Acute Liver Failure Etiology Determines Long-Term Outcomes in Patients Undergoing Liver Transplantation: An Analysis of the UNOS Database

<b>Background</b>: Acute liver failure (ALF) involves rapid liver injury, often leading to multi-organ failure. Liver transplantation (LT) has improved survival rates, with U.S. rates reaching 92%. This study analyzes UNOS data (2002-2020) to evaluate long-term survival and identify risk factors affecting waitlist and post-LT outcomes in ALF patients. <b>Methods</b>: A retrospective analysis was performed on adult ALF patients waitlisted for LT (Status 1/1A). ALF etiologies, including viral infections, drug-induced liver injury (DILI), acetaminophen (APAP) overdose, autoimmune hepatitis (AIH), Wilson disease (WD), and unknown causes, were assessed with patient and donor characteristics. Kaplan-Meier and Cox regression analyses identified predictors of patient and graft survival. Sensitivity analysis confirmed the model's robustness. <b>Results</b>: We identified 2759 ALF patients. APAP (HR 1.7; <i>p</i> < 0.001) and unknown etiology (HR 1.3; <i>p</i> = 0.037) were linked to higher waitlist removal risk, while WD (HR 0.36; <i>p</i> < 0.001) increased LT probability. Among 2014 LT recipients, WD showed improved survival (HR 0.53; <i>p</i> = 0.002). Black/African American race (HR 1.47; <i>p</i> < 0.001), diabetes (HR 1.81; <i>p</i> < 0.001), and encephalopathy (HR 1.27; <i>p</i> < 0.001) predicted higher mortality. AIH had the lowest 1- and 10-year survival (83% and 62%), while APAP had the lowest 5-year survival (76%). WD had the highest graft survival at 1, 5, and 10 years (93%, 88%, and 80%). <b>Conclusions</b>: ALF etiology significantly affects survival outcomes. AIH and APAP are associated with worse survival, while WD shows favorable outcomes. Tailored post-LT management is essential to improve survival in ALF patients.