Deep learning helps discriminate between autoimmune hepatitis and primary biliary cholangitis
JHEP Reports, vol. 7, pp. 101198
Abstract
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.
Authors 33
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
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Universitätsklinikum Aachen · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden · RWTH Aachen University
Affiliation as printed
Department of Diagnostic and Interventional Radiology, University Hospital RWTH Aachen, Aachen, Germany
Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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Affiliation as printed
Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, Università di Milano-Bicocca, Monza, Italy
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Affiliation as printed
Rulex Innovation Labs, Rulex Inc., Genoa, Italy
Rulex Innovation Labs, Rulex Inc., 16122 Genoa, Italy
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
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Medizinische Hochschule Hannover · ERN RARE-LIVER
Affiliation as printed
Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
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Medizinische Hochschule Hannover · ERN RARE-LIVER
Affiliation as printed
Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
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Humanitas University · IRCCS Humanitas Research Hospital
Affiliation as printed
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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Humanitas University · IRCCS Humanitas Research Hospital
Affiliation as printed
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
Department of Pathology, IRCSS Humanitas Research Hospital, Rozzano-Milan, Italy
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Humanitas University · IRCCS Humanitas Research Hospital
Affiliation as printed
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
Department of Pathology, IRCSS Humanitas Research Hospital, Rozzano-Milan, Italy
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Humanitas University · IRCCS Humanitas Research Hospital
Affiliation as printed
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
Department of Pathology, IRCSS Humanitas Research Hospital, Rozzano-Milan, Italy
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Humanitas University · IRCCS Humanitas Research Hospital
Affiliation as printed
Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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Affiliation as printed
Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
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Università degli Studi del Piemonte Orientale “Amedeo Avogadro” · Azienda Ospedaliero Universitaria Maggiore della Carita
Affiliation as printed
Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
Department of Translational Medicine, Università del Piemonte Orientale, Division of Internal Medicine, AOU Maggiore della Carità, Novara
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Affiliation as printed
Pathology Institute, PROMISE, University of Palermo, Palermo, Italy
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Affiliation as printed
Gastrointestinal and Liver Unit, Department of Health Promotion Sciences, Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
Gastroenterology Unit, Department of Health Promotion Sciences, Maternal and Infantile Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
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Affiliation as printed
Department of Medical and Surgical Sciences and Advanced Technologies, "G. F. Ingrassia", University of Catania, Catania, Italy
Department of Pathology, Hospital "Gravina e Santo Pietro", Caltagirone, Italy
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Affiliation as printed
Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
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Affiliation as printed
Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, Università di Milano-Bicocca, Monza, Italy
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Affiliation as printed
Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, Università di Milano-Bicocca, Monza, Italy
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Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
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Affiliation as printed
Rulex Innovation Labs, Rulex Inc., Genoa, Italy
Rulex Innovation Labs, Rulex Inc., 16122 Genoa, Italy
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Inserm · Université Paris-Est Créteil · Centre Hospitalier Universitaire Henri-Mondor · Assistance Publique – Hôpitaux de Paris · Hôpitaux Universitaires Henri-Mondor · Hôpital Albert-Chenevier · Institut Mondor de Recherche Biomédicale
Affiliation as printed
Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, Créteil, France
Inserm, U955, Team 18, Créteil, France
Université Paris Est Créteil, INSERM, IMRB, Créteil, France
Assistance Publique-Hôpitaux de Paris, Henri Mondor-Albert Chenevier University Hospital, Department of Pathology, CréteilFrance
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National and Kapodistrian University of Athens · Aretaeio Hospital · Newcastle University
Affiliation as printed
Department of Pathology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Affiliation as printed
Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, Università di Milano-Bicocca, Monza, Italy
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Affiliation as printed
Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, Università di Milano-Bicocca, Monza, Italy
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Affiliation as printed
Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, Università di Milano-Bicocca, Monza, Italy
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Pietro Invernizzi corresponding
Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
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Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda · University of Milano-Bicocca
Affiliation as printed
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Liver Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Milano, Italy
Liver Unit, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
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Jakob Nikolas Kather corresponding
University Hospital Heidelberg · National Center for Tumor Diseases · University Hospital Carl Gustav Carus · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Department of Medicine 1, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
Else Kroener Fresenius Center for Digital Health, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
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