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Ayadi S, Merhaben S, Hadj Kacem L, Rammeh S, Mensi A, Belhadj Mabrouk E, Zaimi Y, Mouelhi L. Infliximab-induced autoimmune-like hepatitis in a patient with Crohn's disease: a case report. Future Sci OA 2025; 11:2482496. [PMID: 40166860 PMCID: PMC11970776 DOI: 10.1080/20565623.2025.2482496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 03/12/2025] [Indexed: 04/02/2025] Open
Abstract
As medical treatments advance, drug-induced liver injury (DILI) becomes more prevalent, occurring at a rate of 14 to 19 cases per 100,000 individuals. We present a unique case of a female patient with Crohn's disease developing autoimmune-like hepatitis during infliximab treatment. Autoimmune-like hepatitis can pose diagnostic challenges when distinguishing it from idiopathic autoimmune hepatitis. The diagnostic journey, including the absence of distinct pathognomonic criteria, is discussed. The only discriminative factor observed was the absence of relapse in autoimmune-like hepatitis patients after discontinuation of immuno-suppressive therapy. The case highlights the importance of recognizing this adverse event in clinical practice and underscores the challenges in balancing the benefits and risks of powerful immunomodulatory agents.
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Affiliation(s)
- Shema Ayadi
- Gastroenterology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Salma Merhaben
- Gastroenterology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Linda Hadj Kacem
- Histopathology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Soumaya Rammeh
- Histopathology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Asma Mensi
- Gastroenterology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | | | - Yosra Zaimi
- Gastroenterology Department, Charles Nicolle Hospital, Tunis, Tunisia
| | - Leila Mouelhi
- Gastroenterology Department, Charles Nicolle Hospital, Tunis, Tunisia
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Ikeda K, Fukui S, Kobayashi M, Shimada Y, Nakazawa Y, Mizutani H, Nisiura Y, Suga D, Moritani I, Yamanaka Y, Inoue H, Fukutome K, Shiraki K. Clinicopathological characteristics of autoimmune‑like hepatitis after drug‑induced liver injury. Biomed Rep 2025; 22:75. [PMID: 40083601 PMCID: PMC11904752 DOI: 10.3892/br.2025.1953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/10/2025] [Indexed: 03/16/2025] Open
Abstract
Autoimmune hepatitis (AIH) can be induced by drugs, but the underlying mechanisms remain unclear. The present study attempted to elucidate the clinicopathological characteristics of autoimmune-like hepatitis following drug-induced liver injury (DILI-ALH). The medical records of 57 patients diagnosed with AIH at Mie General Medical Center (Yokkaichi, Japan) were retrospectively reviewed, paying particular attention to the history of drug administration. Patients were classified into three groups: De novo AIH, drug-induced ALH (DI-ALH) and DILI-ALH. DILI-ALH was newly defined as cases in which the patient had a history of DILI and where the liver injury initially improved after drug discontinuation, but later worsened and was diagnosed as AIH. Of the 57 patients diagnosed with AIH, 42 patients were included in this study. De novo AIH was diagnosed in 29 patients, DI-ALH in 10 patients and DILI-ALH in 3 patients. Suspected causative drugs for drug-related pathologies were variable, including statins, health foods and supplements. No significant differences in sex or mean age were observed for DI-ALH and DILI-ALH compared with those for AIH. Distinguishing DI-ALH or DILI-ALH from AIH serologically and pathologically is difficult. No significant differences in the number of steroids used or the recurrence rate were observed between any groups. These findings suggest that drugs may present a more diverse cause of ALH than generally predicted. In particular, some AIH cases clearly present with DILI-ALH. Clarifying the involvement of drugs in the pathogenesis of AIH and establishing guidelines for diagnosis and treatment represent important issues for the future.
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Affiliation(s)
- Kohei Ikeda
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Shunsuke Fukui
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Mayu Kobayashi
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Yasuaki Shimada
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Yuichi Nakazawa
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Hiroki Mizutani
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Yuki Nisiura
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Daisuke Suga
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Isao Moritani
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Yutaka Yamanaka
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Hidekazu Inoue
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Kazuo Fukutome
- Department of Pathology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
| | - Katsuya Shiraki
- Department of Gastroenterology, Mie Prefectural General Medical Center, Yokkaichi, Mie 510-8561, Japan
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Gleeson D, Bornand R, Brownlee A, Dhaliwal H, Dyson JK, Hails J, Henderson P, Kelly D, Mells GF, Miquel R, Oo YH, Sutton A, Yeoman A, Heneghan MA. British Society of Gastroenterology guidelines for diagnosis and management of autoimmune hepatitis. Gut 2025:gutjnl-2024-333171. [PMID: 40169244 DOI: 10.1136/gutjnl-2024-333171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 10/22/2024] [Indexed: 04/03/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if untreated, often leads to cirrhosis, liver failure and death. The last British Society of Gastroenterology (BSG) guideline for the management of AIH was published in 2011. Since then, our understanding of AIH has advanced in many areas. This update to the previous guideline was commissioned by the BSG and developed by a multidisciplinary group. The aim of this guideline is to review and summarise the current evidence, in order to inform and guide diagnosis and management of patients with AIH and its variant syndromes. The main focus is on AIH in adults, but the guidelines should also be relevant to older children and adolescents.
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Affiliation(s)
- Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Science, University of Sheffield, Sheffield, UK
| | | | | | - Harpreet Dhaliwal
- Department of Gastroenterology, Manchester Royal Infirmary, Manchester, UK
| | - Jessica K Dyson
- Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Janeane Hails
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
| | - Paul Henderson
- Royal Hospital for Children and Young People, Edinburgh, UK
| | - Deirdre Kelly
- Birmingham Women's & Children's Hospital, Birmingham, UK
- University of Birmingham, Birmingham, UK
| | - George F Mells
- Division of Gastroenterology and Hepatology, Addenbrooke's Hospital, Cambridge, UK
- Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, King's College London, London, UK
| | - Ye H Oo
- Centre for Liver and Gastroenterology research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Biomedical Research Centre, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, UK
- Centre for Rare Diseases, European Reference Network on Hepatological Diseases (ERN-RARE-LIVER) centre, Birmingham, UK
| | - Anthea Sutton
- Sheffield Centre for Health and Related Research, The University of Sheffield, Sheffield, UK
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Das S, Sood V, Rastogi A, Agarwal N, Kaul S, Yadav D, Lal BB, Khanna R, Alam S. Clinico-Pathological Spectrum of Hepatitis A Virus-Induced Autoimmune-Like Hepatitis in Children. J Viral Hepat 2024. [PMID: 39484867 DOI: 10.1111/jvh.14028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 11/03/2024]
Abstract
There is limited evidence that hepatitis A virus (HAV) infection can trigger hepatic autoimmunity, but this area remains largely unexplored. This study was thus planned with the aim to compare HAV-induced autoimmune-like hepatitis (HAV-ALH) with HAV-related liver dysfunction (HAV-acute viral hepatitis or HAV-AVH) and classical autoimmune hepatitis (AIH). This was a retrospective review of 46 patients with HAV infection who underwent liver biopsy (including 17 cases of HAV-ALH: diagnosis based on histopathology), and they were compared to 46 cases of age- and gender-matched classical AIH. Overall, HAV cohort (n = 46) had higher prevalence of pruritus, higher bilirubin levels, higher proportion of cholestasis, lower IgG levels, higher seronegativity and lack of disease recurrence, while the classical AIH group had higher proportion/severity of interface hepatitis, fibrosis, necrosis and pseudorosetting (p < 0.05). In comparison to the classical HAV-AVH group, HAV-ALH group had higher AST levels, higher presence of autoantibodies, and higher prevalence of severe zone 3 perivenulitis and marked pseudorosetting on histology (p < 0.05). Also, HAV-ALH group, in comparison to the AIH group, had more pruritus (OR 7.29, p < 0.004) and more seronegativity (41% vs. 13%, p < 0.031), while duration of illness (p < 0.003), IgG (p < 0.001) levels and liver stiffness measurement (p < 0.006) were significantly higher in AIH group (versus the HAV-ALH and HAV-AVH groups). Histologically, in comparison to AIH, HAV-ALH group had significantly less interface hepatitis (OR 0.03, p < 0.001) and fibrosis (OR 0.08, p < 0.001) and significantly more cholestasis (OR 4.5, p < 0.021). HAV infection can act as a potential trigger for immune-mediated hepatic damage, akin to drug-induced autoimmune-like hepatitis. Larger multicentric studies are needed to further explore this aspect.
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Affiliation(s)
- Samannay Das
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vikrant Sood
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Neha Agarwal
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sanjeevani Kaul
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Deepika Yadav
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Bikrant Bihari Lal
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajeev Khanna
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Ma D, Liu X, Ai G, Pan W, Liu L, Huang Y, Liao Y, Lu Y, Zhang Z, Zhou H, Huang Z, Hao X, Shu S, Fang F. The etiology and differential diagnosis of "autoimmune hepatitis-like liver disease" in children: a single-center retrospective study. Front Pediatr 2024; 12:1377333. [PMID: 38818349 PMCID: PMC11137199 DOI: 10.3389/fped.2024.1377333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 05/09/2024] [Indexed: 06/01/2024] Open
Abstract
Background Children with autoimmune hepatitis (AIH) often present with symptoms similar to those of other liver diseases. This study consists of a comparison between the clinical and histological characteristics of AIH and those of other four AIH-like liver diseases [i.e., drug-induced liver injury (DILI), gene deficiency, infectious liver disease and other etiology of liver disease], as well as an evaluation of the AIH scoring system's diagnostic performance. Methods All children with AIH-like liver disease at our center from January 2013 to December 2022 were included. The clinical and histological characteristics of the AIH group were retrospectively analyzed and compared with those of the other four groups. Results A total of 208 children were included and divided into AIH group (18 patients), DILI group (38 patients), gene deficiency group (44 patients), infectious liver disease group (74 patients), and other etiology group (34 patients). The antinuclear antibodies (ANA) ≥ 1:320 rate was significantly higher in the AIH compared to the other four groups after multiple testing correction (p < 0.0125), while patients with positive antibodies to liver-kidney microsomal-1 (anti-LKM1, n = 3) and smooth muscle antibodies (SMA, n = 2) were only observed in the AIH group. The positive rates of antibodies to liver cytosol type1 (anti-LC1) and Ro52 were higher than those in the other four groups. The serum immunoglobulin G (IgG) and globulin levels, as well as the proportions of portal lymphoplasmacytic infiltration, lobular hepatitis with more than moderate interface hepatitis, and lobular hepatitis with lymphoplasmacytic infiltration, were significantly higher in the AIH group than in the other four groups after multiple testing correction (p < 0.0125). The cirrhosis rate in the AIH group was higher than that in the DILI and infectious liver disease groups (p < 0.0125). Both the simplified (AUC > 0.73) and the revised systems (AUC > 0.93) for AIH have good diagnostic performance, with the latter being superior (p < 0.05). Conclusion Positive autoantibodies (ANA ≥ 1:320 or anti-LKM1 positive, or accompanied by SMA, anti-LC1 or Ro-52 positive) and elevated serum IgG or globulin levels contribute to early recognition of AIH. The presence of lobular hepatitis with more than moderate interface hepatitis and lymphoplasmacytic infiltration contribute to the diagnosis of AIH.
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Affiliation(s)
- Di Ma
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinglou Liu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guo Ai
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen Pan
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingling Liu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Huang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Liao
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuanyuan Lu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhan Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hua Zhou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihua Huang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingjie Hao
- Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sainan Shu
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Fang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Ueno M, Takabatake H, Kayahara T, Morimoto Y, Notohara K, Mizuno M. Long-term outcomes of drug-induced autoimmune-like hepatitis after pulse steroid therapy. Hepatol Res 2023; 53:1073-1083. [PMID: 37347239 DOI: 10.1111/hepr.13940] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/18/2023] [Accepted: 06/19/2023] [Indexed: 06/23/2023]
Abstract
AIM Pulse steroid therapy occasionally causes drug-induced autoimmune-like hepatitis (DI-ALH), but the long-term outcome of treated patients is not well known. In this study, we investigated the long-term outcomes of DI-ALH due to pulse steroid therapy. METHODS We retrospectively reviewed the medical records of 405 patients treated with pulse high-dose methylprednisolone in Kurashiki Central Hospital. The frequency and clinicopathological characteristics of acute liver injury that occurred within 3 months after the therapy were analyzed. The diagnosis of DI-ALH was made according to the revised international autoimmune hepatitis group criteria. RESULTS Among the 405 patients treated with methylprednisolone, 61 (15.1%) had acute liver injury after the pulse steroid therapy, and DI-ALH was diagnosed in five patients (1.2%). Absence of oral prednisolone tapering after the pulse steroid therapy was a significant risk factor for the subsequent development of DI-ALH (odds ratio 11.9; p = 0.017). One patient was treated with 3 days of intravenous methylprednisolone followed by oral prednisolone. Two patients were treated with glycyrrhizin followed by oral prednisolone due to ineffectiveness of glycyrrhizin. Remission was achieved with glycyrrhizin alone, and spontaneous remission without drug therapy occurred in one patient each. During the median follow-up period of 34 months, no relapse was evident in all the patients without maintenance therapy. CONCLUSIONS Pulse steroid therapy can cause DI-ALH, especially when subsequent prednisolone is not tapered. Prednisolone is effective for DI-ALH due to pulse steroid therapy, and can be safely withdrawn once remission is achieved.
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Affiliation(s)
- Masayuki Ueno
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroyuki Takabatake
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Takahisa Kayahara
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Youichi Morimoto
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Motowo Mizuno
- Department of Gastroenterology and Hepatology, Kurashiki Central Hospital, Kurashiki, Japan
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Andrade RJ, Aithal GP, de Boer YS, Liberal R, Gerbes A, Regev A, Terziroli Beretta-Piccoli B, Schramm C, Kleiner DE, De Martin E, Kullak-Ublick GA, Stirnimann G, Devarbhavi H, Vierling JM, Manns MP, Sebode M, Londoño MC, Avigan M, Robles-Diaz M, García-Cortes M, Atallah E, Heneghan M, Chalasani N, Trivedi PJ, Hayashi PH, Taubert R, Fontana RJ, Weber S, Oo YH, Zen Y, Licata A, Lucena MI, Mieli-Vergani G, Vergani D, Björnsson ES. Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report. J Hepatol 2023; 79:853-866. [PMID: 37164270 PMCID: PMC10735171 DOI: 10.1016/j.jhep.2023.04.033] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 04/26/2023] [Accepted: 04/29/2023] [Indexed: 05/12/2023]
Abstract
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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Affiliation(s)
- Raúl J Andrade
- 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; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
| | - Guruprasad P Aithal
- 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
| | - Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, VU University Medical Center, Amsterdam, Netherlands
| | - Rodrigo Liberal
- Gastroenterology Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal
| | | | - Arie Regev
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Christoph Schramm
- 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
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - Eleonora De Martin
- APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM Unit 1193, FHU Hepatinov, Villejuif, France
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Mechanistic Safety, Global Drug Development, Novartis, Basel, Switzerland
| | - Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital University Hospital and University of Bern, Bern, Switzerland
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, India
| | - John M Vierling
- Departments of Medicine and Surgery, Section of Gastroenterology and Hepatology and Division of Abdominal Transplantation, Baylor College of Medicine, Houston, Texas, United States
| | - Michael P Manns
- Hannover Medical School, Centre of ERN RARE-LIVER, Hannover, Germany
| | - Marcial Sebode
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Maria Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; 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
| | - Mark Avigan
- Center for Drug Evaluation and Research, Office of Surveillance and Epidemiology, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Mercedes Robles-Diaz
- 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; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Miren García-Cortes
- 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; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Edmond Atallah
- 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
| | | | - Naga Chalasani
- University School of Medicine & Indiana University Health, Indianapolis, Indiana, USA
| | - Palak J Trivedi
- 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 Applied Health Research, University of Birmingham, Birmingham, UK
| | - Paul H Hayashi
- Division of Hepatology and Nutrition, Food and Drug Administration, Silver Spring, Maryland, USA
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hannover, Germany
| | - Robert J Fontana
- Division of Gastroenterology and Hepatology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Sabine Weber
- Department of Medicine II, LMU Klinikum Munich, Munich, Germany
| | - Ye Htun Oo
- 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
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK
| | - Anna Licata
- Medicina Interna ed Epatologia, Università degli Studi di Palermo, Palermo, Italy
| | - M Isabel Lucena
- 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; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Platform ISCiii for Clinical Research and Clinical Trials SCReN UICEC- IBIMA, Málaga, Spain.
| | - Giorgina Mieli-Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, United Kingdom
| | - Diego Vergani
- MowatLabs, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, London, United Kingdom
| | - Einar S Björnsson
- Faculty of Medicine, University of Iceland, Department of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland
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Teschke R, Danan G. Advances in Idiosyncratic Drug-Induced Liver Injury Issues: New Clinical and Mechanistic Analysis Due to Roussel Uclaf Causality Assessment Method Use. Int J Mol Sci 2023; 24:10855. [PMID: 37446036 DOI: 10.3390/ijms241310855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/26/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Clinical and mechanistic considerations in idiosyncratic drug-induced liver injury (iDILI) remain challenging topics when they are derived from mere case narratives or iDILI cases without valid diagnosis. To overcome these issues, attempts should be made on pathogenetic aspects based on published clinical iDILI cases firmly diagnosed by the original RUCAM (Roussel Uclaf Causality Assessment Method) or the RUCAM version updated in 2016. Analysis of RUCAM-based iDILI cases allowed for evaluating immune and genetic data obtained from the serum and the liver of affected patients. For instance, strong evidence for immune reactions in the liver of patients with RUCAM-based iDILI was provided by the detection of serum anti-CYP 2E1 due to drugs like volatile anesthetics sevoflurane and desflurane, partially associated with the formation of trifluoroacetyl (TFA) halide as toxic intermediates that form protein adducts and may generate reactive oxygen species (ROS). This is accompanied by production of anti-TFA antibodies detected in the serum of these patients. Other RUCAM-based studies on serum ANA (anti-nuclear antibodies) and SMA (anti-smooth muscle antibodies) associated with AIDILI (autoimmune DILI) syn DIAIH (drug-induced autoimmune hepatitis) provide additional evidence of immunological reactions with monocytes as one of several promoting immune cells. In addition, in the blood plasma of patients, mediators like the cytokines IL-22, IL-22 binding protein (IL-22BP), IL-6, IL-10, IL 12p70, IL-17A, IL-23, IP-10, or chemokines such as CD206 and sCD163 were found in DILI due to anti-tuberculosis drugs as ascertained by the prospective updated RUCAM, which scored a high causality. RUCAM-based analysis also provided compelling evidence of genetic factors such as HLA (human leucocyte antigen) alleles contributing to initiate iDILI by a few drugs. In conclusion, analysis of published RUCAM-based iDILI cases provided firm evidence of immune and genetic processes involved in iDILI caused by specific drugs.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Leimenstrasse 20, D-63450 Hanau, Germany
| | - Gaby Danan
- Pharmacovigilance Consultancy, Rue des Ormeaux, 75020 Paris, France
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9
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Teschke R. Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations. Int J Mol Sci 2023; 24:ijms24076663. [PMID: 37047633 PMCID: PMC10095090 DOI: 10.3390/ijms24076663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/16/2023] [Accepted: 03/27/2023] [Indexed: 04/05/2023] Open
Abstract
Drug induced liver injury (DILI) occurs in patients exposed to drugs at recommended doses that leads to idiosyncratic DILI and provides an excellent human model with well described clinical features, liver injury pattern, and diagnostic criteria, based on patients assessed for causality using RUCAM (Roussel Uclaf Causality Assessment Method) as original method of 1993 or its update of 2016. Overall, 81,856 RUCAM based DILI cases have been published until mid of 2020, allowing now for an analysis of mechanistic issues of the disease. From selected DILI cases with verified diagnosis by using RUCAM, direct evidence was provided for the involvement of the innate and adapted immune system as well as genetic HLA (Human Leucocyte Antigen) genotypes. Direct evidence for a role of hepatic immune systems was substantiated by (1) the detection of anti-CYP (Cytochrome P450) isoforms in the plasma of affected patients, in line with the observation that 65% of the drugs most implicated in DILI are metabolized by a range of CYP isoforms, (2) the DIAIH (drug induced autoimmune hepatitis), a subgroup of idiosyncratic DILI, which is characterized by high RUCAM causality gradings and the detection of plasma antibodies such as positive serum anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA), rarely also anti-mitochondrial antibodies (AMA), (3) the effective treatment with glucocorticoids in part of an unselected RUCAM based DILI group, and (4) its rare association with the immune-triggered Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) caused by a small group of drugs. Direct evidence of a genetic basis of idiosyncratic DILI was shown by the association of several HLA genotypes for DILI caused by selected drugs. Finally, animal models of idiosyncratic DILI mimicking human immune and genetic features are not available and further search likely will be unsuccessful. In essence and based on cases of DILI with verified diagnosis using RUCAM for causality evaluation, there is now substantial direct evidence that immune mechanisms and genetics can account for idiosyncratic DILI by many but not all implicated drugs, which may help understand the mechanistic background of the disease and contribute to new approaches of therapy and prevention.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany
- Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, D-60590 Frankfurt am Main, Germany
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10
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Tan CK, Ho D, Wang LM, Kumar R. Drug-induced autoimmune hepatitis: A minireview. World J Gastroenterol 2022; 28:2654-2666. [PMID: 35979160 PMCID: PMC9260871 DOI: 10.3748/wjg.v28.i24.2654] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/15/2021] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Drug-induced autoimmune hepatitis (DIAIH) is a specific phenotype of drug-induced liver injury that may lead to the devastating outcome of acute liver failure requiring liver transplantation. Drugs implicated in DIAIH include antimicrobials such as nitrofurantoin and minocycline, non-steroidal anti-inflammatory drugs, statins as well as anti-tumor necrosis agents. The clinical features of drug-induced liver injury are indistinguishable from idiopathic autoimmune hepatitis (AIH) as both may have positive AIH-related autoantibodies, elevated immunoglobulin G, as well as similar histopathological findings. In patients who show no clinical improvement, or there is progressive liver injury despite cessation of the suspected drug, a liver biopsy should be considered, whereby the presence of advance fibrosis on histology favors the diagnosis of idiopathic AIH. Empirical treatment with corticosteroids may be required in patients with non-resolving liver injury. A typical clinical scenario supportive of DIAIH includes a history of drug exposure with spontaneous resolution of liver injury after drug withdrawal and the absence of relapse after rapid steroid taper. In this article we report two cases of DIAIH secondary to Sorafenib and Atorvastatin along with a review of currently available literature. Early identification and treatment often lead to a favorable outcome in DIAIH.
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Affiliation(s)
- Chin Kimg Tan
- Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
- Medicine Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore 529889, Singapore
| | - Danielle Ho
- Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
| | - Lai Mun Wang
- Section of Pathology, Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore
- Pathology Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore 529889, Singapore
| | - Rahul Kumar
- Gastroenterology and Hepatology, Changi General Hospital, Singapore 529889, Singapore
- Medicine Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre, Singapore 529889, Singapore
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11
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Fan JH, Liu GF, Lv XD, Zeng RZ, Zhan LL, Lv XP. Pathogenesis of autoimmune hepatitis. World J Hepatol 2021; 13:879-886. [PMID: 34552694 PMCID: PMC8422914 DOI: 10.4254/wjh.v13.i8.879] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/15/2021] [Accepted: 08/02/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic progressive liver disease whose etiology and pathogenesis are not yet clear. It is currently believed that the occurrence of AIH is closely related to genetic susceptibility and immune abnormalities, and other factors such as environment, viral infection and drugs that may cause immune dysfunction. This article reviews the pathogenesis of AIH and describes the latest research results in the past 5 years.
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Affiliation(s)
- Jun-Hua Fan
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Geng-Feng Liu
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Dan Lv
- Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Rui-Zhi Zeng
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Ling-Ling Zhan
- Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Ping Lv
- Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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12
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Jenkins A, Austin A, Hughes K, Sadowski B, Torres D. Infliximab-induced autoimmune hepatitis. BMJ Case Rep 2021; 14:14/5/e239944. [PMID: 34031069 DOI: 10.1136/bcr-2020-239944] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an inflammatory disorder of the liver with a wide spectrum of disease presentation, from asymptomatic elevations in liver-associated enzymes to acute liver failure. AIH is classically associated with elevated immunoglobulins and autoantibodies, although approximately 20% of patients with features of AIH lack circulating antibodies. Recently, tumour necrosis factor alpha inhibitors have been implicated in several cases of drug-induced AIH which impact treatment regimens for patients with inflammatory bowel disease (IBD). We present a case of infliximab-induced seronegative AIH responding to budesonide therapy with successful alteration of IBD treatment regimen to vedolizumab.
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Affiliation(s)
- Alexander Jenkins
- Internal Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Amy Austin
- Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
| | - Kathryn Hughes
- Internal Medicine, Naval Medical Center San Diego, San Diego, California, USA
| | - Brett Sadowski
- Gastroenterology, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA
| | - Dawn Torres
- Gastroenterology, Naval Medical Center Portsmouth, Portsmouth, Virginia, USA
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13
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Wang Q, Huang A, Wang JB, Zou Z. Chronic Drug-Induced Liver Injury: Updates and Future Challenges. Front Pharmacol 2021; 12:627133. [PMID: 33762948 PMCID: PMC7982586 DOI: 10.3389/fphar.2021.627133] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 01/25/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic drug-induced liver injury (DILI), defined as DILI with persistent liver injury more than one year after the first onset by the latest European guidelines, is a notable challenge globally with big issues of defining causality and establishing effective treatment. About 20% of patients with DILI develop into chronic DILI. Chronic DILI manifests as persistent or repeated inflammatory or diminishing bile ducts, even progresses to cirrhosis and needs liver transplantation eventually. However, research on chronic DILI over the last decades is still lacking, and the incidence, phenotypes, mechanisms, risk factors, and treatment have not been fully understood. In this paper, we reviewed the definition of chronic DILI, updated clinical studies in terms of incidence, special manifestations, and promising risk factors of chronic DILI, along with the recent progress and challenges in glucocorticoid therapy.
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Affiliation(s)
- Qiaoling Wang
- Peking University 302 Clinical Medical School, Beijing, China.,Department of Liver Disease of Chinese PLA General Hospital, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ang Huang
- Department of Liver Disease of Chinese PLA General Hospital, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jia-Bo Wang
- Department of Liver Disease of Chinese PLA General Hospital, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Zhengsheng Zou
- Peking University 302 Clinical Medical School, Beijing, China.,Department of Liver Disease of Chinese PLA General Hospital, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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14
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Apetamin Hepatotoxicity: Potential Consequences of Purchasing a Body Enhancement Drug Off the Internet. ACG Case Rep J 2020; 7:e00398. [PMID: 33062775 PMCID: PMC7535765 DOI: 10.14309/crj.0000000000000398] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 03/31/2020] [Indexed: 12/23/2022] Open
Abstract
We report Apetamin (cyproheptadine lysine and vitamin syrup), a non-US Food and Drug Administration-approved weight gain supplement, causing drug-induced autoimmune hepatitis. A 40-year-old previously healthy woman presented with fatigue, right-sided abdominal discomfort, and jaundice 6 weeks after starting Apetamin, which she learned from social media for figure augmentation. Labs were significant for elevated transaminases, positive smooth muscle antibody, and increased immunoglobulins. Biopsy indicated drug-induced autoimmune hepatitis. Symptoms improved with prednisone, azathioprine, and stopping Apetamin which contains cyproheptadine, a known hepatotoxin. The case reveals the influence of social media and its impact on health and the importance of a complete drug history.
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Kawabata H, Kawakatsu Y, Inoue N, Okazaki Y, Sone D, Yamaguchi K, Ueda Y, Hitomi M, Miyata M, Motoi S, Enoki Y, Minamikawa T. IgG4-related Autoimmune Hepatitis with a Suspected Drug-induced Etiology. Intern Med 2020; 59:1401-1405. [PMID: 32475907 PMCID: PMC7332635 DOI: 10.2169/internalmedicine.4092-19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
A 69-year-old man was referred to our department with acute hepatitis. He had been newly treated with benidipine hydrochloride for two months. His blood test results were as follows: aspartate aminotransferase, 1,614 IU/L; alanine aminotransferase, 1,091 IU/L and anti-smooth muscle antibody, ×80. Needle liver biopsy specimen showed interface hepatitis with mainly lymphocytic infiltration and bridging fibrosis in the periportal area. Immunohistochemistry revealed lymphocytic infiltration positive for IgG4. We diagnosed him with IgG4-related AIH with an etiology that was suspected of being drug-induced. Oral prednisolone was started and then tapered after achieving biochemical remission. Hepatitis recurred after the cessation of steroids; however, remission was achieved with ursodeoxycholic acid.
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Affiliation(s)
- Hideaki Kawabata
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Yukino Kawakatsu
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Naonori Inoue
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Yuji Okazaki
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Daiki Sone
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | | | - Yuki Ueda
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Misuzu Hitomi
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Masatoshi Miyata
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Shigehiro Motoi
- Department of Gastroenterology, Kyoto Okamoto Memorial Hospital, Japan
| | - Yasuyuki Enoki
- Department of Pathology, Kyoto Okamoto Memorial Hospital, Japan
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