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Lee DU, Kwon J, Koo C, Han J, Fan GH, Jung D, Addonizio EA, Chang K, Urrunaga NH. Clinical implications of gender and race in patients admitted with autoimmune hepatitis: updated analysis of US hospitals. Frontline Gastroenterol 2022; 14:111-123. [PMID: 36818796 PMCID: PMC9933617 DOI: 10.1136/flgastro-2022-102113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 08/03/2022] [Indexed: 02/24/2023] Open
Abstract
Background Autoimmune hepatitis (AIH) can result in end-stage liver disease that requires inpatient treatment of the hepatic complications. Given this phenomenon, it is important to analyse the impact of gender and race on the outcomes of patients who are admitted with AIH using a national hospital registry. Methods The 2012-2017 National Inpatient Sample database was used to select patients with AIH, who were stratified using gender and race (Hispanics and blacks as cases and whites as reference). Propensity score matching was employed to match the controls with cases and compare mortality, length of stay and hepatic complications. Results After matching, there were 4609 females and 4609 males, as well as 3688 blacks and 3173 Hispanics with equal numbers of whites, respectively. In multivariate analysis, females were less likely to develop complications, with lower rates of cirrhosis, ascites, variceal bleeding, hepatorenal syndrome, encephalopathy and acute liver failure (ALF); they also exhibited lower length of stay (adjusted OR, aOR 0.96 95% CI 0.94 to 0.97). When comparing races, blacks (compared with whites) had higher rates of ALF and hepatorenal syndrome related to ALF, but had lower rates of cirrhosis-related encephalopathy; in multivariate analysis, blacks had longer length of stay (aOR 1.071, 95% CI 1.050 to 1.092). Hispanics also exhibited higher rates of hepatic complications, including ascites, varices, variceal bleeding, spontaneous bacterial peritonitis and encephalopathy. Conclusion Males and minorities are at a greater risk of developing hepatic complications and having increased hospital costs when admitted with AIH.
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Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology and Hepatology, University of Maryland Medical Center, Baltimore, Maryland, USA
| | - Jean Kwon
- School of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Christina Koo
- School of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - John Han
- School of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Gregory Hongyuan Fan
- School of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Daniel Jung
- School of Medicin, UMKC School of Medicine, Kansas City, Missouri, USA
| | - Elyse Ann Addonizio
- School of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Kevin Chang
- School of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Nathalie Helen Urrunaga
- Division of Gastroenterology and Hepatology, University of Maryland Medical Center, Baltimore, Maryland, USA
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2
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B cells in autoimmune hepatitis: bystanders or central players? Semin Immunopathol 2022; 44:411-427. [PMID: 35488094 PMCID: PMC9256567 DOI: 10.1007/s00281-022-00937-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 04/07/2022] [Indexed: 02/07/2023]
Abstract
B cells are central for the adaptive immune system to mount successful immune responses not only as antibody producers but also as regulators of cellular immunity. These multifaceted features are also reflected in autoimmunity where autoreactive B cells can fuel disease by production of cytotoxic autoantibodies, presentation of autoantigens to autoreactive T cells, and secretion of cytokines and chemokines that either promote detrimental immune activation or impair regulatory T and B cells. The role of B cells and autoantibodies in autoimmune hepatitis (AIH) have been controversially discussed, with typical autoantibodies and hypergammaglobulinemia indicating a key role, while strong HLA class II association suggests T cells as key players. In this review, we summarize current knowledge on B cells in AIH and how different B cell subpopulations may drive AIH progression beyond autoantibodies. We also discuss recent findings of B cell-directed therapies in AIH.
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Couchonnal E, Jacquemin E, Lachaux A, Ackermann O, Gonzales E, Lacaille F, Debray D, Boillot O, Guillaud O, Wildhaber BE, Chouik Y, McLin V, Dumortier J. Long-term results of pediatric liver transplantation for autoimmune liver disease. Clin Res Hepatol Gastroenterol 2021; 45:101537. [PMID: 33077391 DOI: 10.1016/j.clinre.2020.08.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/19/2020] [Accepted: 08/26/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are rare indications for liver transplantation (LT) in children. The aim of the present retrospective multicenter study was to evaluate long-term outcome after LT for autoimmune liver disease in childhood. METHODS Retrospective data from 30 children who underwent a first LT from 1988 to 2018 were collected. RESULTS The study population consisted of 18 girls and 12 boys, transplanted for AIH type 1 (n=14), AIH type 2 (n=7) or PSC (n=9). Mean age at LT was 11.8±5.2 years. The main indications for LT were acute (36.7%) or chronic end-stage liver failure (63.3%). Graft rejection occurred in 19 patients (63.3%); 6 pts required retransplantation for chronic rejection. Recurrence of initial disease was observed in 6 patients (20.0%), all of them with type 1 AIH, after a median time of 42 months, requiring retransplantation in 2 cases. Overall patient survival rates were 96.4%, 84.6%, 74.8%, 68.0%, 68.0%, 68.0% and 68.0% at 1, 5, 10, 15, 20, 25 and 30 years, respectively. Age at LT<1year (p<0.0001), LT for fulminant failure (p=0.023) and LT for type 2 AIH (p=0.049) were significant predictive factors of death. CONCLUSION Long-term outcome after LT for pediatric autoimmune liver disease is impaired in patients with AIH because of consistent complications such as rejection and disease recurrence.
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Affiliation(s)
- Eduardo Couchonnal
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d'Hépato-gastroentérologie et Nutrition Pédiatrique, Bron, France
| | - Emmanuel Jacquemin
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie et Transplantation Hépatique Pédiatriques, Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Université Paris Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France
| | - Alain Lachaux
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service d'Hépato-gastroentérologie et Nutrition Pédiatrique, Bron, France; Centre National de Référence de l'Atrésie des Voies biliaires et des Cholestases Génétiques de Lyon, France; Université Claude Bernard Lyon 1, Lyon, France
| | - Oanez Ackermann
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie et Transplantation Hépatique Pédiatriques, Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Université Paris Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France
| | - Emmanuel Gonzales
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie et Transplantation Hépatique Pédiatriques, Centre National de Référence de l'Atrésie des Voies Biliaires et des Cholestases Génétiques, Université Paris Saclay, Le Kremlin-Bicêtre, France; Inserm U1193, Hepatinov, Université Paris Saclay, Orsay, France
| | - Florence Lacaille
- Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Unité d'Hépatologie pédiatrique, Centre de référence de l'Atrèsie des voies biliaires et cholestases génétiques, filière de santé Filfoie, Paris, France
| | - Dominique Debray
- Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants malades, Unité d'Hépatologie pédiatrique, Centre de référence de l'Atrèsie des voies biliaires et cholestases génétiques, filière de santé Filfoie, Paris, France; Université-Paris centre, Paris, France
| | - Olivier Boillot
- Université Claude Bernard Lyon 1, Lyon, France; Hospices Civils de Lyon, Hôpital Edouard Herriot, Femme-Mère-Enfant, Service d'Hépato-gastroentérologie, Lyon, France
| | - Olivier Guillaud
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Femme-Mère-Enfant, Service d'Hépato-gastroentérologie, Lyon, France; Ramsay Générale de Santé, Clinique de la Sauvegarde, Lyon, France
| | - Barbara E Wildhaber
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva, University of Geneva, Geneva, Switzerland
| | - Yasmina Chouik
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Femme-Mère-Enfant, Service d'Hépato-gastroentérologie, Lyon, France
| | - Valérie McLin
- Swiss Pediatric Liver Center, Department of Pediatrics, Gynecology, and Obstetrics, University Hospitals Geneva, University of Geneva, Geneva, Switzerland
| | - Jérôme Dumortier
- Université Claude Bernard Lyon 1, Lyon, France; Hospices Civils de Lyon, Hôpital Edouard Herriot, Femme-Mère-Enfant, Service d'Hépato-gastroentérologie, Lyon, France.
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Liu G, Zhao W, Bai J, Cui J, Liang H, Lu B. Formononetin protects against concanavalin-A-induced autoimmune hepatitis in mice through its anti-apoptotic and anti-inflammatory properties. Biochem Cell Biol 2021; 99:231-240. [PMID: 33749318 DOI: 10.1139/bcb-2020-0197] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that seriously threatens the health of humans globally. Formononetin (FMN) is a natural herb extract with multiple biological functions. In this study, an experimental model of AIH was established in mice through the use of concanavalin A (ConA). To investigate the effects of FMN on ConA-induced hepatitis, the mice were pretreated with 50 or 100 mg/kg body mass of FMN. The results show that FMN alleviated ConA-induced liver injury of mice in a dose-dependent manner. Moreover, pretreatment with FMN inhibited the apoptosis of hepatocytes in the ConA-treated mice through downregulating the expression of pro-apoptotic proteins (Bax, cleaved caspase 9, and cleaved caspase 3) and upregulating the expression of anti-apoptotic protein (Bcl-2). It was also found that the levels of proinflammatory cytokines were greatly reduced in the serum and liver tissues of mice pretreated with FMN. Further studies showed that FMN reduced the level of phosphorylated nuclear factor kappa B (p-NF-κB) p65 and enhanced the level of IκBα (inhibitor of NF-κB), suggesting that FMN inhibits the activation of the NF-κB signaling pathway. In addition, FMN inhibited activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Therefore, FMN could be a promising agent for the treatment of AIH.
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Affiliation(s)
- Guangwei Liu
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450004, P.R. China
| | - Wenxia Zhao
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450004, P.R. China
| | - Jiameng Bai
- Spleen, Stomach and Hepatobiliary Department, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China
| | - Jianjiao Cui
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450004, P.R. China
| | - Haowei Liang
- Spleen, Stomach and Hepatobiliary Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450004, P.R. China
| | - Baoping Lu
- School of Basic Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, P.R. China
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5
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Afzal W, Haghi M, Hasni SA, Newman KA. Lupus hepatitis, more than just elevated liver enzymes. Scand J Rheumatol 2020; 49:427-433. [PMID: 32942921 DOI: 10.1080/03009742.2020.1744712] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Systemic lupus erythematosus (SLE), a multisystem autoimmune inflammatory disease, may involve any organs, including the liver. Liver involvement in SLE is not part of the American College of Rheumatology criteria and is relatively rare. Liver disease is usually mild, manifesting as subtle elevation of liver enzymes. Jaundice and hepatomegaly can be seen in some patients; advanced liver disease with cirrhosis is extremely rare. Precise pathology remains obscure. SLE may cause non-specific changes, including hepatocellular, cholestatic, or vascular changes. Alcohol, drugs, viral infections, metabolic disorders, autoimmune hepatitis, and other common causes of liver dysfunction should be excluded. Corticosteroids may expedite the recovery process, but may lead to non-alcoholic fatty liver disease and liver damage. Several large-scale multicentre studies have shown that liver involvement is not the major cause of morbidity and mortality in SLE patients. In this review, we discuss the pathogenesis, diagnosis, differential diagnosis, clinical manifestations, management, complications, and prognosis of lupus hepatitis.
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Affiliation(s)
- W Afzal
- Sanford School of Medicine, University of South Dakota , Sioux Falls, SD, USA
| | - M Haghi
- Department of Internal Medicine, Coney Island Hospital , Brooklyn, NY, USA
| | - S A Hasni
- National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health , Bethesda, MD, USA
| | - K A Newman
- School of Medicine, Eisenhower Medical Center, University of California , Rancho Mirage, CA, USA
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6
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Christen U, Hintermann E. Pathogens and autoimmune hepatitis. Clin Exp Immunol 2018; 195:35-51. [PMID: 30113082 DOI: 10.1111/cei.13203] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/30/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe form of hepatitis resulting in the autoimmune-mediated destruction of the liver parenchyma. Whereas many of the immunopathogenic events have been elucidated and some of the drivers of the disease have been identified, little is known about the aetiology of the disease. There are certain risk factors, such as particular human leucocyte antigen (HLA) haplotypes, that enhance the susceptibility for AIH or influence the severity of the disease. However, as for many other autoimmune diseases, the mere presence of such risk factors does not warrant the occurrence of the disease. Not all individuals carrying risk factors develop AIH, and not all patients with AIH are carriers of high-risk alleles. Thus, additional environmental factors need to be considered as triggers for AIH. Environmental factors include diet, sunlight exposure, stress, medication and hygiene, as well as pathogen infections and vaccinations. This review discusses if pathogens should be considered as triggers for the initiation and/or propagation of AIH.
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Affiliation(s)
- U Christen
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - E Hintermann
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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7
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Christen U. Animal models of autoimmune hepatitis. Biochim Biophys Acta Mol Basis Dis 2018; 1865:970-981. [PMID: 29857050 DOI: 10.1016/j.bbadis.2018.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/14/2018] [Accepted: 05/22/2018] [Indexed: 02/06/2023]
Abstract
Many animal models for autoimmune hepatitis (AIH) have been described in the past. Most models had to deal with the relative immunosuppressive environment of the liver. Therefore, some models used a combination of several triggering factors often on a susceptible background to generate an aggressive immune response that targets the liver. In addition, in order to be able to track the immune response the models used specific model autoantigens as targets that are either not present or have not been identified as a natural autoantigen in AIH patients. Thereby the feasibility of such models is somewhat questionable. Although many historic approaches included challenges of experimental animals with liver homogenates it was only in the last decade that natural occurring liver autoantigens have been used in animal models. This article reflects on the requirements for breaking liver tolerance and on how an ideal experimental model for AIH would look like. In addition, it discusses historic as well as recent animal models in the context of feasibility of induction, similarity of the clinical outcome to human AIH, and gain of knowledge for possible future therapies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany.
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8
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Christen U, Hintermann E. Autoantibodies in Autoimmune Hepatitis: Can Epitopes Tell Us about the Etiology of the Disease? Front Immunol 2018; 9:163. [PMID: 29503645 PMCID: PMC5820307 DOI: 10.3389/fimmu.2018.00163] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are serious autoimmune liver diseases that are characterized by a progressive destruction of the liver parenchyma and/or the hepatic bile ducts and the development of chronic fibrosis. Left untreated autoimmune liver diseases are often life-threatening, and patients require a liver transplantation to survive. Thus, an early and reliable diagnosis is paramount for the initiation of a proper therapy with immunosuppressive and/or anticholelithic drugs. Besides the analysis of liver biopsies and serum markers indicating liver damage, the screening for specific autoantibodies is an indispensable tool for the diagnosis of autoimmune liver diseases. Such liver autoantigen-specific antibodies might be involved in the disease pathogenesis, and their epitope specificity may give some insight into the etiology of the disease. Here, we will mainly focus on the generation and specificity of autoantibodies in AIH patients. In addition, we will review data from animal models that aim toward a better understanding of the origins and pathogenicity of such autoantibodies.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
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9
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Brahim I, Brahim I, Hazime R, Admou B. [Autoimmune hepatitis: Immunological diagnosis]. Presse Med 2017; 46:1008-1019. [PMID: 28919271 DOI: 10.1016/j.lpm.2017.08.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 07/09/2017] [Accepted: 08/21/2017] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatopathies (AIHT) including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune cholangitis (AIC), represent an impressive entities in clinical practice. Their pathogenesis is not perfectly elucidated. Several factors are involved in the initiation of hepatic autoimmune and inflammatory phenomena such as genetic predisposition, molecular mimicry and/or abnormalities of T-regulatory lymphocytes. AIHT have a wide spectrum of presentation, ranging from asymptomatic forms to severe acute liver failure. The diagnosis of AIHT is based on the presence of hyperglobulinemia, cytolysis, cholestasis, typical even specific circulating auto-antibodies, distinctive of AIH or PBC, and histological abnormalities as well as necrosis and inflammation. Anti-F actin, anti-LKM1, anti-LC1 antibodies permit to distinguish between AIH type 1 and AIH type 2. Anti-SLA/LP antibodies are rather associated to more severe hepatitis, and particularly useful for the diagnosis of seronegative AIH for other the antibodies. Due to the relevant diagnostic value of anti-M2, anti-Sp100, and anti-gp210 antibodies, the diagnosis of PBC is more affordable than that of PSC and AIC. Based on clinical data, the immunological diagnosis of AIHT takes advantage of the various specialized laboratory techniques including immunofluorescence, immunodot or blot, and the Elisa systems, provided of a closer collaboration between the biologist and the physician.
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Affiliation(s)
- Imane Brahim
- CHU Mohammed VI, laboratoire d'immunologie, Marrakech, Maroc.
| | - Ikram Brahim
- CHU Mohammed VI, centre de recherche clinique, Marrakech, Maroc
| | - Raja Hazime
- CHU Mohammed VI, laboratoire d'immunologie, Marrakech, Maroc
| | - Brahim Admou
- CHU Mohammed VI, laboratoire d'immunologie, Marrakech, Maroc; CHU Mohammed VI, centre de recherche clinique, Marrakech, Maroc; Université Cadi Ayyad, faculté de médecine, laboratoire de recherche PCIM, Marrakech, Maroc
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10
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Yamada M, Shibata H, Masugi Y, Ishi T, Kameyama K, Ebinuma H, Hasegawa T. Histological Changes in Autoimmune Hepatitis with Graves' Disease: A Child Case Report. Intern Med 2017; 56:2139-2143. [PMID: 28781316 PMCID: PMC5596273 DOI: 10.2169/internalmedicine.8417-16] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We herein report a child case of autoimmune hepatitis (AIH) accompanied with Graves' disease. Elevated aminotransferase levels were found in a 12-year-old Japanese girl with Graves' disease. In her first liver biopsy, necrosis and inflammation was limited to the centrilobular area, while the second biopsy showed different findings. Namely, portal injury newly appeared, including interface hepatitis, which represents the histological characteristics of AIH. As the histological findings at the onset of AIH do not always show typical findings, a re-biopsy is considered to be important in individuals suspected to have AIH. AIH should be included in the differential diagnosis of liver dysfunction in Graves' disease, even in children.
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Affiliation(s)
- Mamiko Yamada
- Department of Pediatrics, Keio University School of Medicine, Japan
- Tachikawa Hospital, Federation of National Public Service Personnel Mutual Aid Associations, Japan
| | - Hironori Shibata
- Department of Pediatrics, Keio University School of Medicine, Japan
| | - Yohei Masugi
- Department of Pediatrics, Keio University School of Medicine, Japan
| | - Tomohiro Ishi
- Department of Pediatrics, Keio University School of Medicine, Japan
| | - Kaori Kameyama
- Department of Pathology, Keio University School of Medicine, Japan
| | - Hirotoshi Ebinuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Japan
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11
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Christen U, Hintermann E. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models? Int J Mol Sci 2016; 17:ijms17122007. [PMID: 27916939 PMCID: PMC5187807 DOI: 10.3390/ijms17122007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
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12
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Woynarowski M, Woźniak M, Cukrowska B, Wierzbicka A, Lytton SD. Autoantibody Profile of Adult Patients With Childhood Onset Type 2 Autoimmune Hepatitis. J Clin Lab Anal 2016; 30:590-6. [PMID: 26676069 PMCID: PMC6807217 DOI: 10.1002/jcla.21907] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 10/05/2015] [Accepted: 10/12/2015] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Anti-liver kidney microsome (anti-LKM) autoantibodies are a distinguishing feature of type II autoimmune hepatitis (AIH-2). However, the levels of anti-LKM-1 in adult AIH-2 patients and their role in liver immunopathology remain equivocal. The aim of the study was to survey the autoantibody profile and the activity of liver disease in adult patients diagnosed with AIH-2 at childhood. METHODS The autoantibody profile of adults was compared with the autoantibodies of the pediatric period. Liver function test, Immunoglobulin G (IgG), and gamma globulins were evaluated at the AIH presentation, at the age of 18 years, and at the current adult visit. RESULTS All ten patients tested positive for LKM-1 at least once during the pediatric period. At the adult visit, four patients lost autoantibody positivity. LKM-1 was positive in four, liver cytosol antigen 1 (LC-1) in two, soluble liver antigen in one, and antinuclear antigen in one patient. Additionally three patients with LKM-1 and one patient without LKM-1 were positive for AMA-M2 (where AMA is antimitochondrial antibodies) Immunoglobulin M (IgM). Liver function markedly improved at 18 years and adult visit compared with initial diagnosis of AIH with only a mild decrease of IgG. The six adult patients positive for at least one autoantibody had statistically lower aspartate aminotransferase (AST) and gamma-glutamyltranspeptidase (GGTP) than the four patients autoantibody negative (AST: 52 vs. 88 IU/l, P < 0.05; GGTP 19 vs. 163 IU/l, P < 0.05). CONCLUSION LKM-1 positivity is not a stable condition in all patients with AIH-2. Patients who remained autoantibody positive had better liver function tests than those who lost their positivity. The presence of AMA-M2 autoantibodies suggest that development of AIH/Primary Biliary Cirrhosis (PBC) overlap syndrome should be considered.
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13
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Sarda G, Harvey R. Severe transaminitis in a paediatric patient with systemic lupus erythaematosus and a discussion of the literature. BMJ Case Rep 2016; 2016:10.1136/bcr-2015-214159. [PMID: 27090540 DOI: 10.1136/bcr-2015-214159] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A 15-year-old African-American girl with known systemic lupus erythaematosus (SLE) presented to the emergency room with fever, abdominal distension, pain and vomiting. She was found to have severe transaminitis on laboratory examination, which prompted further work up including imaging and liver biopsy. Although complete diagnostic criteria were not met, histology was suggestive of autoimmune hepatitis (AIH). She was treated with steroids and azathioprine with good response and resolution of liver function tests. Availability of the literature discussing patients of any age with SLE and AIH is minimal, and consists mostly of small case series and some case reports. The juvenile literature on SLE and AIH occurring in the same patient is even scarcer and should be further studied at a multicentre level.
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Affiliation(s)
- Garima Sarda
- Baystate Medical Center Children's Hospital, Springfield, Massachusetts, USA
| | - Rohini Harvey
- Baystate Medical Center Children's Hospital, Springfield, Massachusetts, USA
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14
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Yamagiwa S, Tamura Y, Takamura M, Genda T, Ichida T, Ishikawa T, Kamimura T, Takahashi T, Suda T, Matsuda Y, Nomoto M, Aoyagi Y. Increase of fucosylated alpha-fetoprotein fraction at the onset of autoimmune hepatitis and acute liver failure. Hepatol Res 2014; 44:E368-E375. [PMID: 24612069 DOI: 10.1111/hepr.12318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Revised: 02/13/2014] [Accepted: 02/19/2014] [Indexed: 02/05/2023]
Abstract
AIM Increased serum α-fetoprotein (AFP) has been associated with a good prognosis following acute liver failure (ALF), but the levels of the fucosylated fraction of AFP (Lens culinaris agglutinin-reactive fraction of AFP [AFP-L3]) following acute liver injury remain unknown. The aim of the present study was to investigate the clinical significance of AFP and AFP-L3 in patients with acute liver injury. METHODS We investigated the serum levels of AFP and highly sensitive AFP-L3% in 27 patients with acute-onset autoimmune hepatitis (AIH), 28 patients with acute hepatitis (AH) and 22 patients with ALF at the onset using a highly sensitive immunoassay (micro-total analysis system). RESULTS The serum AFP levels were increased in patients with AIH, AH and ALF, but the levels did not significantly differ among them. However, the mean AFP-L3% level was significantly higher in patients with AIH than in patients with AH (P = 0.0039). Moreover, significantly more patients with AIH demonstrated AFP-L3 positivity (≥10%) when compared with patients with AH (P = 0.014). Although the percentage of AFP-L3 positivity increased with AFP levels, at low serum AFP levels (<10 ng/mL), significantly more patients with AIH demonstrated AFP-L3 positivity than did patients with AH (P = 0.024) or ALF (P = 0.038). CONCLUSION We demonstrated for the first time that highly sensitive AFP-L3% levels were increased at the onset of AIH. The mechanism underlying the increase in AFP-L3 remains to be elucidated, but this finding may reflect an alteration of the glycosylation such as hyperfucosylation, which can influence the modifications of self-antigens in hepatocytes.
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Affiliation(s)
- Satoshi Yamagiwa
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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15
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Wang JB, Pu SB, Sun Y, Li ZF, Niu M, Yan XZ, Zhao YL, Wang LF, Qin XM, Ma ZJ, Zhang YM, Li BS, Luo SQ, Gong M, Sun YQ, Zou ZS, Xiao XH. Metabolomic Profiling of Autoimmune Hepatitis: The Diagnostic Utility of Nuclear Magnetic Resonance Spectroscopy. J Proteome Res 2014; 13:3792-3801. [PMID: 24940827 DOI: 10.1021/pr500462f] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is often confused with other liver diseases because of their shared nonspecific symptoms and serological and histological overlap. This study compared the plasma metabolomic profiles of patients with AIH, primary biliary cirrhosis (PBC), PBC/AIH overlap syndrome (OS), and drug-induced liver injury (DILI) with those of healthy subjects to identify potential biomarkers of AIH. Metabolomic profiling and biomarker screening were performed using proton nuclear magnetic resonance spectroscopy (1H NMR) coupled with a partial least-squares discriminant analysis. Compared with the levels in healthy volunteers and other liver disease patients, AIH patients exhibited relatively high levels of plasma pyruvate, lactate, acetate, acetoacetate, and glucose. Such metabolites are typically related to energy metabolism alterations and may be a sign of metabolic conversion to the aerobic glycolysis phenotype of excessive immune activation. Increased aromatic amino acids and decreased branched-chain amino acids were found in the plasma of AIH patients. The whole NMR profiles were stepwise-reduced, and nine metabolomic biomarkers having the greatest significance in the discriminant analysis were obtained. The diagnostic utility of the selected metabolites was assessed, and these biomarkers achieved good sensitivity, specificity, and accuracy (all above 93%) in distinguishing AIH from PBC, DILI, and OS. This report is the first to present the metabolic phenotype of AIH and the potential utility of 1H NMR metabolomics in the diagnosis of AIH.
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Affiliation(s)
- Jia-Bo Wang
- China Military Institute of Chinese Medicine, 302 Military Hospital , Beijing 100039, PR China
| | - Shi-Biao Pu
- China Military Institute of Chinese Medicine, 302 Military Hospital , Beijing 100039, PR China.,Yunnan University of Traditional Chinese Medicine , Kunming 650500, PR China
| | - Ying Sun
- Diagnosis and Treatment Center for Non-infectious Diseases, 302 Military Hospital , Beijing 100039, PR China
| | - Zhong-Feng Li
- Capital Normal University , Beijing 100089, PR China
| | - Ming Niu
- China Military Institute of Chinese Medicine, 302 Military Hospital , Beijing 100039, PR China
| | - Xian-Zhong Yan
- National Center of Biomedical Analysis, Academy of Military Medical Sciences , Beijing 100850, PR China
| | - Yan-Ling Zhao
- China Military Institute of Chinese Medicine, 302 Military Hospital , Beijing 100039, PR China
| | - Li-Feng Wang
- The Institute of Translational Hepatology, The Research Center for Biological Therapy, 302 Military Hospital , Beijing 100039, PR China
| | - Xue-Mei Qin
- Shanxi University , Taiyuan 030006, PR China
| | - Zhi-Jie Ma
- Beijing Friendship Hospital, Capital Medical University , Beijing 100050, PR China
| | - Ya-Ming Zhang
- China Military Institute of Chinese Medicine, 302 Military Hospital , Beijing 100039, PR China
| | - Bao-Sen Li
- Diagnosis and Treatment Center for Non-infectious Diseases, 302 Military Hospital , Beijing 100039, PR China
| | - Sheng-Qiang Luo
- Integrative Medical Center, 302 Military Hospital , Beijing 100039, PR China
| | - Man Gong
- Integrative Medical Center, 302 Military Hospital , Beijing 100039, PR China
| | - Yong-Qiang Sun
- Integrative Medical Center, 302 Military Hospital , Beijing 100039, PR China
| | - Zheng-Sheng Zou
- Diagnosis and Treatment Center for Non-infectious Diseases, 302 Military Hospital , Beijing 100039, PR China
| | - Xiao-He Xiao
- Integrative Medical Center, 302 Military Hospital , Beijing 100039, PR China
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16
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Abstract
Autoimmune disorders afflicting the liver comprise the bona fide autoimmune diseases, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis as well as drug-induced autoimmune-like diseases, such as halothane hepatitis. Whereas drug-induced forms of acute or chronic hepatitis often have a clear triggering factor, the etiology of classical autoimmune liver diseases is only poorly understood. Besides a genetic component present in disease susceptible individuals, environmental triggering factors are likely to play a role in the initiation and/or propagation of the disease. In this article, we will review on current evidence obtained from epidemiological associations, case studies, and findings in animal models for pathogens, to be involved in the etiology of autoimmune liver disease with a special focus on autoimmune hepatitis.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital , Frankfurt am Main , Germany
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17
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Kaur N, Minz RW, Anand S, Saikia B, Aggarwal R, Das A, Thapa BR, Chawla YK. HLA DRB1 Alleles Discriminate the Manifestation of Autoimmune Hepatitis as Type 1 or Type 2 in North Indian Population. J Clin Exp Hepatol 2014; 4:14-8. [PMID: 25755530 PMCID: PMC4017209 DOI: 10.1016/j.jceh.2013.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Accepted: 12/02/2013] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Autoimmune hepatitis is a polygenic disorder of unknown etiology, where genetic factors affect the occurrence and clinical phenotype of the disease. It has been reported as a rare disease entity in the Indian subcontinent. This study was undertaken to investigate the association of HLA alleles with autoimmune hepatitis type 1 and type 2 in north Indian population and to analyze if distinct human leukocyte antigen (HLA) alleles help in characterization of the subtypes of autoimmune hepatitis. METHODS Sixty-eight patients with autoimmune hepatitis and 128 healthy controls were recruited in the study. Out of 68 patients, 55 were diagnosed with autoimmune hepatitis type 1 and 13 with autoimmune hepatitis type 2. The patients and the controls were typed for HLA class II alleles by PCR-SSP method. RESULTS HLA DRB1*04 and DRB1*08 were found to be significantly associated with autoimmune hepatitis type 1 in north Indian population. It was also observed that DRB1*04, DRB1*13 were significantly associated with pediatric autoimmune hepatitis type 1 and DRB1*08 was significantly associated with adult autoimmune hepatitis type 1. DRB1*14 was significantly associated with autoimmune hepatitis type 2. CONCLUSION The study indicates that autoimmune hepatitis in north Indian population is associated with HLA alleles that may help to discriminate the subtypes as autoimmune hepatitis type 1 and type 2. The study also highlights the ethnic variations in the Indian subcontinent in context to the genetic association of HLA with autoimmune diseases.
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Key Words
- AASLD, American Association for the Study of the Liver
- AIH, autoimmune hepatitis
- ANA, antinuclear antibody
- ASMA, anti smooth muscle antibody
- CI, confidence interval
- HLA, human leukocyte antigen
- IAHG, International Autoimmune Hepatitis Group
- IIF, indirect immuno florescence
- LKM, liver kidney microsomal
- MHC, major histocompatibility complex
- Mb, megabase
- OR, odds ratio
- PCR-SSP, polymerase chain reaction-sequence specific primers
- RR, relative risk
- autoimmune hepatitis
- ethnic variations
- human leukocyte antigen
- north India
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Affiliation(s)
- Navchetan Kaur
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ranjana W. Minz
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Shashi Anand
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Biman Saikia
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ritu Aggarwal
- Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ashim Das
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Babu R. Thapa
- Department of Paediatric Gastroenterology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Yogesh K. Chawla
- Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
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18
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Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J Hepatol 2014; 60:612-7. [PMID: 24326217 DOI: 10.1016/j.jhep.2013.10.020] [Citation(s) in RCA: 239] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 10/10/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Population-based studies of the clinical course of autoimmune hepatitis are scarce. We conducted a nationwide study of incidence, prevalence, prognosis, and causes of death of autoimmune hepatitis in Denmark. METHODS From nationwide healthcare registries we identified all Danish citizens diagnosed with autoimmune hepatitis in 1994-2012 and their liver biopsy data. We followed patients through January 2013 and examined age-standardized incidence and prevalence, mortality, prognostic factors, risk of hepatocellular carcinoma, and causes of death. We used Cox regression to compare patients' mortality relative to a gender- and age-matched general population sample. RESULTS We included 1721 autoimmune hepatitis patients. The incidence rate was 1.68 (95% confidence interval 1.60 to 1.76) per 100,000 population per year, and it doubled during the study period. Of the 1318 patients who were biopsied at diagnosis, 28.3% had cirrhosis. The 10-year cumulative risk of hepatocellular carcinoma was 0.7% (95% confidence interval 0.3 to 1.5). Male gender and cirrhosis were associated with high mortality and development of hepatocellular carcinoma. In the first year after diagnosis, patients with autoimmune hepatitis had six-fold higher mortality than the general population; later, their mortality remained two-fold higher. Their 10-year cumulative mortality was 26.4% (95% confidence interval 23.7 to 29.1). 38.6% of deaths were liver-related including 3.6% from hepatocellular carcinoma. CONCLUSIONS This nationwide population-based study of autoimmune hepatitis showed that the incidence increased during 1994-2012, and that the disease remains associated with a high mortality, particularly in the first year after diagnosis. Male gender and cirrhosis were adverse prognostic factors.
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19
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Pischke S, Gisa A, Suneetha PV, Wiegand SB, Taubert R, Schlue J, Wursthorn K, Bantel H, Raupach R, Bremer B, Zacher BJ, Schmidt RE, Manns MP, Rifai K, Witte T, Wedemeyer H. Increased HEV seroprevalence in patients with autoimmune hepatitis. PLoS One 2014; 9:e85330. [PMID: 24465537 PMCID: PMC3897432 DOI: 10.1371/journal.pone.0085330] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Accepted: 11/25/2013] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection takes a clinically silent, self-limited course in the far majority of cases. Chronic hepatitis E has been reported in some cohorts of immunocompromised individuals. The role of HEV infections in patients with autoimmune hepatitis (AIH) is unknown. METHODS 969 individuals were tested for anti-HEV antibodies (MP-diagnostics) including 208 patients with AIH, 537 healthy controls, 114 patients with another autoimmune disease, rheumatoid arthritis (RA), and 109 patients with chronic HCV- or HBV-infection (HBV/HCV). Patients with AIH, RA and HBV/HCV were tested for HEV RNA. HEV-specific proliferative T cell responses were investigated using CFSE staining and in vitro stimulation of PBMC with overlapping HEV peptides. RESULTS HEV-antibodies tested more frequently positive in patients with AIH (n = 16; 7.7%) than in healthy controls (n = 11; 2.0%; p = 0.0002), patients with RA (n = 4; 3.5%; p = 0.13) or patients with HBV/HCV infection (n = 2; 2.8%; p = 0.03). HEV-specific T cell responses could be detected in all anti-HEV-positive AIH patients. One AIH patient receiving immunosuppression with cyclosporin and prednisolone and elevated ALT levels had acute hepatitis E but HEV viremia resolved after reducing immunosuppressive medication. None of the RA or HBV/HCV patients tested HEV RNA positive. CONCLUSIONS Patients with autoimmune hepatitis but not RA or HBV/HCV patients are more likely to test anti-HEV positive. HEV infection should been ruled out before the diagnosis of AIH is made. Testing for HEV RNA is also recommended in AIH patients not responding to immunosuppressive therapy.
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MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Arthritis, Rheumatoid/blood
- Arthritis, Rheumatoid/diagnosis
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/virology
- Case-Control Studies
- Coinfection
- Female
- Hepatitis Antibodies/blood
- Hepatitis B/blood
- Hepatitis B/diagnosis
- Hepatitis B/immunology
- Hepatitis B/virology
- Hepatitis C/blood
- Hepatitis C/diagnosis
- Hepatitis C/immunology
- Hepatitis C/virology
- Hepatitis E/blood
- Hepatitis E/diagnosis
- Hepatitis E/immunology
- Hepatitis E/virology
- Hepatitis E virus/immunology
- Hepatitis, Autoimmune/blood
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/virology
- Hepatitis, Chronic
- Humans
- Immunocompromised Host
- Male
- Middle Aged
- RNA, Viral/blood
- Seroepidemiologic Studies
- T-Lymphocytes/immunology
- T-Lymphocytes/virology
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Affiliation(s)
- Sven Pischke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Anett Gisa
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Steffen Björn Wiegand
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Richard Taubert
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Jerome Schlue
- Institute for Pathology, Hannover Medical School, Hannover, Germany
| | - Karsten Wursthorn
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Regina Raupach
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Behrend Johann Zacher
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Michael Peter Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Kinan Rifai
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Torsten Witte
- Department of Clinical Immunology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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20
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Hassan N, Siddiqui AR, Abbas Z, Hassan SM, Soomro GB, Mubarak M, Anis S, Muzaffar R, Zafar MN. Clinical Profile and HLA Typing of Autoimmune Hepatitis From Pakistan. HEPATITIS MONTHLY 2013; 13:e13598. [PMID: 24358040 PMCID: PMC3867004 DOI: 10.5812/hepatmon.13598] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 10/22/2013] [Accepted: 11/16/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND Human leukocyte antigen (HLA) typing in autoimmune hepatitis (AIH) has been investigated in different populations and ethnic groups, but no such data is available from Pakistan. OBJECTIVES The aim of this study was to evaluate the clinical profile of autoimmune hepatitis (AIH), and determine the associated antigens and alleles by performing HLA typing. PATIENTS AND METHODS A total of 58 patients, diagnosed and treated as AIH in the last 10 years were reviewed. Diagnosis was based on International AIH Group criteria. Forty one patients underwent liver biopsy. HLA typing was performed in 44 patients and 912 controls by serological method for HLA A and B, and by PCR technique using sequence specific primers for DR alleles. RESULTS Of 58 cases, 35 were females (60.3%). The median age was 14.5 (range 4-70 years), and AIH score was 14 (10-22). Thirty-six (62.0%) patients had type 1 AIH, 10 (17.2%) type 2, and the remaining 12 were seronegative with biopsy proven AIH. Forty-nine patients (84.4%) had cirrhosis. Twenty-four (41.4%) patients had ascites at the time of presentation. Among 41 patients who underwent liver biopsy, thirty-two had advance stages III and IV disease, and twenty had severe grade of inflammation. Fifteen patients had other associated autoimmune diseases and one developed hepatocellular carcinoma. HLA A2 (P = 0.036), HLA A9 (23) (P = 0.018), HLA A10 (25) (P = 0.000), HLA A19 (33) (P = 0.000), HLA B15 (63) (P = 0.007), HLA B40 (61) ( P = 0.002), HLA DR6 (P = 0.001) with its subtypes HLA-DRB1*13 (P = 0.032) and HLA-DRB1*14 (p = 0.017) were more prevalent in AIH with statistical significance than controls. CONCLUSIONS AIH in our region presents with advanced disease affecting predominantly children and adolescents. There is a genetic association of HLA DR6 along with other alleles and antigens in our patients with AIH.
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Affiliation(s)
- Nasir Hassan
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Adeelur Rehman Siddiqui
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Zaigham Abbas
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Syed Mujahid Hassan
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ghous Bux Soomro
- Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Muhammed Mubarak
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Sabiha Anis
- Molecular Diagnostics and Immunology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Rana Muzaffar
- Molecular Diagnostics and Immunology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Mirza Naqi Zafar
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
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21
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Gutkowski K, Hartleb M, Kacperek-Hartleb T, Kajor M, Mazur W, Zych W, Walewska-Zielecka B, Habior A, Sobolewski M. Laboratory-based scoring system for prediction of hepatic inflammatory activity in patients with autoimmune hepatitis. Liver Int 2013; 33:1370-7. [PMID: 23651331 DOI: 10.1111/liv.12198] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 04/13/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS In autoimmune hepatitis (AIH), inflammation is closely related to fibrosis. Although transaminase levels are commonly used to assess hepatic inflammation, they may not relate directly to the histology. We developed a noninvasive diagnostic score as an alternative to liver biopsy to help optimize treatment for AIH and monitor disease progress. METHODS Eighty-two participants with type 1 AIH who had undergone liver biopsy were included (44 in training and 38 in validation sets). Liver histology was assessed according to the histologic activity index (HAI; score 0-18) and Ishak's histologic fibrosis index (HFI; score 0-6). High inflammation was defined as HAI>4, and advanced fibrosis was defined as HFI>2. Routine laboratory test findings and stepwise linear regression were used to develop the best models predicting HAI and HFI. The best cut-off value to predict high inflammation and advanced fibrosis for these formulas was then calculated based on receiver-operating characteristic analysis. RESULTS The cut-off value for a model predicting high inflammation was ≥3.57 (AUROC = 0.93; 95% CI: 0.86-1.00), with 100% sensitivity and 85% specificity. High inflammation was confirmed with an 81% positive predictive value and excluded with a 100% negative predictive value. In the validation set, the sensitivity, specificity, positive predictive value and negative predictive values were 100, 56, 88 and 100% respectively. The diagnostic yield of the fibrosis score was unsatisfactory. CONCLUSIONS The noninvasive inflammatory score based on four routine laboratory parameters discriminated patients with and without significant hepatic inflammation and may facilitate follow-up of type 1 AIH patients.
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Affiliation(s)
- Krzysztof Gutkowski
- Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland
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22
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Anti-soluble liver antigen prevalence in chronic hepatitis. EGYPTIAN LIVER JOURNAL 2013. [DOI: 10.1097/01.elx.0000433594.92552.93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Abstract
Autoimmune hepatitis (AIH) was the first chronic liver disease in which remission was achieved by immunosuppression. Prognosis is poor when left untreated. Since the original description in 1950 by Waldenström, the initially reported treatment option has remained until today and is the core of the basic therapeutic strategy of inducing remission with steroids and azathioprine. Immunosuppression as a treatment concept spans different situations including the induction and maintenance of remission, treatment of nonresponders, avoidance of side effects, perioperative treatment of liver transplantation candidates and the issue of withdrawal. Alternative immunosuppressive drugs such as transplantation immunosuppressants have been administered and reported in small series. In an attempt to optimize side effect management, a recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative for noncirrhotic AIH patients with lower steroid side effects. With an early diagnosis and effective therapy, only 4% of transplant candidates are transplanted for AIH. After liver transplantation there is a considerable risk for graft loss because of recurrent AIH, and lifelong vigilance and therapeutic attention is important.
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Affiliation(s)
- Christian P Strassburg
- Medizinische Klinik und Polikklinik I, University of Bonn Medical Center, Bonn, Germany.
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24
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Barosa R, Ramos LR, Fonseca C, Freitas J. Acute hepatitis in a young woman with systemic lupus erythematosus: a diagnostic challenge. BMJ Case Rep 2013; 2013:bcr-2013-008591. [PMID: 23563681 DOI: 10.1136/bcr-2013-008591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A 48-year-old woman with systemic lupus erythematosus diagnosis was on naproxen, hidroxichloroquine and acetylsalicylic acid. She had self-suspended all medication and resumed 1 year later. Five days after the medication was resumed, she developed acute hepatitis, with biochemical hepatic cytolysis, hypergamaglobulinaemia and a serum antinuclear antibody titre of 1/2560. Idiopathic autoimmune hepatitis was considered, but drug-induced liver injury could not definitely be ruled out. Patient declined liver biopsy. Oral prednisolone was started. Within 3 months with prednisolone being tapered to 10 mg/day, a new flare occurred. Liver biopsy was performed and it favoured autoimmune hepatitis diagnosis. We discuss the diagnostic options and treatment approach in a patient with autoimmune disease and possible drug-induced liver injury who initially declined liver biopsy.
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Affiliation(s)
- Rita Barosa
- Department of Gastrenterology, Hospital Garcia de Orta, Almada, Portugal.
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25
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Abstract
Antibodies play an important role in autoimmune liver diseases, such as autoimmune hepatitis (AIH). On the one hand, they are essential diagnostic markers to identify not only the presentation of AIH, but also the AIH subtype characterized by the presence of particular antibodies to target autoantigens in the liver. On the other hand, such autoantibodies might be directly involved in the etiology and/or pathogenesis of AIH. This review will reflect on the evidence of how specific autoantibodies influence AIH and will further provide insight into the necessities for generating therapeutic antibodies to treat AIH in the future.
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Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany
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26
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Flamenco G, Hall M, Swann AK. Case Study and Review of Autoimmune Hepatitis. Lab Med 2013. [DOI: 10.1309/lml0opqa9yd8tvgy] [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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27
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Kim BH, Kim YJ, Jeong SH, Tak WY, Ahn SH, Lee YJ, Jung EU, Lee JI, Yeon JE, Hwang JS, Um SH, Seo YS, Kim YS, Song BC, Kim JH, Jung YK, Park CK, Kim KA, Min HJ, Cho EY, Lee ES, Kwon SY, Chae HB, Kim DJ, Shin SR. Clinical features of autoimmune hepatitis and comparison of two diagnostic criteria in Korea: a nationwide, multicenter study. J Gastroenterol Hepatol 2013; 28:128-34. [PMID: 23033899 DOI: 10.1111/j.1440-1746.2012.07292.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/29/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM As a rare liver disease, little is known about autoimmune hepatitis (AIH). This study investigated the clinical features and compared two diagnostic criteria of AIH in Korea. METHODS A nationwide, multicenter, retrospective analysis was done of data of adult patients diagnosed with AIH from January 2005 to December 2009. RESULTS The enrolled patients (n = 343; mean age, 52.8 years; range, 19-87 years; 12% male, 88% female) met diagnostic criteria of AIH according to the revised original criteria (n = 311) or the simplified criteria (n = 250). At diagnosis, 30.6% were asymptomatic, 22.7% were cirrhotic, and 4.3% displayed hepatic decompensation. The positive results for anti-nuclear antibody, smooth muscle antibody, and anti-liver/kidney microsomal antibody were 94.2%, 23.0%, and 2.9%, respectively. Definite AIH and probable AIH according to the revised original criteria were 24.8% and 65.3%, respectively, while those according to the simplified criteria were 34.4% and 38.5%, respectively. The diagnostic sensitivity and positive predictive value of simplified criteria in comparison with the revised original criteria were 69.9% and 86.4%, respectively. As an initial therapy, corticosteroid (37.7%) or corticosteroid with azathioprine (36.8%) was administered. Remission, incomplete response, and treatment failure were noted with 85.7%, 10.5%, and 3.9% of patients, respectively. CONCLUSIONS Autoimmune hepatitis in Korea is mostly type I, showing a mean age of 53 years with comparable clinical features to other countries. The concordant rate of the two diagnostic criteria was rather low with modest sensitivity of the simplified criteria. Further studies on the validation of the diagnostic criteria are warranted.
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Affiliation(s)
- Bo Hyun Kim
- Department of Internal Medicine, Bundang Jesaeng General Hospital, Seongnam, Korea
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Drastich P, Honsová E, Lodererová A, Jarešová M, Pekáriková A, Hoffmanová I, Tučková L, Tlaskalová-Hogenová H, Špičák J, Sánchez D. Celiac disease markers in patients with liver diseases: A single center large scale screening study. World J Gastroenterol 2012; 18:6255-6262. [PMID: 23180946 PMCID: PMC3501774 DOI: 10.3748/wjg.v18.i43.6255] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the coincidence of celiac disease, we tested its serological markers in patients with various liver diseases.
METHODS: Large-scale screening of serum antibodies against tissue transglutaminase (tTG), and deamidated gliadin using enzyme-linked immunosorbent assay and serum antibodies against endomysium using immunohistochemistry, in patients with various liver diseases (n = 962) and patients who underwent liver transplantation (OLTx, n = 523) was performed. The expression of tTG in liver tissue samples of patients simultaneously suffering from celiac disease and from various liver diseases using immunohistochemistry was carried out. The final diagnosis of celiac disease was confirmed by histological analysis of small-intestinal biopsy.
RESULTS: We found that 29 of 962 patients (3%) with liver diseases and 5 of 523 patients (0.8%) who underwent OLTx were seropositive for IgA and IgG anti-tTG antibodies. However, celiac disease was biopsy-diagnosed in 16 patients: 4 with autoimmune hepatitis type I, 3 with Wilson's disease, 3 with celiac hepatitis, 2 with primary sclerosing cholangitis, 1 with primary biliary cirrhosis, 1 with Budd-Chiari syndrome, 1 with toxic hepatitis, and 1 with non-alcoholic steatohepatitis. Unexpectedly, the highest prevalence of celiac disease was found in patients with Wilson's disease (9.7%), with which it is only rarely associated. On the other hand, no OLTx patients were diagnosed with celiac disease in our study. A pilot study of the expression of tTG in liver tissue using immunohistochemistry documented the overexpression of this molecule in endothelial cells and periportal hepatocytes of patients simultaneously suffering from celiac disease and toxic hepatitis, primary sclerosing cholangitis or autoimmune hepatitis type I.
CONCLUSION: We suggest that screening for celiac disease may be beneficial not only in patients with associated liver diseases, but also in patients with Wilson's disease.
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Garg D, Nagar A, Philips S, Takahashi N, Prasad SR, Shanbhogue AK, Sahani DV. Immunological diseases of the pancreatico-hepatobiliary system: update on etiopathogenesis and cross-sectional imaging findings. ACTA ACUST UNITED AC 2012; 37:261-74. [PMID: 21597892 DOI: 10.1007/s00261-011-9759-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Immunological diseases of the hepatobiliary system and the pancreas include a broad spectrum of disorders that manifest characteristic histopathology/serology and variable clinical features and imaging findings. Recent studies have thrown fresh light on the complex role of genetics and autoimmunity in the pathogenesis and natural history of these diverse disorders that include autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, IgG4-related cholangitis, overlap/outlier syndromes, and autoimmune pancreatitis.
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Affiliation(s)
- Deepak Garg
- Department of Radiology, University of Texas Health Science Center, San Antonio, TX 78229, USA
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30
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Yapali S, Oruc N, Ilgun S, Yilmaz F, Aksu K, Yilmaz M, Gunsar F. Acute presentation of autoimmune hepatitis in a patient with myasthenia gravis, thymoma, Hashimoto thyroiditis and connective tissue disorder. Hepatol Res 2012; 42:835-9. [PMID: 22776553 DOI: 10.1111/j.1872-034x.2012.00985.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Myasthenia gravis is an antibody-mediated autoimmune disease at the neuromuscular junctions. It can be associated with many other autoimmune diseases. We report a case of acute presentation of autoimmune hepatitis with myasthenia gravis, thymoma, Hashimoto thyroiditis and connective tissue disorder.
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Affiliation(s)
- Suna Yapali
- Departments of Gastroenterology Internal Medicine Pathology Rheumatology, Ege University School of Medicine, Izmir Department of Gastroenterology, Pamukkale University School of Medicine, Denizli, Turkey
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Abstract
PURPOSE This study describes the clinical, histological, and genetic profile of AMA-M2 positive liver disease in north India. METHODS Over 13.5 years, 11,221 patients suspected of AiLD (autoimmune liver disease) and negative for viral markers were screened for autoantibodies, ANA, ASMA, AMA, and LKM, by indirect immunofluorescence. Of these patients, 135 were AMA positive and 132 AMA-M2 positive. Clinical presentation of most of these patients was neither typical of AIH nor PBC. Sera of these patients were further tested for gp 210 and Sp 100. Fifty consecutive consenting patients were typed for HLA class II alleles DR and DQ and their clinical, biochemical, histology and genetic profiles were reviewed to characterize the disease spectrum in north India. RESULTS Only 22 of 50 patients had liver histology reports, and could be categorized on the basis of the criteria by Chazouillers et al. Of these 22, 13 had overlap syndrome, eight had classical PBC, whereas one had probable PBC. The remaining 28 could not be suitably categorized due to lack of liver histology. HLA DRB1*03 was found to be significantly associated with the disease in North Indian population. CONCLUSION This 13.5-year study demonstrates a definite rising annual incidence of AMA-M2-positive liver disease in north India. Complete evaluation of 50 patients indicated that a hepatitic variant of PBC (PBC-AIH), which is significantly associated with DRB1*03, predominates in north India.
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Strassburg CP, Manns MP. Therapy of autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2011; 25:673-87. [PMID: 22117634 DOI: 10.1016/j.bpg.2011.08.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Accepted: 08/18/2011] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis was the first chronic liver disease with a favourable response to drug therapy and a dismal prognosis when left untreated. Since its original description in 1950 and first treatment studies the basic therapeutic strategy of inducing remission with steroids and azathioprine has not been modified in principle. A timely diagnosis before cirrhosis develops, the avoidance of immunosuppressant side effect, non-responders to standard induction therapy, and adherence to therapy are the greatest challenges. Alternative immunosuppressive drugs have been tested in small series and include transplant immunosuppressants. A recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative in non-cirrhotic AIH patients capable of minimizing unwanted steroid effects. The ultimate treatment approach upon drug treatment failure is liver transplantation. Only four percent of transplant candidates are transplanted for AIH but the risk for graft loss because of recurrence has to be considered and recurrent AIH treated after transplantation.
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Affiliation(s)
- Christian P Strassburg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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34
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Geri G, Saadoun D, Cacoub P. Manifestations hépatiques des maladies systémiques. Rev Med Interne 2011; 32:486-93. [DOI: 10.1016/j.revmed.2010.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Revised: 04/24/2010] [Accepted: 07/19/2010] [Indexed: 12/20/2022]
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Selzner N, Guindi M, Renner EL, Berenguer M. Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients. J Hepatol 2011; 55:207-17. [PMID: 21145865 DOI: 10.1016/j.jhep.2010.11.012] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2010] [Revised: 11/23/2010] [Accepted: 11/23/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) re-infection of the graft is universal and interferon based antiviral therapy remains at present the treatment of choice in HCV liver transplant recipients. Apart from the antiviral effects, interferon and ribavirin have both potent immunomodulatory properties resulting in a broad range of immune-related disorders including acute cellular rejection and chronic ductopenic rejection as well as de novo autoimmune hepatitis. Further complicating the picture, HCV infection per se is associated with a variety of autoimmune phenomena. We discuss here the immune-mediated complications and their relationship to chronic HCV and interferon based antiviral therapy.
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Affiliation(s)
- Nazia Selzner
- University Health Network, University of Toronto, Toronto, Canada.
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36
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Martin SR, Alvarez F, Anand R, Song C, Yin W. Outcomes in children who underwent transplantation for autoimmune hepatitis. Liver Transpl 2011; 17:393-401. [PMID: 21445922 PMCID: PMC3078725 DOI: 10.1002/lt.22244] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The outcomes of 113 children with autoimmune hepatitis (AIH), registered with Studies of Pediatric Liver Transplantation and who underwent transplantation between 1995 and 2006, were compared with those who underwent transplantation for other diagnoses (non-AIH). A total of 4.9% of liver transplants were for AIH; 81% of these patients had AIH type 1 and most underwent transplantation for complications of chronic disease (60%), the majority in females (72%). Transplantation for fulminant AIH was more common in males (52.5% versus 47.5% chronic; P = 0.042). Patients with AIH differed from non-AIH patients by: age (13.0 ± 0.4 versus 4.6 ± 0.1 years; P < 0.0001), sex (64.6% female versus 52.9%; P = 0.016), ethnicity (48.7% white versus 58.2%; P < 0.0001), initial immunosuppression (tacrolimus-based: 72.6% versus 62.6%; P = 0.045; mycophenolate mofetil use: 31.0% versus 21.6%; P = 0.02), and immunosuppression at 2 years after transplant (monotherapy: 51.9% versus 17.3%; P < 0.0001). Late (>3 months), but not steroid-resistant or chronic, rejection was more common in AIH (log-rank P = 0.0015). The 5-year posttransplant survival for AIH was 86% (95% confidence interval: 73-93). Patient and graft survival, infectious and metabolic complications, and retransplantation rates did not differ between AIH and non-AIH groups. In conclusion, the higher risk for late acute rejection and greater degree of immunosuppression does not compromise outcomes of liver transplantation for AIH. Children who undergo transplantation for AIH in North America are typically female adolescents with complications of chronic AIH type 1 and include more children of African American or Latino American origin compared to the overall liver transplant population. These observations may inform detection, treatment, and surveillance strategies designed to reduce the progression of autoimmune hepatitis and subsequently, the need for transplantation.
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Affiliation(s)
- Steven R Martin
- Department of Pediatrics, Hôpital Sainte-Justine, University of Montreal
| | - Fernando Alvarez
- Department of Pediatrics, Hôpital Sainte-Justine, University of Montreal
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Stravitz RT, Lefkowitch JH, Fontana RJ, Gershwin ME, Leung PS, Sterling RK, Manns MP, Norman GL, Lee WM. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011; 53:517-26. [PMID: 21274872 PMCID: PMC3080034 DOI: 10.1002/hep.24080] [Citation(s) in RCA: 214] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Accepted: 10/16/2010] [Indexed: 12/11/2022]
Abstract
UNLABELLED Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoimmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty-two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies. CONCLUSION Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow-up. In contrast to classical autoimmune hepatitis, histological features of AI-ALF predominate in the centrilobular zone.
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Affiliation(s)
- R. Todd Stravitz
- Section of Hepatology, Virginia Commonwealth University, Richmond, VA
| | | | | | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
| | - Patrick S.C. Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA
| | | | - Michael P. Manns
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - William M. Lee
- Division of Digestive and Liver Diseases, University of Texas-Southwestern Medical Center, Dallas, TX
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Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue. J Hepatol 2011; 54:374-85. [PMID: 21067838 DOI: 10.1016/j.jhep.2010.09.002] [Citation(s) in RCA: 324] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2010] [Revised: 08/30/2010] [Accepted: 09/02/2010] [Indexed: 12/12/2022]
Abstract
Some patients present with overlapping features between disorders within the spectrum of autoimmune liver diseases (i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC)) and are commonly classified as having an "overlap syndrome". Standardized definitions of "overlap syndromes" are lacking. The aim of this report by the International Autoimmune Hepatitis Group (IAIHG) is to evaluate if there are important reasons to classify conditions with overlapping features between autoimmune liver diseases as separate diagnostic entities. Definition of diagnostic criteria for overlap conditions can only be arbitrary. The IAIHG scoring system for diagnosis of AIH has been widely used to diagnose "overlap syndromes", but was not intended for such use and has not proven to be an efficient tool for this purpose. Some patients with overlapping features between a cholestatic and hepatitic disorder appear to benefit from treatment with a combination of ursodeoxycholic acid and immunosuppressants, but this strategy is not evidence-based, and it seems unjustified to define new diagnostic groups in this regard. The IAIHG suggests that patients with autoimmune liver disease should be categorized according to the predominating feature(s) as AIH, PBC, and PSC/small duct PSC, respectively, and that those with overlapping features are not considered as being distinct diagnostic entities. The IAIHG scoring system should not be used to establish subgroups of patients. Patients with PBC and PSC with features of AIH should be considered for immunosuppressive treatment. Due to the low prevalence of such "overlap syndromes", prospective interventional therapeutic trials cannot be expected in the foreseeable future.
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39
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Genetic background of autoimmune hepatitis in Japan. J Gastroenterol 2011; 46 Suppl 1:42-7. [PMID: 20957499 DOI: 10.1007/s00535-010-0333-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Accepted: 09/15/2010] [Indexed: 02/04/2023]
Abstract
Autoimmune hepatitis (AIH) is an organ-specific autoimmune disease characterized by chronic inflammation of the liver. Several studies from ethnically different countries have clarified that the genetic predisposition to type 1 AIH is linked mainly to human leukocyte antigen (HLA)-class II genes. Recently, molecular analysis using polymerase chain reaction (PCR)-based DNA typing has revealed that susceptibility to type 1 AIH is primarily associated with the HLA class II DRB1 locus, which encodes a polymorphic β chain of the HLA-DR antigen. However, additional susceptibility genes (either HLA or non-HLA) and/or environmental factors may also contribute to the development of type 1 AIH; in Japanese type 1 AIH patients, although the most influential gene in disease susceptibility is HLA-DRB1*04:05, several other genes have been identified as being involved in AIH pathogenesis or resistance and are the currently the focus of single nucleotide polymorphism analysis.
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40
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Strassburg CP. Autoimmune hepatitis. Best Pract Res Clin Gastroenterol 2010; 24:667-82. [PMID: 20955969 DOI: 10.1016/j.bpg.2010.07.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2010] [Revised: 07/22/2010] [Accepted: 07/22/2010] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis is a chronic inflammatory disease of the liver with a dismal prognosis when left untreated. Key for the improvement of prognosis is a timely diagnosis before cirrhosis has developed. This is reached by the exclusion of other causes of hepatitis, elevated immunoglobulin G, autoantibody profile and histological assessment. Treatment achieves remission rates in 80% of individuals and consists of immunosuppression with corticosteroids and azathioprine. A recent randomised controlled multicenter trial has added budesonide to the effective treatment options in non-cirrhotic patients and leads to a reduction of unwanted steroid side effects. Autoimmune hepatitis is an autoimmune disease of unknown aetiology. Association studies of major histocompatibility complex and other genes demonstrate an influence of immunogenetics. However, apart from the autoimmune polyglandular syndrome type 1, in which 10% of patients suffer from an autoantibody-positive autoimmune hepatitis linked to mutations of the autoimmune regulator gene, there is no clear evidence for a hereditary aetiology of this disease.
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Affiliation(s)
- Christian P Strassburg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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41
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Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, Bahr MJ, Günther R, Hultcrantz RW, Spengler U, Lohse AW, Szalay F, Färkkilä M, Pröls M, Strassburg CP. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010; 139:1198-1206. [PMID: 20600032 DOI: 10.1053/j.gastro.2010.06.046] [Citation(s) in RCA: 267] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 05/26/2010] [Accepted: 06/04/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine. METHODS We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, open-label phase during which all patients received budesonide in addition to azathioprine. The primary end point was complete biochemical remission, defined as normal serum levels of aspartate aminotransferase and alanine aminotransferase, without predefined steroid-specific side effects, at 6 months. RESULTS The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%) (P < .001; 97.5% 1-side confidence interval [CI] = 16.2). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone (P = .001; CI: 7.7); 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone group (P < .001; CI = 12.3). Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12 (P < .002). CONCLUSIONS Oral budesonide, in combination with azathioprine, induces and maintains remission in patients with noncirrhotic AIH, with a low rate of steroid-specific side effects.
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Affiliation(s)
- Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
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Corpechot C, Chazouillères O. [Autoimmune hepatitis: diagnostic and therapeutic up-to-date]. Rev Med Interne 2010; 31:606-14. [PMID: 20674103 DOI: 10.1016/j.revmed.2009.05.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2008] [Revised: 04/02/2009] [Accepted: 05/25/2009] [Indexed: 01/08/2023]
Abstract
Autoimmune hepatitis is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation). Autoimmune hepatitis is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type II (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of autoimmune hepatitis that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish autoimmune hepatitis from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. The treatment of autoimmune hepatitis has not changed for the past 30 years. It consists of corticosteroids associated with azathioprine. This treatment is rapidly effective but usually only suspensive. Relapse after treatment withdrawal is the rule (80% of cases). The main risk factor of recurrence is the degree of residual inflammation on liver biopsy. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.
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Affiliation(s)
- C Corpechot
- Service d'hépatologie, hôpital Saint-Antoine, faculté de médecine Pierre-et-Marie-Curie, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France
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Suzuki Y, Ikeda K, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Suzuki F, Saitoh S, Arase Y, Kobayashi M, Miyakawa Y, Kumada H. Association of HLA-DR14 with the treatment response in Japanese patients with autoimmune hepatitis. Dig Dis Sci 2010; 55:2070-6. [PMID: 20094777 DOI: 10.1007/s10620-009-0995-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2008] [Accepted: 08/10/2009] [Indexed: 12/20/2022]
Abstract
BACKGROUND Influence of human lymphocyte antigen (HLA) on the therapeutic response in autoimmune hepatitis (AIH) is not known. AIMS To evaluate if HLA-DR types influence biological and histological responses to corticosteroids in patients with AIH. METHODS During 28 years from 1979 through 2007, 48 patients with definite diagnosis of AIH received long-term corticosteroid therapy (median 9 years [range: 5-28 years]) in a single Japanese center. They were followed for transaminase levels and received liver biopsy before and after the treatment. RESULTS DR4 was detected in 32 and DR14 in 11 patients; seven possessed both DR4 and DR14. DR4 was more frequent in AIH patients than in the general population (67% vs. 22%), while DR14 was comparably frequent between them (23% vs. 17%). Overall, biochemical response was achieved in 43 (90%) of the 48 patients. The sustained biochemical response to a maintenance prednisolone dose < 10 mg was gained more frequently in the patients with than without DR14 (10/11 [91%] vs. 10/37 [27%], P < 0.001). Marked histological improvement with a decrease in histology activity index (HAI) score by > 2 points was achieved in 31 of the 32 (97%) biochemical responders. Histological aggravation with an increase in HAI score occurred in 4 of the 16 (25%) patients without biochemical response (non-responders and relapsers combined), but in none of the 32 responders. CONCLUSION Long-term immunosuppressive treatment can improve the outcome of Japanese patients with AIH, and DR14 is associated with excellent biochemical response.
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Affiliation(s)
- Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, Takatsu-ku, Kawasaki City, Japan.
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Lamers MMH, van Oijen MGH, Pronk M, Drenth JPH. Treatment options for autoimmune hepatitis: a systematic review of randomized controlled trials. J Hepatol 2010; 53:191-8. [PMID: 20400196 DOI: 10.1016/j.jhep.2010.01.037] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 01/14/2010] [Accepted: 01/14/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Predniso(lo)ne with or without azathioprine is considered the mainstay in the treatment of autoimmune hepatitis (AIH), but many therapeutic options are available. The primary objective of this review was to explore the published literature on the optimal induction and subsequent maintenance therapy for AIH. METHODS We performed a systematic search on electronic databases MEDLINE (1950-07.2009), Web of Science, Cochrane, and the website www.clinicaltrials.gov. Randomized controlled trials (RCTs) on apparent beneficial treatment regimens as induction or maintenance treatment in AIH were included. Pediatric studies were excluded. We calculated relative risks (RR) for comparison of treatment options on the primary outcome measure, which was defined as clinical, biochemical and histological remission. RESULTS Eleven RCTs were included, of which 7 studies evaluated the induction therapy in AIH patients: 3 treatment naive (n=253), 2 relapse (n=53), 2 combination of naive and relapse (n=110). The remaining 4 studies (n=162) assessed maintenance therapy. All but one maintenance study (thymostimulin versus no therapy) studied predniso(lo)ne (PRED), azathioprine (AZA) or combination PRED+AZA. We found no differences in primary outcome between induction therapy with PRED and PRED+AZA in treatment naive patients (RR=0.98; 95% CI 0.65-1.47). AZA monotherapy as induction was considered as not viable because of a high mortality rate (30%). This was similar in AIH patients who relapsed: RR for PRED versus PRED+AZA for inducing remission was not different: 0.71 (95% CI 0.37-1.39). PRED+AZA maintained remission more often than PRED (RR=1.40; 95% CI 1.13-1.73). Also AZA maintained a higher remission rate than PRED (RR=1.35; 95% CI 1.07-1.70). Maintenance of remission was not different between PRED+AZA and AZA (RR=1.06; 95% CI 0.94-1.20). CONCLUSIONS Based on available RCTs, PRED monotherapy and PRED+AZA combination therapy are both viable induction therapies for AIH treatment naives and relapsers, while for maintenance therapy PRED+AZA and AZA therapy are superior to PRED monotherapy.
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Affiliation(s)
- Mieke M H Lamers
- Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
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Werner M, Wallerstedt S, Lindgren S, Almer S, Björnsson E, Bergquist A, Prytz H, Sandberg-Gertzén H, Hultcrantz R, Sangfelt P, Weiland O, Ohlsson B, Danielsson A. Characteristics and long-term outcome of patients with autoimmune hepatitis related to the initial treatment response. Scand J Gastroenterol 2010; 45:457-67. [PMID: 20082594 DOI: 10.3109/00365520903555861] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Autoimmune hepatitis (AIH) is a liver disease which, if untreated, may lead to liver cirrhosis and hepatic failure. Limited data exist regarding factors predicting the long-term outcome. The aims of this study were to investigate symptoms at presentation, prognostic features, management and treatment in relation to long-term outcome of AIH. MATERIAL AND METHODS A cohort of 473 Swedish patients with AIH was characterized regarding initial symptoms and signs, factors predicting death and future need for liver transplantation. Survival and causes of death were retrieved from Swedish national registers. RESULTS At diagnosis, fatigue was a predominant symptom (69%), 47% of the patients were jaundiced and 30% had liver cirrhosis. Another 10% developed cirrhosis during follow-up. Markedly elevated alanine aminotransferase levels at presentation were correlated with a better outcome. A high international normalized ratio (INR) at diagnosis was the only risk factor predicting a need for later liver transplantation. Histological cirrhosis, decompensation and non-response to initial treatment were all factors that correlated with a worse outcome. Overall life expectancy was generally favourable. However, most deaths were liver-related, e.g. liver failure, shock and gastrointestinal bleeding. CONCLUSIONS Cirrhosis at diagnosis, a non-response to initial immune-suppressive treatment or elevated INR values were associated with worse outcome and a need for later liver transplantation. In contrast, an acute hepatitis-like onset with intact synthetic capacity indicated a good response to treatment and favourable long-term prognosis. Lifetime maintenance therapy is most often required.
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Affiliation(s)
- Mårten Werner
- Department of Medicine, Sections for Hepatology and Gastroenterology, Umeå University Hospital, Umeå, Sweden.
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Chazouillères O. [A case of autoimmune hepatitis]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2009; 33:F36-F43. [PMID: 19762185 DOI: 10.1016/j.gcb.2009.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
Autoimmune hepatitis (AIH) is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level or serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation) in the absence of other causes. AIH is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type 2 (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of AIH that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish AIH from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. Treatment basis of AIH have not changed for the last 30 years. Initial treatment consists of corticosteroids associated with azathioprine. Budesonide may be at least as effective as systemic corticosteroids and reduces the frequency of side effects in non-cirrhotic patients. Long-term treatment consists of azathioprine. This treatment is rapidly effective but usually only suspensive since relapse after treatment withdrawal is the rule (80 % of cases). The probability of relapse is lower in case of complete biochemical response defined by normalization of transaminases, gamma-globulins and IgG and in case of histological response defined by the lack of interface hepatitis. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.
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Affiliation(s)
- O Chazouillères
- INSERM U680, service d'hépatologie, pôle digestif, centre de référence des maladies inflammatoires des voies biliaires, hôpital Saint-Antoine, université Pierre-et-Marie-Curie Paris-VI, 184 rue du Faubourg-Saint-Antoine, Paris, France.
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Haider AS, Kaye G, Thomson A. Autoimmune hepatitis in a demographically isolated area of Australia. Intern Med J 2009; 40:281-5. [PMID: 19712202 DOI: 10.1111/j.1445-5994.2009.02041.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Previous studies describing autoimmune hepatitis (AIH) come from liver transplant centres in which a skewed distribution of cases may give a misleading picture of the incidence of AIH and its natural history. This series describes AIH in a stable and demographically discrete population of patients in the Australian Capital Territory (ACT) and the surrounding region. METHODS In 42 patients with type 1 AIH (point prevalence 8 per 100,000 population), clinical, laboratory and histological features at presentation, response to initial therapy, details of maintenance therapy and outcome were recorded. RESULTS Consistent with other publications, the male-to-female ratio was 1:3, mean age at presentation was 53 years and 24% had cirrhosis at diagnosis. Most patients (86%) responded to initial therapy and 67% went into long-term remission. One patient died from liver failure and none required liver transplantation. Azathioprine was included in the treatment regimen in 74% of cases with doses generally <2 mg/kg. Azathioprine dose greater than or equal to 2 mg/kg was associated with better clinical outcome, but this did not reach statistical significance. A higher proportion of female patients had cirrhosis at presentation (9/10 vs 1/10; P= 0.24). CONCLUSION In this Australian community-based study, type 1 AIH was primarily a disease of later life, responded to conventional immunosuppressive therapy and generally has a good prognosis. Further study of the use of azathioprine is warranted to determine the optimal dose.
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Affiliation(s)
- A S Haider
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Australian National University, Canberra ACT, Australia
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48
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Volkmann M, Luithle D, Zentgraf H, Schnölzer M, Fiedler S, Heid H, Schulze-Bergkamen A, Strassburg CP, Gehrke SG, Manns MP. SLA/LP/tRNP((Ser)Sec) antigen in autoimmune hepatitis: identification of the native protein in human hepatic cell extract. J Autoimmun 2009; 34:59-65. [PMID: 19683415 DOI: 10.1016/j.jaut.2009.07.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2009] [Revised: 07/02/2009] [Accepted: 07/23/2009] [Indexed: 01/03/2023]
Abstract
A diagnostic subgroup of AIH type 1 is characterized by specific serum antibodies against soluble liver protein. The respective autoantigen was named SLA/LP/tRNP((Ser)Sec), after three homologous recombinant polypeptides were isolated from expression gene libraries. We analyzed human cultured liver cells for the human homologue of recombinant SLA/LP/tRNP((Ser)Sec) by antigen purification. In addition, a monoclonal antibody was generated against recombinant SLA-p35, a truncated recombinant SLA-reactive polypeptide. With a positive patient serum, immune affinity chromatography was performed on the 52 kD-SLA main antigenic determinant pre-enriched by ion exchange chromatography. By mass spectrometry, the 52 kD-SLA/LP/tRNP ((Ser)Sec) autoantigen was unambiguously identified in the purification product. The identity of the recombinant SLA-p35 and its human homologue was further confirmed by a specific signal of the anti SLA-p35 monoclonal antibody with purified human SLA/LP/tRNP((Ser)Sec). The 48 kD-SLA species frequently comigrating in SLA-immunoblotting however was not identified by either approach. We conclude that the native counterpart of recombinant tRNP((Ser)(Sec)) indeed is detectable with a molecular weight of 52 kD in soluble liver extract of human cells as the major antigenic component of SLA/LP/tRNP((Ser)Sec).
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MESH Headings
- Amino Acid Sequence
- Antibodies, Monoclonal/metabolism
- Autoantigens/blood
- Autoantigens/genetics
- Autoantigens/immunology
- Autoantigens/metabolism
- Cell Extracts
- Cell Line, Tumor
- Chromatography, Affinity
- Cloning, Molecular
- Hepatitis, Autoimmune/blood
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/metabolism
- Hepatocytes/immunology
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Humans
- Mass Spectrometry
- Molecular Sequence Data
- Peptide Fragments/blood
- Peptide Fragments/genetics
- Peptide Fragments/immunology
- Peptide Fragments/metabolism
- RNA, Transfer, Amino Acyl/blood
- RNA, Transfer, Amino Acyl/genetics
- RNA, Transfer, Amino Acyl/immunology
- RNA, Transfer, Amino Acyl/metabolism
- Recombinant Proteins/blood
- Recombinant Proteins/genetics
- Recombinant Proteins/immunology
- Recombinant Proteins/metabolism
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Affiliation(s)
- Martin Volkmann
- Labor Prof. Dr. H.-P. Seelig und Kollegen, Karlsruhe, Germany.
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Zhang Y, Xiao X, Li X, Wei H. Rapamycin prevents concanavalin A-induced liver injury by inhibiting lymphocyte activation. J Gastroenterol Hepatol 2009; 24:1457-62. [PMID: 19496899 DOI: 10.1111/j.1440-1746.2009.05866.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Liver injury induced by concanavalin A (Con A) is often used as a model to study the pathophysiology of immune mediated liver injury. Rapamycin (Rapa) is an effective immunosuppressant widely used for preventing immune activation and transplant rejection. However, the effect of Rapa on liver injury caused by Con A has not been carefully examined. In the present study, we examined the effect of Rapa on liver injury caused by Con A. METHODS Mice received intraperitoneal Rapa injection before Con A intravenous administration. The liver injury was examined by measuring serum transaminase and pathology, and the level of cytokines was detected by enzyme linked immunosorbent assay (ELISA). RESULTS In the present study, we examined the effect of Rapa on liver injury after Con A injection in mice. We found that the treatment of mice with Rapa protected the liver from Con A-induced injury. Pretreatment with Rapa dramatically ameliorated Con A-induced mortality. This protection was associated with reduced transaminase levels in the blood and further confirmed by liver histology. ELISA showed that Rapa suppressed pro-inflammatory cytokines IFN-gamma and TNF-alpha production as compared with the untreated controls. Furthermore, intrahepatic lymphocyte proliferation was significantly inhibited. CONCLUSION These findings suggested that Rapa has the therapeutic potential for treatment of immune-mediated liver injury in the clinic.
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Affiliation(s)
- Yuanqing Zhang
- Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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Eyraud V, Chazouilleres O, Ballot E, Corpechot C, Poupon R, Johanet C. Significance of antibodies to soluble liver antigen/liver pancreas: a large French study. Liver Int 2009; 29:857-64. [PMID: 19302185 DOI: 10.1111/j.1478-3231.2009.01986.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Antibodies to soluble liver antigen (SLA)/liver pancreas (LP) are generally considered as highly specific diagnostic markers of type 1 auto-immune hepatitis (AIH-1), and are particularly useful in patients without conventional antibodies. However, the presence of anti-SLA/LP in type 2 auto-immune hepatitis (AIH-2), primary sclerosing cholangitis (PSC) and hepatitis C has recently been reported. The aim was thus to describe the characteristics of anti-SLA/LP-positive patients in the largest series reported to date. METHODS Sera were selected from the period between 1998 and 2005, based on the presence of antibodies to SLA/LP detected by two methods. The clinical status of patients was determined from their medical records. RESULTS Eighty-one anti-SLA/LP-positive patients with available clinical data were included: 89% (72/81) had a diagnosis of AIH-1, including 10 (12%) associated with cholestatic diseases (primary biliary cirrhosis in seven cases and PSC in three cases). Six patients (7%) suffered from another liver disease: hepatitis C (n=3) and drug-induced hepatitis (n=3). No specific diagnosis was made in three patients. CONCLUSIONS Antibodies to SLA/LP are of a major diagnostic value for AIH-1, including paediatric forms and overlap syndromes with cholestatic diseases, but are not found in association with anti-liver/kidney/microsome type 1 or antibodies to liver cytosol type 1. They are rarely present in other liver diseases such as hepatitis C and drug-induced hepatitis.
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Affiliation(s)
- Violaine Eyraud
- AP-HP Hôpital Saint-Antoine, Unité d'Immunologie, Paris, France
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