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Joshi D, Nayagam J, Clay L, Yerlett J, Claridge L, Day J, Ferguson J, Mckie P, Vara R, Pargeter H, Lockyer R, Jones R, Heneghan M, Samyn M. UK guideline on the transition and management of childhood liver diseases in adulthood. Aliment Pharmacol Ther 2024; 59:812-842. [PMID: 38385884 DOI: 10.1111/apt.17904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/15/2023] [Accepted: 02/03/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Jeremy Nayagam
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Lisa Clay
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Jenny Yerlett
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Lee Claridge
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Jemma Day
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - James Ferguson
- National Institute for Health Research, Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Paul Mckie
- Department of Social Work, King's College Hospital NHS Foundation Trust, London, UK
| | - Roshni Vara
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
- Evelina London Children's Hospital, London, UK
| | | | | | - Rebecca Jones
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Michael Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
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Little R, Kamath BM, Ricciuto A. Liver Disease in Pediatric Inflammatory Bowel Disease. PEDIATRIC INFLAMMATORY BOWEL DISEASE 2023:129-149. [DOI: 10.1007/978-3-031-14744-9_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Horwich BH, Liang TZ, Dodge JL, Chopra S, Kahn JA, Saito T. Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis. Transpl Int 2022; 35:10182. [PMID: 35368647 PMCID: PMC8971201 DOI: 10.3389/ti.2022.10182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/04/2022] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of plasma cell hepatitis (PCH). As these histologically and serologically indistinguishable diagnoses are differentiated by clinical context, it remains uncertain whether they represent distinct immunologic phenomena. Improved understanding of immunoglobulin subclass 4-producing plasma cells (IgG4-PC) has brought attention to IgG4 as an immunophenotypic biomarker. To date, degree and clinical significance of IgG4-PC infiltration in PCH remain elusive. This retrospective, single-center study assessed IgG4-PC infiltration in AIH, rAIH, and PCR via standardized immunohistochemistry analysis. Identified cases from 2005 to 2020 (n = 47) included AIH (treatment-naïve AIH (tnAIH): n = 15 and AIH-flare on treatment (fAIH); n = 10), rAIH (n = 8), and PCR (n = 14) were analyzed and correlated with clinical characteristics. IgG4-Positivity (# IgG4-PC/# pan-IgG-expressing cells) distribution was heterogenous and overlapping [tnAIH: 0.060 (IQR 0.040-0.079), fAIH: 0.000 (0.000-0.033), rAIH: 0.000 (0.000-0.035), PCR: 0.228 (0.039-0.558)]. IgG4-Positivity was inversely correlated with corticosteroid use (p < 0.001). IgG4-Positivity ≥0.500 was associated with rapid AST improvement (p = 0.03). The variable IgG4-Positivity of AIH, rAIH and PCR suggests diverse and overlapping immunopathologic mechanisms and that current diagnostic schemes inadequately capture PCH immunopathology. We propose incorporation of IgG4-Positivity to refine current PCH classification and treatment strategies.
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Affiliation(s)
- Brian H. Horwich
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Tom Z. Liang
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jennifer L. Dodge
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Shefali Chopra
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Jeffrey A. Kahn
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- USC Transplant Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Takeshi Saito
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- USC Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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González IA, Hartley CP, Nalbantoglu ILK. Recurrent Autoimmune Hepatitis and De Novo Autoimmune Hepatitis in the Liver Allograft. Am J Clin Pathol 2021; 155:435-445. [PMID: 33252121 DOI: 10.1093/ajcp/aqaa147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Autoimmune hepatitis (AIH) is a form of severe hepatitis that can recur after orthotopic liver transplant (OLT). Presentation of AIH in patients with OLT who do not have a history of AIH is called de novo AIH (DNAIH). We evaluated the clinicopathologic characteristics of AIH and DNAIH. METHODS Clinicopathologic and outcome measures of 11 patients with recurrent AIH (RAIH) and 22 with DNAIH identified between 2000 and 2017 were compared. RESULTS Both cohorts showed female predominance. The mean clinical follow-up was 13 and 7.8 years in the in the RAIH and DNAIH groups, respectively (P = .1). Moderate portal inflammation was more common in patients with RAIH (64% vs 27%, P = .043). A trend was observed for more cases of DNAIH showing severe inflammation (36% vs 9%, P = .09) and submassive necrosis compared with RAIH (23% vs 0%, P = .086). A trend for more advanced fibrosis was also noted in the RAIH group (27% vs 5%, P = .059). Three patients with RAIH lost their grafts because of RAIH. Five-year disease-specific graft survival (GS) (P = .012) and overall GS (P = .015) were worse in patients with RAIH. Complement component 4d immunohistochemistry was positive in 2 patients with RAIH and 3 with DNAIH but showed no correlation with GS or other parameters. CONCLUSIONS RAIH seems to have a more aggressive clinical course than DNAIH and warrants closer clinical follow-up and aggressive treatment.
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Affiliation(s)
- Iván A González
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
- Department of Pathology, Yale School of Medicine, New Haven, CT
| | - Christopher P Hartley
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - ILKe Nalbantoglu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
- Department of Pathology, Yale School of Medicine, New Haven, CT
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Harrington CR, Yang GY, Levitsky J. Advances in Rejection Management: Prevention and Treatment. Clin Liver Dis 2021; 25:53-72. [PMID: 33978583 DOI: 10.1016/j.cld.2020.08.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Extended survival of liver transplant recipients has brought rejection management to the forefront of liver transplant research. This article discusses T-cell-mediated rejection, antibody-mediated rejection, and chronic rejection. We focus on the prevention and then discuss treatment options. Future directions of rejection management include biomarkers of rejection, which may allow for monitoring of patients who are considered high risk for rejection and detection of rejection before there is any clinical evidence to improve graft and patient survival. With improved graft life and survival of liver transplant recipients, the new frontier of rejection management focuses on immunosuppression minimization, withdrawal, and personalization.
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Affiliation(s)
- Claire R Harrington
- Department of Medicine, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 2330, Chicago, IL 60611, USA
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, 251 E Huron St. Chicago, IL 60611, USA
| | - Josh Levitsky
- Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1400, Chicago, IL 60611, USA; Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1900, Chicago, IL 60611, USA.
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Choi C, Botros Y, Shah J, Xue P, Jones A, Galan M, Olivo R, Niazi M, Paterno F, Guarrera J, Pyrsopoulos NT. A Case Report of Alloimmune Hepatitis after Direct-acting Antiviral Treatment in a Liver Transplant Patient. J Clin Transl Hepatol 2020; 8:459-462. [PMID: 33447530 PMCID: PMC7782114 DOI: 10.14218/jcth.2020.00062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/12/2020] [Accepted: 08/24/2020] [Indexed: 01/14/2023] Open
Abstract
Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA.
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Affiliation(s)
- Catherine Choi
- Department of Internal Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Youssef Botros
- Division of Gastroenterology, St. Joseph’s University Medical Center, Paterson, NJ, USA
| | - Jamil Shah
- Division of Gastroenterology & Hepatology, The Brooklyn Hospital Center, Brooklyn, NY, USA
| | - Pei Xue
- Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Anja Jones
- Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mark Galan
- Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Raquel Olivo
- Division of Gastroenterology & Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Mumtaz Niazi
- Division of Gastroenterology & Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Flavio Paterno
- Division of Liver Transplantation & Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - James Guarrera
- Division of Liver Transplantation & Hepatobiliary Surgery, Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Nikolaos T. Pyrsopoulos
- Division of Gastroenterology & Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
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Ip S, Bhanji RA, Ebadi M, Mason AL, Montano-Loza AJ. De novo and recurrent liver disease. Best Pract Res Clin Gastroenterol 2020; 46-47:101688. [PMID: 33158472 DOI: 10.1016/j.bpg.2020.101688] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/03/2020] [Accepted: 09/18/2020] [Indexed: 01/31/2023]
Abstract
Decompensated cirrhosis due to nonalcoholic steatohepatitis (NASH), and autoimmune liver diseases (AILD) are the most common indications for liver transplantation (LT). AILD include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). NASH and AILD share some peculiarities as they can recur in the new graft, compromising the quality of life, and graft and patient survival. De novo NASH or AIH connotes the development of these liver diseases in patients transplanted for other indications. The diagnosis of recurrent or de novo liver disease usually requires a liver biopsy aside from recurrent PSC, which can be diagnosed with compatible imaging studies and exclusion of other causes of biliary strictures. The treatment of recurrent NASH is lifestyle modifications aiming for weight loss. Recurrent and de novo AIH is usually treated with corticosteroids with or without azathioprine. Recurrent PBC should be treated with ursodeoxycholic acid. There are no proven treatment options for recurrent PSC. Patients with graft failure should be considered for repeat LT. Future investigations should use standardized diagnostic criteria for each disease, seek diagnostic biomarkers, and evaluate treatments that improve outcomes.
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Affiliation(s)
- Stephen Ip
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Rahima A Bhanji
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Maryam Ebadi
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Andrew L Mason
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
| | - Aldo J Montano-Loza
- From the Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Alberta, Canada.
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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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Kerkar N, Mayo MJ. Autoimmune Hepatitis: Highlights for Liver Transplant Providers From the American Association for the Study of Liver Diseases 2019 Guidelines. Liver Transpl 2020; 26:973-976. [PMID: 32133751 DOI: 10.1002/lt.25740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 02/26/2020] [Indexed: 01/13/2023]
Affiliation(s)
- Nanda Kerkar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Golisano Childrens Hospital at Strong, University of Rochester Medical Center, Rochester, NY
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, TX
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Stirnimann G, Ebadi M, Czaja AJ, Montano-Loza AJ. Recurrent and De Novo Autoimmune Hepatitis. Liver Transpl 2019; 25:152-166. [PMID: 30375180 DOI: 10.1002/lt.25375] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/23/2018] [Indexed: 02/07/2023]
Abstract
Clinical indications for liver transplantation (LT) in patients with autoimmune hepatitis (AIH) are identical to those of patients with other chronic liver diseases that end in acute or semiacute liver failure, decompensated cirrhosis, or hepatocellular carcinoma. Recurrent disease after LT has been reported in 10%-50% of patients with AIH, and the frequency of detection is influenced in part by the use of protocol or clinically indicated liver biopsy. De novo AIH connotes the development of AIH in patients transplanted for liver diseases other than AIH, and it has been reported in 5%-10% of pediatric and 1%-2% of adult recipients. Recurrent disease can negatively impact on graft and patient survival, and retransplantation has been required in 8%-23%. De novo AIH is within the spectrum of graft dysfunction that includes plasma cell-rich rejection, and it can also progress to cirrhosis and graft failure. Treatment for recurrent or de novo disease is based on the conventional regimens for AIH, and corticosteroid therapy alone or combined with azathioprine is standard. Better control of disease activity prior to LT has been associated with less recurrence, and maintenance corticosteroid treatment after LT can reduce its frequency. In conclusion, recurrent AIH is far more frequent than de novo AIH. Both may have negative impacts on graft and patient survival, and early detection and treatment are key objectives. Future investigations must codify the diagnostic criteria for each graft dysfunction, seek diagnostic biomarkers, and evaluate treatments that improve outcomes without increasing the risk of pre- and post-LT infections.
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Affiliation(s)
- Guido Stirnimann
- Department of Visceral Surgery and Medicine, Inselspital Bern, Bern University Hospital and University of Bern, Bern, Switzerland.,Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Maryam Ebadi
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, University of Alberta Hospital, Edmonton, Alberta, Canada
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11
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De novo autoimmune hepatitis –is this different in adults compared to children? J Autoimmun 2018; 95:26-33. [DOI: 10.1016/j.jaut.2018.10.023] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 02/06/2023]
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12
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De Novo Autoimmune Hepatitis Following Liver Transplantation. Transplant Proc 2018; 50:1451-1456. [DOI: 10.1016/j.transproceed.2018.02.066] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 02/01/2018] [Accepted: 02/17/2018] [Indexed: 02/07/2023]
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13
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Mieli-Vergani G, Vergani D, Baumann U, Czubkowski P, Debray D, Dezsofi A, Fischler B, Gupte G, Hierro L, Indolfi G, Jahnel J, Smets F, Verkade HJ, Hadžić N. Diagnosis and Management of Pediatric Autoimmune Liver Disease: ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr 2018; 66:345-360. [PMID: 29356770 DOI: 10.1097/mpg.0000000000001801] [Citation(s) in RCA: 192] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Paediatric autoimmune liver disease is characterized by inflammatory liver histology, circulating autoantibodies, and increased levels of IgG, in the absence of a known etiology. Three conditions have a likely autoimmune pathogenesis: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis, and de novo AIH after liver transplantation. Two types of pediatric AIH are recognized according to seropositivity for smooth muscle and/or antinuclear antibody (AIH-1) or liver kidney microsomal type 1 and/or anti-liver cytosol type 1 antibodies (AIH-2).Pertinent issues addressing the diagnosis, treatment, and long-term follow-up were formulated by a core group of ESPGHAN members. They have commissioned the first authors with execution of this project. Initially, they have performed a systematic literature search on MEDLINE, ResearchGate, and Mendeley databases during the last 30 years and produced a document focusing on prospective and retrospective studies in children. The ESPGHAN core group and ESPGHAN Hepatology Committee members voted on each recommendation, using a formal voting technique.
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Affiliation(s)
| | - Diego Vergani
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Ulrich Baumann
- Pädiatrische Gastroenterologie und Hepatologie, Medizinische Hochschule, Hannover, Germany
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dominique Debray
- Pediatric Hepatology Unit, AP-HP-Hôpital Necker Enfants Malades, Paris, France
| | - Antal Dezsofi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Björn Fischler
- Department of Pediatrics, Karolinska University Hospital, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Girish Gupte
- Liver Unit (Including Small Bowel Transplantation), Department of Gastroenterology and Nutrition, Birmingham Children's Hospital, Birmingham, UK
| | - Loreto Hierro
- Hospital Infantil Universitario La Paz, Madrid, Spain
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Firenze, Italy
| | - Jörg Jahnel
- Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Françoise Smets
- UCL, Cliniques Universitaires Saint-Luc, Pediatric Gastroenterology and Hepatology, Brussels, Belgium
| | - Henkjan J Verkade
- Dept of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, the Netherlands
| | - Nedim Hadžić
- MowatLabs, Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Satapathy SK, Jones OD, Vanatta JM, Kamal F, Kedia SK, Jiang Y, Nair SP, Eason JD. Outcomes of Liver Transplant Recipients With Autoimmune Liver Disease Using Long-Term Dual Immunosuppression Regimen Without Corticosteroid. Transplant Direct 2017; 3:e178. [PMID: 28706981 PMCID: PMC5498019 DOI: 10.1097/txd.0000000000000693] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 04/15/2017] [Accepted: 05/01/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Liver transplant (LT) recipients with autoimmune liver disease (primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis) are at increased risk of developing acute cellular rejection (ACR), and in many cases graft failure due to recurrent disease. We describe our experience with dual immunosuppression without steroid maintenance and analyze its effect on disease recurrence; ACR; patient and graft survivals; and complications, such as sepsis and de novo malignancy. METHODS We included 74 consecutive LT recipients (April 2006 to April 2013) with autoimmune liver disease (primary sclerosing cholangitis, 20; primary biliary cholangitis, 23; autoimmune hepatitis, 31) from a single transplant center. Immunosuppression protocol included rabbit antithymocyte globulin for induction and mycophenolate mofetil with tacrolimus or sirolimus/everolimus indefinitely for maintenance. RESULTS Overall 1-, 3-, 5-, and 7-year patient survival was 95.9%, 90.4%, 82,2% and 74.9%, re-graft-free survival was 93.2%, 86.3%, 79.9%, and 72.8%, respectively (median follow-up, 5.5 years). In a multivariate Cox regression analysis, sepsis during post-LT period (P = 0.040; hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.04-6.11), steroid use for ACR (P = 0.037; HR, 2.60; 95% CI, 1.06-6.34), and younger age (<40 years) at LT (P = 0.038; HR, 2.53; 95% CI, 1.05-6.10) predicted graft survival, whereas steroid use for ACR was the only variable that was predictive of overall patient survival (P = 0.004; HR, 4.10; 95% CI, 1.59-10.52). Overall, 34 biopsy-proven ACR was noted in 22 LT recipients (30%), 13 (17.5%) had disease recurrence, and 34 episodes of sepsis occurred in 19 patients. CONCLUSIONS Dual immunosuppression protocol in LT recipients with autoimmune liver disease without corticosteroid maintenance had acceptable rates of survival and ACR without predisposing patients to the adverse effects of long-term steroid therapy.
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Affiliation(s)
- Sanjaya K. Satapathy
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - Ollie D. Jones
- Department of Gastroenterology, University of Tennessee Health Sciences Center, Memphis, TN
| | - Jason M. Vanatta
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - Faisal Kamal
- Department of Internal Medicine, University of Tennessee Health Sciences Center, Memphis, TN
| | | | - Yu Jiang
- School of Public Health, University of Memphis, Memphis, TN
| | - Satheesh P. Nair
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
| | - James D. Eason
- Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN
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16
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Abstract
Recurrent autoimmune hepatitis (AIH) and de novo AIH are 2 important causes of late graft failure after liver transplantation (LT). Recurrent AIH occurs in patients who undergo LT for AIH. De novo AIH occurs in patients who are transplanted for etiologies other than AIH. Although typically treated with standard treatment for AIH, including corticosteroids and azathioprine, both recurrent and de novo AIH may progress to end-stage liver disease requiring retransplantation.
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Affiliation(s)
- Eliza W Beal
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Sylvester M Black
- Division of Transplantation, Department of Surgery, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 100, Columbus, OH 43210, USA
| | - Anthony Michaels
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 395 West 12th Avenue, Suite 200, Columbus, OH 43210, USA.
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17
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Affiliation(s)
- Albert J. Czaja
- Professor Emeritus of Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
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18
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Joshi D, Gupta N, Samyn M, Deheragoda M, Dobbels F, Heneghan MA. The management of childhood liver diseases in adulthood. J Hepatol 2017; 66:631-644. [PMID: 27914924 DOI: 10.1016/j.jhep.2016.11.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 11/20/2016] [Accepted: 11/21/2016] [Indexed: 12/12/2022]
Abstract
An increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson's disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
| | - Nitika Gupta
- Division of Paediatric Gastroenterology, Emory University School of Medicine, Atlanta, USA
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Fabienne Dobbels
- Academic Centre for Nursing and Midwifery, Katholieke Universiteit Leuven, Belgium
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19
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Ibáñez-Samaniego L, Salcedo M, Vaquero J, Bañares R. De novo autoimmune hepatitis after liver transplantation: A focus on glutathione S-transferase theta 1. Liver Transpl 2017; 23:75-85. [PMID: 27712026 DOI: 10.1002/lt.24652] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 09/13/2016] [Indexed: 02/07/2023]
Abstract
De novo autoimmune hepatitis (DAIH) is a rare clinical condition with features that resemble those of autoimmune hepatitis (AIH) in patients undergoing liver transplantation (LT) for nonautoimmune liver disease. The diagnosis of this entity has been based on the presence of biochemical and histological patterns similar to those observed in the primary AIH, although several considerations must be taken into account. The impact of DAIH on graft survival is relevant, and early diagnosis and treatment is associated with a good longterm outcome. Although glutathione S-transferase theta 1 (GSTT1) alloimmune recognition has been shown to be involved in the pathogenesis of DAIH, further studies are necessary to fully determine its pathogenic mechanisms and risk factors. We review the pathophysiology, the most common histological patterns, the treatment strategies, and the longterm outcomes of DAIH after LT with a special focus on GSTT1. Liver Transplantation 23:75-85 2017 AASLD.
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Affiliation(s)
- Luis Ibáñez-Samaniego
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Javier Vaquero
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Rafael Bañares
- Digestive Disease Department and Liver Transplantation Unit, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria del Hospital Gregorio Marañón, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.,Facultad de Medicina, Universidad Complutense, Madrid, Spain
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20
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Liberal R, Grant CR. Cirrhosis and autoimmune liver disease: Current understanding. World J Hepatol 2016; 8:1157-1168. [PMID: 27729952 PMCID: PMC5055585 DOI: 10.4254/wjh.v8.i28.1157] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/14/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) constitute the classic autoimmune liver diseases (AILDs). While AIH target the hepatocytes, in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells. Persistent liver injury, associated with chronic AILD, leads to un-resolving inflammation, cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts. Liver cirrhosis, and the resultant loss of normal liver function, inevitably ensues. Patients with cirrhosis have higher risks or morbidity and mortality, and that in the decompensated phase, complications of portal hypertension and/or liver dysfunction lead to rapid deterioration. Accurate diagnosis and monitoring of cirrhosis is, therefore of upmost importance. Liver biopsy is currently the gold standard technique, but highly promising non-invasive methodology is under development. Liver transplantation (LT) is an effective therapeutic option for the management of end-stage liver disease secondary to AIH, PBC and PSC. LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy; in addition, LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
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21
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Liberal R, Vergani D, Mieli-Vergani G. Recurrence of autoimmune liver disease and inflammatory bowel disease after pediatric liver transplantation. Liver Transpl 2016; 22:1275-83. [PMID: 27257963 DOI: 10.1002/lt.24490] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 05/23/2016] [Accepted: 05/23/2016] [Indexed: 02/07/2023]
Abstract
Approximately 10% of children with autoimmune hepatitis (AIH) and 30% of those with sclerosing cholangitis (SC) require liver transplantation (LT). LT is indicated in patients who present with fulminant hepatic failure (ie, with encephalopathy) and in those who develop end-stage liver disease despite treatment. After LT, recurrent AIH is reported in approximately 30% of patients and recurrent SC in up to 50%. Diagnosis of recurrence is based on biochemical abnormalities, seropositivity for autoantibodies, interface hepatitis on histology, steroid dependence, and, for SC, presence of cholangiopathy. Recurrence of SC after LT is often associated with poorly controlled inflammatory bowel disease (IBD). Recurrence may even appear years after LT; therefore, steroid-based immunosuppression should be maintained at a higher dose than that used for patients transplanted for nonautoimmune liver diseases. Although the impact of recurrent disease on graft function is controversial, it seems that in pediatric LT recipients recurrence of AIH or SC is associated with compromised graft survival. Exacerbation of preexistent IBD may be observed after LT for SC or AIH, and IBD appears to have a more aggressive course than before LT. In addition, IBD can develop de novo following LT. Liver Transplantation 22 1275-1283 2016 AASLD.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies and Transplantation, King's College London School of Medicine, King's College Hospital, London, UK.,Department of Gastroenterology, Centro Hospitalar São João, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Diego Vergani
- Institute of Liver Studies and Transplantation, King's College London School of Medicine, King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Institute of Liver Studies and Transplantation, King's College London School of Medicine, King's College Hospital, London, UK.,Paediatric Liver, GI and Nutrition Centre, King's College Hospital, London, UK
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22
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van Gerven NMF, de Boer YS, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Auto immune hepatitis. World J Gastroenterol 2016; 22:4651-4661. [PMID: 27217697 PMCID: PMC4870072 DOI: 10.3748/wjg.v22.i19.4651] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: “auto immune hepatitis”, “clinical presentation”, “symptoms”, “signs”, “diagnosis”, “auto antibodies”, “laboratory values”, “serology”, “histopathology”, “histology”, “genetics”, “HLA genes”, “non-HLA genes”, “environment”, “epidemiology”, “prevalence”, “incidence”, “demographics”, “complications”, “HCC”, “PBC”, “PSC”, “corticosteroid”, “therapy”, “treatment”, “alternative treatment”. English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.
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23
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Vukotic R, Vitale G, D’Errico-Grigioni A, Muratori L, Andreone P. De novo autoimmune hepatitis in liver transplant: State-of-the-art review. World J Gastroenterol 2016; 22:2906-2914. [PMID: 26973387 PMCID: PMC4779914 DOI: 10.3748/wjg.v22.i10.2906] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necro-inflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of non-organ specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.
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24
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Kerkar N, Yanni G. ‘De novo’ and ‘recurrent’ autoimmune hepatitis after liver transplantation: A comprehensive review. J Autoimmun 2016; 66:17-24. [DOI: 10.1016/j.jaut.2015.08.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 08/23/2015] [Indexed: 02/08/2023]
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25
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Faisal N, Renner EL. Recurrence of autoimmune liver diseases after liver transplantation. World J Hepatol 2015; 7:2896-905. [PMID: 26689244 PMCID: PMC4678376 DOI: 10.4254/wjh.v7.i29.2896] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 11/07/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT.
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Affiliation(s)
- Nabiha Faisal
- Nabiha Faisal, Eberhard L Renner, Liver Transplant Program/Multiorgan Transplant Program, University Health Network/Toronto General Hospital, University of Toronto, Toronto, ON M5G 2N2, Canada
| | - Eberhard L Renner
- Nabiha Faisal, Eberhard L Renner, Liver Transplant Program/Multiorgan Transplant Program, University Health Network/Toronto General Hospital, University of Toronto, Toronto, ON M5G 2N2, Canada
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26
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Abstract
Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT.
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27
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Bittencourt PL, Cançado ELR, Couto CA, Levy C, Porta G, Silva AEB, Terrabuio DRB, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes Neto EPA, Luz GO, Oliveira P, Oliveira EMGD, Schiavon JLN, Seva-Pereira T, Parise ER, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52 Suppl 1:15-46. [DOI: 10.1590/s0004-28032015000500002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
ABSTRACT In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.
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28
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Ennaifer R, Ayadi H, Romdhane H, Cheikh M, Mestiri H, Khalfallah T, Hadj NB. De novo autoimmune hepatitis following liver transplantation for primary biliary cirrhosis: an unusual cause of late grafts dysfunction. Pan Afr Med J 2015; 21:2. [PMID: 26401196 PMCID: PMC4561156 DOI: 10.11604/pamj.2015.21.2.6789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 04/15/2015] [Indexed: 11/11/2022] Open
Abstract
De novo autoimmune hepatitis (AIH) is a rare disorder first described in 1998. It occurs in patients who underwent liver transplantation for a different etiology. We present the case of a 56-year-old woman who was diagnosed with primary biliary cirrhosis and had liver transplantation for refractory pruritis. Seven years after transplantation, she presented alterations in the hepatic profile with hypertransaminasemia, elevated alkaline phosphatase and gamma-glutamyl-transferase. Her liver functions test also showed elevated IgG levels. Serum autoantibodies were negative except for antimitochondrial antibodies. Histological findings indicated features of AIH without bile duct damage or loss. She had a pretreatment AIH score of 13 points and a post treatment score of 15 points according to the International AIH Group. The patient was treated effectively with prednisolone and her liver function and globulin levels rapidly returned to normal.
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Affiliation(s)
- Rym Ennaifer
- Department of Hepato-Gastro-Enterology, Mongi Slim Hospital, Tunis, Tunisia ; University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia
| | - Hend Ayadi
- Department of Hepato-Gastro-Enterology, Mongi Slim Hospital, Tunis, Tunisia ; University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia
| | - Haifa Romdhane
- Department of Hepato-Gastro-Enterology, Mongi Slim Hospital, Tunis, Tunisia ; University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia
| | - Meriem Cheikh
- Department of Hepato-Gastro-Enterology, Mongi Slim Hospital, Tunis, Tunisia ; University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia
| | - Hafedh Mestiri
- University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia ; Departement of Surgery, Mongi Slim Hospital, Tunis, Tunisia
| | - Taher Khalfallah
- University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia ; Departement of Surgery, Mongi Slim Hospital, Tunis, Tunisia
| | - Najet Bel Hadj
- Department of Hepato-Gastro-Enterology, Mongi Slim Hospital, Tunis, Tunisia ; University of Tunis El Manar, Faculty of Medicine, Tunis, Tunisia
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29
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Liberal R, Vergani D, Mieli-Vergani G. Update on Autoimmune Hepatitis. J Clin Transl Hepatol 2015; 3:42-52. [PMID: 26357634 PMCID: PMC4542083 DOI: 10.14218/jcth.2014.00032] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 12/08/2014] [Accepted: 12/08/2014] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
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Affiliation(s)
- Rodrigo Liberal
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Diego Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
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30
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Alexandropoulos K, Bonito AJ, Weinstein EG, Herbin O. Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model. Int J Mol Sci 2015; 16:1980-2000. [PMID: 25603179 PMCID: PMC4307344 DOI: 10.3390/ijms16011980] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 01/07/2015] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.
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Affiliation(s)
- Konstantina Alexandropoulos
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
| | - Anthony J Bonito
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
| | - Erica G Weinstein
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA
| | - Olivier Herbin
- Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA.
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31
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Abstract
AIH is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and production of autoantibodies. Based on the nature of the serum autoantibodies, two types of AIH are recognized: type 1 (AIH-1), positive for ANA and/or anti-smooth muscle antibody, and type 2 (AIH-2), defined by the positivity for anti-liver kidney microsomal type 1 antibody or for anti-liver cytosol type 1 antibody. AIH demonstrates a female preponderance with the female-to-male ratio of 4:1 in AIH-1 and 10:1 in AIH-2. Several genes confer susceptibility to AIH and influence clinical manifestation, response to treatment, and overall prognosis. Most are located within the human leukocyte antigen (HLA) region, which is involved in the presentation of antigenic peptides to T cells and thus in the initiation of adaptive immune responses. The strongest associations are found within the HLA-DRB1 locus. In patients with increased genetic susceptibility to AIH, immune responses to liver autoantigens could be triggered by molecular mimicry. Because of molecular mimicry, different environmental agents, drugs, and viruses might produce AIH. In AIH, T cells are numerically and functionally impaired, permitting the perpetuation of effector immune responses with ensuing persistent liver destruction. AIH is rare but highly treatable inflammatory condition of the liver. Subclinical and asymptomatic disease is common. AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes. Clinical response to immunosuppressive therapy is characteristic and supports the diagnosis.
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Affiliation(s)
- Libia Moy
- Division of Pediatric Gastroenterology, New York University School of Medicine, New York, NY
| | - Jeremiah Levine
- Division of Pediatric Gastroenterology, New York University School of Medicine, New York, NY.
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32
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Goldmann G, Zeitler H, Marquardt N, Horneff S, Balta Z, Strassburg CP, Oldenburg J. Long-term outcome of liver transplantation in HCV/HIV coinfected haemophilia patients. A single centre study of 10 patients. Hamostaseologie 2014; 35:175-80. [PMID: 25374048 DOI: 10.5482/hamo-14-07-0027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 10/21/2014] [Indexed: 11/05/2022] Open
Abstract
UNLABELLED The outcome and clinical features during long term follow-up of 10 haemophilia patients (haemophilia A n = 9, haemophilia B n = 1), who underwent successful orthotopic liver transplantation (OLT) due to hepatitis associated liver disease, are summarised. PATIENTS Eight patients were HIV/HCV co-infected. Despite severe postoperative complications, which were not bleeding-associated, all patients survived OLT. RESULTS Long-term survival was 70% after in mean 8 years follow-up. Twelve years after OLT one patient developed a cyclosporine-induced nephropathy requiring haemodialysis. HIV-HAART was initiated in all patients after OLT, and allowed a successful HCV treatment in 6 patients. Factor VIII production was sufficient in mean 72 h after OLT and remained stable at subnormal to normal FVIII levels of in median 30% (range 14-96%) also during long-term follow-up. Post-OLT spontaneous bleeding events were rare compared to pre-OLT, therefore, the performance status improved in all patients. DISCUSSION OLT substitutes the hepatic FVIII but has no effect on the extra-hepatic endothelial FVIII production, suggesting that in case of severe tissue injury enhanced bleeding might occur. Additionally, after OLT there is no acute phase reaction of the FVIII protein. Therefore, our OLT patients received in case of a reduced FVIII activity a peri-interventional prophylactic short-term FVIII substitution in surgical and diagnostic interventions with high bleeding risk. CONCLUSION Bleeding and wound healing disturbances were not seen.
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Affiliation(s)
| | - H Zeitler
- Zeitler Heike, MD, Internal Medical Clinic I, CETA, University of Bonn, Sigmund-Freud-Str. 27, 53127 Bonn, Germany, Tel. +49/(0)2 28/28 71 36-28, Fax -30, E-mail:
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Yamagiwa S, Kamimura H, Takamura M, Genda T, Ichida T, Nomoto M, Aoyagi Y. Presence of antibodies against self human leukocyte antigen class II molecules in autoimmune hepatitis. Int J Med Sci 2014; 11:850-856. [PMID: 25013363 PMCID: PMC4081305 DOI: 10.7150/ijms.8633] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 05/15/2014] [Indexed: 12/16/2022] Open
Abstract
Autoimmune hepatitis (AIH) can arise de novo after liver transplantation (LT) for non-autoimmune liver diseases. Considering the identical features of de novo AIH after LT and classical AIH, as well as the importance of anti-human leukocyte antigen (HLA) antibodies in graft rejection, we investigated the presence of circulating anti-HLA class II antibodies in the sera of 35 patients with AIH, 30 patients with primary biliary cirrhosis (PBC), and 30 healthy donors using fluorescent dye-impregnated beads bound to HLA molecules. We then investigated the allele specificity of the antibodies and identified the HLA alleles in each patient using DNA-based HLA typing. We also examined HLA class II expression in liver samples using immunohistochemistry. Anti-HLA class II antibodies were detected significantly more frequently in the patients with AIH (88.1%) than in the patients with PBC (33.3%) or in the healthy donors (13.3%) (both P <0.01). We confirmed that the anti-HLA class II antibodies in the AIH patients showed specificity for several HLA class II alleles, including self HLA class II alleles. Moreover, positive reactivity with anti-self HLA class II antibodies was associated with higher serum transaminase levels. In conclusion, we demonstrated, for the first time, that antibodies against self HLA class II alleles were detectable in patients with AIH. Our results suggest that an antibody-mediated immune response against HLA class II molecules on hepatocytes may be involved in the pathogenesis or acceleration of liver injury in AIH.
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Affiliation(s)
- Satoshi Yamagiwa
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Hiroteru Kamimura
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Masaaki Takamura
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Takuya Genda
- 2. Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni 410-2295, Japan
| | - Takafumi Ichida
- 2. Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni 410-2295, Japan
| | - Minoru Nomoto
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
| | - Yutaka Aoyagi
- 1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan
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Abstract
Liver transplantation for autoimmune hepatitis (AIH) is usually successful with excellent long-term outcomes, but primary disease may recur. The recurrence of AIH is a significant cause of graft loss. This study was to analyze the effect of splenectomy in preventing AIH relapse. The clinical courses of 12 patients who had transplantation for AIH were analyzed retrospectively. All patients were subjected to transplantation for end-stage liver disease caused by chronic AIH. Based on the duration of immunosuppressive treatment before liver transplantation, simultaneous splenectomy was performed in ten patients. Two patients underwent liver transplantation without splenectomy, one of them developed recurrent AIH and died from graft failure caused by AIH relapse. However, no episode of AIH recurrence was observed in patients who had undergone simultaneous splenectomy. Splenectomy might be an option to prevent AIH relapse in some patients with high risk factors.
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Liberal R, Grant CR, Longhi MS, Mieli-Vergani G, Vergani D. Diagnostic criteria of autoimmune hepatitis. Autoimmun Rev 2014; 13:435-40. [PMID: 24418295 DOI: 10.1016/j.autrev.2013.11.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2013] [Indexed: 12/16/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. A set of inclusion and exclusion criteria for the diagnosis of AIH have been established by the International Autoimmune Hepatitis Group (IAIHG). There are two main types of AIH: type 1, positive for anti-nuclear (ANA) and/or anti-smooth muscle antibodies (SMAs) and type 2, defined by the presence of anti-liver kidney microsomal antibody type 1 (LKM-1) and/or anti-liver cytosol type 1 (LC-1) autoantibodies. The central role of autoantibodies in the diagnosis of AIH has led the IAIHG to produce a consensus statement detailing appropriate and effective methods for their detection. Autoantibodies should be tested by indirect immunofluorescence at an initial dilution of 1/40 in adults and 1/10 in children on a freshly prepared rodent substrate that includes kidney, liver and stomach sections to allow for the simultaneous detection of all reactivities relevant to AIH. Anti-LKM-1 is often confused with anti-mitochondrial antibody (AMA) if rodent kidney is used as the sole immunofluorescence substrate. The identification of the molecular targets of anti-LKM-1 and AMA has led to the establishment of immuno-assays based on the use of the recombinant or purified autoantigens. Perinuclear anti-nuclear neutrophil antibody (p-ANNA) is an additional marker of AIH-1; anti soluble liver antigen (SLA) antibodies are specific for autoimmune liver disease, can be present in AIH-1 and AIH-2 and are associated with a more severe clinical course. Anti-SLA are detectable by ELISA or radio-immuno-assays, but not by immunofluorescence. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival.
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Affiliation(s)
- Rodrigo Liberal
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK; Faculty of Medicine, University of Porto, Porto, Portugal
| | - Charlotte R Grant
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Maria Serena Longhi
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Diego Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK.
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Nakano T, Goto S, Lai CY, Hsu LW, Tseng HP, Chen KD, Chiu KW, Wang CC, Cheng YF, Chen CL. Induction of antinuclear antibodies by de novo autoimmune hepatitis regulates alloimmune responses in rat liver transplantation. Clin Dev Immunol 2013; 2013:413928. [PMID: 24454474 PMCID: PMC3886613 DOI: 10.1155/2013/413928] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 10/31/2013] [Accepted: 11/13/2013] [Indexed: 01/10/2023]
Abstract
Concanavalin A (Con A) is a lectin originating from the jack-bean and well known for its ability to stimulate T cells and induce autoimmune hepatitis. We previously demonstrated the induction of immunosuppressive antinuclear autoantibody in the course of Con A-induced transient autoimmune hepatitis. This study aimed to clarify the effects of Con A-induced hepatitis on liver allograft rejection and acceptance. In this study, we observed the unique phenomenon that the induction of transient de novo autoimmune hepatitis by Con A injection paradoxically overcomes the rejection without any immunosuppressive drug and exhibits significantly prolonged survival after orthotopic liver transplantation (OLT). Significantly increased titers of anti-nuclear Abs against histone H1 and high-mobility group box 1 (HMGB1) and reduced donor specific alloantibody response were observed in Con A-injected recipients. Induction of Foxp3 and IL-10 in OLT livers of Con A-injected recipients suggested the involvement of regulatory T cells in this unique phenomenon. Our present data suggest the significance of autoimmune responses against nuclear histone H1 and HMGB1 for competing allogeneic immune responses, resulting in the acceptance of liver allografts in experimental liver transplantation.
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Affiliation(s)
- Toshiaki Nakano
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - Shigeru Goto
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Iwao Hospital, 3059-1 Kawakami, Yufu, Oita 879-5102, Japan
| | - Chia-Yun Lai
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Department of Veterinary Medicine, National Pingtung University of Science & Technology, 1 Shuehfu Road, Neipu, Pingtung 912, Taiwan
| | - Li-Wen Hsu
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - Hui-Peng Tseng
- Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - Kuang-Den Chen
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - King-Wah Chiu
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - Chih-Chi Wang
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - Yu-Fan Cheng
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Program, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
- Division of Transplant Immunology, Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan
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Abstract
Autoimmune liver disorders in childhood include autoimmune hepatitis (AIH) and AIH/sclerosing cholangitis overlap syndrome (henceforth referred to as autoimmune sclerosing cholangitis, ASC). These inflammatory liver disorders are characterised histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by autoantibodies and increased levels of immunoglobulin G. AIH is particularly aggressive in children and progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment, 80% of patients achieve remission and long-term survival. For non-responders and difficult-to-treat patients, novel and more effective therapeutic approaches are sought. ASC responds to the same treatment used for AIH in regards to parenchymal inflammation, but bile duct disease progresses in about 50% of cases, leading to a worse prognosis and a higher liver transplantation requirement; moreover, it has a high recurrence rate after transplant. Progression of liver disease and recurrence after transplant are more common in patients with associated poorly controlled inflammatory bowel disease. Though the mechanisms underlying the pathogenesis of liver autoimmunity are not fully understood, genetic and environmental factors are likely to be involved. A deeper understanding of the pathogenesis of these conditions will contribute to the development of novel treatments, aimed ultimately at the restoration of tolerance to liver-derived antigens.
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Affiliation(s)
- Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, King's College London School of Medicine at King's College Hospital, , London, UK
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Liberal R, Zen Y, Mieli-Vergani G, Vergani D. Liver transplantation and autoimmune liver diseases. Liver Transpl 2013; 19:1065-77. [PMID: 23873751 DOI: 10.1002/lt.23704] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Accepted: 06/23/2013] [Indexed: 12/16/2022]
Abstract
Liver transplantation (LT) is an effective treatment for patients with end-stage autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Indications for LT for these diseases do not differ substantially from those used for other acute or chronic liver diseases. Despite the good outcomes reported, the recurrence of autoimmune liver disease is relatively common in the allograft. In addition, it has become apparent that autoimmunity and autoimmune liver disease can arise de novo after transplantation for nonautoimmune liver disorders. An awareness of the existence of recurrent autoimmune liver diseases and de novo autoimmune hepatitis after LT has important clinical implications because their management differs from the standard antirejection treatment and is similar to the management of classic autoimmune liver diseases in the native liver.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, United Kingdom; Faculty of Medicine, University of Porto, Porto, Portugal
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Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun 2013; 46:17-24. [DOI: 10.1016/j.jaut.2013.08.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 08/04/2013] [Indexed: 01/14/2023]
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Floreani A, Liberal R, Vergani D, Mieli-Vergani G. Autoimmune hepatitis: Contrasts and comparisons in children and adults - a comprehensive review. J Autoimmun 2013; 46:7-16. [PMID: 24035197 DOI: 10.1016/j.jaut.2013.08.004] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Revised: 08/13/2013] [Accepted: 08/14/2013] [Indexed: 12/24/2022]
Abstract
This review concentrates on autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, characterized by inflammatory liver histology, elevated transaminase levels, circulating non-organ-specific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known aetiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1, while antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. There is a female predominance in both types. AIH is particularly aggressive in children/adolescents, progressing rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. In childhood/adolescence, sclerosing cholangitis with strong autoimmune features, including interface hepatitis and serological features identical to AIH type 1, is as prevalent as AIH, but it affects boys and girls equally. The differential diagnosis relies on cholangiographic studies. In autoimmune sclerosing cholangitis, liver parenchymal damage responds satisfactorily to immunosuppressive treatment, whereas bile duct disease progresses in 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a higher recurrence rate after transplant than AIH. AIH can arise de novo in patients transplanted for non-autoimmune liver disease. Post transplant de novo AIH affects children and adults and responds well to the same treatment schedule used for classical AIH, but not to that used for acute rejection.
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Affiliation(s)
- Annarosa Floreani
- Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Italy.
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Recurrent diseases following liver transplantation: current concepts. Curr Opin Organ Transplant 2013; 17:293-302. [PMID: 22498649 DOI: 10.1097/mot.0b013e32835365f6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Liver transplantation is the treatment of choice for patients with chronic end-stage liver disease. The posttransplant setting is complex, and an improved long-term graft and patient survival adds to the complexity. There are often multiple causes of graft dysfunction and the associated morbidity and disorder are varied. This review focuses on the current concepts of several recurrent diseases, emphasizing the interpretation of the posttransplant liver biopsies in long-term survivors as challenging and clinically more relevant then ever. It confirms the importance and the necessity of clinico-pathologic correlation in the posttransplant setting. RECENT FINDINGS The long-term graft and patient survival following liver transplantation has improved significantly over the past decade. The spectrum of histopathologic patterns seen in liver biopsies and our understanding of them have evolved and expanded considerably, so much so, that both pathologists and clinicians alike now recognize new and emerging disease patterns not previously encountered in the nontransplant setting. SUMMARY Typical histopathologic features are usually easily identified and interpreted in liver biopsies. There are, however, a number of atypical histopathologic patterns, especially in the setting of recurrent diseases, often modified by immunosuppression, or altered by other immune-mediated processes, autoimmunity, or hepatotoxicity. Several conditions and entities, especially in the late posttransplant setting, including atypical allograft rejection, idiopathic posttransplant hepatitis, the spectrum of changes seen in recurrent hepatitis C, nodular regenerative hyperplasia, and de-novo disease occurrence, to name a few, have all been recognized in the past several years.
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Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: A comprehensive review. J Autoimmun 2013; 41:126-39. [DOI: 10.1016/j.jaut.2012.11.002] [Citation(s) in RCA: 147] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 11/05/2012] [Indexed: 12/12/2022]
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Abstract
Nonsteroidal medications, previously unfamiliar in the management of autoimmune hepatitis, can supplement or replace conventional corticosteroid regimens, especially in problematic patients. Mycophenolate mofetil is a next-generation purine antagonist that has been useful in treating patients with azathioprine intolerance. It has been less effective in salvaging patients with steroid-refractory disease. Azathioprine is the choice as a corticosteroid-sparing agent in treatment-naive patients and in individuals with corticosteroid intolerance, incomplete response and relapse after drug withdrawal. Tacrolimus is preferred over cyclosporine for recalcitrant disease because of its established preference in organ transplantation, but replacement with cyclosporine should be considered if the disease worsens on treatment. Rapamycin has antiproliferative and proapoptotic actions that warrant further study in autoimmune hepatitis. The nonstandard, nonsteroidal medications are mainly salvage therapies with off-label indications that must be used in highly individualized and well-monitored clinical situations.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.
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Czaja AJ. Diagnosis, pathogenesis, and treatment of autoimmune hepatitis after liver transplantation. Dig Dis Sci 2012; 57:2248-66. [PMID: 22562533 DOI: 10.1007/s10620-012-2179-3] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis can recur or appear de novo after liver transplantation, and it can result in hepatic fibrosis, graft loss, and re-transplantation. The goals of this review are to describe the prevalence, manifestations, putative pathogenic mechanisms, outcomes, and management of these occurrences. Autoimmune hepatitis recurs in 8-12 % of transplanted patients at 1 year and 36-68 % at 5 years. Recurrence may be asymptomatic and detected only by surveillance liver test abnormalities or protocol liver tissue examination. Autoantibodies that characterized the original disease, hypergammaglobulinemia, increased serum immunoglobulin G level, and histological findings of interface hepatitis, lymphoplasmacytic infiltration, perivenular hepatocyte necrosis, pseudo-rosetting, and acidophil bodies typify recurrence. Premature corticosteroid withdrawal and pre-transplant severity of the original disease are possible risk factors. De novo autoimmune hepatitis occurs in 1-7 % of patients 0.1-9 years after transplantation, especially in children. The appearance of autoantibodies may herald its emergence, and antibodies to glutathione-S-transferase T1 have been predictive of the disease. Recurrent disease may reflect recruitment of residual memory T lymphocytes and host-specific genetic predispositions, whereas de novo disease may reflect an allo-antigenic immune response and molecular mimicries that override self-tolerance. Treatment should be appropriate for autoimmune hepatitis and not based on anti-rejection drugs. Corticosteroid therapy alone or combined with azathioprine is the essential treatment. The substitution of mycophenolate mofetil for azathioprine and switch of the calcineurin inhibitor or its replacement with rapamycin have also been used for refractory disease. Re-transplantation has been necessary in 8-23 %.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Abstract
Prednisone and prednisolone are the mainstays of treatment for autoimmune hepatitis. Prednisone is converted in the liver to the active metabolite, prednisolone. The principal therapeutic action of prednisolone is to suppress cytokine gene expression and to inhibit the differentiation and proliferation of activated lymphocytes. It also has anti-inflammatory effects that include decreased production of adhesion molecules, increased apoptosis of lymphocytes and decreased hepatic collagen deposition. Advanced liver disease does not sufficiently suppress hepatic conversion of prednisone to warrant the preferential use of prednisolone. Budesonide combined with azathioprine has been more effective and safer than the conventional prednisone-based regimen when given for 6 months to treatment-naive patients. It is emerging as a frontline treatment, especially for noncirrhotic patients with uncomplicated disease.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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HORTON S, MARTLEW V, WILDE J, THACHIL J. Re-emergence of a low-titre factor VIII inhibitor after liver transplant. Haemophilia 2012; 18:e69-71. [DOI: 10.1111/j.1365-2516.2012.02811.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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