The endothelial growth factor Angiopoietin-2 is an accurate prognostic biomarker in patients with acetaminophen-induced acute liver failure.

Background and Aims: Acetaminophen (APAP) overdose is the leading individual cause of acute liver failure (ALF) in the United States, with many patients rapidly progressing to hyperacute liver failure. While hepatocytes are the main target of APAP toxicity, endothelial cells (ECs) are also affected. However, the efficacy of an endothelial-specific biomarker to predict patient outcomes remains unknown. This study aimed to evaluate angiopoietin-2 (ANGPT2) as a prognostic biomarker for poor outcomes in APAP-induced ALF. Approach and Results: Using human and mouse single-cell RNA sequencing (scRNAseq) data, we found that ANGPT2 expression was significantly elevated in ECs following APAP exposure. We measured circulating ANGPT2 levels from two independent APAP-ALF cohorts: a Phoenix cohort (n=43) and a cohort from the ALF Study Group (n=80). In the Phoenix cohort, ANGPT2 levels were significantly higher in non-survivors with an AUROC of 0.938. In the ALFSG cohort, we stratified patients based on time of symptom onset finding that ANGPT2 had improved prognostic value in early-presenting patients, with day 1 and day 3 AUC values of 0.825 and 0.918, respectively. Lastly, we combined the patient cohorts (n=110) finding that ANGPT2 alone or in combination with MELD outperformed MELD alone based on AUC (ANGPT2: 0.87, MELD 0.83, ANGPT2+MELD 0.90). Conclusions: ANGPT2 is a promising prognostic biomarker for APAP-induced ALF, reflecting endothelial stress and offering superior predictive value compared to MELD alone, especially in early-presenting patients. Its capacity for predicting poor outcomes underscores its value in improving patient prognosis and therapeutic intervention strategies in APAP overdose cases. Lay Summary: Accidental or intentional overdosing on acetaminophen can cause liver injury and in severe cases acute liver failure. Under these circumstances, receiving a liver transplant may be the only remaining therapeutic option. However, a liver transplant is a major surgery and commits the patient to a lifetime of anti-rejection medication. Because there is only a limited time window to decide who will recover and who needs a transplant to survive, prognostic biomarkers are essential to identify transplant candidates as early as possible after the overdose. In this study we discovered that plasma levels of the endothelial growth factor angiopoietin-2 can accurately predict at the peak of injury who will need a liver transplant to survive. In addition, this biomarker can be rapidly measured, which allows the data to be available for clinical decision making. Highlights: Acetaminophen-induced liver injury can cause hyper-acute liver failure within 3 to 7 days with a high probability of negative outcome.Under these conditions, a liver transplant may be the only therapeutic option.In two independent cohorts, angiopoietin 2 was identified as an early prognostic biomarker for poor outcome.Angiopoietin can more accurately inform clinical management during the initial stages of hospital presentation than the MELD score.