Surgical Research Laboratory, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Hume-Lee Transplant Center of Virginia Commonwealth University, Richmond, Virginia, USA.
Hepatology. 2022 Mar;75(3):623-633. doi: 10.1002/hep.32174. Epub 2021 Dec 12.
Acute liver failure (ALF) is characterized by significant changes in the hemostatic system and by systemic inflammation. The formation of neutrophil extracellular traps (NETs), in which an activated neutrophil expels its DNA, histones, and granular enzymes, such as myeloperoxidase (MPO), has been associated with immune-mediated and thrombotic diseases. We hypothesized that formation of NETs in patients with ALF contributes to progression of disease.
A total of 676 patients with ALF (international normalized ratio [INR], ≥1.5) or severe acute liver injury (ALI; INR, ≥2.0) were recruited from the U.S. ALF Study Group Registry between 2011 and 2018, of whom 308 patients (45.6%) had acetaminophen-induced ALF. Up to 21 days after admission, 483 patients (71.5%) survived without liver transplantation (LT). Levels of cell-free DNA (cfDNA) and the specific NET marker MPO-DNA complexes were measured in plasma samples obtained on admission and compared to levels in healthy controls. In addition, liver tissue obtained at transplantation of 20 ALF patients was stained for NETs. Levels of cfDNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. cfDNA levels were not associated with 21-day transplant-free survival, but were higher in those patients with more-severe disease on admission, as reflected by various laboratory and clinical parameters. MPO-DNA levels were 30% higher in patients with ALF who died or required urgent LT. Liver tissue of ALF patients stained positive for NETs in 12 of 18 evaluable patients.
Here, we provide evidence for NET formation in patients with ALF. Elevated plasma levels of MPO-DNA complexes in patients with ALF were associated with poor outcome, which suggests that NET formation contributes to disease progression.
急性肝衰竭（ALF）的特征是止血系统和全身炎症发生显著变化。中性粒细胞胞外诱捕网（NETs）的形成，其中激活的中性粒细胞排出其 DNA、组蛋白和颗粒酶，如髓过氧化物酶（MPO），与免疫介导和血栓形成疾病有关。我们假设 ALF 患者中 NETs 的形成会导致疾病的进展。
2011 年至 2018 年，美国 ALF 研究组登记处共招募了 676 名 ALF（国际标准化比值 [INR]≥1.5）或严重急性肝损伤（ALI；INR≥2.0）患者，其中 308 名患者（45.6%）为对乙酰氨基酚诱导的 ALF。入院后 21 天内，483 名患者（71.5%）无肝移植（LT）存活。入院时采集血浆样本，测量游离细胞 DNA（cfDNA）和特定 NET 标志物 MPO-DNA 复合物的水平，并与健康对照进行比较。此外，对 20 名 ALF 患者移植的肝组织进行 NET 染色。与健康对照组相比，ALF 患者的 cfDNA 水平高 7.1 倍，MPO-DNA 复合物高 2.5 倍。cfDNA 水平与 21 天无移植存活率无关，但与入院时疾病更严重的患者更高，这反映在各种实验室和临床参数上。cfDNA 水平在死亡或需要紧急 LT 的 ALF 患者中升高 30%。18 例可评估患者中有 12 例 ALF 患者的肝组织 NETs 染色阳性。
在这里，我们提供了 ALF 患者 NET 形成的证据。ALF 患者中 MPO-DNA 复合物的血浆水平升高与不良预后相关，这表明 NET 形成有助于疾病进展。
