Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome.
Serum mitochondrial biomarkers and damage-associated molecular patterns are higher in acetaminophen overdose patients with poor outcome.
复制标题
对乙酰氨基酚过量且预后不良的患者的血清线粒体生物标志物和损伤相关分子模式较高。
DOI：
10.1002/hep.27265
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发表时间：
2014-10
期刊：
影响因子：
13.5
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
McGill, Mitchell R.;Staggs, Vincent S.;Sharpe, Matthew R.;Lee, William M.;Jaeschke, Hartmut
扑热息痛(APAP)过量是急性肝功能衰竭(ALF)的主要原因。大量研究表明，APAP对小鼠的肝毒性涉及线粒体功能障碍，最近的数据表明，人类也是如此。我们先前已经证明，谷氨酸脱氢酶(GDH)、线粒体DNA(MtDNA)和核DNA(NDNA)片段可以在过量服药患者的循环中被检测到，作为线粒体损伤和损伤相关分子模式的机械性生物标志物。在目前的研究中，我们的目标是确定APAP诱导的ALF(AALF)死亡者的血清中这些生物标志物是否比存活者更高。分别检测34例AALF患者和35例AALF患者血清中GdH、mtDNA和nDNA片段。重要的是，死亡患者的GDH450±73vs.930±145U/L；线粒体DNA：21±6vs.48±13和33±10vs.43±7 ng/mL；nDNA片段：148±13vs.210±13%。受试者工作特征(ROC)曲线分析显示，nDNA片段、GDH和mtDNA可预测预后(AUC，入院时分别为0.73、0.70和0.71或0.76，p<；0.05；AUC，ALT峰值时间分别为0.78、0.71和0.71或0.76，p<；0.05)，其结果与终末期肝病(MELD)模型的结果相似(AUC，峰值MELD：0.77，p<；0.05)。我们的数据表明，线粒体损伤较多的患者存活的可能性较小，这表明线粒体在人类APAP肝毒性机制中处于核心地位。临床上，血清nDNA片段、GDH和mtDNA可作为预测患者预后的一组生物标志物的一部分。
Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our goal was to determine if these biomarkers are higher in serum from non-survivors of APAP-induced ALF (AALF) compared with survivors. GDH, mtDNA and nDNA fragments were measured in serum from AALF patients who did (n = 34) or did not (n = 35) recover. Importantly, all three were significantly increased in patients who died compared with those who survived (GDH: 450±73 vs. 930±145 U/L; mtDNA: 21±6 vs. 48±13 and 33±10 vs. 43±7 ng/mL for two different genes; nDNA fragments: 148±13 vs. 210±13 % of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH and mtDNA were predictive of outcome (AUC, study admission: 0.73, 0.70 and 0.71 or 0.76, respectively, p < 0.05; AUC, time of peak ALT: 0.78, 0.71 and 0.71 or 0.76, respectively, p < 0.05) and the results were similar to those from the model for end-stage liver disease (MELD) (AUC, peak MELD: 0.77, p < 0.05). Our data suggest that patients with more mitochondrial damage are less likely to survive, demonstrating that mitochondria are central in the mechanisms of APAP hepatotoxicity in humans. Clinically, serum nDNA fragments, GDH and mtDNA could be useful as part of a panel of biomarkers to predict patient outcome.
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影响因子：
13.5
作者：
Antoine, Daniel J.;Dear, James W.;Lewis, Philip Starkey;Platt, Vivien;Coyle, Judy;Masson, Moyra;Thanacoody, Ruben H.;Gray, Alasdair J.;Webb, David J.;Moggs, Jonathan G.;Bateman, D. Nicholas;Goldring, Christopher E.;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
4.1
作者：
Chen, Chi;Krausz, Kristopher W.;Shah, Yatrik M.;Idle, Jeffrey R.;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.
影响因子：
25.7
作者：
Antoine, Daniel J.;Jenkins, Rosalind E.;Dear, James W.;Williams, Dominic P.;McGill, Mitchell R.;Sharpe, Matthew R.;Craig, Darren G.;Simpson, Kenneth J.;Jaeschke, Hartmut;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
5.9
作者：
Jaeschke H;McGill MR;Ramachandran A
通讯作者：
Ramachandran A
影响因子：
13.5
作者：
Kon, K;Kim, JS;Lemasters, JJ
通讯作者：
Lemasters, JJ