南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (11): 1655-1661.doi: 10.12122/j.issn.1673-4254.2022.11.09

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慢性药物性肝损伤的复发风险与肝纤维化程度高度相关

邓 亚，王春艳，付懿铭，李忠斌，纪 冬   

  1. 南方医科大学第二临床医学院，广东 广州 510515；解放军总医院第五医学中心肝病医学部，北京 100039
  • 出版日期:2022-11-20 发布日期:2022-11-30

A high relapse risk of chronic drug-induced liver injury is correlated with a greater severity of liver fibrosis

DENG Ya, WANG Chunyan, FU Yiming, LI Zhongbin, JI Dong   

  1. Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China; Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
  • Online:2022-11-20 Published:2022-11-30

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摘要： 目的 构建慢性药物性肝损伤（DILI）复发风险预测模型，进而评价DILI复发风险与肝纤维化的关系。方法 回顾性收集2017年1月~2022年1月在解放军总医院第五医学中心住院经肝活检证实的慢性DILI患者的临床资料，按照是否复发分为复发组(n=154)和无复发组（n=984）。根据Logistic单因素和多因素回归分析的结果构建相关风险预测模型，采用AUC值及Hosmer-Lemeshow检验评价模型的区分度及校准度，应用200次5、10、20折交叉验证法对模型进行验证。Spearman等级相关分析评价新建模型与纤维化的相关性，并绘制ROC曲线比较新建模型与APRI、FIB-4诊断肝纤维化的效能。结果 共纳入慢性DILI患者1138例，平均年龄44.9±11.7岁，女性524例（46.0%），复发组较未复发组肝纤维化程度更重，复发组较未复发组肝纤维化程度更重，复发组中 S0、S1、S2、S3、S4 分别为 1.9%、13.1%、42.2%、27.9%、14.9%，而未复发组分别为 8.9%、43.5%、26.1%、17.1%、4.4%。Logistic多因素分析结果显示LSM≥13.7kPa（OR=4.35，95% CI：2.61~7.25，P<0.001），CHE<2500 U/L（OR=5.17，95% CI：2.13~12.53，P<0.001），CHE 2500~5000 U/L（OR=4.07，95% CI：2.75~6.01，P<0.001），AST>2×ULN（OR=2.29，95%CI：1.38~3.80，P=0.001）是慢性DILI复发的危险因素。基于以上无创指标构建ACLS预测模型，AUC值为0.803（95% CI：0.78-0.83），Hosmer-Lemeshow拟合优度检验示χ2=7.73（P=0. 46），200次5、10、20折交叉验证显示平均AUC值为0.803，表明该模型稳定性良好。Spearman等级相关分析显示ACLS评分与肝纤维化程度呈正相关（rho=0.530，P<0.001），ACLS模型诊断中度肝纤维化的最佳界值3分，AUC值为0.78（特异度72.7%，灵敏度73.3%），效能优于APRI和FIB-4（P<0.001）；诊断重度肝纤维化的界值为6分，AUC值为0.83（特异度75.7%，灵敏度72.7%），效能优于APRI（P<0.001），但与FIB-4差异无统计学意义（P=0.38）。结论 复发风险高的慢性DILI患者，肝纤维化程度更重，此类患者需要密切随访并适时采取积极的治疗。

关键词: 慢性药物性肝损伤；复发；肝纤维化；危险因素；预测模型

Abstract: Objective To construct a risk prediction model for relapse of chronic drug-induced liver injury (DILI) and explore the correlation between DILI relapse risk and liver fibrosis. Methods We retrospectively collected the clinical data of 1138 patients with chronic DILI hospitalized from January, 2017 to January, 2022, including 154 patients with and 984 without DILI relapse. Based on the results of univariable and multivariable logistic regression analyses, a risk prediction model for DILI relapse was constructed, evaluated for its discrimination and calibration using AUC value and Hosmer-Lemeshow test, and verified with a 200 times 5, 10 and 20 folds cross validation method. Spearman correlation analysis was used to evaluate the correlation between the new model and liver fibrosis, and its diagnostic efficiency for liver fibrosis was assessed by comparison with APRI and FIB-4 using ROC curve. Results The proportions of patients with S0, S1, S2, S3 and S4 liver fibrosis were 1.9%, 13.1%, 42.2%, 27.9% and 14.9% in the relapse group, respectively, as compared with 8.9%, 43.5%, 26.1%, 17.1% and 4.4% in the non- relapse group, respectively, showing severer liver fibrosis in patients with than those without DILI relapse. Multivariable logistic regression analysis identified LSM≥13.7 kPa (OR=4.35, 95%CI: 2.61-7.25, P<0.001), CHE <2500 U/L (OR=5.17, 95%CI: 2.13-12.53, P<0.001), CHE of 2500-5000 U/L (OR=4.07, 95%CI: 2.75-6.01, P<0.001), and AST >2×ULN (OR=2.29, 95%CI: 1.38-3.80, P=0.001) as risk factors for relapse of chronic DILI. The ACLS model constructed based on these non-invasive indicators had an AUC value of 0.803 (95%CI: 0.78-0.83). The results of Hosmer-Lemeshow goodness of fit test (χ2=7.73, P=0.46) and the cross validation tests (average AUC of 0.803) all showed a good stability of the model. Spearman correlation analysis showed that ACLS score was positively correlated with the severity of liver fibrosis (rho=0.530, P<0.001). At the optimal cut-off value of 3 points for diagnosing moderate liver fibrosis, the ACLS model had an AUC value of 0.78 (with specificity of 72.7% and sensitivity of 73.3% ), demonstrating a better efficacy than that of APRI and FIB-4 (P<0.001). At the cut-off value of 6 for severe liver fibrosis, the diagnostic efficacy of the model (AUC=0.83; specificity 75.7%, sensitivity 72.7% ) was still better than that of APRI (P<0.001) but comparable with that of FIB-4 (P=0.38). Conclusion The patients at high risks of chronic DILI relapse have severer liver fibrosis and should be followed up regularly for timely aggressive treatment.

Key words: chronic drug-induced liver injury; relapse; liver fibrosis; risk factors; prediction model