Generation of neutrophil extracellular traps in patients with acute liver failure is associated with poor outcome.

Background and aims 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. Methods A total of 676 patients with ALF (INR ≥1.5) or severe acute liver injury (ALI; INR ≥2.0) were recruited from the US 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. Levels of cell-free DNA 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. Results Levels of cell-free DNA were 7.1-fold, and MPO-DNA complexes 2.5-fold, higher in patients with ALF compared to healthy controls. Cell-free DNA 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 liver transplantation. Liver tissue of ALF patients stained positive for NETs in 12/18 evaluable patients. Conclusions 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.