From prognostication to therapeutics: Four key questions to accelerate the development of therapeutics for patients with acute-on-chronic liver failure

Acute-on-chronic liver failure (ACLF) has come a long way as a clinical concept within the hepatology and liver transplant communities. Though the term was proposed in 1995, the first recognition of the entity along with a consensus definition emerged in 2009. Subsequently, the entity has sparked great interest, inspired several consensus conferences, and inspired national societies to form professional ACLF affinity groups (eg, special interest group). Multicenter consortia have been established all over the world to study this condition, including the North American Consortium for the Study of End-Stage Liver Disease, Chronic Liver Failure consortium, Asian Pacific Association for the Study of Liver Diseases ACLF Research Consortium, Chronic Liver disease Evolution And Registry for Events and Decompensation, and the LiverHope Consortium. Collectively, these consortia have enrolled tens of thousands of patients with or at risk for ACLF across dozens of countries and characterized in detail the predictors, pathogenesis, and progression of patients with ACLF. Perhaps most importantly, they have produced essential data characterizing the excess morbidity and mortality that patients with ACLF face, making a compelling case for the urgent need for therapeutic strategies for this condition.