.As detailed in the original proposal, we set out to identify signatures in non-invasive liquid biopsy that distinguish AIH from other acute liver diseases at the time of diagnosis.
Here is a summary of our results in a structured abstract format:
Background Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease associated with substantial morbidity and mortality. Diagnosis and monitoring typically rely on liver biopsy, despite its invasiveness and limitations. Liquid biopsies hold potential as non-invasive alternatives, but their utility in AIH remains underexplored.
Objective To evaluate whether plasma-based chromatin immunoprecipitation followed by sequencing (cfChIP-seq) can detect hepatocyte-specific transcriptional activity in AIH and serve as a diagnostic and monitoring biomarker.
Design We profiled circulating cell-free nucleosomes marked by H3K4me3—a histone modification marking active and poised promoters—in plasma samples from AIH patients (43 pediatric, 49 adult), healthy controls (6 pediatric, 1240 adults), and patients diagnosed with other liver diseases (15 pediatric, 175 adult).
Results cfChIP-seq revealed immune-related hepatocyte transcriptional signatures representing intrahepatic activity unique to AIH patients. RNA-seq of matched liver biopsies further corroborates these findings. A score trained on cfChIP-seq profiles from AIH and metabolically associated steatohepatitis (MASH) patients discriminated liver autoimmune diseases (including AIH) from other liver conditions, including MASH and drug-induced liver injury (DILI), with high accuracy on independent validation cases (AUC = 0.94; 95% CI 0.84-1). Combined with a second cfChIP-seq-based classifier for AIH vs. PSC/PBC, we distinguish between AIH and biliary autoimmune diseases (AUC = 0.92; 95% CI 0.83-1).
Conclusion Plasma cfChIP-seq captures hepatocyte disease-specific gene activity in AIH patients and offers a non-invasive, accurate method for diagnosing and monitoring AIH. This approach has the potential to reduce the reliance on liver biopsy, improve diagnostic precision, and provide novel insights into AIH pathogenesis.
What is already known on this topic Autoimmune hepatitis (AIH) is a chronic liver disease diagnosed and monitored primarily through liver biopsy, an invasive procedure with associated risks and sampling errors. Non-invasive alternatives are urgently needed but have shown limited disease specificity to date.
What this study adds This study shows that cfChIP-seq,a plasma-based assay detecting gene activity in turned-over cells, including those from the liver, can accurately distinguish AIH from other liver conditions. The cfChIP-seq signal in AIH patients reflects intrahepatic immune activity and correlates with findings from liver biopsy.
How this study might affect research, practice or policy By capturing disease-specific intrahepatic disease activity, cfChIP-seq provides a positive indication of disease etiology. As such, cfChIP-seq has the potential to reduce the need for liver biopsies in AIH by providing a specific, non-invasive diagnostic tool. Its application in clinical practice could improve patient monitoring, support earlier intervention, and guide personalized management.
