Environmental shaping of tolerance failure in autoimmune liver diseases: a phenotype-specific framework with primary biliary cholangitis as the strongest model

Autoimmune liver diseases (primary biliary cholangitis, PBC; primary sclerosing cholangitis, PSC; autoimmune hepatitis, AIH) are distinct organ-specific autoimmune disorders. They share loss of immune tolerance as a central mechanism, but differ in target tissue, age of onset, genetic background, and environmental associations. This review examines how environmental exposures may shape tolerance failure and tissue injury in each disease. The evidence is strongest in PBC, where smoking, recurrent urinary tract infections, xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), cholangiocyte apotope biology, and emerging exposomic data point in a similar direction. PSC is best interpreted through gut-liver-microbiome interactions. AIH, including pediatric AIH, has a weaker and more heterogeneous environmental signal and overlaps diagnostically with drug-induced autoimmune-like hepatitis (DI-ALH). We also discuss limitations of current exposomic methods and disease-specific research priorities. Environmental factors do not replace loss of tolerance as the central paradigm; they help explain how tolerance failure may become sustained and tissue-selective.