Future directions in acute liver failure

Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (i.e., an international normalized ratio of prothrombin time (INR) of ≥ 1.5) and any degree of mental status alteration (hepatic encephalopathy, HE). As a rare, orphan disease, it seemed an obvious target for a multi-center network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3,364 adult patients were enrolled in the study registry (2,614 ALF and 857 acute liver injury—INR 2.0 but no encephalopathy--ALI) and more than 150,000 bio-samples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, four prospective substudies were conducted and published, two interventional (N-acetylcysteine (NAC) and ornithine phenylacetate (OPA)), one prognostic (13C-methacetin breath test (MBT)), and one mechanistic (rotational thromboelastometry (ROTEM)). To review ALFSG’s accomplishments and consider next steps, a two-day in-person conference was held at UT Southwestern Medical Center, Dallas, Texas, entitled “Acute Liver Failure: Science and Practice,” in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.