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Treeful AE, Coffey EL, Friedenberg SG. A scoping review of autoantibodies as biomarkers for canine autoimmune disease. J Vet Intern Med 2022; 36:363-378. [PMID: 35192227 PMCID: PMC8965235 DOI: 10.1111/jvim.16392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 02/06/2022] [Accepted: 02/09/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Autoantibody biomarkers are valuable tools used to diagnose and manage autoimmune diseases in dogs. However, prior publications have raised concerns over a lack of standardization and sufficient validation for the use of biomarkers in veterinary medicine. OBJECTIVES Systematically compile primary research on autoantibody biomarkers for autoimmune disease in dogs, summarize their methodological features, and evaluate their quality; synthesize data supporting their use into a resource for veterinarians and researchers. ANIMALS Not used. METHODS Five indices were searched to identify studies for evaluation: PubMed, CAB Abstracts, Web of Science, Agricola, and SCOPUS. Two independent reviewers (AET and ELC) screened titles and abstracts for exclusion criteria followed by full-text review of remaining articles. Relevant studies were classified based on study objectives (biomarker, epitope, technique). Data on study characteristics and outcomes were synthesized in independent data tables for each classification. RESULTS Ninety-two studies qualified for final analysis (n = 49 biomarker, n = 9 epitope, and n = 34 technique studies). A high degree of heterogeneity in study characteristics and outcomes reporting was observed. Opportunities to strengthen future studies could include: (1) routine use of negative controls, (2) power analyses to inform sample sizes, (3) statistical analyses when appropriate, and (4) multiple detection techniques to confirm results. CONCLUSIONS These findings provide a resource that will allow veterinary clinicians to efficiently evaluate the evidence supporting the use of autoantibody biomarkers, along with the varied methodological approaches used in their development.
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Affiliation(s)
- Amy E. Treeful
- Department of Veterinary Population MedicineCollege of Veterinary Medicine, University of MinnesotaSt. PaulMinnesotaUSA
- Department of Veterinary Clinical SciencesCollege of Veterinary Medicine, University of MinnesotaSt. PaulMinnesotaUSA
| | - Emily L. Coffey
- Department of Veterinary Clinical SciencesCollege of Veterinary Medicine, University of MinnesotaSt. PaulMinnesotaUSA
| | - Steven G. Friedenberg
- Department of Veterinary Clinical SciencesCollege of Veterinary Medicine, University of MinnesotaSt. PaulMinnesotaUSA
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Wu H, Tang S, Zhou M, Xue J, Yu Z, Zhu J. Tim-3 suppresses autoimmune hepatitis via the p38/MKP-1 pathway in Th17 cells. FEBS Open Bio 2021; 11:1406-1416. [PMID: 33728805 PMCID: PMC8091815 DOI: 10.1002/2211-5463.13148] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/01/2021] [Accepted: 03/15/2021] [Indexed: 01/15/2023] Open
Abstract
T‐cell immunoglobulin‐ and mucin‐domain‐containing molecule‐3 (Tim‐3) mediates T‐cell suppression in various autoimmune diseases, such as chronic inflammatory liver disease. However, the regulatory effect of Tim‐3 on Th17 cells in autoimmune hepatitis (AIH) is incompletely understood. Here, we studied the expression and function of Tim‐3 in T cells in AIH patients and in a Con A (concanavalin A)‐induced mouse AIH model. We report that the frequency of CD4+Tim‐3+ T cells in peripheral blood samples of AIH patients was lower than that in the control group. The p38/MKP‐1 and p‐JNK pathways were activated, and the expression of interleukin‐17A protein was elevated in patients with AIH. Furthermore, the extent of pathological damage in the livers of mice with a blocked Tim‐3 signaling pathway (anti‐Tim‐3 group) was markedly increased and correlated with elevated alanine aminotransferase and aspartate aminotransferase levels. In addition, the frequency of CD4+ IL‐17+ T (Th17) cells in the anti‐Tim‐3 group was increased, while that in mice with blocked p38 activity was decreased. Finally, the expression of MKP‐1 (p‐p38) gradually increased in the control, Con A, and anti‐Tim‐3 groups, but the levels of interleukin‐17A were decreased in the p38‐blocked group. In summary, our results suggest that Tim‐3 suppresses AIH by regulating Th17 cells through the p38/MKP‐1 pathway.
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Affiliation(s)
- Hongwei Wu
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
| | - Shiyue Tang
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
| | - Mengya Zhou
- Department of Pathology, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
| | - Jiji Xue
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
| | - Zhenjun Yu
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
| | - Jiansheng Zhu
- Department of Infectious Diseases, Affiliated Taizhou Hospital of Wenzhou Medical University, Linhai, China
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Fedrizzi RS, Coral GP, Mattos AAD, Mattos ÂZD, Tovo CV. EVALUATION OF PATIENTS WITH AUTOIMMUNE HEPATITIS IN A SPECIALIZED OUTPATIENT CLINIC IN SOUTHERN BRAZIL. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:361-365. [PMID: 33237214 DOI: 10.1590/s0004-2803.202000000-69] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 07/22/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by necroinflammation and autoimmune etiology. Studies evaluating the characteristics of patients with AIH are scarce in Brazil. OBJECTIVE Our objective was to evaluate the profile of patients with AIH in a specialized center in Southern Brazil and to verify factors related to treatment response. METHODS this was a retrospective cohort study, which analyzed demographic, epidemiological, clinical, laboratory, and histologic data. Patients with AIH diagnosed according to the criteria of the International Autoimmune Hepatitis Group (IAIHG) were included. In liver biopsies, the degree of fibrosis, histological activity, presence of hepatocyte rosettes, plasma cell infiltrates, and confluent necrosis were evaluated. In the statistical analysis, the significance level was 5%. RESULTS Forty adults patients diagnosed with AIH were included. The evaluated population predominantly consisted of women (75.0%) and the average age at diagnosis was 44.2 years. The association with extrahepatic autoimmune diseases occurred in 20.0% of cases. Clinically, 35.0% of patients presented with acute onset hepatitis, 37.5% with cirrhosis, and 27.5% with other forms of presentation. The most common clinical manifestation was jaundice (47.5%). Thirty-five patients were treated, and of these, 97.1% used prednisone combined with azathioprine. The average treatment time was 2.7 years. Response to treatment was complete or partial in 30 (85.7%) and absent in 5 (14.3%) patients. There was no statistically significant difference when evaluating response to treatment in relation to forms of presentation, histological findings, and the presence of autoantibodies. Regarding fibrosis, regression was observed in 18.75% of the cases. CONCLUSION Most patients with AIH were young at presentation and of female sex. The association with extrahepatic autoimmune diseases and cirrhosis at presentation was seen in a considerable proportion of patients. Treatment was effective, but there were no clinical, histological or serological parameters capable of predicting treatment response.
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Affiliation(s)
- Renata S Fedrizzi
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Gabriela P Coral
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Angelo A de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Ângelo Z de Mattos
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
| | - Cristiane V Tovo
- Universidade Federal de Ciências da Saúde de Porto Alegre, Programa de Pós-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brasil
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Khayeka-Wandabwa C, Ma X, Cao X, Nunna V, Pathak JL, Bernhardt R, Cai P, Bureik M. Plasma membrane localization of CYP4Z1 and CYP19A1 and the detection of anti-CYP19A1 autoantibodies in humans. Int Immunopharmacol 2019; 73:64-71. [PMID: 31082724 DOI: 10.1016/j.intimp.2019.05.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Revised: 04/14/2019] [Accepted: 05/02/2019] [Indexed: 12/15/2022]
Abstract
It is thought that autoantibody (aAb) production can be caused by (aberrant) protein targeting to the plasma surface of cells. We recently demonstrated the presence of the human cytochrome P450 enzyme CYP4Z1 on the plasma membrane of MCF-7 breast cancer cells and the detection of high titers of anti-CYP4Z1 aAbs in breast cancer patients, but not in healthy controls. In the present study we show that cells of the normal breast cell line MCF-10A do not display CYP4Z1 on their surface. By contrast, we detected CYP19A1 (aromatase) on the plasma membrane of both cell lines. Interestingly, the presence of CYPs on the cell surface did not correlate with their relative expression levels in these cell lines. Indirect ELISA experiments demonstrated the presence of anti-CYP19A1 aAbs in female breast cancer patient sera as well as in male and female controls, respectively; aAb titers in all three groups varied considerably and overall, the results obtained for each group were not significantly different from those of either of the other two groups. Based on these data we propose the hypothesis that CYP translocation to the plasma membrane, but not the intracellular expression level, is the crucial precondition for the generation of anti-CYP aAbs.
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Affiliation(s)
- Christopher Khayeka-Wandabwa
- School of Pharmaceutical Science and Technology (SPST), Health Science Platform, Tianjin University, Tianjin, China
| | - Xiaoshuang Ma
- School of Pharmaceutical Science and Technology (SPST), Health Science Platform, Tianjin University, Tianjin, China
| | - Xiaolin Cao
- School of Pharmaceutical Science and Technology (SPST), Health Science Platform, Tianjin University, Tianjin, China
| | - Venkatrao Nunna
- School of Pharmaceutical Science and Technology (SPST), Health Science Platform, Tianjin University, Tianjin, China
| | - Janak L Pathak
- School of Pharmaceutical Science and Technology (SPST), Health Science Platform, Tianjin University, Tianjin, China
| | - Rita Bernhardt
- Institute of Biochemistry, Saarland University, Saarbruecken, Germany
| | - Pengcheng Cai
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Matthias Bureik
- School of Pharmaceutical Science and Technology (SPST), Health Science Platform, Tianjin University, Tianjin, China.
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Elalfy H, El-Maksoud MA, Abed S, El Aziz MA, Elsamanoudy AZ, Abo El-Khair SM, Mohamed MA, Elkashef W, Zalata K, Farag R, Arafa M. Clinicopathological impact of anti-smooth muscle antibodies in patients with non-alcoholic fatty liver disease. Br J Biomed Sci 2019; 76:101-103. [PMID: 30700210 DOI: 10.1080/09674845.2019.1575532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 01/05/2019] [Indexed: 01/21/2023]
Affiliation(s)
- H Elalfy
- a Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - M A El-Maksoud
- a Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - S Abed
- a Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - M A El Aziz
- a Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - A Z Elsamanoudy
- b Department of Medical Biochemistry and Molecular biology, Faculty of Medicine , Mansoura University , Mansoura , Egypt
- c Department of Clinical Biochemistry, Faculty of Medicine , King Abdulaziz University , Saudi Arabia
| | - S M Abo El-Khair
- d Department of Medical Biochemistry and Molecular biology, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - M A Mohamed
- e Pathology Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - W Elkashef
- e Pathology Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - K Zalata
- e Pathology Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - R Farag
- a Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - M Arafa
- a Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
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Missoum H, Alami M, Bachir F, Arji N, Bouyahya A, Rhajaoui M, El Aouad R, Bakri Y. Prevalence of autoimmune diseases and clinical significance of autoantibody profile: Data from National Institute of Hygiene in Rabat, Morocco. Hum Immunol 2019; 80:523-532. [PMID: 30807792 DOI: 10.1016/j.humimm.2019.02.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/15/2019] [Accepted: 02/22/2019] [Indexed: 12/19/2022]
Abstract
AIM The objective of this study was to explore the prevalence of various autoimmune diseases (AIDs) in a large cohort of patients and to characterize the autoantibody profile in the patients with and without AIDs to confirm the diagnosis and to refine the Moroccan databases. PATIENTS AND METHOD Retrospective study was conducted in the Laboratory of autoimmunity National Institute of Hygiene (NIH) of Rabat in Morocco. A total of 3182 consecutive Moroccan patients (2183 females and 999 males) whose sera were tested for 14 autoantibody profile between 2010 and 2016. RESULTS Only 944 (29.7%) patients were diagnosed with AIDs of those suspected. The prevalence of systemic lupus erythematosus (SLE), intestinal malabsorption (IM) and arthritis polyarthralgia (AP) were the highest (4.2, 4.1 and 4%), subsequently followed by rheumatoid arthritis (RA) (2.8%), cholestatic syndrome (CS) (1.8%), interstitial lung disease (ILD) (1.6%).In females IM, AP and SLE also showed the highest prevalence (5.4%, 5.3% and 4.9% respectively), while of male, SLE showed the highest prevalence (1.9%). The prevalence of ANA was increased in most patients with systemic especially in neuropathy (NP), hemolytic anemia (HA), primary Sjogren's syndrome (pSS), dermatomyositis (DM), thrombocytopenia (Tb), systemic sclerosis (SSc), ANCA-associated vasculitis (AAV), AP, Renal impairment (RI), SLE, and mixed connective tissue disease (MCTD). Anti-dsDNA antibodies were higher in SLE and ENA showed the highest titers in MCTD. Others are relatively specific for certain disease, such as anti β2GP1 for thrombosis syndrome, anti ANCA for primary sclerosing cholangitis (PSC), AAV, ILD and RI, anti CCP2 for RA, ILD and AP. the prevalence of anti AMA was higher in primary biliary cirrhosis (PBC), followed in CS, also, ANA have been identified in up to 25% of patients with primary biliary cirrhosis. The prevalence of anti-SMA was higher in PBC, treated patients for Chronic hepatitis C (HCV), and autoimmune hepatitis (AIH) and anti-PCA was higher in biermer anemia patients with vitamin B12 deficiency (BA/Def vit B12). The prevalence of IgA EMA, IgA tTG and IgA AGA were higher in patients IM and celiac disease (CD). The prevalence of anti thyroperoxidase (TPO) was significantly increased in the autoimmune thyroiditis (AIT). CONCLUSION Our study shows the diagnostic value of auto antibodies in AIDs. It would be interesting to carry out prospective studies on each pathology separately, in order to fill the classic vagaries of the retrospective study and objectively estimate the prevalence in different AIDs. These data on the prevalence of each autoimmune disease are valuable for the public health system.
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Affiliation(s)
- Hakima Missoum
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco; Laboratory Autoimmunity, Department of Immunology, National Institute of Hygiene, Rabat, Morocco.
| | - Mohammed Alami
- Laboratory of Microbiology and Molecular Biology, Faculty of Science, Mohammed V University, Rabat, Morocco
| | | | - Naima Arji
- National Institute of Hygiene, Rabat, Morocco
| | - Abdelhakim Bouyahya
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco
| | | | - Rajae El Aouad
- Hassan II Academy of Science and Technology Rabat, Morocco
| | - Youssef Bakri
- Laboratory of Human Pathologies Biology, Department of Biology, Faculty of Sciences, and Genomic Center of Human Pathologies, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco
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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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Mitra S, Minz RW. Autoantibodies in Autoimmune Liver Diseases-Methods of Detection and Interpretation: An Update for the Reporting Pathologist. Int J Surg Pathol 2016; 24:576-85. [PMID: 27388199 DOI: 10.1177/1066896916657643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Autoimmune liver disease (AILD) is a type of chronic liver disease with autoimmune etiology. The diagnosis of the disease is multipronged and detection of autoantibodies in AILDs is an important diagnostic tool and it also helps in the classification of the disease. There are multiple autoantibodies that are detected in AILDs but none is diagnostic. Moreover, these autoantibodies are detected in many other pathological and nonpathological conditions. So the significance of seropositivity for these autoantibodies should be known by both the pathologists as well as the clinicians. In addition, there is prognostic significance associated with some of the antibodies and they also sometimes help in the disease monitoring. The whole array of antibodies detected in AILDs is discussed in detail in this review along with their clinical significance and interpretation.
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Affiliation(s)
- Suvradeep Mitra
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
| | - Ranjana Walker Minz
- PGIMER (Post-Graduate Institute of Medical Education and Research), Chandigarh, India
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9
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Maeda Y, Migita K, Higuchi O, Mukaino A, Furukawa H, Komori A, Nakamura M, Hashimoto S, Nagaoka S, Abiru S, Yatsuhashi H, Matsuo H, Kawakami A, Yasunami M, Nakane S. Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population. PLoS One 2016; 11:e0146048. [PMID: 26807576 PMCID: PMC4726510 DOI: 10.1371/journal.pone.0146048] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 11/24/2015] [Indexed: 11/25/2022] Open
Abstract
Background/Aims Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies. Methodology/Principal Findings Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies. Methodology/ Methods We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies. Conclusions/Significance The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR.
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Affiliation(s)
- Yasuhiro Maeda
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan.,Department of Neuroimmunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kiyoshi Migita
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Osamu Higuchi
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan
| | - Akihiro Mukaino
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan
| | - Hiroshi Furukawa
- Department of Molecular and Genetic Epidemiology, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Atsumasa Komori
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
| | - Satoru Hashimoto
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Shinya Nagaoka
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Seigo Abiru
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hidenori Matsuo
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan
| | - Atsushi Kawakami
- First Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
| | - Michio Yasunami
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Shunya Nakane
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
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Furumoto Y, Asano T, Sugita T, Abe H, Chuganji Y, Fujiki K, Sakata A, Aizawa Y. Evaluation of the role of HLA-DR antigens in Japanese type 1 autoimmune hepatitis. BMC Gastroenterol 2015; 15:144. [PMID: 26489422 PMCID: PMC4618735 DOI: 10.1186/s12876-015-0360-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 10/01/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The role of HLA-DR antigens in the clinicopathological features of autoimmune hepatitis (AIH) is not clearly understood. We examined the implications of HLA-DR antigens in Japanese AIH, including the effect of HLA-DR4 on the age and pattern of AIH onset, clinicopathological features, and treatment efficacy. METHODS A total of 132 AIH patients consecutively diagnosed and treated in 2000-2014 at 2 major hepatology centers of eastern Tokyo district were the subjects of this study. The frequency of HLA-DR phenotypes was compared with that in the healthy Japanese population. AIH patients were divided into HLA-DR4-positive or HLA-DR4-negative groups and further sub-classified into elderly and young-to-middle-aged groups, and differences in clinical and histological features were examined. Clinical features associated with the response to immunosuppressive therapy were also determined. RESULTS The frequency of the HLA-DR4 phenotype was significantly higher in AIH than in control subjects (59.7 % vs. 41.8 %, P < 0.001), and the relative risk was 2.14 (95 % CI; 1.51-3.04). HLA-DR4-positive AIH patients were younger than HLA-DR4-negative patients (P = 0.034). Serum IgG and IgM levels were higher (P < 0.001 and P = 0.007, respectively) in HLA-DR4-positive patients. These differences were more prominent in elderly AIH patients. However, there was no difference in IgG and IgM levels between HLA-DR4-positive and HLA-DR4-negative patients of the young-to-middle-aged group. There were no differences in the histological features. In patients with refractory to immunosuppressive therapy, higher total bilirubin, longer prothrombin time, lower serum albumin, and lower platelet count were found. Imaging revealed splenomegaly to be more frequent in refractory patients than in non-refractory patients (60.0 % vs. 30.8 %, P = 0.038). HLA-DR phenotype distribution was similar regardless of response to immunosuppressive therapy. CONCLUSIONS HLA-DR4 was the only DR antigen significantly associated with Japanese AIH. The clinical features of HLA-DR4-positive AIH differed between elderly patients and young-to-middle-aged patients. Treatment response depended on the severity of liver dysfunction but not on HLA-DR antigens.
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Affiliation(s)
- Yohei Furumoto
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Toru Asano
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Tomonori Sugita
- Department of Gastroenterology and Hepatology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| | - Hiroshi Abe
- Department of Gastroenterology and Hepatology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| | - Yoshimichi Chuganji
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Kazuhiko Fujiki
- Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, 4-23-15 Kotobashi, Sumida, Tokyo, Japan.
| | - Akihiko Sakata
- Department of Pathology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
| | - Yoshio Aizawa
- Department of Gastroenterology and Hepatology, the Jikei University School of Medicine Katsushika Medical Center, Tokyo, Japan.
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Sener AG. Autoantibodies in autoimmune liver diseases. APMIS 2015; 123:915-9. [DOI: 10.1111/apm.12442] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 08/03/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Asli Gamze Sener
- Medical Microbiology Department; Izmir Katip Celebi University; Ataturk Training and Research Hospital; Izmir Turkey
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12
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Liberal R, Vergani D, Mieli-Vergani G. Update on Autoimmune Hepatitis. J Clin Transl Hepatol 2015; 3:42-52. [PMID: 26357634 PMCID: PMC4542083 DOI: 10.14218/jcth.2014.00032] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 12/08/2014] [Accepted: 12/08/2014] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH), a liver disorder affecting both children and adults, is characterized by inflammatory liver histology, elevated transaminase levels, circulating nonorganspecific autoantibodies, and increased levels of immunoglobulin G, in the absence of a known etiology. Two types of AIH are recognized according to seropositivity: smooth muscle antibody and/or antinuclear antibody define AIH type 1 and antibodies to liver-kidney microsome type 1 and/or liver cytosol type 1 define AIH type 2. AIH type 1 affects both adults and children, while AIH type 2 is mainly a paediatric disease, though it does occasionally affects young adults. AIH should be considered during the diagnostic workup of any patient with increased liver enzyme levels. AIH is exquisitely responsive to immunosuppressive treatment with prednisolone with or without azathioprine, with symptom free long-term survival for the majority of patients. For those who do not respond to standard treatment, or who are difficult-to-treat, mycophenolate mofetil and, in the absence of a response, calcineurin inhibitors should be tried in addition to steroids. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4 T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigenspecific regulatory T-cells, which ultimately aim at restoring tolerance to liver-derived antigens.
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Affiliation(s)
- Rodrigo Liberal
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Diego Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI & Nutrition Centre and Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK
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13
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Ferucci ED, Choromanski TL, Hurlburt KJ, Livingston S, Plotnik J, Manns MP, McMahon BJ, James JA. Autoimmune hepatitis in the Alaska Native population: autoantibody profile and HLA associations. Liver Int 2014; 34:1241-9. [PMID: 24939565 DOI: 10.1111/liv.12372] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Accepted: 10/27/2013] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS The Alaska Native population is one of few populations in the world with a high prevalence of autoimmune hepatitis. The objective of this study was to determine the frequency and HLA and clinical associations of autoantibodies in Alaska Native people with autoimmune hepatitis. METHODS Alaska Native individuals with autoimmune hepatitis were recruited in clinics conducted statewide. Sera were tested for the presence of autoantibodies described in either autoimmune hepatitis or rheumatic disease. Associations between autoantibodies and HLA alleles and clinical features were assessed. RESULTS Seventy-one patients were included. At the study visit, 34 patients (47.9%) had antibodies to double-stranded DNA by immunofluorescence; 27 (38.0%) had anti-neutrophil cytoplasmic antibodies; and 11 (15.5%) had anti-Ro antibodies. Only one person had antibodies against soluble liver antigen, and in that person, anti-Ro was absent. Associations were found between autoantibodies and HLA alleles, including positive associations between HLA DR3 and anti-double-stranded DNA antibodies and between HLA DR14 and antineutrophil cytoplasmic antibodies. There was no association between autoantibodies and clinical outcomes. CONCLUSIONS As in other populations, the prevalence of anti-double-stranded DNA antibodies and antineutrophil cytoplasmic antibodies is high in Alaska Native people with autoimmune hepatitis. In contrast to data from other populations, there is a lower prevalence of anti-soluble liver antigen and a lack of association between anti-Ro and anti-soluble liver antigen. In addition, the HLA profile and associations with autoantibodies are unique. No clear prognostic implications of autoantibodies have emerged in this population.
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Affiliation(s)
- Elizabeth D Ferucci
- Division of Community Health Services, Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
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14
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Liberal R, Grant CR, Sakkas L, Bizzaro N, Bogdanos DP. Diagnostic and clinical significance of anti-centromere antibodies in primary biliary cirrhosis. Clin Res Hepatol Gastroenterol 2013; 37:572-85. [PMID: 23876351 DOI: 10.1016/j.clinre.2013.04.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 03/31/2013] [Accepted: 04/23/2013] [Indexed: 02/04/2023]
Abstract
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterised by biochemical evidence of cholestasis, elevated alkaline phosphatase levels and the presence of the highly disease specific anti-mitochondrial autoantibodies. Extra-hepatic autoimmune manifestations are common, including rheumatic disorders, such as systemic sclerosis (SSc). Notably, PBC is the most frequent autoimmune liver disease in SSc patients. Based on skin lesion extension, two major SSc disease subgroups are recognised: limited cutaneous SSc (lSSc) and diffuse cutaneous SSc. Anti-centromere antibody (ACA) positivity is highly characteristic of SSc, with up to 90% prevalence in lSSc patients. ACA has also been found in up to 30% of PBC patients and 80% of patients with a PBC/SSc overlap syndrome. The diagnostic and clinical significance of ACA positivity in patients with PBC without SSc has recently been under investigation, with several studies highlighting links to severe bile duct injury and portal hypertension. This review discusses the diagnostic and clinical relevance of ACA in patients with PBC, with or without SSc.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill Campus, London SE5 9RS, UK; Faculty of Medicine, University of Porto, Porto, Portugal.
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15
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Liberal R, Mieli-Vergani G, Vergani D. Clinical significance of autoantibodies in autoimmune hepatitis. J Autoimmun 2013; 46:17-24. [DOI: 10.1016/j.jaut.2013.08.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 08/04/2013] [Indexed: 01/14/2023]
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16
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Tang J, Lu J, Yan HP. Diagnostic and predictive significance of autoantibody profiles in autoimmune liver disease. Shijie Huaren Xiaohua Zazhi 2013; 21:2544-2550. [DOI: 10.11569/wcjd.v21.i25.2544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [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
Autoimmune liver disease (AILD) is a chronic inflammatory disease presumably induced by a disorder of immune homeostasis within the liver, which can lead to damage to or loss of the hepatic parenchyma or bile duct epithelia. Indirect immunofluorescence and antibody specificity assays are important tools for the diagnosis of AILD. Over the last decade, there have been an increasing number of newly characterized target antigens for autoantibodies in AILD. Autoantibodies, as biomarkers, are used not only for disease diagnosis, but also for monitoring disease activity and progression and predicting prognosis and treatment responses.
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17
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Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: A comprehensive review. J Autoimmun 2013; 41:126-39. [DOI: 10.1016/j.jaut.2012.11.002] [Citation(s) in RCA: 147] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Accepted: 11/05/2012] [Indexed: 12/12/2022]
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Himoto T, Nishioka M. Autoantibodies in liver disease: important clues for the diagnosis, disease activity and prognosis. AUTOIMMUNITY HIGHLIGHTS 2013; 4:39-53. [PMID: 26000142 PMCID: PMC4389052 DOI: 10.1007/s13317-013-0046-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 01/18/2013] [Indexed: 12/18/2022]
Abstract
It has been well established that numerous kinds of autoantibodies have been detected in liver disease. Some kinds of autoantibodies may be helpful in the diagnosis of autoimmune liver diseases including autoimmune hepatitis, primary biliary cirrhosis or primary sclerosing cholangitis. However, these autoantibodies are present even in sera of patients with viral hepatitis, drug-induced hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease and hepatocelluar carcinoma as well as in sera of patients with autoimmune liver diseases. Other kinds of autoantibodies are recognized as predictive hallmarks for disease activity or prognosis in liver diseases. On the other hand, treatment with interferon initiates the production of several types of autoantibodies in patients with chronic hepatitis C virus infection. Some of autoantibodies induced by interferon may postulate the treatment outcome in those patients. Recent studies also revealed the close correlation between oxidative stress and the production of autoantibodies in liver diseases. This article primarily reviews the recent advances of autoantibodies in the liver diseases and discusses the clinical significance of these autoantibodies.
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Affiliation(s)
- Takashi Himoto
- Department of Integrated Medicine, Kagawa University School of Medicine, Kagawa, 761-0793 Japan ; Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, 761-0793 Japan
| | - Mikio Nishioka
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa, 761-0793 Japan
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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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20
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Pereira TC, Saron MLG, Carvalho WAD, Vilela MM, Hoehr NF, Hessel G. Research on zinc blood levels and nutritional status in adolescents with autoimmune hepatitis. ARQUIVOS DE GASTROENTEROLOGIA 2011; 48:62-5. [PMID: 21537545 DOI: 10.1590/s0004-28032011000100013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Accepted: 09/21/2010] [Indexed: 11/22/2022]
Abstract
CONTEXT Zinc deficiency in children and adolescents impairs their growing, development and immune system. OBJECTIVES To verify the existence of plasma and leukocyte zinc deficiency in adolescents with autoimmune hepatitis. METHODS The study comprised 23 patients with autoimmune hepatitis, aged 10-18 years, assisted at the Ambulatory Service of Pediatric Hepatology of the University of Campinas Teaching Hospital, Campinas, SP, Brazil, and adolescents with ages compatible with the patients' ages comprised the control group. Sample of blood in both groups was collected for the analyses of plasma zinc and leukocyte zinc by atomic absorption spectrophotometry, beyond the nutritional status was evaluated in each adolescent. The following statistical tests were used: Mann-Whitney, Spearman's correlation and interclass concordance analysis. RESULTS The significance level adopted was 5%. The average zinc level in plasma in patients was 71.91 ± 11.79 µg/dL and, in the control group, it was 80.74 ± 10.92 µg/dL, showing a significant difference (P = 0.04). The leukocyte zinc level in patients was 222.33 ± 166.13 pmol/10⁶ cells and, in the control group, it was 226.64 ± 217.81 pmol/10⁶ cells; there was no statistical significance between them (P = 0.45). CONCLUSION The evaluation of the nutritional status showed that eutrophy is prevalent in patients, and they presented a higher body fat value than the control group, with a significant difference. More research is needed with adolescents with autoimmune hepatitis regarding levels of essential micronutrients, such as zinc, because a good nutritional status can improve the prognostic of liver disease.
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21
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Sutti S, Vidali M, Mombello C, Sartori M, Albano E. Conformational anti-cytochrome P4502E1 (CYP2E1) auto-antibodies contribute to necro-inflammatory injury in chronic hepatitis C. J Viral Hepat 2010; 17:685-690. [PMID: 20738774 DOI: 10.1111/j.1365-2893.2010.01359.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Circulating auto-antibodies against cytochrome P4502E1 (CYP2E1) have been observed in a significant fraction of patients with chronic hepatitis C (CHC). This study investigated the clinical significance of these auto-antibodies in relation to their antigen specificity. The presence of anti-CYP2E1 IgG was investigated in 137 consecutive patients with biopsy-proven CHC. Anti-CYP2E1 IgG above control threshold levels was detected in 52 (38%) subjects. By combined immunoprecipitation and western blotting, we observed that among anti-CYP2E1 IgG-positive sera, 23 (44%) were unreactive towards denaturated CYP2E1, indicating a prevalent recognition of conformational CYP2E1 antigens. Conformational anti-CYP2E1 auto-antibodies were unrelated to circulating gamma-globulins, alcohol intake or infection by specific HCV genotypes. The presence of anti-CYP2E1 auto-antibodies was associated with an 11-fold (OR 10.9 95%CI 1.4-86.6 P = 0.008) increased prevalence of necro-inflammatory grading ≥ 4 (Ishack's criteria) and 4-fold (OR 4.0; 95%CI 1.3-11-7: P = 0.014) increased prevalence of fibrosis staging ≥ 2, respectively. Multivariate analysis confirmed conformational anti-CYP2E1 IgG (P = 0.005) and age (P = 0.033) as independent predictors of necro-inflammatory grading ≥ 4. The development of anti-CYP2E1 auto-antibodies targeting conformational CYP2E1 epitopes is associated with more severe liver damage in CHC.
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Affiliation(s)
- S Sutti
- Department of Medical Sciences and Interdisciplinary Research Centre for Autoimmune Diseases (IRCAD), University Amedeo Avogadro of East Piedmont, Novara, Italy
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22
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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: 20] [Impact Index Per Article: 1.3] [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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23
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Czaja AJ. Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis. Dig Dis Sci 2010; 55:2712-26. [PMID: 20108036 DOI: 10.1007/s10620-009-1122-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2009] [Accepted: 12/28/2009] [Indexed: 02/08/2023]
Abstract
Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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24
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Sutti S, Vidali M, Mombello C, Sartori M, Ingelman-Sundberg M, Albano E. Breaking self-tolerance toward cytochrome P4502E1 (CYP2E1) in chronic hepatitis C: possible role for molecular mimicry. J Hepatol 2010; 53:431-438. [PMID: 20576306 DOI: 10.1016/j.jhep.2010.03.030] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Revised: 03/09/2010] [Accepted: 03/22/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Circulating auto-antibodies targeting conformational antigens on cytochrome P4502E1 (CYP2E1) are detectable in patients with chronic hepatitis C (CHC) and are associated with more severe necro-inflammation. This study investigated the antigen specificity and the possible origin of these auto-antibodies. METHODS CYP2E1 site-directed mutagenesis and molecular simulation were used to characterize the epitope specificity of CHC-associated anti-CYP2E1 auto-antibodies. RESULTS Immunoprecipitation experiments using differently mutated human CYP2E1s revealed that conformational anti-CYP2E1 antibodies targeted two epitopes located on the molecule surface in an area between Lys(324)-Glu(346) at J-K'' helices overlapping. Such epitopes were not recognized by the sera targeting linear CYP2E1 antigens. The CYP2E1(324-346) peptide showed good homology with two sequences (NS5b(438-449) and NS5b(456-465)) within the NS5b protein of hepatitis C virus (HCV). Consistently, conformational anti-CYP2E1 IgG bind to GST-conjugated NS5b(438-449) and NS5b(456-465) more efficiently than those recognizing CYP2E1 linear antigens. Competition experiments confirmed the cross-reactivity of conformational anti-CYP2E1 IgG with both NS5b(438-449) and NS5b(456-465). Moreover, mice immunized with GST-conjugated NS5b(438-449) or NS5b(456-465) peptides developed antibodies recognizing human CYP2E1. CONCLUSIONS In CHC patients cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.
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Affiliation(s)
- Salvatore Sutti
- Department of Medical Sciences and Interdisciplinary Research Centre for Autoimmune Diseases, University Amedeo Avogadro of East Piedmont Novara, Italy
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25
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Autoantibodies and liver disease: uses and abuses. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2010; 24:225-31. [PMID: 20431809 DOI: 10.1155/2010/431913] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Confirming whether a patient has autoimmune liver disease is challenging, given its varied presentation and complex definitions. In the continued absence of pathognomonic serum markers, diagnosis requires evaluation of laboratory investigations and, frequently, a liver biopsy - all of which need to be interpreted in the correct clinical context, with an emphasis on exclusion of viral infections, drug toxicity and metabolic disease. However, clear diagnosis is important for appropriate and timely therapy. Autoantibodies remain important tools for clinicians, and were the first proposed serological markers to aid in differentiating viral from chronic autoimmune hepatitis. Their presence is occasionally considered to be synonymous with autoimmune liver disease - a misinterpretation of their clinical significance. The present article summarizes the serum autoantibodies currently investigated in clinical and research practice, along with a description of their value in adult chronic liver diseases, with an emphasis on their appropriate use in the diagnosis and management of patients with autoimmune liver disease.
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Antunes H, Rocha R, Silva N, Pontes T, Antunes A, Martins S. Immune disease expressed in liver and platelets in an adolescent: a case report. Ital J Pediatr 2010; 36:42. [PMID: 20540743 PMCID: PMC2892502 DOI: 10.1186/1824-7288-36-42] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2010] [Accepted: 06/11/2010] [Indexed: 11/10/2022] Open
Abstract
We report a case of a 15-year-old boy with autoimmune hepatitis lacking common serologic markers and normal gammaglobulinemia associated with immune thrombocytopenia and family history of psoriasis. He presented to our department with a 4-year history of a cervical posterior lymphadenopathy and recent petechiae. Previous laboratory results 6 months before already showed hepatocellular injury. After exclusion of other causes, the diagnosis of autoimmune hepatitis was made based on clinical grounds, associated immune disorder and histological features of liver biopsy. The authors alert for this atypical presentation of autoimmune hepatitis and associated immune thrombocytopenia.
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Affiliation(s)
- Henedina Antunes
- Adolescents Unit and Gastrenterology, Hepatology and Nutrition Unit, Pediatrics Department, Braga Hospital, and Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
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27
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Andrade LEC. Future perspective for diagnosis in autoimmune diseases. AN ACAD BRAS CIENC 2010; 81:367-80. [PMID: 19722009 DOI: 10.1590/s0001-37652009000300004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Accepted: 09/03/2009] [Indexed: 11/22/2022] Open
Abstract
Human beings have taken successive approaches for the understanding and management of diseases. Initially brewed in supernatural concepts and mystical procedures, a vigorous scientific approach has emerged on the grounds of fundamental disciplines such as anatomy, microbiology, biochemistry, physiology, immunology, pathology, and pharmacology. The resulting integrated knowledge contributed to the current classification of diseases and the way Medicine is carried out today. Despite considerable progress, this approach is rather insufficient when it comes to systemic inflammatory conditions, such as systemic lupus erythematosus, that covers clinical conditions ranging from mild pauci-symptomatic diseases to rapidly fatal conditions. The treatment for such conditions is often insufficient and novel approaches are needed for further progress in these areas of Medicine. A recent breakthrough has been achieved with respect to chronic auto-inflammatory syndromes, in which molecular dissection of underlying gene defects has provided directions for target-oriented therapy. Such approach may be amenable to application in systemic auto-immune diseases with the comprehension that such conditions may be the consequence of interaction of specific environmental stimuli and an array of several and interconnected gene polymorphisms. On the bulk of this transformation, the application of principles of pharmacogenetics may lead the way towards a progressively stronger personalized Medicine.
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Affiliation(s)
- Luis E C Andrade
- Divisão de Reumatologia, Universidade Federal de São Paulo, Escola de Medicina, São Paulo, SP, Brasil.
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Abstract
The etiology of liver disease in childhood varies significantly from its etiology in the adult population. More children with complex diseases are surviving into adulthood, providing challenges to the primary care provider. Adults with pediatric liver disease differ in management, treatment, complications, and extrahepatic considerations. To provide these patients with an optimal transition into the adult health care system, the provider needs a comprehensive knowledge of the common causes of childhood liver disease and their implications and must understand the differences in caring for these patients. This review addresses some of the most common childhood liver diseases, their causes, presentation, evaluation, management, complications, and additional concerns.
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Affiliation(s)
- Michelle Rook
- Pediatric Gastroenterology, Hepatology and Nutrition, University of California San Francisco, 500 Parnassus Avenue, MU4E, Box 0136, San Francisco, CA 94143, USA
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29
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Abstract
Endocrine diseases, such as diabetes mellitus and thyroid dysfunction, have been rarely associated with increased serum transaminase activity. The association of Addison's disease with abnormal liver function tests has received less attention. Addison's disease as a part of autoimmune polyglandular syndrome-1 may be associated with autoimmune hepatitis. Addison's disease may also coexist with celiac disease, an autoimmune disorder commonly associated with hypertransaminasemia. On the other hand, a number of case reports have suggested hypertransaminasemia to be one of the few diagnostic clues to the underlying adrenal insufficiency, allowing the introduction of steroid replacement and obviation of a potential adrenal crisis. We performed a thorough literature review on the prevalence and pathogenesis of hypertransaminasemia as a feature of Addison's disease in an attempt to highlight an as yet under-recognized association.
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Affiliation(s)
- George Kalambokis
- a Lecturer of Internal Medicine, Department of Internal Medicine, School of Medicine, University of Ioannina, 451 10, Ioannina, Greece
| | - Haralampos J Milionis
- b Assistant Professor of Internal Medicine, Department of Internal Medicine, School of Medicine, University of Ioannina, 451 10, Ioannina, Greece.
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The use of budesonide in the treatment of autoimmune hepatitis in Canada. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2008; 22:388-92. [PMID: 18414714 DOI: 10.1155/2008/509459] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic inflammatory disease that is successfully treated with prednisone and/or azathioprine immunosuppressive therapy in 70% to 80% of patients. The remaining patients are intolerant or refractory to these standard medications. Budesonide, a synthetic glucocorticoid, undergoes a high degree of first-pass metabolism, reducing its systemic bioavailability, and has a 15-fold greater affinity for the glucocorticoid receptor than prednisolone. Budesonide may be a potentially useful systemic steroid-sparing immunosuppressive agent in the treatment of AIH. OBJECTIVE To review the Canadian experience using budesonide to treat AIH. METHODS Patients with AIH currently or previously treated with budesonide were identified through the Canadian Association for the Study of the Liver membership. Data were collected regarding their clinical and treatment history. RESULTS A total of nine patients were identified. All patients were female, with an average age of 39 years (range 12 to 66 years). The indications for budesonide were adverse side effects of prednisone in two patients, noncompliance with prednisone and azathioprine in one patient and intolerance to azathioprine resulting in prednisone dependence in the remaining six patients. Patients were treated in doses ranging from 9 mg daily to 3 mg every other day for 24 weeks to eight years. Seven of nine patients had a complete response, defined as sustained normalization of the aminotransferase levels. The remaining two patients were classified as nonresponders (less than a 50% reduction in pretreatment aminotransferase levels). CONCLUSIONS In Canada, budesonide has been successfully used in seven of nine patients with autoimmune hepatitis who were either intolerant to prednisone and azathioprine or prednisone-dependent. No adverse effects were reported with budesonide. Budesonide is potentially a valuable treatment option for AIH patients refractory or intolerant to standard therapy, and is deserving of further study.
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Seo S, Toutounjian R, Conrad A, Blatt L, Tong MJ. Favorable outcomes of autoimmune hepatitis in a community clinic setting. J Gastroenterol Hepatol 2008; 23:1410-4. [PMID: 18373564 DOI: 10.1111/j.1440-1746.2008.05365.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM Autoimmune hepatitis (AIH) is an idiopathic disease with diverse clinical manifestations. The aims of the present study were: (i) to describe the clinical characteristics of AIH patients in a community clinic setting; and (ii) to determine factors which were associated with poor clinical outcomes. METHODS A retrospective review was performed on 72 AIH patients who: (i) had pretreatment sera: (ii) were treatment-naïve at presentation; and (iii) had a minimum of 24 months of follow up. RESULTS On initial presentation, 22 (30%) had an acute onset of symptoms simulating acute viral hepatitis, 34 (47%) had chronic symptoms of greater than 6 months duration, and the remaining 16 (22%) were asymptomatic. Twenty-six (36%) had coexisting autoimmune diseases. Anti-nuclear antibody (ANA) was positive in 73% of the patients, and antismooth muscle antibody was positive in 15% of ANA-negative patients. Those few patients who tested positive for soluble liver antigen, anti-liver-kidney, microsomal antibody type-1, and anti-mitochondrial antibody were all also ANA positive. The median (range) duration of follow up was 98 (24-331) months. After immunosuppressive therapy, 26 of 72 (36%) remained in remission without further treatment. However, 46 (64%) required maintenance immunosuppression. Three patients who presented under the age of 20 years progressed to liver failure while on therapy and died while waiting for liver transplantation. Two other patients developed hepatocellular carcinoma (HCC) while on therapy and died. CONCLUSIONS A majority of AIH patients have an excellent prognosis. However, presentation at a younger age is a predictor of poor disease outcome and, although uncommon, HCC may develop during the late stages of cirrhosis.
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Affiliation(s)
- Suk Seo
- Medicine and Surgery, David Geffen School of Medicine at UCLA, The Pfleger Liver Institute, Los Angeles, California 90095-7302, USA.
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Abstract
Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.
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Affiliation(s)
- Teru Kumagi
- Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Abe K, Ohira H, Kobayashi H, Saito H, Takahashi A, Rai T, Kanno Y, Monoe K, Watanabe H, Irisawa A, Sato Y. Breakthrough of immune self-tolerance to calreticulin induced by CpG-oligodeoxynucleotides as adjuvant. Fukushima J Med Sci 2008; 53:95-108. [PMID: 18402289 DOI: 10.5387/fms.53.95] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Reportedly, bacterial DNA containing unmethylated cytosine-guanosine dinucleotide motif-containing oligodeoxynucleotides (CpG-ODNs) can induce Th1-type adjuvant effects. We produced autoantibodies and induced hepatitis in mice using extracted proteins from human hepatocytes with CpG-ODNs as adjuvant. Western blot analysis was performed of sera from immunized mice and two patients with autoimmune hepatitis (AIH). When a common band was detected, N-terminal amino acid sequencing was performed to determine its site. For detection of antibodies against the identified protein (calreticulin), ELISA was performed of sera of 50 patients with AIH: 45 with primary biliary cirrhosis (PBC), 24 with chronic hepatitis C (CH), and 24 healthy controls. Mice were immunized with calreticulin protein with CpG-ODNs as adjuvant. Several reacted bands were detected in their sera; in addition, a common band to the sera of patients with AIH was detected at 60 kDa. Subsequent N-terminal amino acid sequencing revealed that the protein was human calreticulin. ELISA showed that, of patients with AIH, PBC, and CH, 30.0% (15/50), 17.8% (8/45), and 12.5% (3/24), respectively, were positive for anti calreticulin antibodies. Splenocytes from immunized mice produced IFN-gamma after they were pulsed with calreticulin protein. Histological analyses of liver specimens taken from mice immunized with calreticulin protein together with CpG-ODNs showed spotty and focal necrosis. Immunofluorescence analysis showed increased expression of calreticulin in the liver treated with CpG-ODNs. These results suggest that a breakthrough of immune self tolerance to calreticulin is induced with CpG-ODNs as adjuvant and that calreticulin protein might be a target antigen in this model.
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Affiliation(s)
- Kazumichi Abe
- Department of Internal Medicine II, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan
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Xia Q, Lu F, Yan HP, Wang HX, Feng X, Zhao Y, Liu BY, Wang J, Li P, Xue Y, Hu MR, Qian L, Guo N, Yang SC, Li MY, Ma YF, Li BA, Zhang XM, Shen BF. Autoantibody profiling of Chinese patients with autoimmune hepatitis using immunoproteomic analysis. J Proteome Res 2008; 7:1963-70. [PMID: 18355017 DOI: 10.1021/pr700861s] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
In the present study, immunoproteomic analysis was utilized to systemically characterize global autoantibody profiles in autoimmune hepatitis (AIH). Sera from 21 patients with AIH and 15 healthy controls were analyzed for the antibody reactivity against the protein antigens of HepG2, a human hepatoma cell line. The lysates of HepG2 cells were separated by two-dimensional electrophoresis and then immunoblotted with each serum sample. Matrix-assisted laser desorption/ionization mass spectrometry or/and nanoelectrospray ionization MS/MS were then used to identify antigens, among which a bifunctional enzyme in mitochondrial, fumarate hydratase (FH), was further analyzed by ELISA using recombinant FH as a coating antigen. A total of 18 immunoreactive spots were identified as 13 proteins, 8 of which have not been reported in AIH. Immune reactivity to FH was detected in 66.67% of patients with AIH, 19.35% of patients with primary biliary cirrhosis (PBC), 12.31% of patients with chronic hepatitis B (CHB), 6.35% of patients with chronic hepatitis C (CHC), 11.32% of patients with systemic lupus erythematosus (SLE), and 3.57% of normal individuals. The differences of prevalence between AIH patients and healthy controls as well as other diseases were of statistical significance (P<0.001). These data demonstrate the serological heterogeneity in AIH and suggest the diversity of the mechanisms underlying AIH. FH, recognized mainly in AIH rather than in viral hepatitis and other autoimmune diseases, may have utility in improved diagnosis of AIH.
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Affiliation(s)
- Qing Xia
- Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road 27, Beijing 100850, China
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35
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Serum proteomic-based analysis for the identification of a potential serological marker for autoimmune hepatitis. Biochem Biophys Res Commun 2008; 367:284-90. [DOI: 10.1016/j.bbrc.2007.12.075] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2007] [Accepted: 12/13/2007] [Indexed: 11/21/2022]
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Abstract
Chronic liver disease and cirrhosis are the tenth leading causes of death in the United States and results in approximately 25,000 deaths annually. As life expectancy in developed countries has increased, so has the number of elderly patients who have liver disease. With an aging population and chronic liver disease becoming an increasingly significant cause of morbidity and mortality, the various causes for hepatitis will need to be evaluated and available treatments considered, even in elderly population. Common causes for hepatitis in elderly individuals include viral, autoimmune, and drug-induced hepatitis, but evidence for treatment of this population is limited. This article reviews the likely causes of hepatitis in elderly individuals and discusses evidence for treating this population.
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Affiliation(s)
- Omer Junaidi
- Department of Internal Medicine, Saint Louis University School of Medicine, 3635 Vista Avenue, Saint Louis, MO 63110, USA.
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Ma X, Jia YT, Qiu DK. Inhibition of p38 mitogen-activated protein kinase attenuates experimental autoimmune hepatitis: Involvement of nuclear factor kappa B. World J Gastroenterol 2007; 13:4249-54. [PMID: 17696256 PMCID: PMC4250626 DOI: 10.3748/wjg.v13.i31.4249] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of p38 mitogen-activated protein kinase (p38MAPK) in murine experimental autoimmune hepatitis (EAH).
METHODS: To induce EAH, the syngeneic S-100 antigen emulsified in complete Freud's adjuvant was injected intraperitoneally into adult male C57Bl/6 mice. Liver injury was assessed by serum ALT and liver histology. The expression and activity of p38 MAPK were measured by Western blot and kinase activity assays. In addition, DNA binding activities of nuclear factor kappa B (NF-κB) were analyzed by electrophoretic mobility shift assay. The effects of SB203580, a specific p38 MAPK inhibitor, on liver injuries and expression of proinflammatory cytokines (interferon-γ, IL-12, IL-1β and TNF-α) were observed.
RESULTS: The activity of p38 MAPK and NF-κB was increased and reached its peak 14 or 21 d after the first syngeneic S-100 administration. Inhibition of p38 MAPK activation by SB203580 decreased the activation of NF-κB and the expression of proinflammatory cytokines. Moreover, hepatic injuries were improved significantly after SB203580 administration.
CONCLUSION: p38 MAPK and NF-κB play an important role in an animal model of autoimmune hepatitis (AIH) induced by autoantigens.
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Affiliation(s)
- Xiong Ma
- Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200001, China
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Herkel J, Manns MP, Lohse AW. Selenocysteine, soluble liver antigen/liver-pancreas, and autoimmune hepatitis. Hepatology 2007; 46:275-7. [PMID: 17596869 DOI: 10.1002/hep.21807] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Affiliation(s)
- Johannes Herkel
- Department of Medicine I, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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39
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Vidali M, Occhino G, Ivaldi A, Serino R, Moia S, Alchera E, Carini R, Rigamonti C, Sartori M, Albano E. Detection of auto-antibodies against cytochrome P4502E1 (CYP2E1) in chronic hepatitis C. J Hepatol 2007; 46:605-12. [PMID: 17196701 DOI: 10.1016/j.jhep.2006.11.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2006] [Revised: 11/13/2006] [Accepted: 11/21/2006] [Indexed: 12/23/2022]
Abstract
BACKGROUND/AIMS Chronic hepatitis C (CHC) is often associated with auto-immune reactions. In the light of the role of alcohol in promoting CHC progression, we have investigated the possible presence of auto-reactivity against the ethanol-inducible cytochrome P4502E1 (CYP2E1) in CHC patients with and without alcohol consumption. METHODS The IgG reactivity against recombinant human CYP2E1 was evaluated by solid-phase immunoassays in 102 CHC patients with different alcohol consumption and 59 HCV-free controls. RESULTS Auto-antibodies against CYP2E1 were significantly (p<0.0001) increased in CHC patients as compared to controls. Anti-CYP2E1 IgG above the 97th percentile in the controls were evident in 41 (40%) CHC patients. Competition experiments revealed that CYP2E1 recognition was not due to the cross-reactivity with CYP2D6. The detection of anti-CYP2E1 IgG was unrelated to alcohol consumption and no difference in gender, age, aminotransferase levels and virus genotype was evident among the patients with or without anti-CYP2E1 auto-antibodies. However, anti-CYP2E1 auto-reactivity was significantly (p=0.025) associated with the severity of periportal/periseptal interface hepatitis. Moreover, confocal microscopy demonstrated that anti-CYP2E1 IgG associated with CHC recognized CYP2E1 exposed on the outer side of hepatocyte plasma membranes. CONCLUSIONS HCV infection favours the breaking of self-tolerance against CYP2E1 that might contribute to hepatocyte injury.
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Affiliation(s)
- Matteo Vidali
- Department of Medical Sciences, University Amedeo Avogadro of East Piedmont and Interdepartmental Research Centre for Autoimmune Diseases (IRCAD), Novara, Italy
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40
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Sipe WE, Rosenthal P. Autoimmune hepatitis in children: diagnosis, pathology and treatment. Expert Rev Clin Immunol 2007; 3:159-69. [PMID: 20477105 DOI: 10.1586/1744666x.3.2.159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Autoimmune hepatitis (AIH) is characterized by progressive inflammation of the liver and destruction of liver parenchyma. Rare in absolute terms, it is nevertheless an important cause of noninfectious chronic liver disease in children. In many ways, the diagnosis and treatment of children with AIH has changed little over the last 10 years. However, in recent years, steady progress in defining the genetic, immunologic and potential environmental triggers that underlie this disease, in addition to increasing experience with a wider array of therapeutic agents, promises to expand our understanding and ability to treat AIH effectively. This review will summarize the current clinical and pathophysiological understanding of AIH in children, along with therapeutic options.
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Affiliation(s)
- Walter Eb Sipe
- University of California, Division of Pediatric Gastroenterology, Hepatology and Nutrition, 500 Parnassus Avenue, Box 0136, San Francisco, CA 94143-0136, USA.
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Robinson RT, French MA, Kitzmiller TJ, Gorham JD. Restriction of the CD4+ T-cell receptor repertoire prevents immune pathology in TGF-beta1 knockout mice. J Transl Med 2006; 86:815-28. [PMID: 16751781 DOI: 10.1038/labinvest.3700439] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Mice with a targeted deletion in TGF-beta1 spontaneously develop CD4+ T-cell-dependent multifocal inflammatory disease and autoimmune pathology. T cells from TGF-beta1-/- mice are strongly activated, but the mechanisms that lead to T-cell activation and organ pathology are not well understood. Recent work shows that TGF-beta1 raises the threshold for signaling through the TCR, suppressing the response of T cells to mitogenic stimuli. This suggests the possibility that CD4+ T cells in TGF-beta1-/- mice become aberrantly activated and cause damage in response to physiologic inputs that ordinarily are not sufficient for cell activation, such as homeostatic MHC-TCR interactions, cytokines, or adhesion molecules. This model predicts that pathology is largely antigen-independent, and that CD4+ T cells, regardless of antigen specificity, will become activated in TGF-beta1-/- mice, with subsequent organ pathology. To test this model, we crossed BALB/c-TGF-beta1-/- mice with the DO11.10 TCR transgenic mouse. To obviate the possible development of nonclonotypic TCRs, we also bred in a deficiency in RAG-1. Cohorts of highly inbred BALB/c background TGF-beta1-/- mice with an increasingly restricted CD4+ T-cell repertoire (TGF-beta1-/- mice; DO11.10-TGF-beta1-/- mice; DO11.10-RAG-1-/-TGF-beta1-/- mice) were then analyzed for inflammatory organ pathology and T-cell activation. The data show that progressively restricting the CD4+ T-cell repertoire improved survival, ameliorated target organ pathology, and reduced T-cell activation to control levels. Therefore, these results find no support for the involvement of atypical T-cell activation pathways in disease in TGF-beta1-/- mice. Rather, T-cell activation and pathology in TGF-beta1-/- mice appear to be functions of typical TCR activation pathways. This supports the hypothesis that immune pathology in TGF-beta1-/- mice is self-antigen triggered.
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Affiliation(s)
- Richard T Robinson
- Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA
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43
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Sipe WEB, Su M, Posselt A, Kim GE, Quiros JA, Rosenthal P. Propylthiouracil-associated liver failure presenting as probable autoimmune hepatitis in a child with Graves' disease. Pediatr Transplant 2006; 10:525-8. [PMID: 16712616 DOI: 10.1111/j.1399-3046.2006.00487.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.
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Farias AQ, Gonçalves LL, Bittencourt PL, De Melo ES, Abrantes-Lemos CP, Porta G, Nakhle MC, Carrilho FJ, Cancado ELR. Applicability of the IAIHG scoring system to the diagnosis of antimitochondrial/anti-M2 seropositive variant form of autoimmune hepatitis. J Gastroenterol Hepatol 2006; 21:887-93. [PMID: 16704541 DOI: 10.1111/j.1440-1746.2006.04130.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS According to the International Autoimmune Hepatitis Group (IAIHG) criteria, circulating antimitochondrial antibodies (AMA) do not support the diagnosis of autoimmune hepatitis (AIH). The aims of this study were to characterize a subset of patients with AIH who have AMA and antiM2 seropositivity, and to assess the applicability of the revised scoring system of the IAIHG in the diagnosis of this variant form of AIH. METHODS Eighteen patients with AMA-AIH were enrolled and compared with 206 classical AIH and 85 primary biliary cirrhosis (PBC) controls. Human leukocyte antigen (HLA) class II alleles were determined by polymerase chain reaction (PCR) amplification with sequence-specific primers, and biopsies were blindly reevaluated. RESULTS The patients with AMA-AIH were, on average, older than patients with classical AIH and had an hepatocellular pattern of elevated liver enzymes, hypergammaglobulinemia and lower levels of cholesterol, when compared with PBC controls. There were no histological signs of PBC or overlapping forms in any AMA-AIH biopsies. The majority of patients with AMA-AIH carried HLA antigens associated with classical AIH (DRB1*03, n = 5; DRB1*04, n = 7, and DRB1*13, n = 6). Pretreatment scores classified all AMA-AIH patients with probable (n = 17) or improbable (n = 1) AIH. After treatment, only 28% of AMA-AIH patients reached scores for definite diagnosis, compared with 90.1% of AIH-1 and 96.4 AIH-2. In the AMA-AIH group, only patients who relapsed after immunosuppressive drug withdrawal could be classified with definite AIH. CONCLUSIONS AMA-AIH shares common features with classical AIH. The diagnosis of AMA-AIH may be swayed by the IAIHG criteria, rendering questionable the applicability of the revised scoring system to this variant form of AIH.
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Affiliation(s)
- Alberto Queiroz Farias
- Department of Gastroenterology, Institute of Tropical Medicine, Division of Pathology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil.
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Bellomo-Brandão MA, Costa-Pinto EALD, De Tommaso AMA, Hessel G. Clinical and biochemical features of autoimmune hepatitis in 36 pediatric patients. ARQUIVOS DE GASTROENTEROLOGIA 2006; 43:45-9. [PMID: 16699618 DOI: 10.1590/s0004-28032006000100012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND: Few studies on autoimmune hepatitis have enrolled non-Caucasian groups. AIMS: To evaluate Brazilian children with type 1 and 2 autoimmune hepatitis regarding outcome and clinical and biochemical parameters. PATIENTS AND METHODS: Thirty-six patients were submitted to a protocol that evaluated the clinical history, physical and biochemical data, and the course of the disease. Twenty-four children had type 1 autoimmune hepatitis, seven had type 2 and five had unclassified autoimmune hepatitis. Most patients were females (77%), with a median age at diagnosis of 11 years, and the median duration of symptoms was 5.5 and 8 months for types 1 and 2, respectively. Jaundice and choluria were the most common clinical manifestations. RESULTS: Treatment with azathioprine and prednisone was successful in patients with type 1 and 2 autoimmune hepatitis. AST and ALT decreased after 4 to 8 weeks of treatment compared to pretreatment levels in type 1 autoimmune hepatitis. Increased GGT values returned to pretreatment levels after 1 year in the two types. Three patients died and three other patients underwent liver transplantation. CONCLUSIONS: Non-Caucasian children had a similar disease when compared to Caucasian ones with autoimmune hepatitis. Increased levels of GGT during the first year of treatment should not be the only parameter for the indication of cholangiopathy.
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Abstract
In 1950, Waldenström was the first to describe a chronic form of hepatitis in young women. Subsequently, the disease was found to be associated with other autoimmune syndromes and was later termed "lupoid hepatitis" because of the presence of antinuclear antibodies. In 1965, it became designated by Mackay et al. as "autoimmune hepatitis" at an international meeting, at which the general concept of autoimmunity was endorsed by the scientific community. In the early 1960s and 1970s, the value of immunosuppressive therapy with glucocorticoids and/or azathioprine was well documented in several studies. The original association of autoimmune hepatitis (AIH) and HLA alleles, which has remarkably stood the test of time, was published in 1972. In the 1970s and 1980s, several autoantibodies were identified in patients with autoimmune hepatitis directed against proteins of the endoplasmatic reticulum expressed in liver and kidney and against soluble liver antigens. Subsequently, the molecular targets of these antibodies were identified and more precisely characterized. In the last two decades many additional pieces of the AIH puzzle have been collected leading to the identification of additional antibodies and genes associated with AIH and to the emergence of new therapeutic agents. Meanwhile, the immunoserological and genetic heterogeneity of AIH is well established and it has become obvious that clinical manifestations, disease behavior, and treatment outcome may vary by racial groups, geographical regions and genetic predisposition. Currently, the International Autoimmune hepatitis group is endorsing multi-center collaborative studies to more precisely define the features at disease presentation and to define prognostic indices and appropriate treatment algorithms. Given the importance of serological testing, the IAHG is also working on guidelines and procedures for more reliable and standardized testing of autoantibodies.
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Affiliation(s)
- Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
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Abstract
Autoimmune hepatitis (AIH) is an intermittently progressive liver disease characterized by hypergammaglobulinemia, autoantibodies, predominately periportal hepatitis, and a favorable response to corticosteroid therapy in most cases. There are no pathognomonic markers of autoimmune liver disease; rather, the diagnosis must be based on the presence of a constellation of characteristic clinical, laboratory, and histologic features in patients without other causes of such liver pathology. Although prednisone or prednisolone are the mainstays in initial therapy of AIH, azathioprine or other drugs with similar immunosuppressive mechanisms are of benefit for steroid-sparing effects or for use as monotherapy to maintain long-term remission. A fraction of patients meeting diagnostic criteria for AIH remains in long-term remission following withdrawal of immunosuppressive therapies, but in most patients, this disease represents a chronic condition requiring life-long monitoring and therapy.
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Affiliation(s)
- Dwain L Thiele
- Department of Internal Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9151, USA.
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Wiegand J, Schüler A, Kanzler S, Lohse A, Beuers U, Kreisel W, Spengler U, Koletzko S, Jansen PLM, Hochhaus G, Möllmann HW, Pröls M, Manns MP. Budesonide in previously untreated autoimmune hepatitis. Liver Int 2005; 25:927-934. [PMID: 16162148 DOI: 10.1111/j.1478-3231.2005.01122.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic liver disease that is effectively treated with immunosuppressive therapy. Predniso(lo)ne, often in combination with azathioprine, is the basic therapeutic option to induce remission. However, this regimen can cause numerous side effects. The aim of the present study was to evaluate budesonide as a treatment option in the induction of remission in patients with previously untreated AIH. METHODS Between October 1998 and August 1999, 12 patients were treated with 3 mg budesonide thrice daily for 3 months in this open one-arm multicenter phase IIa study. Primary end point was induction of remission indicated by a drop of aspartate aminotransferase and alanine aminotransferase levels below two times the upper limit of normal. RESULTS Seven of the 12 patients (58%) reached complete remission, three patients (25%) had a partial response. Thus, 10/12 individuals (83.3%) responded to therapy. Therapy was tolerated well in 10/12 cases (83.3%). CONCLUSIONS Budesonide monotherapy was effective in the induction of remission and well tolerated in treatment naïve patients with AIH. It should be further evaluated in prospective controlled trials and should be compared to predniso(lo)ne both in monotherapy and in combination with azathioprine.
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Affiliation(s)
- Johannes Wiegand
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
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Zachou K, Rigopoulou E, Dalekos GN. Autoantibodies and autoantigens in autoimmune hepatitis: important tools in clinical practice and to study pathogenesis of the disease. JOURNAL OF AUTOIMMUNE DISEASES 2004; 1:2. [PMID: 15679907 PMCID: PMC544946 DOI: 10.1186/1740-2557-1-2] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2003] [Accepted: 10/15/2004] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver characterized by hypergammaglobulinemia, characteristic autoantibodies, association with HLA DR3 or DR4 and a favorable response to immunosuppressive treatment. The etiology is unknown. The detection of non-organ and liver-related autoantibodies remains the hallmark for the diagnosis of the disease in the absence of viral, metabolic, genetic, and toxic etiology of chronic hepatitis or hepatic injury. The current classification of AIH and the several autoantibodies/target-autoantigens found in this disease are reported. Current aspects on the significance of these markers in the differential diagnosis and the study of pathogenesis of AIH are also stated. AIH is subdivided into two major types; AIH type 1 (AIH-1) and type 2 (AIH-2). AIH-1 is characterized by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Determination of antineutrophil cytoplasmic autoantibodies (ANCA), antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies against to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of patients who are seronegative for ANA/SMA. AIH-2 is characterized by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). Cytochrome P450 2D6 (CYP2D6) has been documented as the major target-autoantigen of anti-LKM-1 autoantibodies in both AIH-2 and HCV infection. Recent convincing data demonstrated the expression of CYP2D6 on the surface of hepatocytes suggesting a pathogenetic role of anti-LKM-1 autoantibodies for the liver damage. Family 1 of UDP-glycuronosyltransferases has been identified as the target-autoantigen of anti-LKM-3. For these reasons the distinction between AIH and chronic viral hepatitis (especially of HCV) is of particular importance. Recently, the molecular target of anti-SLA/LP and anti-LC1 autoantibodies were identified as a 50 kDa UGA-suppressor tRNA-associated protein and a liver specific enzyme, the formiminotransferase cyclodeaminase, respectively. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate closely with disease severity and response to treatment suggesting a pathogenetic role of these autoantibodies for the hepatocellular injury. In general however, autoantibodies should not be used to monitor treatment, predict AIH activity or outcome. Finally, the current aspects on a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) are also given. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies detected in AIH as a disease component of APECED but also in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target-autoantigen of anti-LM autoantibodies in both APECED-related AIH and dihydralazine-induced hepatitis. The latter may indicate that similar autoimmune pathogenetic mechanisms can lead to liver injury in susceptible individuals irrespective of the primary defect. Characterization of the autoantigen-autoantibody repertoire continues to be an attractive and important tool to get access to the correct diagnosis and to gain insight into the as yet unresolved mystery of how hepatic tolerance is given up and AIH ensues.
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Affiliation(s)
- Kalliopi Zachou
- Research Laboratory of Internal Medicine, Department of Medicine, Larissa Medical School, University of Thessaly, Larissa 41222, Greece
| | - Eirini Rigopoulou
- Academic Liver Unit, Department of Medicine, Larissa Medical School, University of Thessaly, Larissa 41222, Greece
| | - George N Dalekos
- Research Laboratory of Internal Medicine, Department of Medicine, Larissa Medical School, University of Thessaly, Larissa 41222, Greece
- Academic Liver Unit, Department of Medicine, Larissa Medical School, University of Thessaly, Larissa 41222, Greece
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Abstract
Autoimmune hepatitis (AIH) remains an enigmatic condition that affects children of all ages. Although much knowledge has emerged over the past four decades regarding autoimmune diseases, the lack of a spontaneous animal model has hindered a more complete understanding of the pathophysiology of AIH. Serum autoimmune markers, combined with biochemical and histologic evidence of hepatocellular injury and absent other diagnostic considerations, are necessary to diagnose AIH. The clinical spectrum ranges from asymptomatic elevation of aminotransferase levels to acute liver failure. Patients with AIH type 1 are more likely to be older and have cirrhosis at the time of diagnosis, whereas those with AIH type 2 may have a more fulminant course and require life-long immunosuppressant medications. Overlap syndromes occur in children but are rare. Treatment with prednisone and azathioprine, alone or in combination, reverses the clinical course and improves biochemical abnormalities. Should liver transplantation be necessary, autoimmune injury may recur in the allograft.
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Affiliation(s)
- Robert H Squires
- Division of Gastroenterology/Hepatology, Children's Hospital of Pittsburgh and the University of Pittsburgh Medical Center, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA.
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