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

Acetaminophen (APAP) overdose is the leading 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. Using human and mouse single-cell RNA sequencing data, we found that ANGPT2 expression was significantly elevated in ECs following APAP exposure. We measured circulating ANGPT2 levels in two independent APAP-ALF cohorts: a cohort from Phoenix (n = 43) and the ALF Study Group (n = 80). In the Phoenix cohort, ANGPT2 levels were significantly higher in non-survivors with an area under the receiver-operating-characteristic-curve (AUROC) of 0.938. In the ALF Study Group 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 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 Model for End-Stage Liver Disease (MELD) score 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.