GLDH、GR对药物性肝损伤临床诊断的应用价值

摘要/Abstract

摘要： 目的探讨GLDH及GR对药物性肝损伤(DILI)的诊断价值。方法回顾性分析2021年1月至2022年3月东部战区总医院秦淮医疗区全军肝病中心收治的111例DILI患者及同期体检中心100名健康者的临床资料。分析GLDH与GR在DILI组与健康组之间的差异、对DILI的诊断效能,与其他肝功能指标的相关性。评估 GR 不同活性水平时,其他肝功能的指标以及DILI患者住院期间的肝功能指标变化。结果 DILI组GLDH及GR分别为12.1(6.8,24.8)U/L、87(74,108.7)U/L,均高于健康组的3.80(2.50,5.68)U/L、58.15(51.35,62.80)U/L(P<0.01)。GLDH与ALT、AST、GGT、ALP、LDH的相关系数分别为0.296、0.328、0.308、0.262、0.234,GR分别为0.464、0.612、0.322、0.375、0.543。GLDH的AUC、敏感度、特异度和约登指数分别为0.861、72.97%、89.0%和0.620,而GR分别为0.941、90.99%、95.00%和0.824。将GR结果按照四分位距分成4组,发现在Q1至Q2阶段肝功能指标差异均无统计学意义(P>0.05),而到了Q3、Q4阶段变化最显著的指标是AST[165(97,256) U/L,282(171,501) U/L]、ALT[302(158,502)U/L,545(234,974.75)U/L]、LDH[221(185,243)U/L,294(225.5,376.25)U/L]及PA[(154±80.23)mg/L,(103.07±86.00)mg/L](P<0.01)。分析56例DILI住院患者住院期间的肝功能指标变化,发现入院时GLDH为20.05(13.45,31.3)U/L,入院(5±2)d后降低到8.3(4.53,15.38)U/L,而在(10±2)d后大部分可恢复到正常范围5.5(2.93,10.7)U/L。结论 GLDH与GR相对于传统肝功能指标在DILI诊断效能、早期诊断、疗效观察等方面有很大的补充作用,可以作为新型的DILI血清标志物。

关键词: 药物性肝损伤, 谷氨酸脱氢酶, 谷胱甘肽还原酶

Abstract: Objective To explore the clinical value of glutamate dehydrogenase (GLDH) and glutathione reductase (GR) in the diagnosis of drug-induced liver injury (DILI).Methods The clinical data and serum liver function indexes of 111 DILI patients hospitalized in the military liver disease center of Qinhuai Medical Treatment Area of General Hospital of Eastern Theater CommandPLA from January 2021 to March 2022 and 100 healthy people in the physical examination center of the hospital in the same period were retrospectively analyzed. A total of 56 DILI patients were hospitalized for more than 10 days and had at least three liver function tests. The differences between DILI group and healthy group and the diagnostic efficiency of GLDH and GR were analyzed, Correlation with other liver function indexes, the indexes of other liver functions at different activity levels of GR and the changes of liver function indexes in DILI patients during hospitalization were evaluated by stratified comparison.Results GLDH and GR in DILI group [12.1 (6.8, 24.8) U/L, 87 (74, 108.7) U/L] were significantly higher than those in healthy group [3.80 (2.50, 5.68) U/L, 58.15 (51.35, 62.80) U/L] (P<0.001); The correlation coefficients of GLDH with alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were 0.296, 0.328, 0.308, 0.262 and 0.234 respectively, and the correlation coefficients of GR with ALT, AST, GGT, ALP and LDH were 0.464, 0.612, 0.322, 0.375 and 0.543 respectively. The area under the AUC curve, sensitivity, specificity, and Jordan index of GLDH were 0.861, 72.97%, 89.0% and 0.620 respectively, while those of GR were 0.941, 90.99%, 95.00% and 0.824 respectively. The GR results were stratified according to the interquartile distance and divided into four groups. It was found that there was no statistical significance in liver function indicators from Q1 to Q2 (P>0.05), while the most significant indicators in Q3 and Q4 were AST [165 (97, 256) U/L, 282 (171, 501) U/L], ALT [302 (158, 502) U/L, 545 (234, ,974.75) U/L], LDH [221 (185, 243) U/L, 294 (225.5, 376.25) U/L] and PA [(154 ± 80.23) mg/l, (103.07 ± 86.00) mg/L] (P<0.001) were used to analyze the changes of liver function indexes of 56 hospitalized DILI patients during hospitalization. It was found that GLDH was 20.05 (13.45, 31.3) U/L at admission, and decreased to 8.3 (4.53, 15.38) U/L after (5 ± 2) days of admission, most of them can return to the normal range of 5.5 (2.93, 10.7) U/L after (10 ± 2) days.Conclusion Compared with traditional liver function indexes, GLDH and GR play a great supplementary role in clinical diagnosis and treatment of DILI in terms of diagnostic efficacy, early diagnosis and curative effect observation. They can be used as new serum markers of DILI in clinical popularization.

Key words: Drug induced liver injury, Glutamate dehydrogenase, Glutathione reductase

杨帆, 王兰, 顾畅, 张薇薇, 朱月蓉, 邱红. GLDH、GR对药物性肝损伤临床诊断的应用价值[J]. 肝脏, 2022, 27(12): 1327-1330.

YANG Fan, WANG Lan, GU Chang, ZHANG Wei-wei, ZHU Yue-rong, QIU Hong. Application value of GLDH and GR in clinical diagnosis of drug-induced liver injury[J]. Chinese Hepatolgy, 2022, 27(12): 1327-1330.

参考文献 15

[1]	Zheng J, Yuan Q, Zhou C, et al. Mitochondrial stress response in drug-induced liver injury. Mol Biol Rep, 2021, 48(10):6949-6958.
[2]	Zhao L, Wang Y, Zhang Y. The potential diagnostic and therapeutic applications of exosomes in drug-induced liver injury. Toxicol Lett, 2021, 1, 337:68-77.
[3]	European Association for the Study of the Liver. EASL clinical practice guidelines:Drug -induced liver injury. J Hepatol, 2019, 70(6):1222 -1261.
[4]	Llewellyn HP, Vaidya VS, Wang Z, et al. Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans. Toxicol Sci, 2021, 181(1):23-34.
[5]	Miller CG, Kundert JA, Prigge JR, et al. Supplemental Ascorbate Diminishes DNA Damage Yet Depletes Glutathione and Increases Acute Liver Failure in a Mouse Model of Hepatic Antioxidant System Disruption. Antioxidants (Basel), 2021, 10(3):359.
[6]	Korver S, Bowen J, Pearson K, et al. The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Arch Toxicol, 2021, 95(11):3435-3448.
[7]	Church RJ, Schomaker SJ, Eaddy JS, et al. Glutamate dehydrogenase as a biomarker for mitotoxicity; insights from furosemide hepatotoxicity in the mouse. PLoS One, 2020, 15(10):e0240562.
[8]	Schomaker S, Potter D, Warner R, et al. Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments. PLoS One, 2020, 15(5):e0229753.
[9]	Church RJ, Kullak-Ublick GA, Aubrecht J, et al. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort. Hepatology, 2019, 69(2):760-773.
[10]	Villanueva-Paz M, Morán L, López-Alcántara N, et al. Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice. Antioxidants (Basel), 2021, 10(3):390.
[11]	Kıvanç MR, Türkoglu V. Investigation of the effects of natural compounds isolated from Arum rupicola var. rupicola on glutathione reductase enzyme purified from bovine liver. Biomed Chromatogr, 2019, 33(8):e4560.
[12]	Chowdhury A, Nabila J, Adelusi TI, et al.Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity. Pharmacol Res, 2020, 161:105102.
[13]	Ntamo Y, Ziqubu K, Chellan N, et al. Drug-Induced Liver Injury: Clinical Evidence of N-Acetyl Cysteine Protective Effects. Oxid Med Cell Longev, 2021, 2021:3320325.
[14]	Cipriano M, Pinheiro PF, Sequeira CO, et al. Nevirapine biotransformation insights: an integrated in vitro approach unveils the biocompetence and glutathiolomic profile of a human hepatocyte-like cell 3D model. Int J Mol Sci, 2020, 21:3998.
[15]	Xu J, Oda S, Yokoi T. Cell-based assay using glutathione-depleted HepaRG and HepG2 human liver cells for predicting drug-induced liver injury. Toxicol In Vitro, 2018, 48:286-301.