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Dalekos G, Gatselis N, Drenth JP, Heneghan M, Jørgensen M, Lohse AW, Londoño M, Muratori L, Papp M, Samyn M, Tiniakos D, Lleo A. EASL Clinical Practice Guidelines on the management of autoimmune hepatitis. J Hepatol 2025:S0168-8278(25)00173-4. [PMID: 40348684 DOI: 10.1016/j.jhep.2025.03.017] [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: 03/20/2025] [Accepted: 03/20/2025] [Indexed: 05/14/2025]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
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Appell ML, Hindorf U, Almer S, Haglund S. Response to azathioprine treatment in autoimmune hepatitis is dependent on glutathione transferase genotypes. Dig Liver Dis 2025; 57:885-892. [PMID: 39863504 DOI: 10.1016/j.dld.2024.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 11/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Azathioprine (AZA) is part of the standard treatment for autoimmune hepatitis (AIH). The first step in the complex bioconversion of AZA to active metabolites is mediated by glutathione transferases (GSTs). AIMS Elucidate the association between GSTM1 and GSTT1 copy number variation (CNV), genetic variation in GSTA2, GSTP1, and inosine-triphosphate-pyrophosphatase, and the response to AZA in AIH. METHODS Genotyping was performed in AIH patients (n = 131) on AZA, and in a Swedish background population (n = 283). Thiopurine metabolites in blood erythrocytes were determined by high performance liquid chromatography. RESULTS GSTM1 and GSTT1 CNV were associated with treatment response to AZA. Gene deletion of GSTM1-but not of GSTT1-was associated with the liver transaminase levels. None of the studied genetic variants were associated with the thiopurine metabolite concentrations, suggesting non-enzymatic mechanisms of GSTM1 and GSTT1 in the context of AZA efficacy in AIH. The prevalence of GSTM1 and GSTT1 CNV genotypes was similar in AIH and in the background population. CONCLUSION This study shows the effects of GSTM1 and GSTT1 CNV on AZA efficacy in AIH, not previously described. It also elaborates on the impact of the definition of treatment response, on the importance of the various GSTs studied. Furthermore, the GSTM1 and GSTT1 CNV frequencies previously reported in European populations were confirmed.
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Affiliation(s)
- Malin Lindqvist Appell
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
| | - Ulf Hindorf
- Department of Gastroenterology and Nutrition, University Hospital Lund, Lund, Sweden.
| | - Sven Almer
- Centre for Digestive Health, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
| | - Sofie Haglund
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Laboratory Medicine, Region Jönköping County, Jönköping, Sweden.
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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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Cananzi M, Jørgensen MH, Buescher G, De Bruyne R, Samyn M. Current practice in the management of paediatric autoimmune liver disease in Europe. J Pediatr Gastroenterol Nutr 2025; 80:260-270. [PMID: 39618087 DOI: 10.1002/jpn3.12424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 02/04/2025]
Abstract
OBJECTIVE Paediatric autoimmune liver disease (pAILD) is a rare condition with serious health implications. Notwithstanding treatment advancements, areas of uncertainty and knowledge gaps still exist. We here investigated the real-life approach to pAILD management in Europe. METHODS A survey was distributed to members of the European Rare Liver Disease Reference Network (ERN RARE-LIVER) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Hepatology Interest Group. Information was gathered regarding clinical activity, medications used, and access to paediatric drug formulations at each site. RESULTS Thirty-six centres from 22 European countries responded to the survey. The majority are exclusively paediatric units (86%). Among participants, 80% follow <50 children with pAILD, of which 25%-50% are <10 years old in 44% of centres. All centres use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36). Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21), respectively. Tacrolimus is used as third-line agent in 15/36 centres. Proactive measurement of drug metabolites and target levels vary widely among centres. Paediatric predniso(lo)ne formulations are commercially available in 7/22 European countries, azathioprine in 3, mycophenolate in 14, tacrolimus in 15 and ursodeoxycholic acid in 14. When paediatric formulations are unavailable, children are treated with magisterial preparations or 'solid' formulations (crushed or intact). CONCLUSIONS Treatment of pAILD in Europe varies widely in terms of medications used and treatment monitoring. Availability of paediatric drug formulations across Europe is limited. Collaborative initiatives are needed to define evidence-based strategies for management of pAILD and to promote an equal, age-appropriate treatment for affected children.
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Affiliation(s)
- Mara Cananzi
- Unit of Paediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | | | - Gustav Buescher
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ruth De Bruyne
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Belgium
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King's College Hospital NHS Trust, London, UK
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Chung Y, IIkay E, Heneghan MA. Optimizing thiopurine therapy in autoimmune hepatitis: A multicenter study on monitoring metabolite profiles and co-therapy with allopurinol. Hepatology 2024; 80:1000-1002. [PMID: 39436225 DOI: 10.1097/hep.0000000000000997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 06/06/2024] [Indexed: 10/23/2024]
Affiliation(s)
- Yooyun Chung
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Ergenc IIkay
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Michael A Heneghan
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- Institute of Liver Studies, King's College Hospital, London, UK
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Weltzsch JP, Bartel CF, Waldmann M, Renné T, Schulze S, Terziroli Beretta-Piccoli B, Papp M, Oo YH, Ronca V, Sebode M, Lohse AW, Schramm C, Hartl J. Optimizing thiopurine therapy in autoimmune hepatitis: A multicenter study on monitoring metabolite profiles and co-therapy with allopurinol. Hepatology 2024; 80:1026-1040. [PMID: 39162583 DOI: 10.1097/hep.0000000000000940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 04/09/2024] [Indexed: 08/21/2024]
Abstract
BACKGROUND AND AIMS In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response. APPROACH AND RESULTS The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 mL) compared to those failing to maintain CBR (181 pmol/0.2 mL; p = 0.0014) or never achieving CBR (153 pmol/0.2 mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223 pmol/0.2 mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321 pmol/0.2 mL; p < 0.0001) and lowered 6MMP (2125→184 pmol/0.2 mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%. CONCLUSIONS Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223 pmol/0.2 mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative.
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Affiliation(s)
- Jan Philipp Weltzsch
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Claudius F Bartel
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Moritz Waldmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Thomas Renné
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Stephanie Schulze
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Benedetta Terziroli Beretta-Piccoli
- Epatocentro Ticino, Lugano, Switzerland
- Faculty of Biochemical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
- Mowat Labs, Faculty of Life Sciences & Medicine, King's College London, King's College Hospital, London, UK
| | - Maria Papp
- Department of Gastroenterology, Institute of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ye H Oo
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Centre for Liver Research and National Institute of Health Research Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham
- Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust
| | - Vincenzo Ronca
- Centre for Liver Research and National Institute of Health Research Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Christoph Schramm
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
- Hamburg Centre for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Johannes Hartl
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
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Alric L. Should MMF treatment be the first-line therapy in autoimmune hepatitis? J Hepatol 2024; 81:e40. [PMID: 38403032 DOI: 10.1016/j.jhep.2024.02.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 02/27/2024]
Affiliation(s)
- Laurent Alric
- Internal Medicine- Department of Gastroenterology and Hepatology, Rangueil Hospital, Toulouse 3 University, Toulouse, France.
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8
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Tiwari A, Khanikar D, Rathod SG. Autoimmune hepatitis: Azathioprine or mycophenolate mofetil for inducing remission? J Hepatol 2024; 81:e38-e39. [PMID: 38403031 DOI: 10.1016/j.jhep.2024.02.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 02/11/2024] [Indexed: 02/27/2024]
Affiliation(s)
- Avinash Tiwari
- Department of Gastroenterology, Regency Hospital Ltd: Kanpur, Uttar Pradesh, 208005, India.
| | - Duncan Khanikar
- Department of Oncology, Assam Cancer Care Foundation(Dibrugarh Branch): Guwahati, Assam, India
| | - Santosh Govind Rathod
- Department of Hematology, Sher-i-Kashmir Institute of Medical Sciences. Soura, Srinagar, Jammu, and Kashmir, 190011, India
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Taubert R, Engel B. [Treatment of autoimmune hepatitis-First-line, second-line and third-line treatment]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:325-333. [PMID: 38456902 DOI: 10.1007/s00108-024-01679-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/09/2024] [Indexed: 03/09/2024]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune inflammation of the liver mostly with a chronic course, which can also be acutely manifested up to acute liver failure. It affects women 3-4 times more frequently than men and can be diagnosed in all age groups. In one third of the patients a liver cirrhosis is present at the time of diagnosis. It is characterized by a hepatic inflammation pattern, a polyclonal hypergammaglobulinemia of immunoglobulin G and the detection of autoantibodies. A liver biopsy is necessary to make the diagnosis. The AIH is histologically characterized in particular by a lymphoplasmacytic infiltrate in the portal fields. In cases with a relevant disease activity, AIH is typically treated by immunosuppression. The immunosuppressive treatment is associated with a prevention of disease progression to liver cirrhosis and a better survival. The success of treatment is measured by achieving biochemical remission, i.e., normalization of the transaminase and immunoglobulin G levels as a good noninvasive predictor of a histological remission. Another treatment target is an improvement of the symptoms of the patient. The first-line treatment consists of a glucocorticoid, mostly prednisolone or in cases without advanced fibrosis budesonide, and azothioprine. For reduction of steroid-specific treatment side effects the maintenance treatment should be carried out steroid-free whenever possible. In cases of insufficient response to azothioprine or side effects a treatment attempt using antimetabolites, such as 6‑mercaptopurine or mycophenolate mofetil is primarily carried out as second-line treatment. For patients who do not achieve biochemical remission through first-line or second-line treatment, a variety of medications are available for third-line treatment, e.g., rituximab, calcineurin inhibitors or antitumor necrosis factor (anti-TNF) antibodies. Third-line treatment should be carried out in expert centers and registered in the European Reference Network for Rare Liver Diseases in order to improve the currently sparse database for these forms of treatment in the future.
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Affiliation(s)
- Richard Taubert
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.
| | - Bastian Engel
- Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland
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Zhang Y, Zhang D, Chen L, Zhou J, Ren B, Chen H. The progress of autoimmune hepatitis research and future challenges. Open Med (Wars) 2023; 18:20230823. [PMID: 38025543 PMCID: PMC10655690 DOI: 10.1515/med-2023-0823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIH treatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.
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Affiliation(s)
- Yang Zhang
- Graduate Department of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dehe Zhang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ling Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jing Zhou
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Binbin Ren
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Haijun Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Weltzsch JP, Ziegler A, Lohse A. [Autoimmune hepatitis : From autoantibodies to cirrhosis]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2023:10.1007/s00108-023-01519-9. [PMID: 37306752 DOI: 10.1007/s00108-023-01519-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Accepted: 04/12/2023] [Indexed: 06/13/2023]
Abstract
Autoimmune Hepatitis (AIH) is an immune-mediated liver disease of unknown origin. Its clinical presentation is heterogeneous and ranges from asymptomatic courses over several years to acute forms with acute liver failure. Accordingly, the diagnosis is only made at the stage of cirrhosis in about one third of affected individuals. Early diagnosis and a consistent, adequate, individualized, immunosuppressive therapy are crucial for the prognosis, which is excellent when treated properly. AIH is rare in the general population and can be easily overlooked due to its variable clinical picture and sometimes difficult diagnosis. AIH should be considered as a differential diagnosis in any unclear acute or chronic hepatopathy. The therapy initially consists of remission induction and subsequently maintenance therapy with (often lifelong) immunosuppressants.
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Affiliation(s)
- Jan Philipp Weltzsch
- I. Med. Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Deutschland.
| | - Annerose Ziegler
- I. Med. Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Deutschland
| | - Ansgar Lohse
- I. Med. Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Deutschland
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12
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Gerussi A, Halliday N, Carbone M, Invernizzi P, Thorburn D. Open challenges in the management of autoimmune hepatitis. Minerva Gastroenterol (Torino) 2023; 69:61-83. [PMID: 33267568 DOI: 10.23736/s2724-5895.20.02805-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy - .,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy - .,Ancient DNA Lab Dan David Center for Human Evolution and Biohistory Research, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel -
| | - Neil Halliday
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Douglas Thorburn
- Institute for Liver and Digestive Health, University College London, London, UK
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Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology 2022; 76:1862-1879. [PMID: 35611859 PMCID: PMC9796683 DOI: 10.1002/hep.32591] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare disease of unclear etiology characterized by loss of self-tolerance that can lead to liver injury, cirrhosis, and acute liver failure. First-line treatment consists of systemic corticosteroids, or budesonide, and azathioprine, to which most patients are initially responsive, although predictors of response are lacking. Relapses are very common, correlate with histological activity despite normal serum transaminases, and increase hepatic fibrosis. Furthermore, current regimens lead to adverse effects and reduced quality of life, whereas medication titration is imprecise. Biomarkers that can predict the clinical course of disease, identify patients at elevated risk for relapse, and improve monitoring and medication dosing beyond current practice would have high clinical value. Herein, we review novel candidate biomarkers in adult and pediatric AIH based on prespecified criteria, including gene expression profiles, proteins, metabolites, and immune cell phenotypes in different stages of AIH. We also discuss biomarkers relevant to AIH from other immune diseases. We conclude with proposed future directions in which biomarker implementation into clinical practice could lead to advances in personalized therapeutic management of AIH.
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Affiliation(s)
- Claire Harrington
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
| | - Swathi Krishnan
- Medicine DepartmentYale School of MedicineNew HavenConnecticutUSA
| | - Cara L. Mack
- Section of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Hospital ColoradoUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Paolo Cravedi
- Division of NephrologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - David N. Assis
- Section of Digestive DiseasesYale School of MedicineNew HavenConnecticutUSA
| | - Josh Levitsky
- Division of Gastroenterology & HepatologyNorthwestern University Feinberg School of MedicineChicagoIllinoisUSA
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14
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Olivas I, Rodríguez-Tajes S, Londoño MC. Hepatitis autoinmune: retos y novedades. Med Clin (Barc) 2022; 159:289-298. [DOI: 10.1016/j.medcli.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 04/04/2022] [Accepted: 04/06/2022] [Indexed: 10/18/2022]
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Hayashi M, Abe K, Fujita M, Takahashi A, Sekine H, Ohira H. Circulating complement factor H levels are associated with disease severity and relapse in autoimmune hepatitis. JHEP Rep 2022; 4:100497. [PMID: 35677590 PMCID: PMC9167978 DOI: 10.1016/j.jhepr.2022.100497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 03/17/2022] [Accepted: 04/13/2022] [Indexed: 11/19/2022] Open
Abstract
Background & Aims The complement system plays pivotal roles in innate immunity. Mannose-binding lectin-associated serine protease (MASP)-2 plays essential roles in the activation of the lectin complement pathway. Complement factor H acts as a critical negative regulator of the alternative complement pathway. The association of circulating MASP-2 and factor H with the clinical features of patients with autoimmune hepatitis (AIH) is unclear. Methods A total of 63 patients with AIH were recruited for this study. The serum levels of MASP-2, factor H, and C3a were measured, and their associations with the clinical features of AIH were analyzed. Results The circulating C3a levels were higher in patients with AIH than in the controls. The circulating MASP-2 and factor H levels were decreased depending on the severity of AIH. Multivariate logistic analysis showed that low circulating factor H levels were associated with features of severe AIH (odds ratio 0.36; 95% CI 0.15-0.84; p = 0.018). Multivariate Cox proportional hazards model analysis showed that low circulating factor H levels were associated with a high incidence of relapse (hazard ratio: 5.19; 95% CI 1.07–25.2; p = 0.041). Patients with low circulating factor H levels showed higher rates of relapse than the controls (log-rank, p = 0.006). Conclusion Circulating factor H levels were associated with severe disease and with the incidence of relapse, suggesting a role for the complement system in the pathophysiology of AIH. Lay summary Autoimmune hepatitis is an immune-mediated liver disease. Despite effective treatments, patients often relapse, which can lead to clinical deterioration and adverse outcomes. Herein, we studied the importance of the complement system (a form of innate immunity) in patients with autoimmune hepatitis. We found that the levels of a protein called factor H, which regulates the complement system, could be a potential biomarker of disease severity and relapse, and could even have therapeutic potential for patients with AIH.
We measured serum MASP-2 and factor H in patients with AIH. Serum MASP-2 and factor H levels were lower in patients with severe AIH. Patients with AIH and low factor H before treatment showed a high rate of relapse.
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16
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Bolia R, Srivastava A. The search for optimum thiopurine metabolite levels in autoimmune hepatitis continues…. J Hepatol 2022; 76:220-222. [PMID: 34242697 DOI: 10.1016/j.jhep.2021.06.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/18/2022]
Affiliation(s)
- Rishi Bolia
- Division of Paediatric Gastroenterology, Department of Paediatrics, All India Institute of Medical Sciences, Rishikesh, India.
| | - Anshu Srivastava
- Department of Paediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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17
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Armandi A, Actis GC, Ribaldone DG. Autoimmunity of the liver. TRANSLATIONAL AUTOIMMUNITY 2022:309-331. [DOI: 10.1016/b978-0-12-824466-1.00012-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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18
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Rahim MN, Heneghan MA. Reply to: "The search for optimum thiopurine metabolite levels in autoimmune hepatitis continues…". J Hepatol 2022; 76:222-224. [PMID: 34592367 DOI: 10.1016/j.jhep.2021.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 09/18/2021] [Indexed: 12/04/2022]
Affiliation(s)
- Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, United Kingdom
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, United Kingdom.
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19
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Lemoinne S, Heurgue A, Bouzbib C, Hanslik B, Gournay J, Nguyen-Khac E, Bureau C, de Lédinghen V, Ganne-Carrié N, Bourlière M. Non-invasive diagnosis and follow-up of autoimmune hepatitis. Clin Res Hepatol Gastroenterol 2022; 46:101772. [PMID: 34332126 DOI: 10.1016/j.clinre.2021.101772] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a liver disease characterised by necrotico-inflammatory lesions of hepatocytes, the presence of specific autoantibodies and response to corticosteroid treatment. AIH must be considered in any patient with acute or chronic liver disease. As there is no pathognomonic sign of AIH, the diagnosis is based on a combination of clinical, biological, immunological and histological findings, after excluding other causes of liver disease. The clinical and biological presentation of AIH is variable and AIH can be associated with an autoimmune biliary disease, primary biliary cholangitis or primary sclerosing cholangitis in an overlap syndrome. For these reasons, diagnosis of AIH can be challenging. Even if liver histology remains essential in the diagnosis of AIH, non-invasive tests can be used at different steps of the management of AIH: diagnosis of AIH, notably diagnosis of an overlap syndrome, assessment of severity of AIH, searching for extra-hepatic disease frequently associated to AIH, evaluation of response to therapy, decision of treatment withdrawal. This review aims to provide practical guidelines for the use of non-invasive tests for the diagnosis and the follow-up of AIH.
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Affiliation(s)
- Sara Lemoinne
- Assistance publique-hopitaux de Paris (AP-HP), Service d'hépatologie, Centre de référence pour les maladies inflammatoires des voies biliaires et les hépatites auto-immunes ( CMR MIVB-H, ERN RARE-LIVER), Hôpital Saint-Antoine, Paris France; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of cardiometabolism and Nutrition ( ICAN), Paris, France.
| | - Alexandra Heurgue
- Service d'hépato-gastroentérologie et cancérologie digestive, CHU Reims, Reims, France
| | - Charlotte Bouzbib
- Service d'Hépatologie, Hopital Pitié Salpêtrière, APHP, Paris, France
| | - Bertrand Hanslik
- Centre Montpelliérain des maladies du foie et de l'appareil digestif, Montpellier, France
| | - Jérôme Gournay
- Service d'hépato-gastroentérologie, cancérologie digestive et assistance nutritionnelle, CHU Nantes, Nantes, France
| | - Eric Nguyen-Khac
- Service d'hépato-gastroentérologie, CHU Amiens-Picardie, Amiens, France
| | - Christophe Bureau
- Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse, France
| | - Victor de Lédinghen
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
| | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP, Université Sorbonne Paris Nord, Bobigny & INSERM UMR 1138, Centre de Recherche des Cordeliers, Université de Paris, France
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille, France
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20
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Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. A reasoned approach to the treatment of autoimmune hepatitis. Dig Liver Dis 2021; 53:1381-1393. [PMID: 34162505 DOI: 10.1016/j.dld.2021.05.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
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Affiliation(s)
- Diego Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland
| | - Benedetta Terziroli Beretta-Piccoli
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Epatocentro Ticino, Lugano, Switzerland; Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.
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21
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Bolia R, Goel A, Srivastava A. Systematic Review and Meta-Analysis of Thiopurine Metabolite Levels and Biochemical Remission in Autoimmune Hepatitis. Ther Drug Monit 2021; 43:609-616. [PMID: 33346628 DOI: 10.1097/ftd.0000000000000848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 11/17/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND The utility of measuring thiopurine metabolites (TM) to individualize therapy in autoimmune hepatitis (AIH) has not been defined, and the evidence regarding its use in clinical practice is heterogeneous. This systematic review and meta-analysis aimed to compare the mean concentration of TM between patients in biochemical remission and those not in remission. METHODS A systematic literature search was conducted using PubMed, Scopus, the Cochrane Library, and Google Scholar for keywords related to TM and AIH. Two reviewers independently searched and selected studies comparing the levels of 6-methyl mercaptopurine (6-MMP) and 6-thioguanine nucleotide (6-TGN) and their ratio in cases of AIH in remission and otherwise. Meta-analysis was performed by calculating the weighted mean difference using the inverse variance heterogeneity model. RESULTS A total of 1066 records were identified through systematic search; of which, 7 (n = 3 pediatric, n = 4 adults) were considered for inclusion, and 442 TM measurements (n = 128 in children) were analyzed. Mean 6-TGN levels were significantly higher among patients in remission than in those who were not, with a pooled weighted mean difference (WMD) of 15.67 [95% confidence interval (CI), 6.68-24.66] pmol/8 × 108 red blood cells (RBC). The difference was higher in the pediatric age group (WMD, 56.11; 95% CI, 13.60-98.62) than in adults (WMD, 13.77; 95% CI, 4.58-22.97). There was no significant difference in the 6-MMP levels (WMD, -431.7; 95% CI, -1237.4 to 373.9 pmol/8 × 108 RBC; I2 = 82%; n = 3 studies) or 6-MMP/6-TGN ratio among the patients who were in biochemical remission and those who were not (WMD, -0.97; 95% CI, -5.77 to 3.84; I2 = 82%; n = 3 studies). CONCLUSIONS This meta-analysis suggests a link between 6-TGN levels and biochemical remission in AIH. Further high-quality studies are required to determine the therapeutic cutoff of 6-TGN.
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Affiliation(s)
- Rishi Bolia
- Division of Pediatric Gastroenterology, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh
| | - Akhil Goel
- Department of Community and Family Medicine, All India Institute of Medical Sciences, Jodhpur; and
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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22
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Dorsey YC, Oloruntoba O, Pendse AA, King LY. More Than Meets the Eye? Clin Liver Dis (Hoboken) 2021; 18:173-178. [PMID: 34745573 PMCID: PMC8549717 DOI: 10.1002/cld.1107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/12/2021] [Indexed: 02/04/2023] Open
Abstract
Content available: Author Audio Recording.
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Affiliation(s)
- Ying Claire Dorsey
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| | - Omobonike Oloruntoba
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
| | - Avani A. Pendse
- Department of PathologyDuke University School of MedicineDurhamNC
| | - Lindsay Y. King
- Division of Gastroenterology and HepatologyDuke University School of MedicineDurhamNC
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23
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Candels LS, Rahim MN, Shah S, Heneghan MA. Towards personalised medicine in autoimmune hepatitis: Measurement of thiopurine metabolites results in higher biochemical response rates. J Hepatol 2021; 75:324-332. [PMID: 33872691 DOI: 10.1016/j.jhep.2021.03.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with autoimmune hepatitis (AIH) usually receive maintenance therapy with thiopurines, such as azathioprine (AZA) or mercaptopurine. Genetic polymorphisms in AZA metabolism can lead to variations in thioguanine nucleotide (TGN) and 6-methylmercaptopurine, both of which can cause adverse drug reactions (ADRs). In inflammatory bowel disease, a therapeutic TGN range (225-450 pmol/8x108 erythrocytes) has been identified to optimise effectiveness. We evaluated the benefits of a personalised medicine approach to thiopurine dosing, in comparison to standard weight-based dosing. METHODS A retrospective matched cohort study of 214 patients with AIH who were seen at King's College between 1999-2019 was performed. Metabolite levels were measured in 109 patients. The control group included 105 patients on weight-based thiopurine dosing with no metabolite monitoring. RESULTS Biochemical response (BR) occurred more frequently at 6-month follow-up in patients with metabolite monitoring compared to those on a weight-based regimen (77% vs. 60%, p = 0.008). This remained true with data analysis based on clinicians who measure metabolites and those who do not (BR at 6 months: 84% vs. 64%, p = 0.016). Patients with BR had TGN levels within the therapeutic range of 225-450 pmol/8x108 erythrocytes significantly more often than those who failed to achieve or lost BR (40% vs. 13%, p <0.0001). Moreover, TGN levels within the pre-defined therapeutic range predicted more stable disease within 6 months of testing compared to levels outside the range (p <0.0001). A high proportion of patients with sub-therapeutic TGN levels (75-225 pmol/8x108 erythrocytes) remained in BR (75% vs. 81%, p = 0.589) with fewer ADRs (44% vs. 86%, p = 0.0002) when compared to patients with therapeutic TGN levels. CONCLUSION A strategy of personalised medicine using metabolite levels can optimise treatment regimens in AIH, resulting in fewer ADRs whilst maintaining BR. LAY SUMMARY This study looked to see if measuring the breakdown products of a medication used in autoimmune hepatitis increases the chances of gaining good control of the disease, when compared to a group of patients who were on a dose of this medication based on their weight. A group of 214 patients with autoimmune hepatitis were split into 2 groups: roughly half had their medication dose adjusted according to measurements of breakdown products in the blood, whilst the other half received their weight-based dose as normal. The results confirmed that using a personalised approach and checking drug breakdown products resulted in fewer side effects and potentially improved control of disease.
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Affiliation(s)
- Lena S Candels
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Mussarat N Rahim
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; School of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Sital Shah
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, SE5 9RS, UK; School of Transplantation, Immunology and Mucosal Biology, Faculty of Life Sciences and Medicine, King's College London, London, UK; European Reference Network - Hepatological Diseases (ERN RARE-LIVER).
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24
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Liberal R, de Boer YS, Heneghan MA. Established and novel therapeutic options for autoimmune hepatitis. Lancet Gastroenterol Hepatol 2021; 6:315-326. [DOI: 10.1016/s2468-1253(20)30328-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 08/14/2020] [Accepted: 09/25/2020] [Indexed: 02/06/2023]
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Liberal R, Gaspar R, Lopes S, Macedo G. Long-term outcome of patients with difficult-to-treat autoimmune hepatitis receiving mycophenolate mofetil. Clin Res Hepatol Gastroenterol 2021; 45:101487. [PMID: 32651078 DOI: 10.1016/j.clinre.2020.06.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/22/2020] [Accepted: 06/15/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Most patients with autoimmune hepatitis (AIH) respond to a combination of prednisolone and azathioprine. For patients who are intolerant or refractory to azathioprine, proposed alternative therapies are based on scarce data, limited to transplant centres and with short-term follow-up periods. OBJECTIVE To evaluate the long-term efficacy and safety of MMF as a second-line therapy in patients with AIH managed at a tertiary non-transplant centre. METHODS Retrospective analysis of a prospectively collated database identified AIH patients who received MMF from 2006 to 2015. Clinical, biochemical and immunological parameters were assessed at 3-, 6- and 12-months, and at last follow-up. Biochemical response (BR) was defined as improvement of transaminases, complete remission (CR) as normalisation of transaminases and IgG, while others were considered non-responders (NR). RESULTS Eighteen out of 151 (12%) AIH patients received MMF. Nine received MMF due to azathioprine-intolerance (group 1), while nine due to refractory disease (group 2). In group 1, CR and BR was achieved in six (67%) and two (22%) patients respectively. In group 2, CR and BR was achieved in one (11%) and five (56%) patients respectively. Adverse events occurred in eight patients (44%), with one patient requiring drug discontinuation. After a medium follow-up of 78 (31-116) months, there was a significant decrease in transaminase levels, mirrored by decrease in prednisolone dose from 25 to 6.25 mg/day (P<0.05). CONCLUSION Long-term therapy with MMF is safe and effective in AIH patients requiring second-line therapies, and these patients can be effectively managed at tertiary non-liver transplant centres.
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Affiliation(s)
- Rodrigo Liberal
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal.
| | - Rui Gaspar
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
| | - Susana Lopes
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Sao Joao, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal; World Gastroenterology Organization (WGO) Porto Training Center, Portugal
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26
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Second-line and third-line therapy for autoimmune hepatitis: A position statement from the European Reference Network on Hepatological Diseases and the International Autoimmune Hepatitis Group. J Hepatol 2020; 73:1496-1506. [PMID: 32707224 DOI: 10.1016/j.jhep.2020.07.023] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 02/06/2023]
Abstract
Most patients with autoimmune hepatitis respond well to standard immunosuppressive therapy with steroids and azathioprine, and while untreated disease is usually fatal, patients who respond well to therapy have an excellent prognosis. However, insufficient response to standard therapy or intolerable side effects requiring dose adaptions or treatment changes occur in 10-20% of patients. While there is fairly good agreement on second-line treatment options, there is very wide variation in the indication and use of possible third-line therapies. Herein, the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) and the International Autoimmune Hepatitis Group (IAIHG) outline a treatment algorithm for both children and adults that should help to standardise treatment approaches, in order to improve patient care and to enable the comparison of treatment results between scientific publications.
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27
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Affiliation(s)
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, The Netherlands
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28
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Pape S, Gevers TJG, Vrolijk JM, van Hoek B, Bouma G, van Nieuwkerk CMJ, Taubert R, Jaeckel E, Manns MP, Papp M, Sipeki N, Stickel F, Efe C, Ozaslan E, Purnak T, Nevens F, Kessener DJN, Kahraman A, Wedemeyer H, Hartl J, Schramm C, Lohse AW, Heneghan MA, Drenth JPH. High discontinuation rate of azathioprine in autoimmune hepatitis, independent of time of treatment initiation. Liver Int 2020; 40:2164-2171. [PMID: 32410363 PMCID: PMC7496382 DOI: 10.1111/liv.14513] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/20/2020] [Accepted: 05/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2-4 weeks. The safety and efficacy of both strategies have been unexplored. METHODS We established a cohort of 900 AIH patients from 12 centres in 7 European countries. There were 631 patients who used AZA as part of the therapeutic regimen. We distinguished two groups: patients with early AZA (<2 weeks) or delayed AZA initiation (≥2 weeks). Primary outcome was discontinuation of AZA in the first year of treatment. Cox regression and propensity score matching was performed to determine difference in outcomes between groups. RESULTS Patients with early AZA initiation had significantly lower transaminases and bilirubin at baseline. Discontinuation rates of AZA did not differ between early and delayed starters (16.6% vs 14.2%), which did not reach statistical significance (hazard ratio 0.97, 95% confidence interval 0.61-1.55, P = .90). Stratification according to baseline disease activity or propensity score matching did not alter the results. Main reason for AZA discontinuation was intolerance to treatment (14.0% vs 13.2%, P = .78) with nausea and vomiting as main side effects. AIH remission rates were comparable among groups. CONCLUSION The discontinuation rate of AZA in AIH treatment is ~15% in the first year of treatment. Early or delayed AZA initiation does not differ in remission and discontinuation rates in AIH induction therapy. Our data suggest that either strategy may be used as part of AIH treatment.
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Affiliation(s)
- Simon Pape
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenThe Netherlands
- European Reference Network RARE‐LIVERHamburgGermany
| | - Tom J. G. Gevers
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenThe Netherlands
- European Reference Network RARE‐LIVERHamburgGermany
| | - Jan Maarten Vrolijk
- Department of Gastroenterology and HepatologyRijnstate HospitalArnhemThe Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and HepatologyLeiden University Medical CenterLeidenThe Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and HepatologyVU University Medical CenterAmsterdamThe Netherlands
| | | | - Richard Taubert
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
- European Reference Network RARE‐LIVERHamburgGermany
| | - Elmar Jaeckel
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
- European Reference Network RARE‐LIVERHamburgGermany
| | - Michael P. Manns
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
- European Reference Network RARE‐LIVERHamburgGermany
| | - Maria Papp
- Division of GastroenterologyDepartment of Internal MedicineFaculty of MedicineUniversity of DebrecenDebrecenHungary
| | - Nora Sipeki
- Division of GastroenterologyDepartment of Internal MedicineFaculty of MedicineUniversity of DebrecenDebrecenHungary
| | - Felix Stickel
- Department of Gastroenterology and HepatologyUniversity Hospital of ZurichZurichSwitzerland
| | - Cumali Efe
- Department of GastroenterologyHarran University HospitalUrfaTurkey
| | - Ersan Ozaslan
- Department of GastroenterologyNumune Research and Education HospitalAnkaraTurkey
| | - Tugrul Purnak
- Department of GastroenterologyHacettepe UniversityAnkaraTurkey
| | - Frederik Nevens
- Department of Gastroenterology and HepatologyUniversity Hospital KU LeuvenLeuvenBelgium
- European Reference Network RARE‐LIVERHamburgGermany
| | - Dominik J. N. Kessener
- Department of Gastroenterology and HepatologyUniversity Clinic of Essen DuisburgEssenGermany
| | - Alisan Kahraman
- Department of Gastroenterology and HepatologyUniversity Clinic of Essen DuisburgEssenGermany
| | - Heiner Wedemeyer
- Department of Gastroenterology and HepatologyUniversity Clinic of Essen DuisburgEssenGermany
| | - Johannes Hartl
- 1st Department of Internal MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- European Reference Network RARE‐LIVERHamburgGermany
| | - Christoph Schramm
- 1st Department of Internal MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- Martin Zeitz Centre for Rare DiseasesUniversity Medical Centre Hamburg‐EppendorfHamburgGermany
- European Reference Network RARE‐LIVERHamburgGermany
| | - Ansgar W. Lohse
- 1st Department of Internal MedicineUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- European Reference Network RARE‐LIVERHamburgGermany
| | - Michael A. Heneghan
- Institute of Liver StudiesKing's College HospitalLondonUK
- European Reference Network RARE‐LIVERHamburgGermany
| | - Joost P. H. Drenth
- Department of Gastroenterology and HepatologyRadboud University Medical CenterNijmegenThe Netherlands
- European Reference Network RARE‐LIVERHamburgGermany
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29
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 548] [Impact Index Per Article: 109.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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30
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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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31
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Pape S, Schramm C, Gevers TJG. Clinical management of autoimmune hepatitis. United European Gastroenterol J 2019; 7:1156-1163. [PMID: 31700628 PMCID: PMC6826525 DOI: 10.1177/2050640619872408] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 07/31/2019] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare and chronic liver disease that is characterised by increased serum transaminases and immunoglobulin G, inflammatory liver histology and presence of circulating autoantibodies. An autoimmune hepatitis diagnosis justifies life-long treatment in most patients in order to prevent development of cirrhosis and end-stage liver disease. The cornerstone of treatment is steroid induction therapy followed by maintenance therapy with azathioprine, which is effective in most cases. For patients who do not respond to standard treatment, second-line treatment with other immunosuppressants can be effective. Treatment should be aimed at biochemical remission of the disease, which is defined as normalization of transaminases and immunoglobulin G. Patients should be monitored intensively during the first months of treatment in order to monitor side-effects, assess symptoms and individualise treatment. Specialist consultation should be sought in difficult-to-treat patients. Future studies and networking initiatives should result in optimization of current treatment strategies in autoimmune hepatitis.
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Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
| | - Christoph Schramm
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
- 1st Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Tom JG Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany
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32
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Doycheva I, Watt KD, Gulamhusein AF. Autoimmune hepatitis: Current and future therapeutic options. Liver Int 2019; 39:1002-1013. [PMID: 30716203 DOI: 10.1111/liv.14062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 01/13/2019] [Accepted: 01/17/2019] [Indexed: 02/13/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.
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Affiliation(s)
- Iliana Doycheva
- Division of Gastroenterology and Hepatology, Medical University, Sofia, Bulgaria
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto, ON, Canada
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33
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Harrison L, Gleeson D. Stopping immunosuppressive treatment in autoimmune hepatitis (AIH): Is it justified (and in whom and when)? Liver Int 2019; 39:610-620. [PMID: 30667576 DOI: 10.1111/liv.14051] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/07/2019] [Accepted: 01/10/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND Initial treatment of autoimmune hepatitis (AIH) with prednisolone ± azathioprine is based on randomised controlled trials. Many patients receive long-term immunosuppressive treatment to prevent disease relapse; this strategy has a weaker evidence base. AIM To consider whether immunosuppressive treatment (IST) withdrawal in AIH is justified and to develop a rationale for patient selection. METHODS We reviewed published papers between 1972 and 2018, which addressed the outcomes of IST withdrawal and/or complications of IST in AIH. RESULTS (1) AIH relapse rates after withdrawal of IST vary between 25% and 100%. There is heterogeneity in these studies regarding relapse definition, IST duration prior to withdrawal and criteria for biochemical and histological remission prior to withdrawal. (2) Factors associated with relapse following IST withdrawal include: (a) absence of an identifiable initial disease trigger, (b) presence of other autoimmune diseases, (c) longer time to biochemical remission and (d) elevated serum transaminases on treatment withdrawal. Reports of associations between relapse and age, IST duration and failure of histological remission have been inconsistent. (3) Continued IST reduces risk of AIH relapse over at least 5 years. However, there is no evidence that routine (as opposed to selective) long-term IST improves disease outcome. (4) Patients with AIH have an increased risk of extrahepatic cancer, notably non-melanoma skin cancer, to which long-term IST may contribute. Long-term corticosteroid therapy is associated with weight gain, low-trauma fractures, diabetes and possibly vascular disease. CONCLUSIONS While further studies are needed, evidence supports a strategy of IST withdrawal in some patients with AIH who have achieved remission.
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Affiliation(s)
- Laura Harrison
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospital's NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Medical School, Sheffield, UK
| | - Dermot Gleeson
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospital's NHS Foundation Trust, Sheffield, UK
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34
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Trivedi PJ, Hubscher SG, Heneghan M, Gleeson D, Hirschfield GM. Grand round: Autoimmune hepatitis. J Hepatol 2019; 70:773-784. [PMID: 30465775 DOI: 10.1016/j.jhep.2018.11.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2018] [Revised: 10/11/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis is a corticosteroid-responsive liver disease arising consequent to immunogenetic and environmental risk factors. The clinical course reflects relapsing and remitting, hepatocyte targeted immunologic damage, which is countered by reparative responses to cell injury. Appropriate and timely immunosuppressive therapy drives the disease into remission, albeit with inevitable side effects. Many challenges faced in the clinic reflect practice that must capture a heterogeneous disease presentation, course, and treatment response, as well as treatment tolerability. In this Grand Round we appraise the evidence supporting current treatment approaches, address the impact of autoimmune liver disease 'crossover or overlap' presentations, explore important clinical correlates to immune-serological classifiers, and discuss the factors influencing choice of alternative therapy in difficult-to-treat situations.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Stefan G Hubscher
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK; Dept. of Cellular Pathology, University Hospitals Birmingham, UK
| | | | - Dermot Gleeson
- Liver Unit, Sheffield Teaching Hospitals Foundation Trust, UK
| | - Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Liver Unit, University Hospitals Birmingham, Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK; Toronto Centre for Liver Disease, University of Toronto and University Health Network, Toronto, Canada.
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35
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Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
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Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
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36
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Janmohamed A, Hirschfield GM. Autoimmune hepatitis and complexities in management. Frontline Gastroenterol 2019; 10:77-87. [PMID: 30651962 PMCID: PMC6319158 DOI: 10.1136/flgastro-2018-101015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/01/2018] [Accepted: 07/09/2018] [Indexed: 02/04/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a rare heterogenous immune-mediated liver disease that for the majority has effective therapy, usually resulting in excellent prognosis. Treatment is based on immunosuppression using standard therapy with corticosteroids and azathioprine. Second-line therapeutic options exist for those who are non-responders ('difficult to treat AIH') or intolerant to standard therapy; however, their use is not standardised, and in addition, there is vast variation in practice and efficacy. Given the rarity of AIH, expertise in its management can be limited to large referral programmes. In this case-based review, we aim to discuss common clinical dilemmas encountered by clinicians managing adult patients with AIH and address the related competencies in the 2010 Gastroenterology curriculum.
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Affiliation(s)
- Ashnila Janmohamed
- Centre for Liver Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK,University Hospitals Birmingham NHS Foundation Trust Birmingham UK, Birmingham, UK
| | - Gideon M Hirschfield
- Centre for Liver Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK,University Hospitals Birmingham NHS Foundation Trust Birmingham UK, Birmingham, UK,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK,Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
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37
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Lowe D, John S. Autoimmune hepatitis: Appraisal of current treatment guidelines. World J Hepatol 2018; 10:911-923. [PMID: 30631396 PMCID: PMC6323516 DOI: 10.4254/wjh.v10.i12.911] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis affects patients of all ages and gender, across all geographic regions. Although still rare, its incidence and prevalence are increasing. Genetic predisposition conveyed by human leucocyte antigen is a strong risk factor for the disease and may be responsible in part for the wide variation in presentation in different geographic regions. Our understanding of the underlying pathogenic mechanisms is evolving and may lead to development of more targeted immunotherapies. Diagnosis is based on elevated levels of serum aminotransferases, gamma globulins, autoantibodies and characteristic findings on histology. Exclusion of other causes of chronic hepatitis is important. Although undiagnosed disease is associated with poor outcomes, it is readily treatable with timely immunosuppressive therapy in the majority of patients. International guidelines are available to guide management but there exists a disparity in the standard treatment regimens. This minireview aims to review the available guidelines and summarize the key recommendations involved in management of this complex autoimmune disease.
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Affiliation(s)
- Dhruv Lowe
- Division of Gastroenterology and Hepatology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13202, United States
| | - Savio John
- Division of Gastroenterology and Hepatology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13202, United States.
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38
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Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized by circulating autoantibodies, hypergammaglobulinemia, and a lymphoplasmocytic infiltration with interface hepatitis on liver biopsy. Treatment with corticosteroids and other immunosuppressive agents is effective and early diagnosis can result in near-normal life expectancy. Untreated patients, however, can progress to cirrhosis and liver failure. The clinical presentation is heterogeneous and may pose diagnostic and therapeutic dilemmas. This case-based review will address the diagnosis and management of this disease, in addition to difficult but commonly encountered clinical scenarios.
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39
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Mieli-Vergani G, Vergani D, Czaja AJ, Manns MP, Krawitt EL, Vierling JM, Lohse AW, Montano-Loza AJ. Autoimmune hepatitis. Nat Rev Dis Primers 2018; 4:18017. [PMID: 29644994 DOI: 10.1038/nrdp.2018.17] [Citation(s) in RCA: 272] [Impact Index Per Article: 38.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that affects children and adults worldwide. The diagnosis of AIH relies on increased serum transaminase and immunoglobulin G levels, presence of autoantibodies and interface hepatitis on liver histology. AIH arises in genetically predisposed individuals when a trigger, such as exposure to a virus, leads to a T cell-mediated autoimmune response directed against liver autoantigens; this immune response is permitted by inadequate regulatory immune control leading to a loss of tolerance. AIH responds favourably to immunosuppressive treatment, which should be started as soon as the diagnosis is made. Standard regimens include fairly high initial doses of corticosteroids (prednisone or prednisolone), which are tapered gradually as azathioprine is introduced. For those patients who do not respond to standard treatment, second-line drugs should be considered, including mycophenolate mofetil, calcineurin inhibitors, mechanistic target of rapamycin (mTOR) inhibitors and biologic agents, which should be administered only in specialized hepatology centres. Liver transplantation is a life-saving option for those who progress to end-stage liver disease, although AIH can recur or develop de novo after transplantation. In-depth investigation of immune pathways and analysis of changes to the intestinal microbiota should advance our knowledge of the pathogenesis of AIH and lead to novel, tailored and better tolerated therapies.
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Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King's College Hospital, Denmark Hill, SE5 9RS London, UK
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany
| | - Edward L Krawitt
- Department of Medicine, University of Vermont, Burlington, VT, USA.,Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA
| | - John M Vierling
- Division of Abdominal Transplantation and Section of Gastroenterology and Hepatology, Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada
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40
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Guillotin V, Galli G, Viallard JF. [Usefulness of thiopurine methyltransferase polymorphism study and metabolites measurement for patients treated by azathioprine]. Rev Med Interne 2018; 39:421-426. [PMID: 29370945 DOI: 10.1016/j.revmed.2017.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 12/18/2017] [Accepted: 12/28/2017] [Indexed: 11/18/2022]
Abstract
Azathioprine is widely used in internal medicine and frequently implicated in occurrence of adverse events. Among these adverse events the bone marrow suppression, a dose-related one, is the most serious because of is potential morbidity and mortality. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism that results in a high variability of its activity with 89% of patients with a normal activity, 11% with an intermediate activity, and 0.3% with very low activity leading to a very high risk of bonne marrow suppression. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques to identify patients for which the standard dose is not advisable. Furthermore, azathioprine metabolites monitoring is helpful for the follow up of patients, especially in therapeutic failure, to distinguish non-compliant patients from under-dosed, "shunters" or resistant patients.
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Affiliation(s)
- V Guillotin
- Laboratoire d'immunologie de l'hôpital Pellegrin, place Amélié-Raba-Léon, 33000 Bordeaux, France.
| | - G Galli
- Service de médecine interne et immunologie clinique, Hôpital Saint-André, rue Jean-Burguet, 33000 Bordeaux, France
| | - J-F Viallard
- Service de médecine interne, hôpital du Haut-Lévêque, avenue Magellan, 33604 Pessac, France
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41
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Guedes ALV, Andrade AR, Nunes VS, Lima FR, de Mello ES, Ono SK, Terrabuio DRB, Cançado ELR. Histological remission of autoimmune hepatitis after the addition of allopurinol and azathioprine dose reduction. AUTOPSY AND CASE REPORTS 2017; 7:35-42. [PMID: 28740837 PMCID: PMC5507567 DOI: 10.4322/acr.2017.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 06/02/2017] [Indexed: 12/30/2022] Open
Abstract
The standard therapy for some autoimmune diseases consists of a combination of corticosteroids and thiopurines. In non-responders to thiopurine drugs, the measurement of the metabolites of azathioprine, 6-thioguanine, and 6-methylmercaptopurine, can be a useful tool. The measurement has been used during the treatment of inflammatory bowel diseases and, less commonly, in autoimmune hepatitis. Many patients preferentially metabolize thiopurines to 6-methylmercaptopurine (6-MMP), which is potentially hepatotoxic, instead of 6-thioguanine, the active immunosuppressive metabolite. The addition of allopurinol shifts the metabolism of thiopurine towards 6-thioguanine, improving the immunosuppressive effect. We present the case of a 51-year-old female with autoimmune hepatitis who had a biochemical response after azathioprine and prednisone treatment without histological remission, and who preferentially shunted to 6-MMP. After the addition of allopurinol, the patient’s 6-thioguanine levels increased, and she reached histological remission with a reduction of 67% of the original dose of azathioprine. The patient did not develop clinical manifestations as a consequence of her increased immunosuppressive state. We also review the relevant literature related to this issue. In conclusion, the addition of allopurinol to thiopurine seems to be an option for those patients who do not reach histological remission and who have a skewed thiopurine metabolite profile.
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Affiliation(s)
- Ana Luiza Vilar Guedes
- University of São Paulo, School of Medicine, Department of Gastroenterology. São Paulo, SP, Brazil
| | - Adriana Ribas Andrade
- University of São Paulo, School of Medicine, Department of Gastroenterology. São Paulo, SP, Brazil
| | - Vinicius Santos Nunes
- University of São Paulo, School of Medicine, Department of Gastroenterology. São Paulo, SP, Brazil
| | - Fabiana Roberto Lima
- University of São Paulo, School of Medicine, Department of Pathology. São Paulo, SP, Brazil
| | | | - Suzane Kioko Ono
- University of São Paulo, School of Medicine, Department of Gastroenterology. São Paulo, SP, Brazil
| | | | - Eduardo Luiz Rachid Cançado
- University of São Paulo, School of Medicine, Department of Gastroenterology. São Paulo, SP, Brazil.,University of São Paulo, Institute of Tropical Medicine of São Paulo. São Paulo, SP, Brazil
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Liberal R, de Boer YS, Andrade RJ, Bouma G, Dalekos GN, Floreani A, Gleeson D, Hirschfield GM, Invernizzi P, Lenzi M, Lohse AW, Macedo G, Milkiewicz P, Terziroli B, van Hoek B, Vierling JM, Heneghan MA. Expert clinical management of autoimmune hepatitis in the real world. Aliment Pharmacol Ther 2017; 45:723-732. [PMID: 28004405 DOI: 10.1111/apt.13907] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/12/2016] [Accepted: 11/27/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.
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Deswal S, Srivastava A. Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review. J Clin Exp Hepatol 2017; 7:55-62. [PMID: 28348471 PMCID: PMC5357743 DOI: 10.1016/j.jceh.2017.01.115] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 01/29/2017] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6-thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH.
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Key Words
- 6-MTIMP, 6-methyl thioinosine monophosphate
- 6MMP, 6-methyl mercaptopurine
- 6MP, 6-mercaptopurine
- 6TG, 6-thioguanine
- AIH, autoimmune hepatitis
- ANA, antinuclear antibody
- AZA, azathioprine
- HGPRT, hypoxanthine guanine phosphoribosyl transferase
- IBD, inflammatory bowel disease
- IgG, immunoglobulin G
- LC, liver cytosol
- LKM, liver kidney microsomal
- PBC, primary biliary cirrhosis
- PSC, primary sclerosing cholangitis
- SMA, smooth muscle antibody
- TIMP, thioinosine monophosphate
- TPMT, thiopurine methyltransferase
- XO, xanthine oxidase
- allopurinol
- autoimmune hepatitis
- azathioprine
- hepatotoxicity
- overlap syndrome
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Affiliation(s)
- Shivani Deswal
- Department of Pediatrics, PGIMER and Dr RML Hospital, New Delhi, India
| | - Anshu Srivastava
- Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Chapdelaine A, Mansour AM, Troyanov Y, Williamson DR, Doré M. Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases. Clin Rheumatol 2017; 36:1341-1348. [PMID: 28130685 DOI: 10.1007/s10067-017-3554-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/22/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023]
Abstract
6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 108 erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 108 erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.
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Affiliation(s)
- Aurélie Chapdelaine
- Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.
| | - Anne-Marie Mansour
- Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada
- Faculty of Medicine, Université de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada
| | - Yves Troyanov
- Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada
| | - David R Williamson
- Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada
- Faculty of Pharmacy, Université de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada
| | - Maxime Doré
- Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada
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Abstract
Autoimmune hepatitis (AIH) is a complex autoimmune disease characterized by immune-mediated destruction of hepatic parenchyma which can result in cirrhosis, liver failure, and death. Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of Liver (EASL) guidelines recommend corticosteroids alone or in combination with azathioprine as first-line treatment strategies. However, a significant proportion of patients may not be able to tolerate or achieve complete biochemical response with these options. In this article, we discuss approaches to these patients and other challenging AIH patient groups such as the asymptomatic, pregnant, elderly, and liver transplant recipients.
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46
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Meijer B, Bouma G, de Boer NKH. Optimize Thiopurine Therapy in Autoimmune Hepatitis. Clin Gastroenterol Hepatol 2016; 14:1062-3. [PMID: 26872401 DOI: 10.1016/j.cgh.2016.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 01/21/2016] [Accepted: 02/04/2016] [Indexed: 02/07/2023]
Affiliation(s)
- Berrie Meijer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
| | - Nanne K H de Boer
- Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands
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Hübener S, Than NN, Oo YH, Lohse AW, Schramm C. Reply. Clin Gastroenterol Hepatol 2016; 14:1063-4. [PMID: 27094582 DOI: 10.1016/j.cgh.2016.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sina Hübener
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nwe Ni Than
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Ye Htun Oo
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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48
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Janmohamed A, Hirschfield GM. Editorial: autoimmune hepatitis - identifying options for treatment. Aliment Pharmacol Ther 2016; 43:1236-7. [PMID: 27137725 DOI: 10.1111/apt.13607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- A Janmohamed
- Centre for Liver Research, NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK
| | - G M Hirschfield
- Centre for Liver Research, NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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49
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Hübener S, Lohse AW, Schramm C, Than NN, Oo YH. WITHDRAWN: Reply. Clin Gastroenterol Hepatol 2016:S1542-3565(16)00265-2. [PMID: 26972982 DOI: 10.1016/j.cgh.2016.03.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.cgh.2016.03.013. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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Affiliation(s)
- Sina Hübener
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nwe Ni Than
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Ye Htun Oo
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
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50
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Hübener S, Oo YH, Than NN, Hübener P, Weiler-Normann C, Lohse AW, Schramm C. Efficacy of 6-Mercaptopurine as Second-Line Treatment for Patients With Autoimmune Hepatitis and Azathioprine Intolerance. Clin Gastroenterol Hepatol 2016; 14:445-53. [PMID: 26492846 DOI: 10.1016/j.cgh.2015.09.037] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 09/01/2015] [Accepted: 09/30/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that requires long-term immunosuppressive therapy. Although most patients have an excellent response to standard therapy (azathioprine in combination with corticosteroids), approximately 10%-15% have intolerance or an insufficient response to azathioprine treatment. We investigated whether 6-mercaptopurine (6-MP) is an effective second-line therapy for patients with AIH. METHODS We performed a retrospective study of 22 patients with AIH who were switched to 6-MP therapy after treatment with the combination of azathioprine and prednisolone at 2 tertiary care institutions in Europe (Germany and the United Kingdom) before November 15, 2014. We performed statistical analyses of data on clinical and biochemical responses collected 4 weeks after 6-MP treatment and then at regular physician visits. RESULTS A total of 15 of 20 patients with prior azathioprine intolerance (75%) responded to 6-MP treatment; 8 of these patients had a complete response and 7 had partial remission, based on biochemical features. In these 15 patients, 6-MP was well tolerated, whereas the 5 remaining patients had to be switched to different immunosuppressive regimes because of 6-MP intolerance. The 2 patients with insufficient response to azathioprine treatment also showed no response to 6-MP. CONCLUSIONS In patients with AIH and azathioprine intolerance, 6-MP seems to be an effective and well-tolerated second-line treatment. 6-MP might be ineffective in patients with insufficient response to azathioprine.
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Affiliation(s)
- Sina Hübener
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ye Htun Oo
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Nwe Ni Than
- Centre for Liver Research, University of Birmingham Liver Unit, Birmingham, United Kingdom
| | - Peter Hübener
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Schramm
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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