圳市三名工程 (SZSM201612014)

详细信息

通信作者:
叶晓光，yexiaoguang@126.com

中图分类号: R575.1
计量
- 文章访问数: 401
- HTML全文浏览量: 195
- PDF下载量: 55
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-01
- 录用日期: 2021-04-06
- 出版日期: 2021-10-20

Clinical features of liver injury induced by anti-tuberculosis drugs and related risk factors

Deliang HUANG^{1, 2},
Wei DAI²,
Jun CHEN²,
Xiaoguang YE^{1
, ,}

1.
Department of Infectious Diseases, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China
2.
National Clinical Research Center for Infectious Diseases, Fourth Department of Liver Diseases, Medical Center for Liver Diseases, The Second Affiliated Hospital of Southern University of Science and Technology & Shenzhen Third People's Hospital, Shenzhen, Guangdong 518100, China

Research funding:

The Construction of Key Medical Disciplines in Shenzhen and the Sanming Project of Medicine in Shenzhen (SZSM201612014)

摘要

摘要: 目的总结分析抗结核药物导致肝损伤的临床特征及危险因素。方法选取2017年1月—2018年12月在深圳市第三人民医院诊断为抗结核药物导致肝损伤的129例住院患者，分为肝功能异常组51例(39.53%)，药物性肝损伤组78例(60.47%)，其中肝衰竭13例(10.08%)。回顾性分析患者的实验室指标、治疗和预后资料。计数资料两组间比较采用χ²检验，正态分布的计量资料两组间比较采用独立样本t检验，非正态分布的计量资料两组间比较采用Mann-Whitney U秩和检验。通过多因素logistic回归分析药物性肝损伤、肝衰竭的风险因素。结果药物性肝损伤组和肝功能指标异常组间合并慢性HBV感染比例(χ²=5.616，P=0.018)、无症状肝损伤比例(χ²=9.451，P=0.002)、肝衰竭比例(χ²=9.453，P=0.002)、需调整抗结核方案比例(χ²=16.787，P＜0.001)、首次肝损伤时间(Z=-4.001, P＜0.001)、肝功能恢复时间(Z=-1.735, P＜0.001)、肝性脑病比例(χ²=4.114，P=0.043)比较，差异均有统计学意义。多因素logistic回归分析显示，首次肝损伤时间＞8周(OR=3.94, 95%CI: 1.02~15.25, P=0.047)、无症状肝损伤(OR=7.64, 95%CI: 1.63~35.86，P=0.010)是发生药物性肝损伤的独立危险因素。合并慢性HBV感染(OR=14.42, 95%CI: 2.66~78.09，P=0.002)、首次肝损伤时间＞8周(OR=11.97, 95%CI: 2.03~70.50，P=0.006)是发生肝衰竭的独立危险因素，Alb≥35 g/L(OR=0.07, 95%CI: 0.01~0.51，P=0.010)是其保护因素。结论抗结核药物会导致严重肝损伤，合并HBV感染、无症状肝损伤、发现肝损伤时间晚、低蛋白会增加严重肝损伤发生风险。定期随访、肝功能监测、适当营养支持和HBV筛查对降低抗结核期间的肝损伤风险具有重要意义。
- 化学性与药物性肝损伤 /
- 结核 /
- 抗结核药 /
- 疾病特征 /
- 危险因素
Abstract: Objective To investigate the clinical features of liver injury induced by anti-tuberculosis drugs and related risk factors. Methods A total of 129 patients who were diagnosed with liver injury induced by anti-tuberculosis drugs in Shenzhen Third People's Hospital from January 2017 to December 2018 were enrolled and divided into abnormal liver function group with 51 patients (39.53%) and drug-induced liver injury (DILI) group with 78 patients (60.47%), and among these 129 patients, 13 (10.08%) had liver failure. A retrospective analysis was performed for their laboratory markers as well as treatment and prognosis data. The chi-square test was used for comparison of categorical data between two groups; the independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. The multivariable logistic regression model was used to investigate the risk factors for DILI and liver failure. Results There were significant differences between the DILI group and the abnormal liver function group in chronic HBV co-infection (χ²=5.616, P=0.018), asymptomatic liver injury (χ²=9.451, P=0.002), liver failure (χ²=9.453, P=0.002), need to adjust anti-tuberculosis regimen (χ²=16.787, P < 0.001), time to identification of liver injury (Z=-4.001, P < 0.001), time to liver function recovery (Z=-1.735, P < 0.001), and hepatic encephalopathy (χ²=4.114, P=0.043). The multivariate logistic regression analysis showed that time to identification of liver injury > 8 weeks (odds ratio [OR]=3.94, 95% confidence interval [CI]: 1.02-15.25, P=0.047) and asymptomatic liver injury (OR=7.64, 95% CI: 1.63-35.86, P=0.010) were independent risk factors for DILI; chronic HBV co-infection (OR=14.42, 95% CI: 2.66-78.09, P=0.002) and time to identification of liver injury > 8 weeks (OR=11.97, 95% CI: 2.03-70.50, P=0.006) were independent risk factors for liver failure, while albumin ≥35 g/L (OR=0.07, 95% CI: 0.01-0.51, P=0.010) was a protective factor. Conclusion Anti-tuberculosis drugs may induce severe liver injury, and HBV co-infection, asymptomatic liver injury, long time to identification of liver injury, and low albumin level may increase the risk of severe liver injury. Regular follow-up, liver function monitoring, appropriate nutritional support, and HBV screening are important for reducing the risk of liver injury during anti-tuberculosis therapy.
- Chemical and Drug Induced Liver Injury /
- Tuberculosis /
- Antitubercular Agents /
- Disease Attributes /
- Risk Factors

HTML全文

表 1 患者基本特征

指标	总体(n=129)	肝功能指标异常组(n=51)	药物性肝损伤组(n=78)	统计值	P值
男/女(例)	95/34	41/10	54/24	χ²=1.979	0.159
年龄(岁)	37.0(28.0~51.0)	34.0(26.5~49.0)	40.0(31.0~53.7)	Z=-1.528	0.058
合并慢性HBV感染[例(%)]	26(20.2)	5(9.8)	21(26.9)	χ²=5.616	0.018
无症状肝损伤[例(%)]	21(16.3)	2(3.9)	19(24.4)	χ²=9.451	0.002
首次肝损伤时间(d)	21.0(9.0~45.0)	12.0(7.0~20.5)	30.0(14.0~63.8)	Z=-4.001	＜0.001
肝功能恢复时间(d)	17.0(11.0~35.0)	12.0(8.0~22.5)	20.0(14.0~45.8)	Z=-1.735	＜0.001
需调整抗结核药[例(%)]	111(86.1)	36(70.6)	75(96.2)	χ²=16.787	＜0.001
肝衰竭[例(%)]	13(10.1)	0	13(16.7)	χ²=9.453	0.002
肝性脑病[例(%)]	6(4.7)	0	6(7.7)	χ²=4.114	0.043
腹水[例(%)]	13(10.1)	1(2.0)	12(15.4)	χ²=6.132	0.013
腹膜炎[例(%)]	5(3.9)	0	5(6.4)	χ²=3.401	0.065
肝肾综合征[例(%)]	2(1.6)	0	2(2.6)	χ²=1.328	0.249
人工肝[例(%)]	10(7.8)	0	10(12.3)	χ²=7.088	0.008
死亡[例(%)]	8(6.2)	0	8(10.3)	χ²=5.577	0.018
因肝病死亡[例(%)]	6(4.7)	0	6(7.7)	χ²=4.114	0.043

下载: 导出CSV

表 2 肝损伤程度分组实验室检查结果比较

指标	肝功能指标异常组(n=51)	药物性肝损伤组(n=78)	统计值	P值
首次肝损伤时
INR	1.0(1.0~1.1)	1.1(1.0~1.2)	Z=-2.654	0.023
ALT(U/L)	74.4(58.0~106.5)	325.5(138.5~655.0)	Z=-7.691	＜0.001
AST(U/L)	79.0(58.0~104.0)	275.5(126.3~507.3)	Z=-5.064	＜0.001
ALP(U/L)	85.0(67.5~108.0)	108.0(85.0~147.0)	Z=-2.218	0.021
GGT(U/L)	77.0(41.9~120.0)	96.5(62.3~192.8)	Z=-3.351	0.008
TBil(μmol/L)	9.5(6.2~12.8)	19.0(9.5~41.8)	Z=-3.702	＜0.001
DBil(μmol/L)	3.6(2.3~5.4)	8.4(3.2~18.1)	Z=-3.302	＜0.001
Alb(g/L)	37.8±6.3	37.0±5.5	t=0.749	0.443
停抗结核药时
INR	1.0(1.0~1.1)	1.1(1.0~1.2)	Z=-2.830	0.007
ALT(U/L)	96.0(70.0~125.5)	367.0(208.0~731.3)	Z=-7.990	＜0.001
AST(U/L)	97.0(77.3~131.5)	295.0(190.0~565.1)	Z=-5.140	＜0.001
ALP(U/L)	82.0(68.0~108.0)	108.0(85.0~156.5)	Z=-2.262	0.017
GGT(U/L)	65.0(41.9~112.0)	105.0(68.3~192.5)	Z=-3.214	0.004
TBil(μmol/L)	10.5(7.4~15.3)	19.4(11.1~53.0)	Z=-3.651	＜0.001
DBil(μmol/L)	3.8(2.6~7.8)	8.8(3.6~26.8)	Z=-3.696	＜0.001
Alb(g/L)	38.1±6.4	36.8±6.0	t=1.050	0.282
肝损伤高峰时
INR	1.0(1.0~1.1)	1.1(1.0~1.3)	Z=-2.824	0.030
ALT(U/L)	97.0(70.0~127.5)	441.30(223.3~777.5)	Z=-8.897	＜0.001
AST(U/L)	90.0(66.0~124.8)	317.0(197.8~644.1)	Z=-5.689	＜0.001
ALP(U/L)	85.0(71.0~108.0)	116.5(88.5~194.0)	Z=-2.787	0.003
GGT(U/L)	84.0(51.5~130.0)	115.5(70.8~228.8)	Z=-3.439	0.004
TBil(μmol/L)	10.4(7.3~15.3)	22.8(11.5~94.3)	Z=-4.461	＜0.001
DBil(μmol/L)	3.9(2.9~7.9)	9.4(4.0~54.5)	Z=-4.617	＜0.001
Alb(g/L)	37.3±6.8	35.6±6.6	t=0.725	0.147
肌酐(μmol/L)	62.0(52.0~69.7)	63.5(53.0~72.1)	Z=-1.167	0.245

下载: 导出CSV

表 3 合并慢性HBV感染者治疗及预后

指标	肝功能指标异常组(n=5)	药物性肝损组(n=21)	χ²值	P值
HBeAg[例(%)]			0.014	0.907
阴性	3(60.00)	12(57.14)
阳性	2(40.00)	9(42.86)
抗HBV治疗[例(%)]	2(40.00)	16(76.19)	2.483	0.115
抗结核前启动抗病毒[例(%)]	2(40.00)	1(4.76)	4.913	0.027
肝损后启动抗病毒[例(%)]	0	15(71.43)	8.442	0.004
抗HBV治疗[例(%)]			7.491	0.024
恩替卡韦	0	14 (66.67)
替诺福韦	2 (40.00)	2 (9.52)
人工肝[例(%)]	0	8 (38.10)	2.751	0.097
因肝病死亡[例(%)]	0	4 (19.05)	1.126	0.289

下载: 导出CSV

表 4 药物性肝损伤、肝衰竭风险因素分析

参数	例数	单因素分析			多因素分析
参数	例数	OR	95%CI	P值	OR	95%CI	P值
药物性肝损伤
慢性HBV感染	26	3.39	1.19~9.68	0.023	2.16	0.66~7.04	0.203
女性	34	1.82	0.79~4.23	0.163	2.05	0.81~5.17	0.129
首次肝损伤时间＞8周	25	6.29	1.77~22.30	0.004	3.94	1.02~15.25	0.047
Alb≥35 g/L	90	0.80	0.37~1.75	0.578	0.77	0.33~1.80	0.542
≥60岁	24	1.75	0.67~4.58	0.253	2.00	0.71~5.66	0.190
无症状肝损伤	21	7.89	1.75~35.55	0.007	7.64	1.63~35.86	0.010
肝衰竭
慢性HBV感染	26	20.83	5.17~83.98	＜0.001	14.42	2.66~78.09	0.002
女性	34	0.82	0.21~3.19	0.778	1.28	0.20~7.99	0.795
首次肝损伤时间＞8周	25	14.06	3.87~51.12	＜0.001	11.97	2.03~70.50	0.006
Alb≥35 g/L	90	0.16	0.04~0.54	0.003	0.07	0.01~0.51	0.010
≥60岁	24	0.78	0.16~3.76	0.754	0.90	0.13~6.43	0.914
无症状肝损伤	21	0.93	0.19~4.53	0.927	1.08	0.11~10.44	0.947

下载: 导出CSV

参考文献(31)

[1]	WHO. Global tuberculosis report 2020[R/OL]. https://www.who.int/tb/publications/global_report/en/(2020-10-14).
[2]	Tuberculosis Society of Chinese Medical Association. Guidelines for anti-tuberculosis drug-induced liver injury[J]. Chin J Tuberc Respir Dis, 2019, 42(5): 343-356. DOI: 10.3760/cma.j.issn.1001-0939.2019.05.007. 中华医学会结核病学分会. 抗结核药物性肝损伤诊治指南(2019年版)[J]. 中华结核和呼吸杂志, 2019, 42(5): 343-356. DOI: 10.3760/cma.j.issn.1001-0939.2019.05.007.
[3]	SHEN T, LIU Y, SHANG J, et al. Incidence and etiology of drug induced liver injury in mainland China[J]. Gastroenterology, 2019, 156: 2230-2241. DOI: 10.1053/j.gastro.2019.02.002.
[4]	SHARMA SK, BALAMURUGAN A, SAHA PK, et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment[J]. Am J Respir Crit Care Med, 2002, 166(7): 916-919. DOI: 10.1164/rccm.2108091.
[5]	van HEST R, BAARS H, KIK S, et al. Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment[J]. Clin Infect Dis, 2004, 39(4): 488-496. DOI: 10.1086/422645.
[6]	SHARIFZADEH M, RASOULINEJAD M, VALIPOUR F, et al. Evaluation of patient-related factors associated with causality, preventability, predictability and severity of hepatotoxicity during antituberculosis[correction of antituberclosis] treatment[J]. Pharmacol Res, 2005, 51(4): 353-358. DOI: 10.1016/j.phrs.2004.10.009.
[7]	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. DOI: 10.1164/rccm.200510-1666ST.
[8]	WU YH, WU QH. Literature analysis of 1 949 cases liver injury induced by anti-TB drugs[J]. Northwest Pharm J, 2015, 30(6): 750-753. DOI: 10.3969/j.issn.1004-2407.2015.06.028. 吴玉华, 武谦虎. 抗结核药致肝损害1949例文献分析[J]. 西北药学杂志, 2015, 30(6): 750-753. DOI: 10.3969/j.issn.1004-2407.2015.06.028.
[9]	ZHANG T, DU J, YIN X, et al. Adverse events in treating smear-positive tuberculosis patients in China[J]. Int J Environ Res Public Health, 2015, 13(1): 86. DOI: 10.3390/ijerph13010086.
[10]	GE QP, WANG QF, DUAN HF. Clinical analysis of protionamide and para-aminosalicylic acid induced hepatotoxicity in 129 cases[J]. Chin J Tuberc Respir Dis, 2013, 36(10): 737-740. DOI: 10.3760/cma.j.issn.1001-0939.2013.10.008. 戈启萍, 王庆枫, 段鸿飞. 含丙硫异烟胺和对氨基水杨酸治疗方案发生药物性肝损伤129例临床分析[J]. 中华结核和呼吸杂志, 2013, 36(10): 737-740. DOI: 10.3760/cma.j.issn.1001-0939.2013.10.008.
[11]	ZHANG MY, LEI JP, YAN SM, et al. Liver injury induced by anti-tuberculosis drugs and anti-tuberculosis therapy for patients with liver disease: Introduction of the experience of diagnosis and treatment in Chinese mainland and "Taiwan Guidelines for TB Diagnosis & Treatment"[J]. J Clin Hepatol, 2015, 31(11): 1776-1781. DOI: 10.3969/j.issn.1001-5256.2015.11.004. 张明媛, 雷建平, 闫世明, 等. 抗结核药物所致肝损伤及肝病患者抗结核药物治疗——大陆地区诊治建议与台湾《结核病诊治指引》相关介绍[J]. 临床肝胆病志, 2015, 31(11): 1776-1781. DOI: 10.3969/j.issn.1001-5256.2015.11.004.
[12]	YU YC, MAO YM, CHEN CW. Guidelines for the management of drug-induced liver injury[J]. J Pract Hepatol, 2017, 20(2): 257-274. DOI: 10.3969/j.issn.1672-5069.2017.02.039. 于乐成, 茅益民, 陈成伟. 药物性肝损伤诊治指南[J]. 实用肝脏病杂志, 2017, 20(2): 257-274. DOI: 10.3969/j.issn.1672-5069.2017.02.039.
[13]	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. DOI: 10.1038/clpt.2011.58.
[14]	JIN XL, YANG ZB, ZHAN SH, et al. Influencing factor of liver dysfunction of inpatients of tuberculosis with initial treatment[J/CD]. Chin J Exp Clin Infect Dis(Electronic Edition), 2020, 14(5): 394-400. 金小琳, 杨智彬, 詹淑华, 等. 1501例初治住院结核病患者肝功能异常的影响因素[J/CD]. 中华实验和临床感染病杂志(电子版), 2020, 14(5): 394-400.
[15]	LI HL, WEN DD, BEI CL, et al. Analysis of anti-tuberculosis drug induced liver injury and its drug use cost in the hospital before and after the special rectification[J]. Chin J Clin Pharmacol Ther, 2019, 24(9): 1030-1036. DOI: 10.12092/j.issn.1009-2501.2019.09.011. 李红丽, 文丹丹, 贝承丽, 等. 专项整治前后结核患者肝损伤及药物使用费用对比分析[J]. 中国临床药理学与治疗学, 2019, 24(9): 1030-1036. DOI: 10.12092/j.issn.1009-2501.2019.09.011.
[16]	LEE AM, MENNONE JZ, JONES RC, et al. Risk factors for hepatotoxicity associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection: Experience from three public health tuberculosis clinics[J]. Int J Tuberc Lung Dis, 2002, 6(11): 995-1000.
[17]	NOOREDINVAND HA, CONNELL DW, ASGHEDDI M, et al. Viral hepatitis prevalence in patients with active and latent tuberculosis[J]. World J Gastroenterol, 2015, 21(29): 8920-8926. DOI: 10.3748/wjg.v21.i29.8920.
[18]	KIM WS, LEE SS, LEE CM, et al. Hepatitis C and not hepatitis B virus is a risk factor for anti-tuberculosis drug induced liver injury[J]. BMC Infect Dis, 2016, 16: 50. DOI: 10.1186/s12879-016-1344-2.
[19]	LIU YM, CHENG YJ, LI YL, et al. Antituberculosis treatment and hepatotoxicity in patients with chronic viral hepatitis[J]. Lung, 2014, 192(1): 205-210. DOI: 10.1007/s00408-013-9535-8.
[20]	KANEKO Y, NAGAYAMA N, KAWABE Y, et al. Drug-induced hepatotoxicity caused by anti-tuberculosis drugs in tuberculosis patients complicated with chronic hepatitis[J]. Kekkaku, 2008, 83(1): 13-19. http://europepmc.org/abstract/MED/18283910
[21]	WANG NT, HUANG YS, LIN MH, et al. Chronic hepatitis B infection and risk of antituberculosis drug-induced liver injury: Systematic review and meta-analysis[J]. J Chin Med Assoc, 2016, 79(7): 368-374. DOI: 10.1016/j.jcma.2015.12.006.
[22]	CHEN L, BAO D, GU L, et al. Co-infection with hepatitis B virus among tuberculosis patients is associated with poor outcomes during anti-tuberculosis treatment[J]. BMC Infect Dis, 2018, 18(1): 295. DOI: 10.1186/s12879-018-3192-8.
[23]	ZHENG J, GUO MH, PENG HW, et al. The role of hepatitis B infection in anti-tuberculosis drug-induced liver injury: A meta-analysis of cohort studies[J]. Epidemiol Infect, 2020, 148: e290. DOI: 10.1017/S0950268820002861.
[24]	ZHU CH, ZHAO MZ, CHEN G, et al. Baseline HBV load increases the risk of anti-tuberculous drug-induced hepatitis flares in patients with tuberculosis[J]. J Huazhong Univ Sci Technolog Med Sci, 2017, 37(1): 105-109. DOI: 10.1007/s11596-017-1702-3.
[25]	CHENG SQ. Diagnosis and treatment of coinfection of pulmonary tuberculosis and chronic hepatitis B[J]. World Chin J Dig, 2016, 24(18): 2785-2798. DOI: 10.11569/wcjd.v24.i18.2785. 程书权. 应重视乙型肝炎合并肺结核的临床诊断与治疗[J]. 世界华人消化杂志, 2016, 24(18): 2785-2798. DOI: 10.11569/wcjd.v24.i18.2785.
[26]	TWEED CD, WILLS GH, CROOK AM, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study[J]. BMC Med, 2018, 16(1): 46. DOI: 10.1186/s12916-018-1033-7.
[27]	MASINI EO, MANSOUR O, SPEER CE, et al. Using survival analysis to identify risk factors for treatment interruption among new and retreatment tuberculosis patients in Kenya[J]. PLoS One, 2016, 11(10): e0164172. DOI: 10.1371/journal.pone.0164172.
[28]	TELEMAN MD, CHEE CB, EARNEST A, et al. Hepatotoxicity of tuberculosis chemotherapy under general programme conditions in Singapore[J]. Int J Tuberc Lung Dis, 2002, 6(8): 699-705. http://old.med.wanfangdata.com.cn/viewHTMLEn/PeriodicalPaper_JJ029828197.aspx
[29]	SUN HY, CHEN IL, GAU CS, et al. A prospective study of hepatitis during antituberculous treatment in taiwanese patients and a review of the literature[J]. J Formos Med Assoc, 2009, 108(2): 102-111. DOI: 10.1016/s0929-6646(09)60040-1.
[30]	LEE CM, LEE SS, LEE JM, et al. Early monitoring for detection of antituberculous drug-induced hepatotoxicity[J]. Korean J Intern Med, 2016, 31(1): 65-72. DOI: 10.3904/kjim.2016.31.1.65.
[31]	PATTERSON B, ABBARA A, COLLIN S, et al. Predicting drug-induced liver injury from anti-tuberculous medications by early monitoring of liver tests[J]. J Infect, 2021, 82(2): 240-244. DOI: 10.1016/j.jinf.2020.09.038.