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      Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report

      research-article
      1 , 2 , * , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 33 , 14 , 15 , 16 , 17 , 18 , 2 , 19 , 20 , 1 , 2 , 1 , 2 , 3 , 21 , 22 , 23 , 24 , 25 , 26 , 7 , 27 , 28 , 29 , 1 , 2 , 30 , * , 31 , 31 , 32
      Journal of hepatology
      Liver injury, hepatotoxicity, drug-induced liver injury, DILI, autoimmune hepatitis, AIH, DI-ALH, Drug-induced autoimmune-like hepatitis, epidemiology, diagnosis, management, outcome

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          Summary

          Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.

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          Most cited references88

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          EASL Clinical Practice Guidelines: Autoimmune hepatitis.

          (2015)
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            EASL Clinical Practice Guidelines: Drug-induced liver injury

            Idiosyncratic (unpredictable) drug-induced liver injury is one of the most challenging liver disorders faced by hepatologists, because of the myriad of drugs used in clinical practice, available herbs and dietary supplements with hepatotoxic potential, the ability of the condition to present with a variety of clinical and pathological phenotypes and the current absence of specific biomarkers. This makes the diagnosis of drug-induced liver injury an uncertain process, requiring a high degree of awareness of the condition and the careful exclusion of alternative aetiologies of liver disease. Idiosyncratic hepatotoxicity can be severe, leading to a particularly serious variety of acute liver failure for which no effective therapy has yet been developed. These Clinical Practice Guidelines summarize the available evidence on risk factors, diagnosis, management and risk minimization strategies for drug-induced liver jury.
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              EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.

              The term acute liver failure (ALF) is frequently applied as a generic expression to describe patients presenting with or developing an acute episode of liver dysfunction. In the context of hepatological practice, however, ALF refers to a highly specific and rare syndrome, characterised by an acute abnormality of liver blood tests in an individual without underlying chronic liver disease. The disease process is associated with development of a coagulopathy of liver aetiology, and clinically apparent altered level of consciousness due to hepatic encephalopathy. Several important measures are immediately necessary when the patient presents for medical attention. These, as well as additional clinical procedures will be the subject of these clinical practice guidelines.
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                Author and article information

                Journal
                8503886
                4786
                J Hepatol
                J Hepatol
                Journal of hepatology
                0168-8278
                1600-0641
                15 December 2023
                September 2023
                08 May 2023
                21 December 2023
                : 79
                : 3
                : 853-866
                Affiliations
                [1 ]Servicio Aparato Digestivo and Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
                [2 ]Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
                [3 ]Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine; NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
                [4 ]Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, Netherlands
                [5 ]Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
                [6 ]Faculty of Medicine of the University of Porto, Porto, Portugal
                [7 ]Department of Medicine II, LMU Klinikum Munich, Munich, Germany
                [8 ]Eli Lilly and Company, Indianapolis, IN, USA
                [9 ]Università della Svizzera Italiana, Facoltà di Scienze Biomediche. Epatocentro, Lugano, Switzerland
                [10 ]Department of Medicine, University Medical Center Hamburg-Eppendorf. Hamburg Center for Translational Immunology. Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
                [11 ]Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, USA
                [12 ]APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, FHU Hepatinov, Villejuif, France
                [13 ]Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
                [14 ]Department of Visceral Surgery and Medicine, Inselspital University Hospital and University of Bern, Bern, Switzerland
                [15 ]Department of Gastroenterology and Hepatology, St. John’s Medical College Hospital, Bangalore, India
                [16 ]Departments of Medicine and Surgery, Section of Gastroenterology and Hepatology and Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, United States
                [17 ]Hannover Medical School, Centre of ERN RARE-LIVER, Hannover, Germany
                [18 ]Department of Internal Medicine, University Medical Center Hamburg-Eppendorf; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
                [19 ]Liver Unit, Hospital Clínic de Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Institut d’ Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
                [20 ]Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA
                [21 ]Institute of Liver Studies, King’s College Hospital, London, UK
                [22 ]University School of Medicine & Indiana University Health, Indianapolis, Indiana, USA
                [23 ]NIHR Birmingham BRC, Institute of Immunology and Immunotherapy, Centre for Liver and Gastrointestinal Research; Liver Unit, University Hospitals Birmingham National Health Service Foundation Trust Queen Elizabeth; Institute of Immunology and Immunotherapy; Institute of Applied Health Research, University of Birmingham, Birmingham, UK
                [24 ]Division of Hepatology and Nutrition, Food and Drug Administration, Silver Spring, Maryland, USA
                [25 ]Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
                [26 ]Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, United States
                [27 ]Center for Liver and Gastro Research & National Institute of Health Research Birmingham Biomedical Research Centre, University of Birmingham; Centre for Rare Disease and ERN Rare Liver Centre, Liver Transplant and Hepatobiliary Unit, University Hospital Birmingham NHS Foundation Trust, UK
                [28 ]Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK
                [29 ]Medicina Interna ed Epatologia, Università degli Studi di Palermo, Palermo, Italy
                [30 ]Platform ISCiii for Clinical Research and Clinical Trials SCReN UICEC- IBIMA, Málaga, Spain
                [31 ]MowatLabs, Faculty of Life Sciences and Medicine, King’s College London, King’s College Hospital, London, United Kingdom
                [32 ]Faculty of Medicine, University of Iceland, Department of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
                [33 ]Mechanistic Safety, Global Drug Development, Novartis, Basel, Switzerland
                Author notes
                [†]

                Co-first authors

                [#]

                Shared senior authorship

                Authors’ contributions

                Conceptualization, thematic structure, introduction, scientific committee (RJA, GPA, YdB, RL MIL, DV, GMV, EA, ESB); Terminology and case definitions (RJA, MM,ESB, YdB, MR-D, BT); Diagnosis (RL, PHH, AG, YZ, DK, MS, CS, GPA); Biomarkers (GS, SW, NC, DV, RT); Natural History, Management (MH, GK-U, EDM, HD, AR, YO, MG-C); Consensus (EB, AL, MCL, PT, MIL, RJA); Gaps and research (RF, GMV, MA, MIL, JV); Critical revision of the manuscript (all authors); Obtaining funding (RJA, MIL, DV, GMV); Overview (RJA,MIL,GPA,ESB).

                [* ]Corresponding authors. Addresses: Medicine Department, School of Medicine, Boulevard Louis Pasteur 32, Universidad de Málaga, 29071 Málaga, Spain; Tel.: +34-952-131615, (R.J. Andrade) or Pharmacology Department, School of Medicine, Boulevard Louis Pasteur 32, Universidad de Málaga, Málaga, 29071, Spain (M.I. Lucena), andrade@ 123456uma.es (R.J. Andrade), lucena@ 123456uma.es (M.I. Lucena).
                Article
                NIHMS1942067
                10.1016/j.jhep.2023.04.033
                10735171
                37164270
                3f8d1b48-4cb2-43b9-a7fa-0087f4a185de

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Article

                Gastroenterology & Hepatology
                liver injury,hepatotoxicity,drug-induced liver injury,dili,autoimmune hepatitis,aih,di-alh,drug-induced autoimmune-like hepatitis,epidemiology,diagnosis,management,outcome

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