Acute Liver Failure with Determinate rather than Indeterminate Etiology Facilitates Therapy and May Avoid Liver Transplantation: A Critical Analysis

Acute liver failure (ALF) is a disorder with various etiologies. Although the causes leading to this disruptive condition are well documented in published ALF cohorts, there is significant concern among patients who experience ALF with indeterminate causes, an issue requiring thorough analysis. This review aimed to analyze cohort studies on ALF with a focus on unknown causes leading to classification as indeterminate ALF. The analysis revealed that, among 67 worldwide adult and pediatric ALF cohorts, indeterminate causes of ALF ranged from 2% to 100%, with an average of 30%. Among the 13 pediatric ALF cohorts, the corresponding range was 22% to 100%, with an average of 47%, while among the 55 adult ALF cohorts, the range was 2% to 78%, with an average of 26%. The percentage values were higher in pediatric cohorts due to the higher incidence of rare genetic causes compared to adult patients. Notably, higher rates of indeterminate causes were found in cohorts studied before the availability of diagnostic serologic screening parameters and polymerase chain reaction techniques for various hepatitis virus infections. Patients with indeterminate ALF may not have received a specific treatment that, if effective, could have helped prevent liver transplantation. It is concluded that, in future cases, all efforts must be undertaken to clearly establish the cause of severe liver injury, enabling effective therapy when available and helping reduce the risk of progression to ALF and the need for liver transplantation.