A cfChIP-seq liquid biopsy for the diagnosis of autoimmune hepatitis

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disorder characterized by immune-mediated hepatocyte injury, associated with significant morbidity and mortality. Patients undergo liver biopsy to confirm diagnosis and affirm subsequent remission. Although liquid biopsies have emerged as promising non-invasive alternatives in oncology, their applicability in liver diseases remains largely unexplored. Here, we use plasma chromatin immunoprecipitation and sequencing (cfChIP-seq) to analyze cell-free nucleosomes carrying an active histone modification, which reports on gene transcription in the dying cells. Comparing cfChIP-seq profiles of plasma samples from AIH patients (46 pediatric and 34 adult) with those of a control group (79/10 adult and pediatric patients, respectively), we identify immune-related transcriptional processes activated in the hepatocytes of AIH patients and verify these using RNA-seq on matched liver biopsies. We develop a classifier that distinguishes plasma cfChIP-seq profiles of AIH from other conditions involving liver injury. This classifier achieves a high level of performance, with an area under the ROC curve (AUC) of 0.92. Our work demonstrates the potential of plasma cfChIP-seq as a non-invasive diagnostic tool for AIH, offering opportunities to reduce the need for liver biopsies, enhance diagnostic precision, and advance our understanding of AIH pathogenesis.