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总胆红素反弹率与总胆红素清除率在人工肝治疗重症药物性肝损伤预后评估中的作用
DOI: 10.3969/j.issn.1001-5256.2023.03.018
伦理学声明：本研究于2022年7月14日经过天津市第三中心医院伦理委员会批准。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：刘莹负责课题设计，资料分析，撰写论文；朱萍负责确定研究方向以及统计分析；向慧玲、梁静负责拟定写作思路，指导撰写文章并最后定稿。
Value of total bilirubin rebound rate and total bilirubin clearance rate in evaluating the prognosis of severe drug-induced liver injury after artificial liver support therapy
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摘要:
目的 评估总胆红素反弹率(TBRR)、总胆红素清除率(TBCR)及治疗1周后总胆红素清除率(ΔTBCR)在人工肝治疗重症药物性肝损伤短期预后评估中的作用。 方法 回顾性分析2013年9月—2021年12月在天津市第三中心医院住院并行人工肝治疗的重症药物性肝损伤患者203例，收集患者的一般资料、生化指标及临床分型，根据患者出院时病情转归分为好转组和未愈组，并计算MELD评分、TBRR、TBCR及ΔTBCR。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检验；计数资料两组间比较采用χ2检验。绘制受试者工作特征曲线(ROC曲线)用来评估各个评价指标对患者预后的预测价值。Kaplan-Meier法用来描述不同评价指标下患者住院时间的差异。 结果 好转组患者的年龄(t=-2.762)、WBC(Z=-3.184)、TBil(t=-2.809)、CBil(t=-2.739)、INR(Z=-2.357)、MELD评分(t=-3.090)、TBRR(t=-4.749)低于未愈组，而Alb(t=2.198)、PTA(t=2.018)、TBCR(t=2.166)、ΔTBCR(t=9.549)则高于未愈组(P值均＜0.05)。MELD评分、TBRR、TBCR及ΔTBCR的ROC曲线下面积分别为0.656、0.727、0.611和0.879，ΔTBCR在预测价值上优于TBRR(Z=3.169，P=0.001 5)。TBRR、ΔTBCR最佳临界值为22.5%(敏感度94.6%，特异度45.2%)、27.4%(敏感度77.7%，特异度86.5%)。而对于不同的临床病理分型，ΔTBCR均显示出良好的预测价值，特别是对混合型DILI患者进行人工肝治疗的疗效评价具有极高的敏感度(91.4%)和特异度(100.0%)。 结论 TBRR、ΔTBCR对人工肝治疗重症药物性肝损伤患者短期预后评估中作用优于MELD评分，其中ΔTBCR评分的预测价值更高。 -
关键词:
- 化学性与药物性肝损伤 /
- 肝, 人工 /
- 胆红素
Abstract:Objective To investigate the value of total bilirubin rebound rate (TBRR), total bilirubin clearance rate (TBCR), and TBCR after 1 week of treatment (ΔTBCR) in evaluating the short-term prognosis of patients with severe drug-induced liver injury (DILI) after artificial liver support therapy. Methods A retrospective analysis was performed for 203 patients with severe DILI who received artificial liver support therapy in Tianjin Third Central Hospital from September 2013 to December 2021, and general information, biochemical parameters, and clinical classification were collected. The patients were divided into improved group and unhealed group according to the prognosis at discharge, and Model for End-Stage Liver Disease (MELD) score, TBRR, TBCR, and ΔTBCR were calculated. The independent samples t-test was used for comparison of normally distributed continuous data between groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups; the chi-square test was used for comparison of categorical data between groups. The receiver operating characteristic (ROC) curve was plotted to investigate the value of assessment indices in predicting the prognosis of patients, and the Kaplan-Meier method was used to investigate the difference in the length of hospital stay in the context of different assessment indices. Results Compared with the unhealed group, the improved group had significantly lower age (t=-2.762, P < 0.05), white blood cell count (Z=-3.184, P < 0.05), total bilirubin (t=-2.809, P < 0.05), conjugated bilirubin (t=-2.739, P < 0.05), international normalized ratio (Z=-2.357, P < 0.05), MELD score (t=-3.090, P < 0.05), and TBRR (t=-4.749, P < 0.05), as well as significantly higher albumin (t=2.198, P < 0.05), prothrombin time activity (t=2.018, P < 0.05), TBCR (t=2.166, P < 0.05), and ΔTBCR (t=9.549, P < 0.05). MELD score, TBRR, TBCR, and ΔTBCR had an area under the ROC curve (AUC) of 0.656, 0.727, 0.611, and 0.879, respectively, and ΔTBCR had a better predictive value than TBRR (Z=3.169, P=0.001 5). The optimal cut-off value was 22.5% for TBRR (with a sensitivity of 94.6% and a specificity of 45.2%) and 27.4% for ΔTBCR (with a sensitivity of 77.7% and a specificity of 86.5%). ΔTBCR showed a good predictive value in different clinicopathological types, with extremely high sensitivity (91.4%) and specificity (100.0%) in evaluating the treatment outcome of patients with mixed-type DILI after artificial liver support therapy. Conclusion TBRR and ΔTBCR have a higher value than MELD score in evaluating the short-term prognosis of patients with severe DILI after artificial liver support therapy, among which ΔTBCR has a higher predictive value. -
Key words:
- Chemical and Drug Induced Liver Injury /
- Liver, Artificial /
- Bilirubin
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表 1 人工肝治疗重症药物性肝损伤好转组与未愈组患者基线资料比较
Table 1. Comparison of baseline characteristics between the improved group and unhealed group in patients with severe drug-induced liver injury
指标 好转组(n=166) 未愈组(n=37) 统计值 P值 年龄(岁) 53.6±14.8 59.5±11.1 t＝-2.762 0.007 住院时间(d) 23.7±10.9 24.4±14.1 t＝-0.295 0.770 性别[例(%)] 男 58(34.9) 15(40.5) χ2=0.412 0.521 女 108(65.1) 22(59.5) 临床分型[例(%)] χ2=3.529 0.171 肝细胞损伤型 82(49.4) 12(32.4) 胆汁淤积型 49(29.5) 15(40.5) 混合型 35(21.1) 10(27.0) WBC(×109/L) 6.2(4.5~8.2) 8.4(5.9~9.7) Z=-3.184 0.001 PLT(×109/L) 214.3±88.4 195.4±106.4 t＝1.132 0.259 Alb(g/L) 33.9±4.3 32.3±3.7 t＝2.198 0.029 GLO(g/L) 24.4±6.2 24.7±8.7 t＝-0.200 0.842 ALT(U/L) 213.5(81.3~521.5) 161.0(72.0~342.6) Z=-0.984 0.325 AST(U/L) 205.5(84.0~556.8) 191.0(79.0~478.0) Z=-0.241 0.809 ALP(U/L) 158.5(116.3~212.8) 200.0(140.0~291.0) Z=-1.800 0.072 GGT(U/L) 197.0(98.3~391.5) 177.0(69.0~397.0) Z=-0.785 0.433 TBil(μmol/L) 294.6±99.0 369.3±154.8 t＝-2.809 0.007 CBil(μmol/L) 233.9±80.0 291.5±122.2 t＝-2.739 0.009 PTA(%) 87.6±35.0 72.3±42.9 t＝2.018 0.049 INR 1.1(0.9~1.4) 1.3(1.0~2.1) Z=-2.357 0.018 AFP(ng/mL) 10.6(3.7~43.5) 5.2(2.2~28.2) Z=-1.772 0.076 Cr(μmol/L) 54.0(47.0~65.8) 59.0(48.0~78.0) Z=-1.692 0.091 注：GLO，球蛋白；CBil，结合胆红素。 
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表 2 药物性肝损伤好转组与未愈组各项评价指标比较
Table 2. Comparison of evaluation indexes between the improved group and unhealed group in patients with drug-induced liver injury
指标 好转组(n=166) 未愈组(n=37) t值 P值 MELD评分 12.4±6.2 17.4±9.4 -3.090 0.003 TBRR(%) 26.8±35.0 56.8±33.2 -4.749 ＜0.001 TBCR(%) 40.2±11.1 35.8±11.5 2.166 0.031 ΔTBCR(%) 44.9±23.6 1.3±30.9 9.549 ＜0.001
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表 3 TBRR、ΔTBCR对不同临床分型DILI患者短期预后的评价价值
Table 3. Evaluation value of TBRR and ΔTBCR on short-term prognosis of patients with different types of drug-induced liver injury
项目 肝细胞损伤型 胆汁淤积型 混合型 TBRR AUC 0.720 0.685 0.789 95%CI 0.592~0.847 0.549~0.821 0.634~0.943 cut-off值 27.6% 22.2% 24.6% 敏感度(%) 91.7 100.0 90.0 特异度(%) 52.4 42.9 57.1 ΔTBCR AUC 0.835 0.833 0.977 95%CI 0.678~0.993 0.722~0.944 0.941~1.000 cut-off值 18.4% 13.1% 27.6% 敏感度(%) 85.4 85.7 91.4 特异度(%) 75.0 73.3 100.0
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