Blasi Annabel, Patel Vishal C, Adelmeijer Jelle, Azarian Sarah, Aziz Fatima, Fernández Javier, Bernal William, Lisman Ton
Anesthesiology Department, Hospital Clínic, University of Barcelona, and Institute d'Investigacions Biomèdica Agustí Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Institute of Liver Studies & Transplantation, King's College Hospital Foundation NHS Trust, London, United Kingdom.
JHEP Rep. 2019 Jun 28;1(3):179-187. doi: 10.1016/j.jhepr.2019.06.002. eCollection 2019 Sep.
Acute-on-chronic liver failure (ACLF) is a recently (re)defined syndrome of acute decompensation of cirrhosis that presents with extrahepatic organ failure(s) and poor outcome. Given the prominent role of inflammation and activation of coagulation in ACLF, we hypothesized that ACLF might be characterized by the generation of neutrophil extracellular traps (NETs), that could drive both activation of coagulation and progression of organ failure.
We measured markers of circulating DNA, activation of coagulation, inflammation, and oxidative stress in 52 patients with acute decompensation (AD) of cirrhosis and 57 patients with ACLF on admission, and compared levels with 40 healthy controls.
All analytes were higher in patients compared to controls. Plasma levels of cell-free DNA, but not of the specific NET marker myeloperoxidase-DNA complexes were higher in patients with ACLF compared to AD cirrhosis. In addition, TAT complexes (coagulation), IL-6 (inflammation), and TBARS (oxidative stress) were higher in ACLF compared to AD. Markers for activation of coagulation were not associated with circulating DNA, IL-6, or TBARS. In contrast, levels of circulating DNA, IL-6, and TBARS were higher in patients with more severe disease, higher in patients with organ failure, and higher in patients that died within 30 days of admission. Importantly, myeloperoxidase-DNA levels did not differ between patients with complications and poor outcome.
Collectively, we show that cell-free DNA, inflammation, and oxidative stress are associated with outcomes in AD and ACLF, but not with activation of coagulation. Our data argue against a role of NETs in activation of coagulation and in progression of organ failure in patients with AD and ACLF.
Acute-on-chronic liver failure is a devastating syndrome that can follow acute decompensation of chronic liver disease. Herein, we demonstrate that these patients accumulate DNA released from dying cells in their blood, and that the quantity of this DNA is related to the outcome of disease. We also show that outcome of disease is not related to recently described neutrophil extracellular traps, which have been shown in animal models to play vital roles in the progression of liver diseases.
慢加急性肝衰竭（ACLF）是一种最近（重新）定义的肝硬化急性失代偿综合征，伴有肝外器官衰竭且预后不良。鉴于炎症和凝血激活在ACLF中起重要作用，我们推测ACLF可能以中性粒细胞胞外诱捕网（NETs）的形成为特征，这可能会推动凝血激活和器官衰竭进展。
我们在52例肝硬化急性失代偿（AD）患者和57例ACLF患者入院时测量了循环DNA、凝血激活、炎症和氧化应激的标志物，并与40名健康对照者的水平进行比较。
与对照组相比，患者的所有分析物水平均较高。与AD肝硬化患者相比，ACLF患者的血浆游离DNA水平较高，但特异性NET标志物髓过氧化物酶-DNA复合物水平无差异。此外，与AD相比，ACLF患者的凝血酶-抗凝血酶复合物（凝血）、白细胞介素-6（炎症）和硫代巴比妥酸反应物（氧化应激）水平更高。凝血激活标志物与循环DNA、白细胞介素-6或硫代巴比妥酸反应物无关。相比之下，病情较重、有器官衰竭以及入院30天内死亡的患者，其循环DNA、白细胞介素-6和硫代巴比妥酸反应物水平更高。重要的是，并发症患者和预后不良患者的髓过氧化物酶-DNA水平无差异。
总体而言，我们表明游离DNA、炎症和氧化应激与AD和ACLF的预后相关，但与凝血激活无关。我们的数据表明NETs在AD和ACLF患者的凝血激活和器官衰竭进展中不起作用。
慢加急性肝衰竭是一种灾难性综合征，可继发于慢性肝病急性失代偿。在此，我们证明这些患者血液中积累了死亡细胞释放的DNA，且这种DNA的数量与疾病预后相关。我们还表明疾病预后与最近描述的中性粒细胞胞外诱捕网无关，而在动物模型中已证明其在肝病进展中起重要作用。
