The transition from acute liver injury (ALI) to acute liver failure (ALF) is marked by the development of serious extrahepatic complications, including hepatic encephalopathy. The mechanisms driving this progression remain largely unknown. Clinical studies suggest that this is not a consequence of increasing hepatocyte injury, as routine laboratory measures of liver injury are poorly predictive of this transition and outcome in patients with ALF. Our studies, utilizing a clinically relevant mouse model of ALF, combined with excellent work by others, suggest that this process may be triggered by damage to the hepatic vasculature. We hypothesize that this injury modifies the hepatic immune response, stimulating Kupffer cells to produce high levels of interleukin-6 (IL-6) and IL-10, which worsen hepatic encephalopathy and inhibit liver repair, respectively. Notably, both of these cytokines, which are typically hepatoprotective in animal models, are also highly elevated in ALF patients with the poorest prognosis. In this presentation, I will review the evidence in support of this hypothesis and attempt to provide some insight into utilizing these findings to identify biomarkers that are better able to predict the transition from ALI to ALF.

The presentation was originally aired on March 13, 2025.

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