Alcohol-Associated Hepatitis: Translating Pathophysiology into Targeted Clinical Trials

Abstract

Purpose of review: Alcohol-associated hepatitis (AH) is a severe manifestation of alcohol-associated liver disease with high short-term mortality and limited treatment options. This review synthesizes mechanistic insights into AH pathogenesis and evaluates both failed and emerging clinical trials to guide targeted therapeutic development. Recent findings: AH arises from intertwined mechanisms including hepatotoxicity, oxidative stress, inflammation, impaired regeneration, and gut-liver axis disruption. Trials targeting inflammatory cytokines or apoptosis pathways have not demonstrated survival benefit and raised safety concerns. Current investigations emphasize therapies that mitigate oxidative stress, enhance hepatocyte regeneration, and restore gut-liver integrity. Novel agents such as interleukin-22 (IL-22), granulocyte colony-stimulating factor (G-CSF), probiotics, fecal microbiota transplantation (FMT), larsucosterol, and farnesoid X receptor (FXR) agonists are under evaluation. Summary: Although no effective pharmacologic therapy is yet available, advances in understanding AH biology provide a framework for mechanism-based strategies. Integrating hepatology with addiction medicine and incorporating stratified trial designs will be essential to advance effective therapies.