结核病患者发生药物性肝损伤风险预测模型的构建与验证

doi:10.19982/j.issn.1000-6621.20240030

摘要/Abstract

摘要：

目的: 探讨结核病患者发生药物性肝损伤的危险因素,建立并验证列线图预测模型。方法: 回顾性收集2017年1月至2023年6月在镇江市第三人民医院接受抗结核治疗的498例结核病患者的临床资料,按照7:3的比例将患者分为建模组和验证组。通过LASSO回归、多因素logistic回归分析筛选影响因素,并建立列线图预测模型进行内外部验证。结果: 经LASSO筛选变量,多因素logistic回归分析结果显示,高血糖(OR=1.183,95%CI:1.037~1.349)、高血红蛋白(OR=1.028,95%CI:1.011~1.045)、合并肺外结核(OR=2.159,95%CI:1.240~3.759)和国际标准化比值高(OR=5.767,95%CI:1.259~26.421)是抗结核药物性肝损伤发生的危险因素,而尿酸水平高(OR=0.998,95%CI:0.996~0.999)和血小板水平高(OR=0.990,95%CI:0.986~0.995)是抗结核药物性肝损伤发生的保护因素。将上述变量构建列线图预测模型,建模组和验证组ROC曲线下面积分别为80.3%和79.1%;两组校准曲线的P值分别为0.318和0.605,预测值和实际值一致性较好;临床决策曲线阈值概率分别在9%~85%和1%~93%。结论: 本研究构建的预测模型具有较好的区分度、校准度和临床净获益,可为防控抗结核药物性肝损伤提供个体化依据。

关键词: 结核, 药物性肝损伤, 预测, 列线图

Abstract:

Objective: To explore the risk factors of drug-induced liver injury in patients with tuberculosis, and to establish and validate a nomogram prediction model. Methods: The clinical data of 498 patients with anti-tuberculosis drug-induced liver injury (ATB-DILI) in the Third People’s Hospital of Zhenjiang from January 2017 to June 2023 were retrospectively collected. The patients were divided into modeling group and validation group according to the ratio of 7:3. The independent risk factors were screened using LASSO regression and multivariate logistic regression analysis, a nomogram prediction model was established for internal and external verification. Results: After LASSO screening variables, multivariate logistic regression analysis showed that hyperglycemia (OR=1.183, 95%CI: 1.037-1.349), high hemoglobin (OR=1.028, 95%CI: 1.011-1.045), extrapulmonary tuberculosis (OR=2.159, 95%CI: 1.240-3.759), and high international normalized ratio (OR=5.767, 95%CI: 1.259-26.421) were independent risk factors for ATLI, while high uric acid (OR=0.998, 95%CI: 0.996-0.999) and low PLT (OR=0.990, 95%CI: 0.986-0.995) were protective factors. The nomogram model was constructed based on the above related factors. The area under the receiver operating characteristic (ROC) curve was 80.3% and 79.1% in the modeling groups and validation groups, calibration curve P-value were 0.318 and 0.605, the decision curve showed that the nomogram model had certain clinical practicability in the high risk threshold range 9%-85% and 1%-93%. Conclusion: The nomogram model for risk predicting ATB-DILI among inpatients with tuberculosis in this study has good predictability, consistency and clinical practicability, which can provide individualized basis for the prevention and control of anti-tuberculosis drug-induced liver injury.

Key words: Tuberculosis, Drug-induced liver injury, Forecasting, Nomograms

中图分类号:

R183

耿俊玲, 张伊楠, 潘洪秋. 结核病患者发生药物性肝损伤风险预测模型的构建与验证[J]. 中国防痨杂志, 2024, 46(6): 699-706. doi: 10.19982/j.issn.1000-6621.20240030

Geng Junling, Zhang Yinan, Pan Hongqiu. Establishment and validation of a risk prediction model for drug-induced liver injury in patients with tuberculosis[J]. Chinese Journal of Antituberculosis, 2024, 46(6): 699-706. doi: 10.19982/j.issn.1000-6621.20240030

图/表 12

表1

表2

图1

图2

表3

患者发生抗结核药物性肝损伤影响因素的多因素logistic回归分析

因素	β值	s $x ˉ$ 值	Wald χ²值	P值	OR(95%CI)值
合并肺外结核	0.770	0.283	7.399	0.007	2.159(1.240~3.759)
血红蛋白(g/L)	0.028	0.008	11.017	0.001	1.028(1.011~1.045)
血糖(mmol/L)	0.168	0.067	6.277	0.012	1.183(1.037~1.349)
尿酸(μmol/L)	―0.002	0.001	7.722	0.005	0.998(0.996~0.999)
血小板(×10⁹/L)	―0.010	0.002	19.636	0.000	0.990(0.986~0.995)
国际标准化比值	1.752	0.777	5.090	0.024	5.767(1.259~26.421)

表3

图3

图4

图5

图6

图7

图8

图9

参考文献 32

[1]	Buabeng RO, Dsane-Aidoo P, Asamoah YK, et al. Under-reporting of adverse drug reactions: Surveillance system evaluation in Ho Municipality of the Volta Region, Ghana. PLoS One, 2023, 18(9): e0291482. doi:10.1371/journal.pone.0291482.
[2]	Shen T, Liu Y, Shang J, et al. Incidence and Etiology of Drug-Induced Liver Injury in Mainland China. Gastroenterology, 2019, 156(8): 2230-2241.e11. doi:10.1053/j.gastro.2019.02.002. pmid: 30742832
[3]	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). 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.
[4]	Zhao H, Wang Y, Zhang T, et al. Drug-Induced Liver Injury from Anti-Tuberculosis Treatment: A Retrospective Cohort Study. Med Sci Monit, 2020, 26: e920350. doi:10.12659/MSM.920350.
[5]	Zhong T, Fan Y, Dong XL, et al. An Investigation of the Risk Factors Associated With Anti-Tuberculosis Drug-Induced Liver Injury or Abnormal Liver Functioning in 757 Patients With Pulmonary Tuberculosis. Front Pharmacol, 2021, 12: 708522. doi:10.3389/fphar.2021.708522.
[6]	王丹. 抗结核治疗中出现药物性肝损伤对结核病疗效的影响. 深圳中西医结合杂志, 2020, 30(13): 154-155. doi:10.16458/j.cnki.1007-0893.2020.13.078.
[7]	中华人民共和国国家卫生和计划生育委员会. WS 288—2017 肺结核诊断. 2017-11-09.
[8]	中华人民共和国国家卫生和计划生育委员会. WS 196—2017 结核病分类. 2017-11-09.
[9]	Ramappa V, Aithal GP. Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management. J Clin Exp Hepatol, 2013, 3(1): 37-49. doi:10.1016/j.jceh.2012.12.001.
[10]	陈静, 赵鹏. 贵阳市7043例结核病患者发生抗结核药物性肝损伤的危险因素分析. 结核与肺部疾病杂志, 2021, 2(4): 335-339. doi:10.3969/j.issn.2096-8493.20210094.
[11]	Sárközi HK, Ianoşi MB, Ciurba BE, et al. Extrapulmonary tuberculosis-a diagnostic and therapeutic challenge. Orv Hetil, 2022, 163(19): 750-757. doi:10.1556/650.2022.32437.
[12]	Hammami F, Koubaa M, Chakroun A, et al. Comparative analysis between tuberculous meningitis and other forms of extrapulmonary tuberculosis. Germs, 2021, 11(1): 23-31. doi:10.18683/germs.2021.1237. pmid: 33898338
[13]	Li T, Yan X, Du X, et al. Extrapulmonary tuberculosis in China: a national survey. Int J Infect Dis, 2023, 128: 69-77. doi:10.1016/j.ijid.2022.12.005.
[14]	赵鹏, 陈静, 杨光红, 等. 住院结核患者抗结核药物性肝损伤的Nomogram风险预测模型构建. 中华结核和呼吸杂志, 2022, 45(2): 171-176. doi:10.3760/cma.j.cn112147-20210705-00467.
[15]	杨松, 王乐乐, 李同心, 等. 肺外结核流行病学研究进展. 中华流行病学杂志, 2021, 42(1): 171-176. doi:10.3760/cma.j.cn112338-20200814-01067.
[16]	Horák P, Horová B, Koutníková H, et al. Splenic abscess as a rare symptom of the extrapulmonary tuberculosis-case report. Rozhl Chir, 2019, 98(7): 297-300.
[17]	丁芹, 陈薇, 张胜康, 等. 肺外结核患者的营养状况调查及影响因素分析. 中国防痨杂志, 2023, 45(9): 839-844. doi:10.19982/j.issn.1000-6621.20230221.
[18]	李永红, 李红恩, 雷世鑫, 等. 抗结核药致中国人群药物性肝损伤危险因素的Meta分析. 中国抗生素杂志, 2021, 46(6): 628-633. doi:10.13461/j.cnki.cja.007056.
[19]	Gonzalez-Curiel I, Castañeda-Delgado J, Lopez-Lopez N, et al. Differential expression of antimicrobial peptides in active and latent tuberculosis and its relationship with diabetes mellitus. Hum Immunol, 2011, 72(8): 656-662. doi:10.1016/j.humimm.2011.03.027. pmid: 21539878
[20]	叶圣莹, 秦燕. 糖尿病致肝损伤机制的研究进展. 肝脏, 2023, 28(6): 737-739. doi:10.14000/j.cnki.issn.1008-1704.2023.06.022.
[21]	Moreira J, Castro R, Lamas C, et al. Hyperglycemia during tuberculosis treatment increases morbidity and mortality in a contemporary cohort of HIV-infected patients in Rio de Janeiro, Brazil. Int J Infect Dis, 2018, 69: 11-19. doi:10.1016/j.ijid.2017.12.014. pmid: 29253707
[22]	田瑶, 刘辉敏, 傅满姣, 等. 结核病与糖尿病共病诊疗现状. 结核与肺部疾病杂志, 2022, 3(2): 91-95. doi:10.19983/j.issn.2096-8493.20210111.
[23]	杨旭堃, 刘权贤, 张娟, 等. 2型糖尿病合并肺结核感染患者初诊临床特征分析. 临床军医杂志, 2023, 51(8): 776-780, 785. doi:10.16680/j.1671-3826.2023.08.02.
[24]	Jiang F, Yan H, Liang L, et al. Incidence and risk factors of anti-tuberculosis drug induced liver injury (DILI): Large cohort study involving 4652 Chinese adult tuberculosis patients. Liver Int, 2021, 41(7): 1565-1575. doi:10.1111/liv.14896. pmid: 33866661
[25]	Juárez-Hernández E, C Chávez-Tapia N, C Brizuela-Alcántara D, et al. Association Between Serum Hemoglobin Levels and Non Alcoholic Fatty Liver Disease in a Mexican Population. Ann Hepatol, 2018, 17(4): 577-584. doi:10.5604/01.3001.0012.0920. pmid: 29893698
[26]	Yu C, Xu C, Xu L, et al. Serum proteomic analysis revealed diagnostic value of hemoglobin for nonalcoholic fatty liver disease. J Hepatol, 2012, 56(1): 241-247. doi:10.1016/j.jhep.2011.05.027. pmid: 21756851
[27]	El Ridi R, Tallima H. Physiological functions and pathogenic potential of uric acid: A review. J Adv Res, 2017, 8(5): 487-493. doi:10.1016/j.jare.2017.03.003. pmid: 28748115
[28]	Wang MG, Wu SQ, Zhang MM, et al. Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study. Front Immunol, 2022, 13: 1002126. doi:10.3389/fimmu.2022.1002126.
[29]	Fathallah-Shaykh SA, Cramer MT. Uric acid and the kidney. Pediatr Nephrol, 2014, 29(6): 999-1008. doi:10.1007/s00467-013-2549-x. pmid: 23824181
[30]	Devarbhavi H, Choudhury AK, Sharma MK, et al. Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients. Am J Gastroenterol, 2019, 114(6): 929-937. doi:10.14309/ajg.0000000000000201. pmid: 31021832
[31]	李飞龙, 黄赵刚, 葛朝亮, 等. 药物性肝损伤的临床特点及预后因素logistic回归分析. 肝胆外科杂志, 2019, 27(4): 258-262.
[32]	Amitrano L, Guardascione MA, Brancaccio V, et al. Coagulation disorders in liver disease. Semin Liver Dis, 2002, 22(1): 83-96. doi:10.1055/s-2002-23205. pmid: 11928081

指标	建模组(348例)	验证组(150例)	统计检验值	P值
年龄组[例(构成比,%)]			χ²=1.052	0.305
<60岁	212(60.9)	84(56.0)
≥60岁	136(39.1)	66(44.0)
性别[例(构成比,%)]			χ²=1.317	0.251
男性	214(61.5)	84(56.0)
女性	134(38.5)	66(44.0)
吸烟[例(构成比,%)]			χ²=0.092	0.761
否	262(75.3)	111(74.0)
是	86(24.7)	39(26.0)
饮酒[例(构成比,%)]			χ²=1.125	0.289
否	319(91.7)	133(88.7)
是	29(8.3)	17(11.3)
高血压[例(构成比,%)]			χ²=3.469	0.063
无	275(79.0)	107(71.3)
有	73(21.0)	43(28.7)
基础肝病史^a[例(构成比,%)]			χ²=0.261	0.878
无	319(91.7)	139(92.7)
病毒性肝炎	14(4.0)	6(4.0)
其他肝病史	15(4.3)	5(3.3)
结核类型[例(构成比,%)]			χ²=0.885	0.347
肺结核	240(69.0)	97(64.7)
肺外结核	108(31.0)	53(32.3)
体质量指数 [M(Q₁,Q₃)]	21.20(19.40,23.40)	22.10(19.50,24.00)	Z=―1.534	0.125
白细胞 [×10⁹/L,M(Q₁,Q₃)]	5.66(4.72,6.89)	5.61(4.41,6.62)	Z=―1.326	0.185
血红蛋白 [g/L,M(Q₁,Q₃)]	131.00(118.00,143.00)	131.00(120.00,147.00)	Z=―0.743	0.458
肌酐 [μmol/L,M(Q₁,Q₃)]	65.30(56.10,76.40)	64.80(55.60,76.00)	Z=―0.445	0.657
尿素 [mmol/L,M(Q₁,Q₃)]	4.44(3.51,5.44)	4.44(3.63,5.38)	Z=―0.260	0.795
尿酸 [μmol/L,M(Q₁,Q₃)]	435.50(295.60,586.30)	482.10(322.40,596.30)	Z=―1.264	0.206
血糖 [mmol/L,M(Q₁,Q₃)]	5.15(4.65,5.88)	5.18(4.74,5.71)	Z=―0.334	0.738
红细胞 [×10¹²/L,M(Q₁,Q₃)]	4.41(4.07,4.84)	4.44(4.07,4.86)	Z=―0.640	0.522
淋巴细胞 [×10⁹/L,M(Q₁,Q₃)]	1.50(1.17,1.94)	1.39(1.10,1.81)	Z=―1.548	0.122
血小板 [×10⁹/L,M(Q₁,Q₃)]	217.00(165.00,163.00)	217.00(165.00,285.00)	Z=―0.514	0.607
胆固醇 [mmol/L,M(Q₁,Q₃)]	3.95(3.47,4.68)	4.07(3.54,4.53)	Z=―0.729	0.466
国际标准化比值 [M(Q₁,Q₃)]	1.00(0.94,1.07)	0.99(0.95,1.05)	Z=―0.723	0.470

指标	非ATB-DILI患者(251例)	ATB-DILI患者(97例)	统计检验值	P值
性别[例(构成比,%)]			χ²=0.007	0.931
男性	154(61.4)	60(61.9)
女性	97(38.6)	37(38.1)
年龄组[例(构成比,%)]			χ²=0.219	0.640
<60岁	151(60.2)	61(62.9)
≥60岁	100(39.8)	36(37.1)
体质量指数[M(Q₁,Q₃)]	21.10(19.30,22.90)	21.50(19.50,24.10)	Z=―1.397	0.053
吸烟[例(构成比,%)]			χ²=0.072	0.788
是	63(25.1)	23(23.7)
否	188(74.9)	74(76.3)
饮酒[例(构成比,%)]			χ²=0.157	0.692
是	20(8.0)	9(9.3)
否	231(92.0)	88(90.7)
高血压[例(构成比,%)]			χ²=0.235	0.628
有	51(20.3)	22(22.7)
无	200(79.7)	75(77.3)
基础肝病史[例(构成比,%)]			χ²=3.302	0.192
无	234(93.2)	85(87.6)
病毒性肝炎	9(3.6)	5(5.2)
其他肝病史	8(3.2)	7(7.2)
结核类型[例(构成比,%)]			χ²=12.896	<0.001
肺结核	187(74.5)	53(54.6)
肺外结核	64(25.5)	44(45.4)
肌酐 [μmol/L,M(Q₁,Q₃)]	65.30(56.10,76.40)	63.80(55.80,76.80)	Z=―0.357	0.721
尿素 [mmol/L,M(Q₁,Q₃)]	4.37(3.50,5.36)	4.58(3.50,5.59)	Z=―0.997	0.319
尿酸 [μmol/L,M(Q₁,Q₃)]	463.10(310.60,595.50)	358.50(275.50,521.20)	Z=―2.872	0.004
红细胞(×10¹²/L,$\bar{x}±s$)	4.40±0.60	4.54±0.55	t=―1.980	0.048
淋巴细胞 [×10⁹/L,M(Q₁,Q₃)]	1.53(1.18,2.00)	1.43(1.14,1.86)	Z=―1.820	0.069
血小板 [×10⁹/L,M(Q₁,Q₃)]	235.00(193.00,281.00)	166.00(136.00,221.00)	Z=―6.824	<0.001
胆固醇 [mmol/L,M(Q₁,Q₃)]	3.90(3.39,4.65)	4.05(3.61,4.84)	Z=―1.944	0.052
国际标准化比值[M(Q₁,Q₃)]	0.99(0.93,1.06)	1.00(0.95,1.08)	Z=―1.203	0.229
血糖 [mmol/L,M(Q₁,Q₃)]	4.99(4.53,5.69)	5.48(4.97,6.82)	Z=―4.935	<0.001
血红蛋白(g/L,$\bar{x}±s$)	128.00±18.00	136.00±17.00	t=―3.714	<0.001
白细胞 [×10⁹/L,M(Q₁,Q₃)]	5.77(4.86,7.00)	5.32(4.37,6.51)	Z=―2.375	0.018