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Background & Aims: Biliary abnormalities in autoimmune hepatitis (AIH) and interface hepatitis in primary biliary cholangitis (PBC) occur frequently, and misinterpretation may lead to therapeutic mistakes with a negative impact on patients. This study investigates the use of a deep learning (DL)-based pipeline for the diagnosis of AIH and PBC to aid differential diagnosis., Methods: We conducted a multicenter study across six European referral centers, and built a library of digitized liver biopsy slides dating from 1997 to 2023. A training set of 354 cases (266 AIH and 102 PBC) and an external validation set of 92 cases (62 AIH and 30 PBC) were available for analysis. A novel DL model, the autoimmune liver neural estimator (ALNE), was trained on whole-slide images (WSIs) with H&E staining, without human annotations. The ALNE model was evaluated against clinico-pathological diagnoses and tested for interobserver variability among general pathologists., Results: The ALNE model demonstrated high accuracy in differentiating AIH from PBC, achieving an area under the receiver operating characteristic curve of 0.81 in external validation. Attention heatmaps showed that ALNE tends to focus more on areas with increased inflammation, associating such patterns predominantly with AIH. A multivariate explainable ML model revealed that PBC cases misclassified as AIH more often had ALP values between 1 × upper limit of normal (ULN) and 2 × ULN, coupled with AST values above 1 × ULN. Inconsistency among general pathologists was noticed when evaluating a random sample of the same cases (Fleiss's kappa value 0.09)., Conclusions: The ALNE model is the first system generating a quantitative and accurate differential diagnosis between cases with AIH or PBC., Impact and Implications: This study demonstrates the significant potential of the autoimmune liver neural estimator model, a transformer-based deep learning system, in accurately distinguishing between autoimmune hepatitis and primary biliary cholangitis using digitized liver biopsy slides without human annotation. The scientific justification for this work lies in addressing the challenge of differentiating these conditions, which often present with overlapping features and can lead to therapeutic mistakes. In addition, there is need for quantitative assessment of information embedded in liver biopsies, which are currently evaluated on qualitative or semi-quantitative methods. The results of this study are crucial for pathologists, researchers, and clinicians, providing a reliable diagnostic tool that reduces interobserver variability and improves diagnostic accuracy of these conditions. Potential methodological limitations, such as the diversity in scanning techniques and slide colorations, were considered, ensuring the robustness and generalizability of the findings., Competing Interests: AG declares consulting services for Ipsen and CAMP4 Therapeutics, and speaker fees from Advanz Pharma. JNK declares consulting services for Owkin, France; DoMore Diagnostics, Norway, Panakeia, UK and Histofy, UK; furthermore, he holds shares in StratifAI GmbH and has received honoraria for lectures by AstraZeneca, Bayer, Eisai, MSD, BMS, Roche, Pfizer, and Fresenius. AL declares consulting fees from Advanz Pharma, GSK, AlfaSigma, Takeda, Ipsen, and Albireo Pharma, and speaker fees from Gilead, Abbvie, MSD, Advanz Pharma, AlfaSigma, GSK, and Incyte. AL declares consulting fees from Advanz Pharma, GSK, AlfaSigma, Takeda, Ipsen, and Albireo Pharma, and speaker fees from Gilead, Abbvie, MSD, Advanz Pharma, AlfaSigma, GSK, and Incyte. MC declares consulting services for Advanz Pharma, Cymabay, GSK, Falk, Ipsen, Albireo, Mirum Pharma, Perspectum, Echosens, Gentic s.p.a. DV works for Rulex, MM is the CEO of Rulex. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)