Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Department of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Toxicol Sci. 2022 Apr 26;187(1):25-34. doi: 10.1093/toxsci/kfac015.
Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n = 28) and nonsurvivors (n = 30) of acetaminophen-induced ALF from the NIH-sponsored Acute Liver Failure Study Group and from control volunteers (n = 10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom alanine aminotransferase was lower on day 1 than day 3, indicating a time point before peak injury (n = 10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1682 quantifiable proteins, 361 were ≥ 4-fold elevated or decreased in ALF patients versus controls and 16 of those were further elevated or decreased ≥ 4-fold in nonsurvivors versus survivors, indicating potential to predict death. Interestingly, 1 of the biomarkers was lactate dehydrogenase (LDH), which is already measured in most clinical laboratories. To validate our proteomics results and to confirm the prognostic potential of LDH, we measured LDH activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the nonsurvivors versus survivors on both days. In addition, it had prognostic value similar to the model for end-stage liver disease and outperformed the King's College Criteria, while a combination of model for end-stage liver disease and LDH together outperformed either alone. Finally, bioinformatics analysis of our proteomics data revealed alteration of numerous signaling pathways that may be important in liver regeneration. Overall, we conclude LDH can predict death in APAP-induced ALF.
需要更好的生物标志物来早期预测急性肝衰竭（ALF）的死亡。为此，我们从 NIH 赞助的急性肝衰竭研究组的无肝移植存活者（n=28）和非存活者（n=30）以及对照志愿者（n=10）中获得了早期（研究第 1 天）和晚期（第 3 天）血清样本。为了确定在 ALF 期间早期血清中增加的蛋白质，我们从该队列中选择了丙氨酸氨基转移酶（ALT）在第 1 天比第 3 天低的个体，这表明在峰值损伤之前的时间点（每组 n=10）。然后，我们对他们的第 1 天样本进行了非靶向蛋白质组学分析。在 1682 种可定量蛋白质中，有 361 种在 ALF 患者与对照组之间≥4 倍升高或降低，其中 16 种在非存活者与存活者之间进一步升高或降低≥4 倍，表明具有预测死亡的潜力。有趣的是，其中一个生物标志物是乳酸脱氢酶（LDH），它已经在大多数临床实验室中进行测量。为了验证我们的蛋白质组学结果并确认 LDH 的预后潜力，我们测量了所有 58 例 ALF 患者的所有第 1 天和第 3 天样本中的 LDH 活性。在第 1 天和第 3 天，非存活者的 LDH 水平均高于存活者。此外，它的预后价值与终末期肝病模型相似，优于 King's 学院标准，而终末期肝病模型和 LDH 的组合优于单独使用任何一种。最后，我们对蛋白质组学数据的生物信息学分析表明，许多信号通路发生了改变，这可能在肝再生中很重要。总体而言，我们得出结论，LDH 可预测 APAP 诱导的 ALF 中的死亡。
