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Cananzi M, Jørgensen MH, Buescher G, De Bruyne R, Samyn M. Current practice in the management of paediatric autoimmune liver disease in Europe. J Pediatr Gastroenterol Nutr 2025; 80:260-270. [PMID: 39618087 DOI: 10.1002/jpn3.12424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 02/04/2025]
Abstract
OBJECTIVE Paediatric autoimmune liver disease (pAILD) is a rare condition with serious health implications. Notwithstanding treatment advancements, areas of uncertainty and knowledge gaps still exist. We here investigated the real-life approach to pAILD management in Europe. METHODS A survey was distributed to members of the European Rare Liver Disease Reference Network (ERN RARE-LIVER) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Hepatology Interest Group. Information was gathered regarding clinical activity, medications used, and access to paediatric drug formulations at each site. RESULTS Thirty-six centres from 22 European countries responded to the survey. The majority are exclusively paediatric units (86%). Among participants, 80% follow <50 children with pAILD, of which 25%-50% are <10 years old in 44% of centres. All centres use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36). Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21), respectively. Tacrolimus is used as third-line agent in 15/36 centres. Proactive measurement of drug metabolites and target levels vary widely among centres. Paediatric predniso(lo)ne formulations are commercially available in 7/22 European countries, azathioprine in 3, mycophenolate in 14, tacrolimus in 15 and ursodeoxycholic acid in 14. When paediatric formulations are unavailable, children are treated with magisterial preparations or 'solid' formulations (crushed or intact). CONCLUSIONS Treatment of pAILD in Europe varies widely in terms of medications used and treatment monitoring. Availability of paediatric drug formulations across Europe is limited. Collaborative initiatives are needed to define evidence-based strategies for management of pAILD and to promote an equal, age-appropriate treatment for affected children.
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Affiliation(s)
- Mara Cananzi
- Unit of Paediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy
| | | | - Gustav Buescher
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Ruth De Bruyne
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Belgium
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition Centre, King's College Hospital NHS Trust, London, UK
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Zhang Q, Zhao C, Zhang L, Sun K, Yu L, Wang X, Ren L, Zhang N, Chen C, Liu J, Wang H, Tian H. Escin Sodium Improves the Prognosis of Acute Pancreatitis via Promoting Cell Apoptosis by Suppression of the ERK/STAT3 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9921839. [PMID: 34422214 PMCID: PMC8378969 DOI: 10.1155/2021/9921839] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/31/2021] [Accepted: 07/08/2021] [Indexed: 12/16/2022]
Abstract
Acute pancreatitis (AP), an inflammatory disorder of the pancreas, can cause systemic inflammatory responses. Escin Sodium (ES), a natural mixture of triterpene saponins extracted from the dry ripe fruit of Fructus Aesculi or horse chestnut crude, has been demonstrated to have antiedematous, anti-inflammatory, and antiexudative effects. We here aim to investigate the effects of ES pretreatment on AP in vivo and in vitro and explore its potential molecular mechanism. In the present study, we demonstrated that ES pretreatment could apparently decrease amylase and lipase, downregulate inflammatory cytokines, and attenuate pancreatic damage. Additionally, the increased expression of apoptotic-related proteins and the results of flow cytometry demonstrated the effects of ES on promoting apoptosis in acinar cells. Moreover, ES could enhance mitochondrial membrane potential (MMP, ΔΨm) and reactive oxygen species (ROS) level and reduce intracellular calcium concentration, which are closely related to mitochondrial-mediated death. The effect of ES pretreatment on acinar cell apoptosis was furtherly confirmed by the regulatory pathway of the ERK/STAT3 axis. These results suggest that ES attenuates the severity of AP by enhancing cell apoptosis via suppressing the ERK/STAT3 signaling pathway. These findings provide evidence for ES which is treated as a novel and potent therapeutic for the treatment of AP.
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Affiliation(s)
- Qian Zhang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, China
| | - Chen Zhao
- Weihai Hospital Affiliated to Shandong University of Traditional Chinese Medicine, No. 29, Qingdao North Road, Huancui District, Weihai City Shandong Province, China
| | - Lei Zhang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, 16369 Jingshi Road, Lixia District, Jinan City, Shandong Province, China
| | - Kai Sun
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan City, Shandong Province, China
| | - Linlin Yu
- Shandong Hospital of Traditional Chinese Medicine Affiliated to Shandong University of Traditional Chinese Medicine, 16369 Jingshi Road, Lixia District, Jinan City, Shandong Province, China
| | - Xianming Wang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan City, Shandong Province, China
| | - Lei Ren
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan City, Shandong Province, China
| | - Nan Zhang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, 16369 Jingshi Road, Lixia District, Jinan City, Shandong Province, China
| | - Chengyu Chen
- Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan City, Shandong Province, China
| | - Ju Liu
- Laboratory of Microvascular Medicine and Medical Research Center, Shandong Provincial Qianfoshan Hospital, The First Affiliated Hospital of Shandong First Medical University, No. 16766, Jingshi Road, Jinan City, Shandong Province, China
| | - Haimei Wang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, 16369 Jingshi Road, Lixia District, Jinan City, Shandong Province, China
| | - Hu Tian
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, No. 16766, Jingshi Road, Jinan City, Shandong Province, China
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Li Q, Wang J, Zhou X, Lu H, Lu M, Huang L. Case Report: Viral Pneumonia Could Prompt the Advancement of Immune-Mediated Liver Disease. Front Med (Lausanne) 2021; 8:582620. [PMID: 34079806 PMCID: PMC8165172 DOI: 10.3389/fmed.2021.582620] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 04/26/2021] [Indexed: 01/08/2023] Open
Abstract
Background: The impact of the influenza A (H1N1) and SARS-CoV-2 virus on the development of autoimmune hepatitis has not been described previously. Methods: In this case series, we evaluated the dynamic changes in liver function of three patients with autoimmune hepatitis who presented with viral infection (two with the H1N1 and one with the SARS-CoV-2 virus) during the recent COVID-19 outbreak. Result: Patient 1 was a 68-year-old woman with a history of hepatitis of unknown origin before being infected with the H1N1 virus. Autoimmune hepatitis with an exacerbation of liver injury was diagnosed during the infection. Patient 2 was a 48-year-old woman with pre-existing autoimmune hepatitis. Despite being on immunosuppressant therapy (using glucocorticoids), liver injury recurred with elevated total bilirubin and gamma-glutamyl transferase levels post H1N1 infection. Patient 3 was a 61-year-old woman with probable autoimmune hepatitis. Liver injury recurred with a flare in alanine transaminase/aspartate transaminase levels post SARS-CoV-2 infection, in spite of the patient being on liver protection therapy (using ursodeoxycholic acid). Conclusion: The case series raises the possibility that COVID-19 or influenza induced pneumonia triggers the progression of autoimmune hepatitis.
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Affiliation(s)
- Qian Li
- Department of Hepatology, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China.,Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China.,Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Jun Wang
- Department of Hepatology, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China.,Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.,Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
| | - Xueshi Zhou
- Department of Hepatology, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
| | - Hongzhou Lu
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Lihua Huang
- Department of Hepatology, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
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Czaja AJ. Autoimmune Hepatitis: Surviving Crises of Doubt and Elimination. Clin Liver Dis (Hoboken) 2020; 15:S72-S81. [PMID: 32140216 PMCID: PMC7050953 DOI: 10.1002/cld.917] [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: 09/23/2019] [Accepted: 12/05/2019] [Indexed: 02/04/2023] Open
Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and HepatologyMayo Clinic College of Medicine and ScienceRochesterMN
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Liberal R, de Boer YS, Andrade RJ, Bouma G, Dalekos GN, Floreani A, Gleeson D, Hirschfield GM, Invernizzi P, Lenzi M, Lohse AW, Macedo G, Milkiewicz P, Terziroli B, van Hoek B, Vierling JM, Heneghan MA. Expert clinical management of autoimmune hepatitis in the real world. Aliment Pharmacol Ther 2017; 45:723-732. [PMID: 28004405 DOI: 10.1111/apt.13907] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 10/12/2016] [Accepted: 11/27/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.
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Nadhem ON, Janabi MA, Omer AR, Wan B. Autoimmune hepatitis with multiple sclerosis and graves disease: coincidence or association? Case Rep Gastroenterol 2014; 8:319-23. [PMID: 25473390 PMCID: PMC4241635 DOI: 10.1159/000368551] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a generally progressive, chronic hepatitis of unknown cause that occurs in children and adults of all ages. It is associated with a variety of autoimmune conditions like thyroid disorders (Hashimoto and Graves disease), celiac disease and multiple sclerosis (MS). We report the case of a 61-year-old woman with MS (untreated) and a history of Graves disease who presented with fatigue and right upper quadrant abdominal pain. She was admitted to our hospital for evaluation. Clinical and laboratory workup revealed AIH. She was successfully treated with prednisone and azathioprine, with complete clinical and laboratory improvement. However, to our knowledge there have been only a few reports of a possible association between AIH and untreated MS.
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Affiliation(s)
- Omar N Nadhem
- Internal Medicine Department, Texas Tech University Health Sciences Center, Amarillo, Tex., USA
| | - Mohammed Al Janabi
- Internal Medicine Department, Texas Tech University Health Sciences Center, Amarillo, Tex., USA
| | - Abdel Rahman Omer
- Internal Medicine Department, Texas Tech University Health Sciences Center, Amarillo, Tex., USA
| | - Bang Wan
- Internal Medicine Department, Texas Tech University Health Sciences Center, Amarillo, Tex., USA
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Abstract
INTRODUCTION Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions. AREAS COVERED PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects. EXPERT OPINION Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, From the Division of Gastroenterology and Hepatology , 200 First Street S.W, Rochester, MN 55905 , USA +1 507 284 2691 ; +1 507 284 0538 ;
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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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Samuel B, Fioravanti G, Polimera H, Mayer A, Dorville F, Little E. Autoimmune hepatitis in a 20-year-old African American man. Lab Med 2014; 45:161-71. [PMID: 24868999 DOI: 10.1309/lmag0di6ee4nycyn] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20:2515-32. [PMID: 24627588 PMCID: PMC3949261 DOI: 10.3748/wjg.v20.i10.2515] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
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Maruoka R, Aoki N, Kido M, Iwamoto S, Nishiura H, Ikeda A, Chiba T, Watanabe N. Splenectomy prolongs the effects of corticosteroids in mouse models of autoimmune hepatitis. Gastroenterology 2013; 145:209-220.e9. [PMID: 23523671 DOI: 10.1053/j.gastro.2013.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Revised: 02/27/2013] [Accepted: 03/08/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Most patients with autoimmune hepatitis (AIH) initially respond to treatment with corticosteroids but often experience a relapse after treatment is withdrawn. BALB/c mice with disruption of programmed cell death 1 (PD-1(-/-) mice) that undergo thymectomy 3 days after birth develop a deregulated immune system, have reduced numbers of Foxp3(+) regulatory T cells, and develop fulminant hepatic failure that resembles acute-onset AIH in humans. We examined whether splenectomy overcomes corticosteroid insufficiency and reduces the severity of AIH in these mice. We also developed a mouse model of chronic AIH to investigate the effects of splenectomy. METHODS After thymectomy, BALB/c PD-1(-/-) mice were treated with dexamethasone before or after induction of AIH; splenectomy was performed in mice that had and had not been treated with dexamethasone. Neonatal C57BL/6 PD-1(-/-) mice underwent thymectomy to create a model of chronic AIH. RESULTS Injection of dexamethasone before or after induction of AIH prevented development of fatal AIH in BALB/c PD-1(-/-) mice. However, injection of dexamethasone after induction of AIH did not suppress splenic production of follicular helper T cells, and discontinuation of dexamethasone led to a relapse of AIH. Splenectomy (even without administration of dexamethasone) prevented AIH. Neonatal C57BL/6 PD-1(-/-) mice that underwent thymectomy developed chronic hepatitis with fibrosis and hypergammaglobulinemia and produced antinuclear antibodies; AIH was found to be induced in the spleen. Splenectomy reduced liver inflammation in these mice and in BALB/c PD-1(-/-) mice with AIH. CONCLUSIONS AIH can be induced in mice via disruption of PD-1 and thymectomy; these cause the same disruptions in immune regulation in BALB/c and C57BL/6 mice but produce different phenotypes. Splenectomy overcomes corticosteroid insufficiency in mice and prolongs the effects of dexamethasone.
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Affiliation(s)
- Ryutaro Maruoka
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuhiro Aoki
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro Kido
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satoru Iwamoto
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hisayo Nishiura
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Aki Ikeda
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tsutomu Chiba
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Norihiko Watanabe
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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Baertling F, Mayatepek E, Gerner P, Baba HA, Franzel J, Schlune A, Meissner T. Liver cirrhosis in glycogen storage disease Ib. Mol Genet Metab 2013; 108:198-200. [PMID: 23357201 DOI: 10.1016/j.ymgme.2013.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 01/05/2013] [Indexed: 01/30/2023]
Abstract
Glycogen storage disease Ib is an inborn error of carbohydrate metabolism leading to impaired glycogenolysis and gluconeogenesis. Cardinal symptoms include fasting hypoglycemia, lactic acidosis and hepatomegaly as well as neutropenia. We report for the first time on the development of liver cirrhosis in a nine-year-old boy in the course of glycogen storage disease Ib and discuss possible underlying pathomechanisms.
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Affiliation(s)
- Fabian Baertling
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Duesseldorf, Heinrich Heine University, Moorenstr. 5, D-40225 Duesseldorf, Germany.
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Autoimmune hepatitis: focusing on treatments other than steroids. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2013; 26:615-20. [PMID: 22993733 DOI: 10.1155/2012/512132] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Corticosteroid therapy has been the time-honoured treatment for autoimmune hepatitis; however, the emergence of new immunosuppressive agents has afforded opportunities to improve or replace the standard regimens. OBJECTIVE To describe technological advances and feasible treatment interventions that promise to supplant the current generation of corticosteroids. METHODS A review of the MEDLINE database for published experiences from 1984 to 2011 was conducted. RESULTS Cyclosporine and tacrolimus have been uniformly successful as salvage therapies for steroid-refractory autoimmune hepatitis. Ten reports of cyclosporine therapy involving 133 patients had positive outcomes in 93%, whereas therapy with tacrolimus in three reports involving 41 patients had positive outcomes in 98%. Salvage therapy with mycophenolate mofetil had a favourable outcome in 47%, especially in patients with azathioprine intolerance. Front-line therapy with mycophenolate mofetil normalized liver parameters in 88% and allowed corticosteroid tapering in 58%. Front-line therapy with budesonide combined with azathioprine for six months normalized liver parameters more frequently (47% versus 18%) and with fewer side effects (28% versus 53%) than prednisone combined with azathioprine. Monoclonal antibodies to CD3 and recombinant cytotoxic T lymphocyte antigen 4 fused with immunoglobulin represent feasible molecular interventions for study in autoimmune hepatitis. DISCUSSION Nonstandard drug therapies must be used in highly selected clinical situations including steroid failure (calcineurin inhibitors), azathioprine intolerance (mycophenolate mofetil), and mild disease or fragile patients (budesonide combined with azathioprine). Molecular interventions for autoimmune hepatitis are feasible for study because of their use in other immune-mediated diseases. CONCLUSION Opportunities to improve or replace standard corticosteroid regimens have emerged.
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Abstract
Autoimmune hepatitis has two major variant phenotypes in which the features of classical disease are co-mingled with those of primary biliary cirrhosis or primary sclerosing cholangitis. These overlap syndromes lack codified diagnostic criteria, established pathogenic mechanisms, and confident management strategies. Their clinical importance relates mainly to the identification of patients who respond poorly to conventional corticosteroid treatment. Scoring systems that lack discriminative power have been used in their definition, and a clinical phenotype based on pre-defined laboratory and histological findings has not been promulgated. The frequency of overlap with primary biliary cirrhosis is 7-13 %, and the frequency of overlap with primary sclerosing cholangitis is 8-17 %. Patients with autoimmune hepatitis and features of cholestatic disease must be distinguished from patients with cholestatic disease and features of autoimmune hepatitis. Variants of the overlap syndromes include patients with small duct primary sclerosing cholangitis, antimitochondrial antibody-negative primary biliary cirrhosis, autoimmune sclerosing cholangitis, and immunoglobulin G4-associated disease. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid (13-15 mg/kg daily) has been variably effective, and cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients. The key cholestatic features that influence the prognosis of autoimmune hepatitis must be defined and incorporated into the definition of the syndrome rather than rely on designations that imply the co-mingling of different diseases with manifestations of variable clinical relevance. The overlap syndromes in autoimmune hepatitis are imprecise, heterogeneous, and unfounded, but they constitute a clinical reality that must be accepted, diagnosed, refined, treated, and studied.
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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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Selvarajah V, Montano-Loza AJ, Czaja AJ. Systematic review: managing suboptimal treatment responses in autoimmune hepatitis with conventional and nonstandard drugs. Aliment Pharmacol Ther 2012; 36:691-707. [PMID: 22973822 DOI: 10.1111/apt.12042] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 07/17/2012] [Accepted: 08/21/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur. AIM To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off-label for these occurrences. METHODS Literature search was made for full-text papers published in English using the keyword 'autoimmune hepatitis'. Authors' personal experience and investigational studies also helped to identify important contributions to the literature. RESULTS Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50-86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents. CONCLUSIONS Once diagnosed, the suboptimal response should be treated by a highly individualised and well-monitored regimen, preferentially using first-line therapy. Nonstandard drugs warrant consideration as salvage or second-line therapies.
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Affiliation(s)
- V Selvarajah
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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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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18
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Yoshizawa K, Matsumoto A, Ichijo T, Umemura T, Joshita S, Komatsu M, Tanaka N, Tanaka E, Ota M, Katsuyama Y, Kiyosawa K, Abe M, Onji M. Long-term outcome of Japanese patients with type 1 autoimmune hepatitis. Hepatology 2012; 56:668-676. [PMID: 22334246 DOI: 10.1002/hep.25658] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 02/07/2012] [Indexed: 12/18/2022]
Abstract
UNLABELLED The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. CONCLUSION Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.
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Affiliation(s)
- Kaname Yoshizawa
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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19
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Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci 2012; 57:1996-2010. [PMID: 22476586 DOI: 10.1007/s10620-012-2151-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Accepted: 03/16/2012] [Indexed: 12/17/2022]
Abstract
Current treatment strategies for autoimmune hepatitis are complicated by frequent relapse after drug withdrawal, medication intolerance, and refractory disease. The objective of this review is to describe advances that have improved treatment outcomes by defining the optimum objectives of initial therapy, managing relapse more effectively, identifying problematic patients early, and incorporating the new pharmacological interventions that have emerged as frontline and salvage therapies. Initial corticosteroid treatment should be continued until serum aminotransferase, γ-globulin, and immunoglobulin G levels are normal, and maintenance of this improvement for 3-8 months before liver tissue assessment. Improvement to normal liver tissue is the ideal histological result that justifies drug withdrawal, but it is achievable in only 22 % of patients. Minimum portal hepatitis, inactive cirrhosis, or minimally active cirrhosis is the most common treatment end point. Relapse after drug withdrawal warrants institution of a long-term maintenance regimen, preferably with azathioprine. Mathematical models can identify problematic adult patients early, as also can clinical phenotype (age ≤ 30 years and HLA DRB1 03), rapidity of treatment response (≤ 24 months), presence of antibodies to soluble liver antigen, and non-white ethnicity. The calcineurin inhibitors (cyclosporine and tacrolimus) can be effective in steroid-refractory disease; mycophenolate mofetil can be corticosteroid-sparing and effective for azathioprine intolerance; budesonide combined with azathioprine can be effective for treatment-naïve, non-cirrhotic patients. Standard treatment regimens for autoimmune hepatitis can be upgraded without adjustments that require major new expertise.
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20
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Trembling PM, Tanwar S, Dusheiko GM. Boceprevir: an oral protease inhibitor for the treatment of chronic HCV infection. Expert Rev Anti Infect Ther 2012; 10:269-79. [PMID: 22397560 DOI: 10.1586/eri.12.8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Chronic hepatitis C (CHC) virus infection affects more than 170 million people globally. The aim of treatment of CHC is to affect sustained elimination of the virus (a sustained virological response [SVR]). The success and duration of therapy with interferon is dependent on HCV genotype. The current standard of care comprises combined treatment with pegylated interferon and ribavirin. Rates of SVR in patients with genotype 1 infection, the least responsive group, are less than 50%. Boceprevir is a ketoamide protease inhibitor that binds reversibly to the HCV nonstructural NS3 protease active site inhibiting intracellular viral replication. Phase III clinical studies have demonstrated that, in combination with the current standard of care, boceprevir significantly increases the SVR rate in both treatment-naive and previously treated patients with genotype 1 CHC. Both the US FDA and EMA have approved boceprevir for the treatment of genotype 1 CHC: the first directly-acting antiviral drug to be licensed for this indication. This article will review the pharmacology and pharmacodynamics of boceprevir, the efficacy and safety of the drug, and explore possible future developments in the management of CHC.
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Affiliation(s)
- Paul M Trembling
- Centre for Hepatology, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
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