The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Division of Hepatology, Department of Internal medicine, College of Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
Front Immunol. 2023 Mar 1;14:1138112. doi: 10.3389/fimmu.2023.1138112. eCollection 2023.
Idiosyncratic drug-induced liver injury (DILI) is caused by the interplay among drugs, their metabolites, and the host immune response. The characterization of infiltrated immune cells in the liver may improve the understanding of the pathogenesis of idiosyncratic DILI. This study investigated the phenotypes and clinical implications of liver-infiltrating immune cells in idiosyncratic DILI.
From January 2017 to June 2021, 53 patients with idiosyncratic DILI who underwent liver biopsy were prospectively enrolled in this study. Immunohistochemical staining and flow cytometry analyses were performed on the biopsy specimens. Serum levels of CXC chemokine ligand 10 (CXCL10) and soluble CD163 were measured. A multivariate cox proportional hazards model was used to evaluate predictors of DILI resolution within 30 days.
The numbers of intrahepatic T cells and mononuclear phagocytes were positively correlated with serum levels of total bilirubin, alanine aminotransferase (ALT), and the model of end-stage liver disease score. The frequency of activated CD8+ T cells among liver-infiltrating CD8+ T cells in DILI livers was higher than that in healthy livers. Notably, the percentages of activated intrahepatic CD8+ T cells and mononuclear phagocytes in DILI livers showed a positive correlation with ALT. Additionally, serum CXCL10 level was positively correlated with intrahepatic T cell infiltration and ALT, and soluble CD163 level was positively correlated with intrahepatic mononuclear phagocyte infiltration and ALT. Thirty-six patients (70.6%) were treated with steroids. In multivariate analysis, total bilirubin and steroid use independently influenced DILI resolution within 30 days.
Activated CD8+ T cells and mononuclear phagocyte are associated with liver injury caused by drugs. Therefore, we suggest that steroids are a potential treatment option for idiosyncratic DILI.
药物诱导的肝损伤（DILI）是由药物、其代谢物和宿主免疫反应相互作用引起的。对肝脏浸润免疫细胞的特征进行描述可能有助于了解药物性肝损伤的发病机制。本研究调查了药物性肝损伤中肝浸润免疫细胞的表型及其临床意义。
本研究前瞻性纳入了 2017 年 1 月至 2021 年 6 月期间因药物性肝损伤接受肝活检的 53 例患者。对肝活检标本进行免疫组织化学染色和流式细胞术分析，并检测血清趋化因子配体 10（CXCL10）和可溶性 CD163 水平。采用多变量 Cox 比例风险模型评估 30 天内 DILI 缓解的预测因素。
肝内 T 细胞和单核吞噬细胞数量与总胆红素、丙氨酸氨基转移酶（ALT）和终末期肝病模型评分呈正相关。DILI 患者肝内浸润 CD8+T 细胞中活化 CD8+T 细胞的频率高于健康肝脏。值得注意的是，DILI 肝脏中活化的肝内 CD8+T 细胞和单核吞噬细胞的比例与 ALT 呈正相关。此外，血清 CXCL10 水平与肝内 T 细胞浸润和 ALT 呈正相关，可溶性 CD163 水平与肝内单核吞噬细胞浸润和 ALT 呈正相关。36 例（70.6%）患者接受了类固醇治疗。多变量分析显示，总胆红素和类固醇的使用独立影响 30 天内 DILI 的缓解。
活化的 CD8+T 细胞和单核吞噬细胞与药物引起的肝损伤有关。因此，我们建议类固醇可能是药物性肝损伤的潜在治疗选择。
