高迁移率族蛋白B1和角蛋白18对慢性药物性肝损伤生物化学未缓解的预测价值

作者： style="font-size: 12px ">杨武才 1 熊渝婷 2 王春艳 1 王文畅 1 李旭阳 1 郭畅 1 付懿铭 1 王建军 1 纪冬 1

单位：. 中国人民解放军总医院 肝病医学部 北京 100039 2. 首都医科大学附属北京天坛医院 高压氧科 北京 100070

关键词：慢性药物性肝损伤 生物化学未缓解 高迁移率族蛋白 B1 角蛋白 18

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出版年,卷(期):页码：2026,18(1):9-15

摘要：

摘要：目的 探讨高迁移率族蛋白 B1（high mobility group box-1 protein，HMGB-1）和 角蛋白 18（keratin 18，K18）对慢性药物性肝损伤（chronic drug-induced liver injury， cDILI）患者生物化学未缓解的预测价值。方法 以 2016 年 1 月 1 日至 2024 年 3 月 31 日 解放军总医院第五医学中心收治的初治 cDILI 患者为研究对象，进行 12 个月随访。采 集患者入院次日空腹血，采用酶联免疫吸附法检测血浆 HMGB-1 浓度，采用磁微粒 化学发光免疫分析法检测血清 caspase 裂解的 K18 片段（caspase-cleaved keratin 18， ccK18）和全长 K18（full-length keratin 18，FL-K18）浓度，计算凋亡指数（ccK18/FL K18）。收集患者入院时年龄、性别、体重指数（body mass index，BMI）、血小板计数 （platelet，PLT）、丙氨酸氨基转移酶（alanine aminotransferase，ALT）、天冬氨酸氨基 转移酶（aspartate aminotransferase，AST）、碱性磷酸酶（alkaline phosphatase，ALP）、 γ-谷氨酰转移酶（gamma-glutamyl transferase，GGT）、总胆红素（total bilirubin，TBil）、 凝 血 酶 原 时 间（prothrombin time，PT）、 免 疫 球 蛋 白 G（immunoglobulin G，IgG） 等。根据随访结果将患者分为生物化学缓解组和生物化学未缓解组。比较两组患者上 述指标的差异。采用单因素和多因素 Logistic 回归分析生物化学未缓解的影响因素。 结果 最终纳入 269 例 cDILI 患者，中位年龄 51.1 岁，女性占 78.1%（210 例），中位 HMGB-1 水平为 5.5 μg/L，ccK18 为 342.4 U/L，FL-K18 为 723.4 U/L。生物化学未缓 解组患者年龄（中位数：49.9 岁比 53.9 岁）和 BMI [（23.2 ± 3.1）kg/m2 比（24.2 ± 3.5）kg/m2 ] 显著低于生物化学缓解组，ALT（中位数：116.0 U/L 比 32.0 U/L）、AST （中位数：175.0 U/L 比 32.0 U/L）、ALP（中位数：121.5 U/L 比 91.0 U/L）、GGT（中 位数：97.5 U/L 比 47.0 U/L）、TBil（中位数：23.3 μmol/L 比 13.4 μmol/L）、PT（中位 数：11.9 s 比 11.5 s）及 IgG（中位数：14.6 g/L 比 12.7 g/L）水平显著高于生物化学缓 解组（P 均 ＜ 0.05）。生物化学未缓解组患者 HMGB-1（中位数：5.6 U/L 比 5.2 U/L）、 ccK18（中位数：676.6 U/L 比 190.4 U/L）及 FL-K18（中位数：1 434.5 U/L 比 401.6 U/L）水平均 显著高于生物化学缓解组，凋亡指数显著低于生物化学缓解组（中位数：0.45比0.50）， 差异均有统计学意义（P 均 ＜ 0.05）。多因素 Logistic 回归分析表明，HMGB-1 水平 （OR = 1.085，95%CI：1.022～1.152，P = 0.007）、IgG 水平（OR = 1.030，95%CI：1.011～ 1.049，P = 0.002）、AST 水 平（OR = 1.002，95%CI：1.000～1.004，P = 0.037）、 肝 细 胞损伤型（OR = 2.642，95%CI：1.190～5.864，P = 0.017）是 cDILI 患者生物化学未缓 解的独立危险因素，凋亡指数是独立保护因素（OR = 0.085，95%CI：0.010～0.749， P = 0.026）。结论 高 HMGB-1、高 IgG、高 AST、低凋亡指数及肝细胞损伤型是 cDILI 患者生物化学未缓解的独立危险因素，HMGB-1 和 K18 可作为预测 cDILI 患者预后的 新型标志物。

Abstract: Objective To investigate the predictive value of high mobility group box-1 protein (HMGB-1) and keratin 18 (K18) for biochemical nonresolution (BNR) in patients with chronic drug-induced liver injury (cDILI). Methods Initial treatment patients with cDILI admitted to the Fifth Medical Center of Chinese PLA General Hospital from the January 1st, 2016 to March 31st, 2024 were enrolled and followed up for 12 months. Fasting blood samples were collected on the day after admission. HMGB-1 concentration was measured by enzyme-linked immunosorbent assay, caspase-cleaved keratin 18 (ccK18) and full-length K18 (FL-K18) were detected by magnetic particle based chemiluminescence immunoassay, the apoptotic index (ccK18/FL-K18) was calculated. Baseline clinical data at admission were collected, including age, gender, body mass index (BMI), platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin (TBil), prothrombin time (PT) and immunoglobulin G (IgG). The patients were divided into biochemical resolution (BR) group and BNR group according to follow-up outcomes. Differences in the above indicators between the two groups were compared, and univariate and multivariate Logistic regression analysis were performed to identify the influencing factors for BNR. Results A total of 269 patients were included with a median age of 51.1 years and 78.1% (210 cases) were female. The median HMGB-1 concentration was 5.5 μg/L, median ccK18 was 342.4 U/L, and median FL-K18 was 723.4 U/L. Patients in BNR group had significantly lower age (median: 49.9 years vs. 53.9 years) and BMI [ (23.2 ± 3.1) kg/m2 vs. (24.2 ± 3.5) kg/m2 ] than those in the BR group. Meanwhile, the levels of ALT (median: 116.0 U/L vs. 32.0 U/L), AST (median: 175.0 U/L vs. 32.0 U/L), ALP (median: 121.5 U/L vs. 91.0 U/L), GGT (median: 97.5 U/L vs. 47.0 U/L), TBil (median: 23.3 μmol/L vs. 13.4 μmol/L), PT (median: 11.9 s vs. 11.5 s) and IgG (median: 14.6 g/L vs. 12.7 g/L) were significantly higher in the BNR group (all P ＜ 0.05). Patients in BNR group had significantly higher levels of HMGB-1 (median: 5.6 U/L vs. 5.2 U/L), ccK18 (median: 676.6 U/L vs. 190.4 U/L) and FL-K18 (median: 1434.5 U/L vs. 401.6 U/L) than those in the BR group, while the apoptosis index was significantly lower in the BNR group (median: 0.45 vs. 0.50). All the above differences were statistically significant (all P ＜ 0.05). Multivariate analysis showed that HMGB-1 (OR = 1.085, 95%CI: 1.022～1.152, P = 0.007), IgG (OR = 1.030, 95%CI: 1.011～1.049, P = 0.002), AST (OR = 1.002, 95%CI: 1.000～1.004, P = 0.037) and hepatocellular damage pattern (OR = 2.642, 95%CI: 1.190～5.864, P = 0.017) were independent risk factors for BNR, and apoptotic index was a protective factor (OR = 0.085, 95%CI: 0.010～0.749, P = 0.026). Conclusions Elevated HMGB-1, elevated IgG, elevated AST, decreased apoptotic index and the hepatocellular damage pattern were risk factors for BNR of patients with cDILI. HMGB-1 and K18 could serve as novel biomarkers for predicting prognosis in cDILI.

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