Weemhoff James L, Woolbright Benjamin L, Jenkins Rosalind E, McGill Mitchell R, Sharpe Matthew R, Olson Jody C, Antoine Daniel J, Curry Steven C, Jaeschke Hartmut
Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Liver Int. 2017 Mar;37(3):377-384. doi: 10.1111/liv.13202. Epub 2016 Aug 6.
BACKGROUND & AIMS: Hypoxic hepatitis is a clinical condition precipitated by prolonged periods of oxygen deprivation to the liver. It can have several underlying causes. Despite its prevalence in critically ill patients, which can reach upwards of 10%, very little is known about the mechanisms of injury. Thus, we set out to measure previously identified circulating biomarkers in an attempt to describe mechanisms of injury following hypoxic hepatitis.
Plasma from patients diagnosed with hypoxic hepatitis was collected for this study. Biomarkers of hepatocellular injury, mitochondrial damage and cell death were measured. These results were compared against results obtained from well-characterized acetaminophen overdose patients.
At peak injury, ALT measured 4082±606 U/L and gradually decreased over 5 days, corresponding to the clinically observed pattern of hypoxic hepatitis. Levels of GDH showed a similar pattern, but neither ALT nor GDH were significantly higher in these patients than in acetaminophen patients. Plasma levels of DNA fragments mimicked hepatocellular injury as measured by ALT and miRNA-122. Interestingly, we found a significant increase in caspase-cleaved cytokeratin-18; however, the full-length form greatly exceeded the cleaved form at the time of maximum injury (45837±12085 vs 2528±1074 U/L). We also found an increase in acHMGB1 at later time points indicating a possible role of inflammation, but cytokine levels at these times were actually decreased relative to early time points.
The mechanism of injury following hypoxic hepatitis involves mitochondrial damage and DNA fragmentation. Importantly, necrosis, rather than apoptosis, is the main mode of cell death.
缺氧性肝炎是一种因肝脏长期缺氧而引发的临床病症。它可能有多种潜在病因。尽管其在重症患者中较为常见，患病率可达10%以上，但人们对其损伤机制知之甚少。因此，我们着手测量先前确定的循环生物标志物，以试图描述缺氧性肝炎后的损伤机制。
本研究收集了被诊断为缺氧性肝炎患者的血浆。测量了肝细胞损伤、线粒体损伤和细胞死亡的生物标志物。将这些结果与从特征明确的对乙酰氨基酚过量患者获得的结果进行比较。
在损伤高峰期，谷丙转氨酶（ALT）测得为4082±606 U/L，并在5天内逐渐下降，这与临床上观察到的缺氧性肝炎模式相符。谷氨酸脱氢酶（GDH）水平呈现类似模式，但这些患者的ALT和GDH水平均未显著高于对乙酰氨基酚患者。血浆DNA片段水平与通过ALT和miRNA - 122测量的肝细胞损伤情况相似。有趣的是，我们发现半胱天冬酶切割的细胞角蛋白 - 18显著增加；然而，在损伤最严重时全长形式大大超过切割形式（45837±12085对2528±1074 U/L）。我们还发现在后期时间点乙酰化高迁移率族蛋白B1（acHMGB1）增加，表明炎症可能起作用，但此时的细胞因子水平相对于早期时间点实际上有所下降。
缺氧性肝炎后的损伤机制涉及线粒体损伤和DNA片段化。重要的是，坏死而非凋亡是细胞死亡的主要方式。
