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Sandler YG, Vinnitskaya EV, Raikhelson KL, Ivashkin KV, Batskikh SN, Aleksandrova EN, Abdurakhmanov DT, Abdulganieva DI, Bakulin IG, Bueverov AO, Vorobyev SL, Gerasimova OA, Dolgushina AI, Zhuravleva MS, Ilchenko LY, Karev VE, Korochanskaya NV, Kliaritskaia IL, Karnaukhov NS, Lapin SV, Livzan MA, Maevskaya MV, Marchenko NV, Nekrasova TP, Nikitin IG, Novikov AA, Saifutdinov RG, Skazyvaeva EV, Syutkin VE, Prashnova MK, Khaymenova TY, Khomerik SG. Diagnosis and Treatment of Patients with Autoimmune Hepatitis (Experts’ Agreement). RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:100-119. [DOI: 10.22416/1382-4376-2024-34-6-100-119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2025]
Abstract
Background. In the last decade, the understanding of the pathogenesis of autoimmune hepatitis (AIH) has significantly deepened, based on the results of new clinical studies some diagnostic issues have been revised and immunosuppressive therapy regimens have been optimized.Materials and methods. The latest Russian clinical guidelines for the diagnosis and treatment of AIH were presented in 2013; and in 2017, the first Russian agreement on the diagnosis and treatment of AIH was held. Updating approaches to the management of patients with AIH necessitated next systematization for use in clinical practice. In February 2024, the final session was held to discuss the provisions of the second agreement on the diagnosis and treatment of AIH.Results. This publication presents the main discussion points of the agreement regarding methods and algorithms for detecting autoantibodies, the role of liver biopsy, revised morphological criteria for AIH, optimized immunosuppressive therapy regimens, updated criteria for assessing the response to therapy.Conclusions. The agreement was the result of the work of a group of experts on the diagnosis and treatment of AIH and represents the basis for the creation of updated federal clinical guidelines.
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Affiliation(s)
| | | | | | - K. V. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | | | | | | | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | - A. O. Bueverov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - S. L. Vorobyev
- OOO National Center for Clinical Morphological Diagnostics
| | - O. A. Gerasimova
- Saint Petersburg State University;
Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov
| | | | - M. S. Zhuravleva
- North-Western State Medical University named after I.I. Mechnikov
| | | | - V. E. Karev
- Pediatric Research and Clinical Center for Infectious Diseases under the Federal Medical Biological Agency
| | | | | | | | - S. V. Lapin
- Academician I.P. Pavlov First St. Petersburg State Medical University
| | | | - M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - N. V. Marchenko
- Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov
| | - T. P. Nekrasova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. G. Nikitin
- N.I. Pirogov Russian National Research Medical University
| | | | - R. G. Saifutdinov
- Kazan State Medical Academy — Branch Campus of the Russian Medical Academy of Continuous Professional Education
| | - E. V. Skazyvaeva
- North-Western State Medical University named after I.I. Mechnikov
| | - V. E. Syutkin
- Medical and Biological University of Innovation and Continuous Education, State Research Center — Byrnasyan Federal Medical Biophysical Center of Federal Biological Agency;
N.V. Sklifosovsky Research Institute for Emergency Care of the Moscow City Health Department
| | - M. K. Prashnova
- Russian Scientific Center for Radiology and Surgical Technologies named after Academician A.M. Granov
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Gan H, Cai J, Li L, Zheng X, Yan L, Hu X, Zhao N, Li B, He J, Wang D, Pang P. Endothelium-targeted Ddx24 conditional knockout exacerbates ConA-induced hepatitis in mice due to vascular hyper-permeability. Int Immunopharmacol 2024; 129:111618. [PMID: 38354508 DOI: 10.1016/j.intimp.2024.111618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/19/2024] [Accepted: 01/29/2024] [Indexed: 02/16/2024]
Abstract
BACKGROUND Acute hepatitis is a progressive inflammatory disorder that can lead to liver failure. Endothelial permeability is the vital pathophysiological change involved in infiltrating inflammatory factors. DDX24 has been implicated in immune signaling. However, the precise role of DDX24 in immune-mediated hepatitis remains unclear. Here, we investigate the phenotype of endothelium-targeted Ddx24 conditional knockout mice with Concanavalin A (ConA)-induced hepatitis. METHODS Mice with homozygous endothelium-targeted Ddx24 conditional knockout (Ddx24flox/flox; Cdh5-Cre+) were established using the CRISPR/Cas9 mediated Cre-loxP system. We investigated the biological functions of endothelial cells derived from transgenic mice and explored the effects of Ddx24 in mice with ConA-induced hepatitis in vivo. The mass spectrometry was performed to identify the differentially expressed proteins in liver tissues of transgenic mice. RESULT We successfully established mice with endothelium-targeted Ddx24 conditional knockout. The results showed migration and tube formation potentials of murine aortic endothelial cells with DDX24 silencing were significantly promoted. No differences were observed between Ddx24flox/flox; Cdh5-Cre+ and control regarding body weight and length, pathological tissue change and embryogenesis. We demonstrated Ddx24flox/flox; Cdh5-Cre+ exhibited exacerbation of ConA-induced hepatitis by up-regulating TNF-α and IFN-γ. Furthermore, endothelium-targeted Ddx24 conditional knockout caused vascular hyper-permeability in ConA-injected mice by down-regulating vascular integrity-associated proteins. Mechanistically, we identified Ddx24 might regulate immune-mediated hepatitis by inflammation-related permeable barrier pathways. CONCLUSION These findings prove that endothelium-targeted Ddx24 conditional knockout exacerbates ConA-induced hepatitis in mice because of vascular hyper-permeability. The findings indicate a crucial role of DDX24 in regulating immune-mediated hepatitis, suggesting DDX24 as a potential therapeutic target in the disorder.
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Affiliation(s)
- Hairun Gan
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Jianxun Cai
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Luting Li
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Xiaodi Zheng
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Leye Yan
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Xinyan Hu
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Ni Zhao
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China
| | - Bing Li
- Department of Ophthalmology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
| | - Jianan He
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
| | - Dashuai Wang
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
| | - Pengfei Pang
- Center for Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong Province 519000, China.
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Enciso J, Vasavada-Patel R, Lien K. A Rare Presentation of Drug-Induced Autoimmune Hepatitis and the Role of Male Enhancement Supplements. Cureus 2024; 16:e51770. [PMID: 38322090 PMCID: PMC10844770 DOI: 10.7759/cureus.51770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 01/06/2024] [Indexed: 02/08/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a condition characterized by an autoimmune response resulting in chronic inflammatory liver disease. Its presentation is marked by significant increases in serum immunoglobulins and the production of active autoantibodies that target liver tissue. AIH is often associated with other autoimmune disorders, which can lead to overlapping clinical syndromes. However, alternative theories propose that exposure to specific environmental triggers can initiate this autoimmune cascade. We present the case of a 45-year-old male who sought evaluation for abdominal discomfort and was subsequently diagnosed with drug-induced AIH (DIAIH) following prolonged use of an over-the-counter male-enhancing supplement.
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Affiliation(s)
- Juan Enciso
- Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, USA
| | - Ruhi Vasavada-Patel
- Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, USA
| | - Kyle Lien
- Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, USA
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Centa M, Thermidor C, Fiel MI, Alexandropoulos K. Profiling of mouse and human liver diseases identifies targets for therapeutic treatment of autoimmune hepatitis. Clin Immunol 2023; 256:109807. [PMID: 37821072 DOI: 10.1016/j.clim.2023.109807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 10/07/2023] [Indexed: 10/13/2023]
Abstract
Autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and non-alcoholic steatohepatitis (NASH) are chronic liver diseases (CLDs) of distinct etiologies that represent a public health risk with limited therapeutic options. A common feature among CLDs is an aggressive T cell response resulting in destruction of liver tissue and fibrosis. Here, we assessed the presence and nature of T cell inflammation in late-stage human AIH, PSC and NASH and examined whether targeting the T cell response can improve disease pathology in a mouse model (Traf6ΔTEC) of spontaneous AIH. T cell infiltration and ensuing inflammatory pathways were present in human AIH and PSC and to a lesser extent in NASH. However, we observed qualitative differences in infiltrating T cell subsets and upregulation of inflammatory pathways among these diseases, while mouse and human AIH exhibited similar immunogenic signatures. While gene expression profiles differed among diseases, we identified 52 genes commonly upregulated across all diseases that included the JAK3 tyrosine kinase. Therapeutic targeting of chronic AIH with the JAK inhibitor tofacitinib reduced hepatic T cell infiltration, AIH histopathology and associated immune parameters in treated Traf6ΔTEC mice. Our results indicate that targeting T cell responses in established hepatic autoimmune inflammation is a feasible strategy for developing novel therapeutic approaches to treat AIH and possibly other CLDs irrespective of etiology.
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Affiliation(s)
- Monica Centa
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Christelle Thermidor
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Maria Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Konstantina Alexandropoulos
- Department of Medicine, Division of Clinical Immunology, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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5
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Rinaldi L, Giorgione C, Mormone A, Esposito F, Rinaldi M, Berretta M, Marfella R, Romano C. Non-Invasive Measurement of Hepatic Fibrosis by Transient Elastography: A Narrative Review. Viruses 2023; 15:1730. [PMID: 37632072 PMCID: PMC10459581 DOI: 10.3390/v15081730] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Transient elastography by FibroScan® (Echosens, Paris, France) is a non-invasive method that can provide a reliable measurement of liver fibrosis through the evaluation of liver stiffness. Despite its limitations and risks, liver biopsy has thus far been the only procedure able to provide data to quantify fibrosis. Scientific evidence and clinical practice have made it possible to use FibroScan® in the diagnostic work-up of several liver diseases to monitor patients' long-term treatment response and for complication prevention. For these reasons, this procedure is widely used in clinical practice and is still being investigated for further applications. The aim of this narrative review is to provide a comprehensive overview of the main applications of transient elastography in the current clinical practice.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Chiara Giorgione
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Andrea Mormone
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Francesca Esposito
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Michele Rinaldi
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, “Federico II” University of Naples, 80131 Naples, Italy;
| | - Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
| | - Ciro Romano
- Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy; (L.R.); (R.M.)
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Buechter M, Dorn D, Möhlendick B, Siffert W, Baba HA, Gerken G, Kahraman A. Characteristics and Long-Term Outcome of 535 Patients with Autoimmune Hepatitis-The 20-Year Experience of a High-Volume Tertiary Center. J Clin Med 2023; 12:4192. [PMID: 37445225 DOI: 10.3390/jcm12134192] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 07/15/2023] Open
Abstract
Background and aims: Autoimmune hepatitis (AIH) is a complex and progressive inflammatory liver disease characterized by immune-mediated destruction of the liver parenchyma, hypergammaglobulinemia, the presence of circulating autoantibodies, and good response to immunosuppressive therapy. Since the prevalence of AIH is relatively rare, data on the clinical course and the long-term outcome are scarce. Patients and methods: We retrospectively analyzed the data of 535 well-documented AIH patients treated at the University Hospital Essen between 2000 and 2020. Results: The majority of patients were middle-aged females (75% women, mean age 45 years) with AIH type 1 (97%). Approximately 32% of patients were diagnosed with cirrhosis due to AIH, 29% had concomitant autoimmune (predominantly autoimmune thyroiditis), and 10% had psychiatric diseases, respectively. Skin tumors were the most common malignant diseases (47% of all tumors), while hepatocellular carcinoma rarely occurred (only six cases). Overall long-term mortality and liver-associated mortality were 9.16% and 4.67%, respectively. However, long-term survival was strongly associated with disease remission. Conclusions: Although AIH is a silent disease and cirrhosis is present in many cases, a favorable long-term prognosis can be achieved by consequent immunosuppressive therapy. The incidence of (liver-associated) complications seems to be lower in comparison to other etiologies, such as viral hepatitis or NASH, and mainly depends on the long-term side effects of immunosuppressive therapy.
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Affiliation(s)
- Matthias Buechter
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Elisabeth Hospital, 58638 Iserlohn, Germany
| | - Dominik Dorn
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Birte Möhlendick
- Institute of Pharmacogenetics, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Winfried Siffert
- Institute of Pharmacogenetics, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Helios Clinic, 42549 Velbert, Germany
| | - Alisan Kahraman
- Department of Gastroenterology and Hepatology, University Clinic of Essen, University of Duisburg-Essen, 45122 Essen, Germany
- Department of Gastroenterology and Hepatology, Max Grundig Clinic, 77815 Bühl, Germany
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Bhumi SA, Wu GY. Seronegative Autoimmune Hepatitis. J Clin Transl Hepatol 2023; 11:459-465. [PMID: 36643052 PMCID: PMC9817061 DOI: 10.14218/jcth.2022.00235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/09/2022] [Accepted: 08/22/2022] [Indexed: 01/18/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare liver disease with varying worldwide incidence of from 0.7 to 2 per 100,000 people. It is characterized by the presence of auto-antibodies. However, an average of 10% of AIH cases have AIH symptoms and pathology but lack autoimmune serology. For such seronegative AIH (snAIH) cases, there is currently no established diagnostic algorithm for diagnosis. and improper or delayed diagnosis of snAIH can lead to no or inappropriate treatment that results in progression to fulminant hepatitis or cirrhosis. This review aims to review the current literature and to present an update of seronegative autoimmune hepatitis, including its pathophysiology, clinical presentation, methods of diagnosis, and treatment in order to increase awareness and emphasize the necessity for timely management.
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Affiliation(s)
- Sriya A. Bhumi
- Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA
- Correspondence to: Sriya A. Bhumi, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington CT 06032, USA. ORCID: https://orcid.org/0000-0002-6336-2119. Tel: +1-860-679-6296, Fax: +1-860-679-1434, E-mail:
| | - George Y. Wu
- Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA
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Ahuja N, Singh J, Minz RW, Anand S, Das A, Taneja S. HLA and Non-HLA gene polymorphisms in autoimmune hepatitis patients of North Indian adults. Front Immunol 2023; 13:984083. [PMID: 36741403 PMCID: PMC9891307 DOI: 10.3389/fimmu.2022.984083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic and progressive disease of the liver. This is a multifactorial autoimmune disease with both environmental factors and genetic factors playing a role in its pathogenesis. Certain environmental agents like viruses, drugs, etc., can trigger the disease in a genetically susceptible individual. The present study was aimed to explore the distribution of human leukocyte antigen (HLA)-DRB1, Protein tyrosine phosphatase non-receptor type 22 (PTPN22) and Cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) polymorphisms in North Indian adult AIH patients and their associations with clinical and pathological characteristics associated with the disease. A total of 147 subjects with 47 cases and 100 healthy controls were enrolled. Diagnosis of AIH was made by Revised International Autoimmune Hepatitis Group scoring system. HLA-DRB1 Typing was done by Luminex-based reverse Sequence-Specific Oligonucleotide Probing (SSOP). Single nucleotide variant (SNV) genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP arrays. Results indicated SLA positive AIH patients are poor responders to therapy. A significant predispositional association of HLA-DRB1*03 was observed in AIH patients from the North Indian population (p= 0.0001, OR=4.83 (2.30-10.15). The frequency of the GG genotype of CTLA-4 CT 60 was significantly increased in AIH patients compared to controls. Multinomial analysis showed that CTLA-4 CT 60 is an independent predictor for cases.
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Affiliation(s)
- Nishtha Ahuja
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jagdeep Singh
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ranjana Walker Minz
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India,*Correspondence: Ranjana Walker Minz,
| | - Shashi Anand
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashim Das
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Tamimi TA, Sallam M, Rayyan D, Farah R, Alkhulaifat D, Al-Ani A, Elmusa R, Sharawi S, Tanash O, Rayyan Y. Clinical Characteristics of Autoimmune Hepatitis in a Middle Eastern Population: A Tertiary Care Center Experience. J Clin Med 2023; 12:629. [PMID: 36675558 PMCID: PMC9861091 DOI: 10.3390/jcm12020629] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease of uncertain cause, and its manifestations appear to vary by race and ethnicity. The literature on AIH in the Middle East, including Jordan, is scarce; therefore, this study aimed to determine the clinical characteristics of AIH in an understudied population. This retrospective chart review study was conducted on AIH patients who presented to Jordan University Hospital over a seven-year period (2014-2020). Retrieved data included sociodemographics, liver function tests, autoimmune serologic markers, viral hepatitis serology, findings on liver biopsies, treatment regimens, post-therapy outcomes and treatment-related complications. The total number of AIH patients included in the study was 30, divided as follows: type 1 AIH (n = 17, 56.7%), type 2 AIH (n = 2, 6.7%), seronegative AIH (n = 9, 30.0%), and two patients who had AIH-primary biliary cirrhosis overlap syndrome (6.7%). The mean age at diagnosis was 44 years (standard deviation: 17 years), with a female predominance (n = 25, 83.3%). Acute presentation was seen among 18 patients (60.0%). Mild to moderate fibrosis (F1 and F2 on METAVIR scoring system) without cirrhosis was observed among patients who underwent liver biopsies (10/19, 52.6%). The majority of patients (73.3%) were initially treated with prednisone, with azathioprine combination in 16.7% of the patients. At 6 months post initial treatment, twenty patients (66.7%) achieved biochemical remission, four patients had incomplete response, two patients failed to improve (one died during the induction of remission period due to AIH-related complications), and four patients were lost to follow-up. This study provided an updated overview of AIH in Jordan. The results showed typical female predominance, and interestingly high rates of acute presentation and seronegative disease. Future longitudinal studies are recommended to address the nature and long-term prognosis of AIH in Jordan.
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Affiliation(s)
- Tarek A. Tamimi
- Section of Gastroenterology, Department of Internal Medicine, Jordan University Hospital, Amman 11942, Jordan
- Department of Internal Medicine, School of Medicine, University of Jordan, Amman 11942, Jordan
| | - Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, University of Jordan, Amman 11942, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Deema Rayyan
- School of Medicine, University of Jordan, Amman 11942, Jordan
| | - Randa Farah
- Department of Internal Medicine, School of Medicine, University of Jordan, Amman 11942, Jordan
- Section of Nephrology, Department of Internal Medicine, Jordan University Hospital, Amman 11942, Jordan
| | | | - Abdallah Al-Ani
- School of Medicine, University of Jordan, Amman 11942, Jordan
| | - Reem Elmusa
- School of Medicine, University of Jordan, Amman 11942, Jordan
| | - Said Sharawi
- School of Medicine, University of Jordan, Amman 11942, Jordan
| | - Omar Tanash
- Section of Gastroenterology, Department of Internal Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Yaser Rayyan
- Section of Gastroenterology, Department of Internal Medicine, Jordan University Hospital, Amman 11942, Jordan
- Department of Internal Medicine, School of Medicine, University of Jordan, Amman 11942, Jordan
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10
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Trevisani VFM, Pinheiro AC, de Magalhães Souza Fialho SC, Fernandes MLMS, Pugliesi A, Pasoto SG, Lopes MLL, Guedes LKN, Miyamoto ST, Dos Santos LC, Appenzeller S, Fidelix T, Ribeiro SLE, de Brito DCSE, Libório-Kimura TN, Santos MCLFS, Cantali DU, Gennari JD'A, Capobianco KG, Civile VT, Pinto ACPN, da Rocha AP, Rocha-Filho CR, Oliveira FR, Valim V. Recommendations for evaluation and diagnosis of extra-glandular manifestations of primary Sjögren syndrome: results of an epidemiologic systematic review/meta-analysis and a consensus guideline from the Brazilian society of rheumatology (hepatic, gastrointestinal and pancreatic). Adv Rheumatol 2022; 62:35. [PMID: 36217186 DOI: 10.1186/s42358-022-00267-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 09/27/2022] [Indexed: 12/28/2022] Open
Abstract
Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs, associated with sicca syndrome but also with systemic involvement with varying degrees of severity. Despite their importance, some systemic manifestations, mainly liver, gastrointestinal, and pancreatic are not routinely evaluated. To address these manifestations, the Sjögren's Syndrome Committee of the Brazilian Society of Rheumatology conducted a broad systematic review of the literature on studies investigating prevalence and diagnosis of these symptoms in Sjogren´s patients and made recommendations based on the findings. Agreement between the experts was achieved using the Delphi method. This is the second part of this guideline, providing 6 recommendations for liver, gastrointestinal, and pancreatic care of SS patients.
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Affiliation(s)
- Virginia Fernandes Moça Trevisani
- Disciplina de Medicina de Urgência e Medicina Baseada em Evidências, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 740, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
- Disciplina de Reumatologia, Universidade de Santo Amaro (UNISA), Rua Enéas Siqueira Neto, Jardim das Imbuias, São Paulo, SP, CEP: 04829-300, Brazil
| | - Aysa César Pinheiro
- Serviço de Reumatologia, Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, CEP: 50670-901, Brazil.
| | | | | | - Alisson Pugliesi
- Disciplina de Reumatologia, Departamento de Clínica Médica, FCM UNICAMP, R. Tessália Vieira de Camargo, 126 - Cidade Universitária, Campinas, SP, CEP: 13083-887, Brazil
| | - Sandra Gofinet Pasoto
- Disciplina de Reumatologia, Laboratório de Autoimunidade (DLC + LIM17), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo, SP, CEP: 05403-010, Brazil
| | - Maria Lucia Lemos Lopes
- Disciplina de Especialidades Clínicas, Departamento de Clínica Médica, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), R. Sarmento Leite, 245 - Centro Histórico de Porto Alegre, Porto Alegre, RS, CEP: 90050-170, Brazil
| | - Lissiane Karine Noronha Guedes
- Disciplina de Reumatologia, Laboratório de Autoimunidade (DLC + LIM17), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, R. Dr. Ovídio Pires de Campos, 225 - Cerqueira César, São Paulo, SP, CEP: 05403-010, Brazil
| | - Samira Tatiyama Miyamoto
- Departamento de Educação Integrada em Saúde, Universidade Federal do Espírito Santo (UFES), Av. Marechal Campos, 1468, Maruípe, Vitória, ES, CEP: 29040-090, Brazil
| | - Laura Caldas Dos Santos
- Departamento de Oftalmologia, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 820, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
| | - Simone Appenzeller
- Disciplina de Reumatologia, Departamento de Clínica Médica, FCM UNICAMP, R. Tessália Vieira de Camargo, 126 - Cidade Universitária, Campinas, SP, CEP: 13083-887, Brazil
| | - Tania Fidelix
- Departamento de Oftalmologia, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 820, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
| | - Sandra Lúcia Euzébio Ribeiro
- Disciplina de Reumatologia, Universidade Federal do Amazonas, Rua Afonso Pena, 1053, Manaus, AM, CEP: 69020-160, Brazil
| | - Danielle Christinne Soares Egypto de Brito
- Disciplina de Reumatologia, Departamento de Medicina Interna, Centro de Ciências Médicas, Universidade Federal da Paraíba (UFPB), Campus I - Lot. Cidade Universitária, Paraíba, PB, CEP: 58051-900, Brazil
| | - Tatiana Nayara Libório-Kimura
- Departamento de Patologia e Medicina Legal, Faculdade de Medicina, Universidade Federal do Amazonas, Rua Afonso Pena, 1053, Manaus, AM, CEP: 69020-160, Brazil
| | - Maria Carmen Lopes Ferreira Silva Santos
- Departamento de Patologia, Hospital Universitário Cassiano Antônio de Moraes, Universidade Federal do Espírito Santo (UFES), Av. Marechal Campos, 1468, Maruípe, Vitória, ES, CEP: 29075-910, Brazil
| | - Diego Ustárroz Cantali
- Serviço de Reumatologia, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande de Sul (PUCRS), Av. Ipiranga, 6690 - Jardim Botânico, Porto Alegre, RS, CEP: 90610-000, Brazil
| | - Juliana D 'Agostino Gennari
- Serviço de Reumatologia da Santa Casa de São Paulo, R. Dr. Cesário Mota Júnior, 112, Vila Buarque, São Paulo, SP, CEP: 01221-020, Brazil
| | - Karina Gatz Capobianco
- Hospital Moinhos de Vento, Rua Ramiro Barcelos 910/803 Floresta, Porto Alegre, RS, CEP: 90035-001, Brazil
| | - Vinicius Tassoni Civile
- Disciplina de Medicina de Urgência e Medicina Baseada em Evidências, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 740, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
| | - Ana Carolina Pereira Nunes Pinto
- Disciplina de Medicina de Urgência e Medicina Baseada em Evidências, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 740, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
- Biological and Health Sciences Department, Universidade Federal do Amapá (AP), Rod. Josmar Chaves Pinto, km 02 - Jardim Marco Zero, Macapá, AP, CEP: 68903-419, Brazil
| | - Aline Pereira da Rocha
- Disciplina de Medicina de Urgência e Medicina Baseada em Evidências, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 740, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
| | - César Ramos Rocha-Filho
- Disciplina de Medicina de Urgência e Medicina Baseada em Evidências, Escola Paulista de Medicina - Universidade Federal de São Paulo (EPM-UNIFESP), Rua Botucatu, 740, Vila Clementino, São Paulo, SP, CEP: 04023-062, Brazil
| | - Fabiola Reis Oliveira
- Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP), Av. Bandeirantes, 3900, Vila Monte Alegre, Ribeirão Preto, SP, CEP: 14049-900, Brazil
| | - Valeria Valim
- Serviço de Reumatologia, Hospital Universitário Cassiano Antônio de Moraes, Universidade Federal do Espírito Santo (UFES), Av. Marechal Campos, 1468, Maruípe, Vitória, ES, CEP: 29075-910, Brazil
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11
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Lad SG, Kolhe K, Chauhan S, Gattani M, Sethiya P, Singh GK, Kiran B, Ingle M, Pandey V. AIH in HIV: A Very Much Possible Entity. J Clin Exp Hepatol 2022; 12:1388-1392. [PMID: 36157146 PMCID: PMC9499873 DOI: 10.1016/j.jceh.2022.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 05/09/2022] [Indexed: 12/12/2022] Open
Abstract
Autoimmune Hepatitis (AIH) is a chronic liver disease Characterized by interface hepatitis, lymphoplasmacytic infiltrate, and hepatic rosettes. HIV infection is a state of immunosuppression; hence, the possibility of AIH is relatively rare, especially in patients with low CD4 counts. Therefore, we present an interesting case series of four patients with autoimmune liver disease with myriad presentations for the first time from India. We propose that despite the rarity of this presentation with immunosuppression, one should never miss such a treatable cause of liver disease leading to good clinical outcomes.
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Key Words
- ACLF, Acute on chronic liver failure
- AIH, Autoimmune Hepatitis
- AKI, Acute kidney injury
- ALT, Alanine transaminase
- ANA, Antinuclear antibody
- ART, Antiretroviral therapy
- ASMA, Anti smooth muscle antibody
- AST, Aspartate aminotransferase
- CAM, Complementary and alternative medications
- DILI, Drug-induced liver injury
- GGT, Gamma-transferase
- HAV, Hepatitis A Virus
- HEV, Hepatitis E Virus
- HIV, Human immunodeficiency Virus
- IRIS, Immune reconstitution inflammatory syndrome
- LFT, Liver function test
- PHG, portal hypertensive gastropathy
- TJLB, Transjugular liver biopsy
- autoimmune hepatitis (AIH)
- cART, Combination antiretroviral therapy
- drug-induced liver injury – AIH (DILI-AIH)
- human immunodeficiency virus (HIV)
- iAIH, Denovo Idiopathic AIH
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Affiliation(s)
- Saiprasad G. Lad
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Kailash Kolhe
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Shamshersingh Chauhan
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Mayur Gattani
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Pratik Sethiya
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Gaurav K. Singh
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - B. Kiran
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Meghraj Ingle
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
| | - Vikas Pandey
- Dept of Gastroenterology, Lokmanya Tilak Municipal Medical College and General Hospital, Sion, Mumbai- 400022, India
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12
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Iyer MH, Kumar JE, Kumar N, Gorelik L, Hussain N, Stein E, Bhatt AM, Bhandary S, Essandoh MK, Flores AS. Transfusion-Related Acute Lung Injury During Liver Transplantation: A Scoping Review. J Cardiothorac Vasc Anesth 2022; 36:2606-2615. [PMID: 34099375 DOI: 10.1053/j.jvca.2021.04.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/30/2021] [Accepted: 04/20/2021] [Indexed: 12/31/2022]
Abstract
Liver transplantation is associated with significant blood loss, often requiring massive blood product transfusion. Transfusion-related acute lung injury (TRALI) is a devastating cause of transfusion-related deaths. While reports have investigated the general incidence of TRALI, the incidence of TRALI specifically following transfusion during liver transplant remains unclear. This scoping review summarizes existing literature regarding TRALI during the liver transplantation perioperative period. Databases were searched for all articles and abstracts reporting on TRALI after liver transplantation. Data collected included number of patients studied, patient characteristics, incidences of TRALI, TRALI characteristics, and patient outcomes. The primary outcome investigated was the incidence of TRALI in the setting of liver transplantation. Thirteen full-text citations were included in this review. The incidence of TRALI post-liver transplant was 0.68% (65 of 9,554). Based on reported transfusion data, patients diagnosed with TRALI received an average of 10.92 ± 10.81 units of packed red blood cells (pRBC), 20.05 ± 15.72 units of fresh frozen plasma, and 5.75 ± 10.00 units of platelets. Common interventions following TRALI diagnosis included mechanical ventilation with positive end-expiratory pressure, inhaled high-flow oxygen, inhaled pulmonary vasodilator, and pharmacologic treatment using pressors or inotropes, corticosteroids, or diuretics. Based on reported mortality data, 26.67% of patients (12 of 45) diagnosed with TRALI died during the postoperative period. This scoping review underscores the importance of better understanding the incidence and presentation of TRALI after liver transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for liver transplant patients at increased risk for developing TRALI.
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Affiliation(s)
| | | | - Nicolas Kumar
- Wexner Medical Center, Columbus, OH; The Ohio State University College of Medicine, Columbus, OH
| | | | | | | | | | - Sujatha Bhandary
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA
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13
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Ahmad A, Dahle C, Rönnelid J, Sjöwall C, Kechagias S. Autoantibodies Associated with Autoimmune Liver Diseases in a Healthy Population: Evaluation of a Commercial Immunoblot Test. Diagnostics (Basel) 2022; 12:diagnostics12071572. [PMID: 35885478 PMCID: PMC9320916 DOI: 10.3390/diagnostics12071572] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 11/16/2022] Open
Abstract
Autoantibodies constitute important tools for diagnosing the autoimmune liver diseases (AILD) autoimmune hepatitis and primary biliary cholangitis. The EUROLINE immunoblot assay, detecting multiple specificities, is widely used, but the clinical importance of weakly positive findings is unclear. The manufacturer’s recommended cut-off was evaluated by investigating AILD-associated autoantibodies in 825 blood donors and 60 confirmed AILD cases. Positive findings were followed up with immunofluorescence microscopy on rat tissue, anti-M2-ELISA, alternative immunoblot assay, and liver function tests. Thirty-six (4.4%) blood donors were positive with EUROLINE. The most common specificities were LC-1 (1.6%), gp210 (1.3%), and AMA-M2 (1.1%). In general, the positive results were higher in patients than in blood donors, whereas anti-LC-1 was higher in blood donors. The liver function tests were slightly elevated in 2 of the 36 immunoblot positive blood donors. The majority of the positive EUROLINE findings could not be confirmed with the follow-up tests. The EUROLINE-Autoimmune Liver Diseases-(IgG) immunoblot detected autoantibodies in 4.4% of blood donors without signs of AILD. Our findings indicate that the recommended cut-off can be raised for most specificities without loss of diagnostic sensitivity. The prevalence of anti-LC-1 among blood donors indicates a problem with the antigen source.
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Affiliation(s)
- Awais Ahmad
- Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Clinical Immunology & Transfusion Medicine, Linköping University, SE-581 83 Linköping, Sweden;
- Correspondence:
| | - Charlotte Dahle
- Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Clinical Immunology & Transfusion Medicine, Linköping University, SE-581 83 Linköping, Sweden;
| | - Johan Rönnelid
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-752 36 Uppsala, Sweden;
| | - Christopher Sjöwall
- Department of Biomedical and Clinical Sciences, Division of Inflammation and Infection/Rheumatology, Linköping University, SE-581 83 Linköping, Sweden;
| | - Stergios Kechagias
- Department of Health, Medicine and Caring Sciences, Division of Diagnostics and Specialist Medicine/Gastroenterology & Hepatology, Linköping University, SE-581 83 Linköping, Sweden;
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14
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Harputluoglu M, Caliskan AR, Akbulut S. Autoimmune hepatitis and liver transplantation: Indications, and recurrent and de novo autoimmune hepatitis. World J Transplant 2022; 12:59-64. [PMID: 35433333 PMCID: PMC8968478 DOI: 10.5500/wjt.v12.i3.59] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/15/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a chronic inflammatory disease of the liver that is characterized by circulating autoantibodies and elevated serum globulin levels. Liver transplantation may be required for patients with acute liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Recurrence is defined as development of the same disease in the allograft following liver transplantation. Autoimmune hepatitis recurs in 36%-68% of the recipients 5 years after liver transplantation. De novo autoimmune hepatitis is the development of autoimmune hepatitis like clinical and laboratory characteristics in patients who had undergone liver transplantation for causes other than autoimmune hepatitis. Diagnostic work up for recurrent and de novo autoimmune hepatitis is similar to the diagnosis of the original disease, and it is usually difficult. Predniso(lo)ne with or without azathioprine is the main treatment for recurrent and de novo autoimmune hepatitis. Early diagnosis and treatment are vital for patient prognosis because de novo autoimmune hepatitis and recurrent autoimmune hepatitis cause graft loss and result in subsequent retransplantation if medical treatment fails.
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Affiliation(s)
- Murat Harputluoglu
- Department of Gastroenterology and Transplant Hepatology, Inonu University Faculty of Medicine, Malatya 44280, Turkey
| | - Ali Riza Caliskan
- Department of Gastroenterology, Adiyaman Education and Research Hospital, Adıyaman 04120, Turkey
| | - Sami Akbulut
- Liver Transplant Institute, Inonu University, Malatya 44280, Turkey
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15
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Zhang K, Li J, Shi Z, Zhu Y, Yang J, Liu X, Que R, Lin L, Chen Y, Li Y. Ginsenosides Regulates Innate Immunity to Affect Immune Microenvironment of AIH Through Hippo-YAP/TAZ Signaling Pathway. Front Immunol 2022; 13:851560. [PMID: 35222444 PMCID: PMC8874200 DOI: 10.3389/fimmu.2022.851560] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/24/2022] [Indexed: 12/02/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by chronic progressive liver inflammatory, but there is still no safe and effective medicine. Therefore, glucocorticoid remains the top choice for AIH treatment. In previous studies, it has been confirmed that ginsenosides (GSS) can produce glucocorticoid-like effects and therapeutic effects on various autoimmune diseases. However, the mechanism of GSS for AIH remains unclear. As an important part of the innate immune system, bone marrow-derived suppressor cells (MDSC) have been identified as an important driver of follow-up acquired immune response in many autoimmune diseases, including AIH. Herein, it was found out that GSS intervention can be effective in regulating the immune microenvironment and liver impairment induced by Con A in AIH mice. In vitro, the MDSCs derived from healthy mice and the T cells deried from AIH mice were co-cultured. Then, different drugs were intervened with to explore the therapeutic mechanism. Besides, the proliferation and differentiation of MDSCs and T cells were analyzed by flow cytometry, while GR, Hippo-YAP signal pathway and the expression of MDSC-related genes and proteins were detected through qRT-PCR and Western Blot. The changes in NO and ROS levels were further analyzed. The trend of related cytokines expression (IFN- γ, TGF- β, IL-10, IL-6, IL-17) was detected by ELISA. Furthermore, an analysis was conducted as to the ALT and liver pathology of mice for evaluating the liver function of mice. It was discovered that MDSCs proliferation was inhibited, and that T cells tended to differentiate into Th17 rather than Treg in AIH mice. Moreover, the intervention of GSS activated GR and Yap, in addition to promoting the proliferation of MDSCs, especially M-MDSCs. This further promoted the differentiation of Treg to enable immune tolerance, thus alleviating liver impairment. Therefore, it was proposed that GSS can alleviate AIH by modulating the innate immunity and adaptive T cell immunity, which may be the underlying mechanism for GSS to mitigate the liver impairment induced by AIH.
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Affiliation(s)
- Kehui Zhang
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacheng Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Shi
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yingying Zhu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Yang
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Vascular Surgery, The Seventh People’s Hospital of Shanghai, Shanghai, China
| | - Xiaolin Liu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Renye Que
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liubing Lin
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yirong Chen
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yong Li,
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16
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Wang Y, Wang YL, Zhu YP, Xu WL, Huang JL, Chai XZ, Li M, Qian F, Zhu CW. Type 3 progressive familial intrahepatic cholestasis combined with autoimmune hepatitis-primary biliary cirrhosis overlap syndrome: A case report. Shijie Huaren Xiaohua Zazhi 2022; 30:56-60. [DOI: 10.11569/wcjd.v30.i1.56] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Autoimmune hepatitis-primary biliary cholangitis (AIH-PBC) overlap syndrome is not uncommon in autoimmune liver disease, but autoimmune liver disease combined with progressive familial intrahepatic cholestasis is relatively rare, which usually makes the diagnosis more complicated and difficult, and thus easily leads to a missed diagnosis and misdiagnosis.
CASE SUMMARY A 32-year-old woman complained of "abnormal liver function and jaundice for 11 years", and was first admitted to our hospital in 2019. She visited different hospitals previously and could not achieve a clear diagnosis. During her first hospitalization in our hospital, a diagnosis of AIH-PBC overlap syndrome was made by the indicators of liver function enzymology, levels of IgG and IgM, autoantibodies related to liver disease, and the pathology of liver biopsy. The patient received the treatment of ursodeoxycholic acid plus glucocorticoid, and her liver function improved but the overall effects were suboptimal. Due to the patient's significantly enlarged spleen unexplained by AIH-PBC overlap syndrome, she was advised to undergo gene sequencing for the detection of potential genetic liver diseases. The findings showed heterozygous deletion mutations in the ABCB4 gene, suggesting that the patient had type 3 progressive familial intrahepatic cholestasis (PFIC3). In 2020 and 2021, the patient was twice admitted to our hospital because of upper gastrointestinal bleeding.
CONCLUSION A clear diagnosis of AIH-PBC overlap syndrome was first made for the patient whose liver disease could not be clearly diagnosed for a long time. Due to the apparent splenomegaly not explained satisfactorily by AIH-PBC overlap syndrome, gene sequencing was permormed, which revealed the presence of ABCB4 gene mutations, resulting in a final diagnosis of PFIC3.
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Affiliation(s)
- Yue Wang
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Yin-Ling Wang
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Yue-Ping Zhu
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Wei-Lu Xu
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Jin-Long Huang
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Xiao-Zhe Chai
- Department of Gastroenterology, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Ming Li
- Department of Hepatology, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Feng Qian
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China,Department of Hepatology, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
| | - Chuan-Wu Zhu
- Department of Infectious Diseases, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China,Department of Hepatology, The Fifth People's Hospital of Suzhou, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou 215131, Jiangsu Province, China
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17
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Huganbuzure Granule Attenuates Concanavalin-A-Induced Immune Liver Injury in Mice via Regulating the Balance of Th1/Th2/Th17/Treg Cells and Inhibiting Apoptosis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:5578021. [PMID: 34539800 PMCID: PMC8443346 DOI: 10.1155/2021/5578021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/30/2021] [Accepted: 08/16/2021] [Indexed: 11/23/2022]
Abstract
In Uygur medicine, Huganbuzure granule (HBG) is one of the classical prescriptions for liver protection. However, its role in immune liver injury remains unknown. This study evaluates the effect of HBG on concanavalin-A- (ConA-) induced immune liver injury and investigates its protective underlying mechanism. BALB/c mice were randomly divided into five groups (n = 24 mice per group): control, ConA, 1.6 g/kg HBG + ConA, 3.2 g/kg HBG + ConA, and 6 mg/kg prednisolone + ConA. HBG was intragastrically administrated once daily for ten consecutive days, prior to ConA (20 mg/kg) injection. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), superoxide dismutase (SOD), and malondialdehyde (MDA) in mouse serum were measured after ConA injection. Moreover, liver-related mRNA levels were evaluated by qPCR. The detection of liver-related proteins was assessed by immunohistochemistry and western blot analysis. Compared with the ConA group, HBG reduced the mRNA expression of IL-17A and IFN-γ and the protein expression of T-bet and ROR-γt. In addition, HBG increased the mRNA expression of IL-4 and TGF-β and protein expression of GATA3 and Foxp3, indicating that HBG regulated the balance of Th1/Th2 and Th17/Treg. Furthermore, HBG alleviated immune liver injury by reducing oxidative stress, inhibiting apoptosis, and decreasing the expression of p-JNK, p-ERK, p-p38, p-JAK1, p-STAT1, p-STAT3, and IRF1. Our data suggested that HBG attenuated ConA-induced immune liver injury by regulating the immune balance and inhibiting JAK1/STATs/IRF1 signaling, thereby reducing apoptosis induced by JNK activation. The findings indicate that HBG may be a promising drug for immune liver injury.
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18
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Ferre-Aracil C, Riveiro-Barciela M, Trapero-Marugán M, Rodríguez-Perálvarez M, Llovet LP, Téllez L, Sánchez-Torrijos Y, Díaz-Fontenla F, Salcedo-Plaza M, Álvarez-López P, de la Mata M, Londoño MC, Bañares-Cañizares R, Calleja JL. Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study. Dig Dis Sci 2021; 66:2826-2832. [PMID: 32860579 DOI: 10.1007/s10620-020-06569-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/19/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. AIMS To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. METHODS Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. RESULTS A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). CONCLUSION Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.
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Affiliation(s)
- Carlos Ferre-Aracil
- Gastroenterology and Hepatology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Joaquin Rodrigo 1, Majadahonda, 28888, Madrid, Spain.
| | - Mar Riveiro-Barciela
- Hepatology - Internal Medicine Unit, Hospital Universitario Vall d'Hebrón, Barcelona, Spain
- CIBERehd, Barcelona, Spain
| | - María Trapero-Marugán
- Gastroenterology and Hepatology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Joaquin Rodrigo 1, Majadahonda, 28888, Madrid, Spain
| | - Manuel Rodríguez-Perálvarez
- Hepatology and Liver Transplantation Unit, Hospital Universitario Reina Sofía, IMBIC, CIBERehd, Córdoba, Spain
| | | | - Luis Téllez
- Gastroenterology and Hepatology Unit, Hospital Universitario Ramón y Cajal, IRYCIS, CIBERehd, Universidad de Alcalá, Madrid, Spain
| | | | - Fernando Díaz-Fontenla
- Gastroenterology and Hepatology Unit, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Magdalena Salcedo-Plaza
- Gastroenterology and Hepatology Unit, Hospital Universitario Gregorio Marañón, Madrid, Spain
| | - Patricia Álvarez-López
- Hepatology - Internal Medicine Unit, Hospital Universitario Vall d'Hebrón, Barcelona, Spain
| | - Manuel de la Mata
- Hepatology and Liver Transplantation Unit, Hospital Universitario Reina Sofía, IMBIC, CIBERehd, Córdoba, Spain
| | | | | | - José Luis Calleja
- Gastroenterology and Hepatology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Joaquin Rodrigo 1, Majadahonda, 28888, Madrid, Spain
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19
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Rao B, Lou J, Lu H, Liang H, Li J, Zhou H, Fan Y, Zhang H, Sun Y, Zou Y, Wu Z, Jiang Y, Ren Z, Yu Z. Oral Microbiome Characteristics in Patients With Autoimmune Hepatitis. Front Cell Infect Microbiol 2021; 11:656674. [PMID: 34094998 PMCID: PMC8170700 DOI: 10.3389/fcimb.2021.656674] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a common cause of liver cirrhosis. To identify the characteristics of the oral microbiome in patients with AIH, we collected 204 saliva samples including 68 AIH patients and 136 healthy controls and performed microbial MiSeq sequencing after screening. All samples were randomly divided into discovery cohorts (46 AIH and 92 HCs) and validation cohorts (22 AIH and 44 HCs). Moreover, we collected samples of 12 AIH patients from Hangzhou for cross-regional validation. We described the oral microbiome characteristics of AIH patients and established a diagnostic model. In the AIH group, the oral microbiome diversity was significantly increased. The microbial communities remarkably differed between the two groups. Seven genera, mainly Fusobacterium, Actinomyces and Capnocytophaga, were dominant in the HC group, while 51 genera, Streptococcus, Veillonella and Leptotrichia, were enriched in the AIH group. Notably, we found 23 gene functions, including Membrane Transport, Carbohydrate Metabolism, and Glycerolipid metabolism that were dominant in AIH and 31 gene functions that prevailed in HCs. We further investigated the correlation between the oral microbiome and clinical parameters. The optimal 5 microbial markers were figured out through a random forest model, and the distinguishing potential achieved 99.88% between 46 AIH and 92 HCs in the discovery cohort and 100% in the validation cohort. Importantly, the distinguishing potential reached 95.55% in the cross-regional validation cohort. In conclusion, this study is the first to characterize the oral microbiome in AIH patients and to report the successful establishment of a diagnostic model and the cross-regional validation of microbial markers for AIH. Importantly, oral microbiota-targeted biomarkers may be able to serve as powerful and noninvasive diagnostic tools for AIH.
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Affiliation(s)
- Benchen Rao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jiamin Lou
- Department of Infectious Diseases, Yiwu Central Hospital, Yiwu, China
| | - Haifeng Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Hongxia Liang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Heqi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yajuan Fan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hua Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ying Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yawen Zou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhongwen Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yan Jiang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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20
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Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China.
- Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China
- Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan
- The University of Tokyo, Tokyo, Japan
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21
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Higuchi T, Oka S, Furukawa H, Tohma S, Yatsuhashi H, Migita K. Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response. Hum Genomics 2021; 15:6. [PMID: 33509297 PMCID: PMC7841991 DOI: 10.1186/s40246-020-00301-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/15/2020] [Indexed: 01/10/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.
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Affiliation(s)
- Takashi Higuchi
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.,Department of Nephrology, Ushiku Aiwa General Hospital, 896 Shishiko-cho, Ushiku, 300-1296, Japan.,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan
| | - Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan.,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. .,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan. .,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan.
| | - Shigeto Tohma
- Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan.,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan.,Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan
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22
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Li Y, Gong L, Weng L, Pan X, Liu C, Li M. Interleukin-39 exacerbates concanavalin A-induced liver injury. Immunopharmacol Immunotoxicol 2021; 43:94-99. [PMID: 33412981 DOI: 10.1080/08923973.2020.1869778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Interleukin (IL)-39 is a novel member of IL-12 family and has been reported to play a pro-inflammatory role in lupus-like mice, but its function in concanavalin A (ConA)-induced liver injury is currently unclear. MATERIALS AND METHODS In this study, we investigated the effects of IL-39 expression in a mouse model of ConA induced-hepatitis. We first showed that delivery of plasmid DNA encoding mouse IL-39 using the hydrodynamic tail vein injection method increased IL-39 mRNA and protein levels in the liver. We then administrated mice with IL-39 plasmid before ConA injection and measured serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, inflammatory infiltration, and hepatocyte necrosis in the liver. Additionally, we further explored the potential mechanism of IL-39 in ConA-induced liver injury by measuring several inflammatory mediators. RESULTS We found that ectopic IL-39 expression promoted the ConA-induced increase in serum ALT and AST levels, inflammatory infiltration, and hepatocyte necrosis in the liver. We also observed that IL-39 plasmid administration significantly increased serum and liver interferon-γ, tumor necrosis factor-α, and IL-17A levels, but did not affect serum and liver IL-10 levels in ConA-induced hepatitis. CONCLUSION Our results suggest that IL-39 can exacerbate ConA-induced hepatitis and may be a therapeutic target in inflammatory liver disease.
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Affiliation(s)
- Yan Li
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
| | - Luping Gong
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China.,School of Marine Sciences, Ningbo University, Ningbo, China
| | - Linjie Weng
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China.,School of Marine Sciences, Ningbo University, Ningbo, China
| | - Xiuhe Pan
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
| | - Chaobo Liu
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
| | - Mingcai Li
- The Affiliated Hospital of Medical School of Ningbo University, and Department of Immunology, Ningbo University School of Medicine, Ningbo, China
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23
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Lou J, Jiang Y, Rao B, Li A, Ding S, Yan H, Zhou H, Liu Z, Shi Q, Cui G, Yu Z, Ren Z. Fecal Microbiomes Distinguish Patients With Autoimmune Hepatitis From Healthy Individuals. Front Cell Infect Microbiol 2020; 10:342. [PMID: 32850468 PMCID: PMC7416601 DOI: 10.3389/fcimb.2020.00342] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 06/04/2020] [Indexed: 12/12/2022] Open
Abstract
Objective: The intestinal microbiome is associated with various autoimmune diseases. Regional difference is the main influencing factor of intestinal microbial difference. This study aimed to identify the differences in fecal microbiome between autoimmune hepatitis (AIH) patients and healthy controls (HCs) in Central China, and to validate the efficacy of fecal microbiome as a diagnostic tool for AIH. Design: We collected 115 fecal samples from AIH patients (N = 37) and HCs (N = 78) in Central China and performed gene sequencing. Fecal microbiomes were characterized and microbial markers for AIH were identified. Results: Fecal microbial diversity showed a downward trend in AIH compared with HCs. Fecal microbial communities significantly differed between both groups. At the phylum level, Verrucomicrobia abundance was significantly increased, while Lentisphaerae and Synergistetes were significantly decreased in the AIH patients vs. the HCs. Compared to the HCs, 15 genera, including Veillonella, Faecalibacterium, and Akkermansia, were enriched, while 19 genera, such as Pseudobutyrivibrio, Lachnospira, and Ruminococcaceae, were decreased in the AIH patients. Ten genera, including Veillonella, Faecalibacterium, and Akkermansia, predominated in the AIH patients. Five microbial biomarkers were deemed optimal diagnostic tools for AIH. The probability of disease was significantly increased in AIH group vs. HCs, achieving 83.25% value of area under the curve. Conclusion: We present the characteristics of AIH patients in Central China for the first time. Five microbial biomarkers, including Lachnospiraceae, Veillonella, Bacteroides, Roseburia, and Ruminococcaceae, achieved a high potential distinguishing AIH patients from HCs.
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Affiliation(s)
- Jiamin Lou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Jiang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Benchen Rao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Suying Ding
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Hang Yan
- Health Management Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Heqi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenguo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingmiao Shi
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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24
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Anand AC, Nandi B, Acharya SK, Arora A, Babu S, Batra Y, Chawla YK, Chowdhury A, Chaoudhuri A, Eapen EC, Devarbhavi H, Dhiman R, Datta Gupta S, Duseja A, Jothimani D, Kapoor D, Kar P, Khuroo MS, Kumar A, Madan K, Mallick B, Maiwall R, Mohan N, Nagral A, Nath P, Panigrahi SC, Pawar A, Philips CA, Prahraj D, Puri P, Rastogi A, Saraswat VA, Saigal S, Shalimar, Shukla A, Singh SP, Verghese T, Wadhawan M, The INASL Task-Force on Acute Liver Failure. Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis. J Clin Exp Hepatol 2020; 10:339-376. [PMID: 32655238 PMCID: PMC7335721 DOI: 10.1016/j.jceh.2020.04.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 04/12/2020] [Indexed: 12/12/2022] Open
Abstract
Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.
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Key Words
- ACLF, acute on chronic liver failure
- AFLP, acute fatty liver of pregnancy
- AKI, Acute kidney injury
- ALF, Acute liver failure
- ALFED, Acute Liver Failure Early Dynamic
- ALT, alanine transaminase
- ANA, antinuclear antibody
- AP, Alkaline phosphatase
- APTT, activated partial thromboplastin time
- ASM, alternative system of medicine
- ASMA, antismooth muscle antibody
- AST, aspartate transaminase
- ATN, Acute tubular necrosis
- ATP, adenosine triphosphate
- ATT, anti-TB therapy
- AUROC, Area under the receiver operating characteristics curve
- BCS, Budd-Chiari syndrome
- BMI, body mass index
- CBF, cerebral blood flow
- CBFV, cerebral blood flow volume
- CE, cerebral edema
- CHBV, chronic HBV
- CLD, chronic liver disease
- CNS, central nervous system
- CPI, clinical prognostic indicator
- CSF, cerebrospinal fluid
- DAMPs, Damage-associated molecular patterns
- DILI, drug-induced liver injury
- EBV, Epstein-Barr virus
- ETCO2, End tidal CO2
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- HAV, hepatitis A virus
- HBV, Hepatitis B virus
- HELLP, hemolysis
- HEV, hepatitis E virus
- HLH, Hemophagocytic lymphohistiocytosis
- HSV, herpes simplex virus
- HV, hepatic vein
- HVOTO, hepatic venous outflow tract obstruction
- IAHG, International Autoimmune Hepatitis Group
- ICH, intracerebral hypertension
- ICP, intracerebral pressure
- ICU, intensive care unit
- IFN, interferon
- IL, interleukin
- IND-ALF, ALF of indeterminate etiology
- INDILI, Indian Network for DILI
- KCC, King's College Criteria
- LC, liver cirrhosis
- LDLT, living donor liver transplantation
- LT, liver transplantation
- MAP, mean arterial pressure
- MHN, massive hepatic necrosis
- MPT, mitochondrial permeability transition
- MUAC, mid-upper arm circumference
- NAPQI, n-acetyl-p-benzo-quinone-imine
- NPV, negative predictive value
- NWI, New Wilson's Index
- ONSD, optic nerve sheath diameter
- PAMPs, pathogen-associated molecular patterns
- PCR, polymerase chain reaction
- PELD, Pediatric End-Stage Liver Disease
- PPV, positive predictive value
- PT, prothrombin time
- RAAS, renin–angiotensin–aldosterone system
- SHF, subacute hepatic failure
- SIRS, systemic inflammatory response syndrome
- SNS, sympathetic nervous system
- TB, tuberculosis
- TCD, transcranial Doppler
- TGF, tumor growth factor
- TJLB, transjugular liver biopsy
- TLR, toll-like receptor
- TNF, tumor necrosis factor
- TSFT, triceps skin fold thickness
- US, ultrasound
- USALF, US Acute Liver Failure
- VZV, varicella-zoster virus
- WD, Wilson disease
- Wilson disease (WD)
- YP, yellow phosphorus
- acute liver failure
- autoimmune hepatitis (AIH)
- drug-induced liver injury
- elevated liver enzymes, low platelets
- sALI, severe acute liver injury
- viral hepatitis
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Affiliation(s)
- Anil C. Anand
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Bhaskar Nandi
- Department of Gastroenterology, Sarvodaya Hospital and Research Centre, Faridababd, Haryana, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
| | - Anil Arora
- Institute of Liver Gastroenterology &Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Sethu Babu
- Department of Gastroenterology, Krishna Institute of Medical Sciences, Hyderabad 500003, India
| | - Yogesh Batra
- Department of Gastroenterology, Indraprastha Apollo Hospital, SaritaVihar, New Delhi, 110 076, India
| | - Yogesh K. Chawla
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, 700020, India
| | - Ashok Chaoudhuri
- Hepatology and Liver Transplant, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
| | - Eapen C. Eapen
- Department of Hepatology, Christian Medical College, Vellore, India
| | - Harshad Devarbhavi
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, 560034, India
| | - RadhaKrishan Dhiman
- Department of Hepatology, Post graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Siddhartha Datta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Ajay Duseja
- Department of Hepatology, Post graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Dinesh Jothimani
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Chrompet, Chennai, 600044, India
| | | | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
| | - Mohamad S. Khuroo
- Department of Gastroenterology, Dr Khuroo’ S Medical Clinic, Srinagar, Kashmir, India
| | - Ashish Kumar
- Institute of Liver Gastroenterology &Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Kaushal Madan
- Gastroenterology and Hepatology, Max Smart Super Specialty Hospital, Saket, New Delhi, India
| | - Bipadabhanjan Mallick
- Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Rakhi Maiwall
- Hepatology Incharge Liver Intensive Care, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
| | - Neelam Mohan
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – the Medicity Hospital, Sector – 38, Gurgaon, Haryana, India
| | - Aabha Nagral
- Department of Gastroenterology, Apollo and Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Preetam Nath
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Sarat C. Panigrahi
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Ankush Pawar
- Liver & Digestive Diseases Institute, Fortis Escorts Hospital, Okhla Road, New Delhi, 110 025, India
| | - Cyriac A. Philips
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682028, Kerala, India
| | - Dibyalochan Prahraj
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
| | - Pankaj Puri
- Department of Hepatology and Gastroenterology, Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
| | - Amit Rastogi
- Department of Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Sanjiv Saigal
- Department of Hepatology, Department of Liver Transplantation, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 29, India
| | - Akash Shukla
- Department of Gastroenterology, LTM Medical College & Sion Hospital, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
| | - Thomas Verghese
- Department of Gastroenterology, Government Medical College, Kozikhode, India
| | - Manav Wadhawan
- Institute of Liver & Digestive Diseases and Head of Hepatology & Liver Transplant (Medicine), BLK Super Speciality Hospital, Delhi, India
| | - The INASL Task-Force on Acute Liver Failure
- Department of Gastroenterology, Kaliga Institute of Medical Sciences, Bhubaneswar, 751024, India
- Department of Gastroenterology, Sarvodaya Hospital and Research Centre, Faridababd, Haryana, India
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
- Institute of Liver Gastroenterology &Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
- Department of Gastroenterology, Krishna Institute of Medical Sciences, Hyderabad 500003, India
- Department of Gastroenterology, Indraprastha Apollo Hospital, SaritaVihar, New Delhi, 110 076, India
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education & Research, Kolkata, 700020, India
- Hepatology and Liver Transplant, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
- Department of Hepatology, Christian Medical College, Vellore, India
- Department of Gastroenterology and Hepatology, St. John's Medical College Hospital, Bangalore, 560034, India
- Department of Hepatology, Post graduate Institute of Medical Education and Research, Chandigarh, 160 012, India
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Centre, Chrompet, Chennai, 600044, India
- Gleneagles Global Hospitals, Hyderabad, Telangana, India
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
- Department of Gastroenterology, Dr Khuroo’ S Medical Clinic, Srinagar, Kashmir, India
- Gastroenterology and Hepatology, Max Smart Super Specialty Hospital, Saket, New Delhi, India
- Department of Gastroenterology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751024, India
- Hepatology Incharge Liver Intensive Care, Institute of Liver & Biliary Sciences, D-1 Vasant Kunj, New Delhi, India
- Department of Pediatric Gastroenterology, Hepatology & Liver Transplantation, Medanta – the Medicity Hospital, Sector – 38, Gurgaon, Haryana, India
- Department of Gastroenterology, Apollo and Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
- Liver & Digestive Diseases Institute, Fortis Escorts Hospital, Okhla Road, New Delhi, 110 025, India
- The Liver Unit and Monarch Liver Lab, Cochin Gastroenterology Group, Ernakulam Medical Centre, Kochi, 682028, Kerala, India
- Department of Hepatology and Gastroenterology, Fortis Escorts Liver & Digestive Diseases Institute (FELDI), Fortis Escorts Hospital, Delhi, India
- Department of Liver Transplantation, Medanta – the MedicityHospital, Sector – 38, Gurgaon, Haryana, India
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raibareli Road, Lucknow, Uttar Pradesh, 226 014, India
- Department of Hepatology, Department of Liver Transplantation, India
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 29, India
- Department of Gastroenterology, LTM Medical College & Sion Hospital, India
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
- Department of Gastroenterology, Government Medical College, Kozikhode, India
- Institute of Liver & Digestive Diseases and Head of Hepatology & Liver Transplant (Medicine), BLK Super Speciality Hospital, Delhi, India
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Mycophenolate mofetil attenuates concanavalin A-induced acute liver injury through modulation of TLR4/NF-κB and Nrf2/HO-1 pathways. Pharmacol Rep 2020; 72:945-955. [PMID: 32048261 DOI: 10.1007/s43440-019-00055-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 11/24/2019] [Accepted: 12/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute liver injury (ALI) is a serious health condition associated with rising morbidity and sudden progression. This study was designed to investigate the possible hepatocurative potential of two dose levels (30 and 60 mg/kg) of Mycophenolate mofetil (MMF), an immune-suppressant agent, against Concanavalin A (Con A)-induced ALI in mice. METHOD A single dose of Con A (20 mg/kg, IV) was used to induce ALI in mice. MMF (30 mg/kg and 60 mg/kg) was administered orally for 4 days post Con A injection. RESULTS MMF (30 mg/kg) failed to cause significant amelioration in Con A-induced ALI while MMF (60 mg/kg) significantly alleviated Con A-induced ALI. Administration of MMF (60 mg/kg) significantly decreased Con A-induced increase in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Additionally, MMF significantly restored the disrupted oxidant/antioxidants status induced by Con A. MMF caused marked increase in hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels. Moreover, MMF significantly reduced Con A-induced increase in the expression of hepatic toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin-1β (Il-1β). Also, MMF administration significantly decreased Con A-induced increase in the immune-expression of pro-apoptotic Bcl-2-associated X protein (Bax) and markedly increased Con A-induced decrease in the anti-apoptotic B-cell lymphoma 2 protein (Bcl2). CONCLUSION The observed ameliorative effect of MMF against Con A-induce ALI may be contributed to its anti-inflammatory, anti-oxidant and anti-apoptotic potentials taking into consideration that TLR4/NF-κB and Nrf2/HO-1 are the main implicated pathways. Schematic diagram summarizing the possible mechanisms underlying the ameliorative potential of Mycophenolate Mofetil against Con A-induced acute liver injury. Bax Bcl-2-associated X protein, Bcl2 B-cell lymphoma 2, MMF Mycophenolate mofetil, Con A Concanavalin A, GSH reduced glutathione, HO-1 Heme oxygenase-1, IL-1β Interleukin-1β, IFN-γ Interferon-γ, MDA Malondialdehyde, NF-κB Nuclear Factor Kappa B, Nrf2 Nuclear factor erythroid 2-related factor 2, NO Nitric Oxide, SOD Superoxide Dismutase, TLR4 Toll-like receptor 4, TNF-α tumor necrosis factor-α.
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26
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Chi G, Pei JH, Ma QY, Ru YX, Feng ZH. Chemical induced inflammation of the liver breaks tolerance and results in autoimmune hepatitis in Balb/c mice. Immunol Lett 2019; 218:44-50. [PMID: 31794800 DOI: 10.1016/j.imlet.2019.11.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 11/10/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease mediated by immunity, and could lead to liver fibrosis and hepatocellular carcinoma. However, the mechanisms for breaking hepatic tolerance and driving AIH still remain elusive. We herein reported that the non-specific liver inflammation triggered by carbon tetrachloride (CCl4) recruited high numbers of CD4+T, CD8+T and B cells, and elevated the expression of proinflammaitory cytokines in Balb/c mice, further breaking liver tolerance and inducing autoimmune response, AIH inflammation and liver fibrosis in the presence of CYP2D6 antigen mimicry. In contrast, adenovirus infection could not break liver tolerance and induce AIH in Balb/c mice even in the presence of CYP2D6 antigen mimicry. These results suggested that genetic predisposition could determine liver tolerance in Balb/c mice. The chemical induced inflammation in the liver breaks tolerance and might be considered important for the initiation and development of AIH in Balb/c mice.
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Affiliation(s)
- Gang Chi
- Department of Biochemistry, Changzhi Medical College, Changzhi, Shanxi 046000, China.
| | - Jin-Hong Pei
- Department of Biochemistry, Changzhi Medical College, Changzhi, Shanxi 046000, China
| | - Qin-Ya Ma
- DNA Laboratory, Changzhi Public Security Bureau, Changzhi, Shanxi 046000, China
| | - Ying-Xia Ru
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China
| | - Zuo-Hua Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, 430030, China.
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27
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Tanaka A, Kono H, Leung PSC, Gershwin ME. Recurrence of disease following organ transplantation in autoimmune liver disease and systemic lupus erythematosus. Cell Immunol 2019; 347:104021. [PMID: 31767117 DOI: 10.1016/j.cellimm.2019.104021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/01/2019] [Accepted: 11/15/2019] [Indexed: 12/15/2022]
Abstract
Disease recurrence after organ transplantation associated with graft failure is a major clinical challenge in autoimmune diseases. Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and autoimmune Hepatitis (AIH) are the three most common (autoimmune liver diseases) ALD for which liver transplantation (LT) is the most effective treatment option for patients with end-stage diseases. Although the 5- and 10-year survival rates of post-LT patients are remarkable (80-84% and 71-79% in PBC, 73-87% and 58-83% in PSC, 76-79% and 67-77% respectively in AIH patients), post-LT disease recurrence is not uncommon. Here, we summarize literature findings on disease recurrence of these ALD with emphasis on the incidence, risk factors and impact on long-term outcome. We noted that the incidence of disease recurrence varies between studies, which ranges from 53% to 10.9% in PBC, 8.2% to 44.7% in PSC and 7% to 42% in AIH. The variations are likely due to differences in study design, such as sample size, duration of studies and follow up time. This is further compounded by the lack of precise clinical diagnosis criteria and biomarkers of disease recurrence in these ALD, variation in post-LT treatment protocols to prevent disease recurrence and a multitude of risk factors associated with these ALD. While recurrence of PBC and AIH does not significantly impact long term outcome including overall survival, recurrent PSC patients often require another LT. Renal transplantation, like LT, is the treatment of choice in patients with end-stage lupus nephritis. While calcineurin inhibitor (CNI) and immunosuppressive drugs have improved the survival rate, post-transplant recurrence of lupus nephritis from surveillance-biopsy proven lupus nephritis range from 30% to 44%. On the other hand, recurrence of post-transplant lupus nephritis from registry survey analysis were only 1.1% to 2.4%. In general, risk factors associated with an increased frequency of post-transplant recurrence of autoimmune diseases are not clearly defined. Large scale multi-center studies are needed to further define guidelines for the diagnosis and clinical management to minimize disease recurrence and improve outcomes of post-transplant patients.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Hajime Kono
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Patrick S C Leung
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, United States
| | - M Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA, United States.
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Chaiteerakij R, Sanpawat A, Avihingsanon A, Treeprasertsuk S. Autoimmune hepatitis in human immunodeficiency virus-infected patients: A case series and review of the literature. World J Gastroenterol 2019; 25:5388-5402. [PMID: 31558881 PMCID: PMC6761245 DOI: 10.3748/wjg.v25.i35.5388] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 08/14/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Abnormal liver chemistry is a common problem in human immunodeficiency virus (HIV)-infected patients. Common causes of abnormal liver enzymes in this population include viral hepatitis B/C or opportunistic infection, drug toxicity, and neoplasm. Autoimmune hepatitis is a rare cause of hepatitis in HIV-infected individuals; however, this condition has been increasingly reported over the past few years. CASE SUMMARY We present 13 HIV-infected patients (5 males and 8 females) who developed autoimmune hepatitis (AIH) after their immune status was restored, i.e. all patients had stable viral suppression with undetectable HIV viral loads, and median CD4+ counts of 557 cells/× 106 L. Eleven patients presented with chronic persistent elevation of aminotransferase enzyme levels. One patient presented with acute hepatitis and the other patient presented with jaundice. The median levels of aspartate aminotransferase and alanine aminotransferase enzymes were 178 and 177 U/mL, respectively. Elevation of immunoglobulin G levels was present in 11 (85%) patients. Antinuclear antibody and anti-smooth muscle antibody were positive in 11 (85%) and 5 (38%) patients. Liver biopsy was performed in all patients. They had histopathological findings compatible with AIH. The patients were started on prednisolone for remission induction, with good response. After improvement of the liver chemistry, the dose of prednisolone was tapered, and azathioprine was added as life-long maintenance therapy. At the last follow-up visit, all were doing well, without HIV viral rebound or infectious complications. CONCLUSION This report underscores the emergence of autoimmune hepatitis in the context of HIV infection.
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Affiliation(s)
- Roongruedee Chaiteerakij
- Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpawat
- Department of Pathology, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anchalee Avihingsanon
- Medical Department, The HIV Netherlands Australia Thailand Research Collaboration, Bangkok 10330, Thailand
| | - Sombat Treeprasertsuk
- Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
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Mubder M, Azab M, Jayaraj M, Cross C, Lankarani D, Dhindsa B, Pan JJ, Ohning G. Autoimmune hepatitis in patients with human immunodeficiency virus infection: A systematic review of the published literature. Medicine (Baltimore) 2019; 98:e17094. [PMID: 31517833 PMCID: PMC6750342 DOI: 10.1097/md.0000000000017094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Liver disease in patients with HIV is common and typically has complex and multifactorial presentations that represent a major cause of morbidity and mortality. Autoimmune hepatitis (AIH) is rarely reported in patient with HIV and the disease course and clinical outcomes for treatment have not been well characterized. We are aiming to determine the patient characteristics, disease prevalence, and treatment outcomes from published articles of patients with HIV and AIH. METHOD A systematic search of PubMed, Web of Science, and Google Scholar through February 20, 2019 identified 15 studies that reported the outcomes of AIH in patients with HIV. Because of the small sample sizes and skewed distributions, resampling tests of mean differences using permutation distributions (MAXn = 10,000 permutations) were utilized; analyses were performed using R (v. 3.5.1). Categorical differences were calculated using Fisher exact test for odds ratio = 1 (equal odds), and Cramer V was calculated for effect size; analyses were completed in SPSS (v. 25). RESULTS By reviewing 15 studies reporting a total of 35 patients with AIH and HIV, male patients were found to have significantly higher aspartate transaminase and alanine transaminase levels at time of diagnosis. No other significant findings identified. The CD4 count and viral load did not show significant correlation with AIH diagnosis or its prognosis. All patients but one who presented with severe immune deficiency and responded to highly active anti-retroviral therapy received immunosuppressive treatment without side effects and achieved remission except 2 lost to follow-up and 3 expired. CONCLUSION Although rare, but AIH can develop in patients with HIV and physicians should consider it in the differential diagnosis for HIV patients presented with abnormal liver function tests, especially after excluding hepatitis C virus and drug-induced liver injury.Patients with immune deficiency disorders who present with AIH can be treated safely with steroid either as monotherapy or in combination with another immune suppressant therapy.
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Affiliation(s)
- Mohamad Mubder
- Department of Internal Medicine, University of Nevada, Las Vegas, NV
| | - Mohamed Azab
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Loma Linda University, Loma Linda, CA
| | - Mahendran Jayaraj
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nevada, Las Vegas, NV
| | | | - Daisy Lankarani
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nevada, Las Vegas, NV
| | - Banreet Dhindsa
- Department of Internal Medicine, University of Nevada, Las Vegas, NV
| | - Jen-Jung Pan
- Department of Internal medicine, Division of Gastroenterology and Hepatology, University of Arizona-College of Medicine, Phoenix, AZ
| | - Gordon Ohning
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nevada, Las Vegas, NV
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Sano A, Inoue J, Kakazu E, Ninomiya M, Iwata T, Morosawa T, Takai S, Nakamura T, Masamune A. Acute-onset Autoimmune Hepatitis in a Patient with Selective Immunoglobulin M Deficiency. Intern Med 2019; 58:2185-2190. [PMID: 30996186 PMCID: PMC6709322 DOI: 10.2169/internalmedicine.2607-18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Selective immunoglobulin M deficiency (SIGMD) is an uncommon primary immunodeficiency disorder. We herein report an SIGMD patient with autoimmune hepatitis. A 21-year-old Japanese man was transferred to our hospital because of acute liver dysfunction. His serum IgM level was low, whereas those of IgG and IgA were normal, indicating that he had SIGMD. We diagnosed him with acute-onset autoimmune hepatitis, and his liver function test findings gradually recovered with corticosteroid administration. Although SIGMD with autoimmune diseases has been reported, the clinical features and pathogenesis have not yet been clarified. We have summarized previous reports on SIGMD patients with autoimmune diseases.
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Affiliation(s)
- Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | | | - Satoshi Takai
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Takuya Nakamura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
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31
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Chen RL, Wang QX, Ma X. Precision medicine for autoimmune hepatitis. J Dig Dis 2019; 20:331-337. [PMID: 31099976 DOI: 10.1111/1751-2980.12786] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 05/07/2019] [Indexed: 01/10/2023]
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease induced by environmental factors in genetically susceptible individuals. AIH is characterized by hypergammaglobulinemia, elevation of serum autoantibodies and transaminases, and interface hepatitis. Personalized therapy is necessary in AIH because of its heterogeneity in clinical manifestations. Precision medicine is a recent and novel therapeutic pattern which ultimately aims to achieve personalized therapy. In this review we summarize the research progress of precision medicine to treat AIH by an exploration of the susceptible genes, precision diagnosis and prognosis of AIH, pharmacogenomics and precision medication, and the precision treatment for special types of AIH.
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Affiliation(s)
- Rui Ling Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Xia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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32
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Shi Y, Wang Q, Rong J, Ren J, Song X, Fan X, Shen M, Xia Y, Wang N, Liu Z, Hu Q, Ye T, Yu L. Synthesis and biological evaluation of (1,2,4)triazole[4,3-a]pyridine derivatives as potential therapeutic agents for concanavalin A-induced hepatitis. Eur J Med Chem 2019; 179:182-195. [PMID: 31254920 DOI: 10.1016/j.ejmech.2019.06.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 05/28/2019] [Accepted: 06/08/2019] [Indexed: 02/06/2023]
Abstract
A series of (1,2,4)triazole[4,3-a]pyridine (TZP) derivatives have been designed and synthesized. Compound 8d was identified as having the most potent inhibitory activity on NO release in response to lipopolysaccharide (LPS) stimulation and inhibition of the migration induced by MCP-1 protein on RAW264.7 macrophages. Based on the screening data, an immunofluorescence assay and a real-time qPCR assay were conducted, indicating that compound 8d suppressed NF-κB p65 translocation and expression of inflammatory genes by concanavalin A (Con A)-induced RAW264.7 macrophages. More importantly, 8d also exhibited potent efficacy, alleviating Con A-induced hepatitis by downregulating the levels of plasma alanine transaminase (ALT), aspartate transaminase (AST) and inflammatory infiltration in a mouse autoimmune hepatitis (AIH) model. In addition, the flow cytometry (FCM) data showed that compound 8d inhibited the accumulation of MDSCs in the liver of Con A-induced mice. These findings raise the possibility that compound 8d might serve as a potential agent for the treatment of AIH.
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Affiliation(s)
- Yaojie Shi
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Qianqian Wang
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Juan Rong
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Jing Ren
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Xuejiao Song
- Research Center for Public Health & Preventive Medicine, West China School of Public Health & Healthy Food Evaluation Research Center/No.4 West China Teaching Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Xiaoli Fan
- Division of Digestive Diseases, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Mengyi Shen
- Division of Digestive Diseases, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China
| | - Yong Xia
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Ningyu Wang
- School of Life Science and Engineering, Southwest JiaoTong University, Chengdu, Sichuan, 611756, China
| | - Zhihao Liu
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Quanfang Hu
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China
| | - Tinghong Ye
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China.
| | - Luoting Yu
- Laboratory of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, China.
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Hao LR, Li XF, Gao C, Cao L, Han ZY, Gao H. Th17/Treg cell level and clinical characteristics of peripheral blood of patients with Sjogren's syndrome complicated with primary biliary cirrhosis. Medicine (Baltimore) 2019; 98:e15952. [PMID: 31192933 PMCID: PMC6587605 DOI: 10.1097/md.0000000000015952] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
This study aims at analyzing the Th17/Treg cell level and clinical characteristics of the peripheral blood of patients with Sjogren's syndrome (SS) complicated with primary biliary cirrhosis (PBC) so as to deepen the understanding of this disease and seek for its possible onset mechanism.A retrospective analysis was conducted on the clinical data of 24 patients [8 (33%) males and 16 (67%) females] with SS complicated with primary biliary cirrhosis, 50 patients with primary SS and 93 healthy volunteers. These patients were divided into 3 groups: experimental group (SS+PBC), control group (SS) and healthy group. Then, peripheral blood was collected and flow cytometry was conducted to detect level of Th17 cells and Treg cells. A fully automatic biochemical detector was used to detect the corresponding liver function index. The correlation analysis was made based on the clinical manifestations and biochemical characteristics.Compared with the healthy group and control group, the experimental group had the highest Th17/Treg cell ratio, and Th17 cell frequency was significantly increased (P <.05). Furthermore, ALT, AST, ALP, γ-GT, TBIL, and other indexes were positively correlated to the Th17/Treg ratio (P <.05).Th17/Treg cell level and its ratio in peripheral blood of patients with SS complicated with primary biliary cirrhosis were significantly unbalanced, indicating that Th17 cells participate in the onset of this disease to a large extent. Furthermore, the Th17/Treg ratio has a certain correlation with some of the liver function indexes, on which a stratified analysis could be made furtherly according to the seriousness of the conditions.
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Affiliation(s)
- Li-Ran Hao
- Department of Rheumatology, Shanxi Medical University, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiao-Feng Li
- Department of Rheumatology, Shanxi Medical University, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Lei Cao
- Department of Rheumatology, Shanxi Medical University, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zi-Yan Han
- Department of Digesgive, Shanxi Medical University, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Hong Gao
- Department of Digesgive, Shanxi Medical University, The Second Hospital of Shanxi Medical University, Taiyuan, China
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Higuchi T, Oka S, Furukawa H, Nakamura M, Komori A, Abiru S, Hashimoto S, Shimada M, Yoshizawa K, Kouno H, Naganuma A, Ario K, Kaneyoshi T, Yamashita H, Takahashi H, Makita F, Yatsuhashi H, Ohira H, Migita K. Role of deleterious single nucleotide variants in the coding regions of TNFAIP3 for Japanese autoimmune hepatitis with cirrhosis. Sci Rep 2019; 9:7925. [PMID: 31138864 PMCID: PMC6538649 DOI: 10.1038/s41598-019-44524-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 05/17/2019] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis. TNFAIP3 gene encodes A20, an inhibitor of nuclear factor-κB pathway, and is a susceptibility gene for autoimmune diseases. We investigated deleterious variants in the coding regions of TNFAIP3 gene of Japanese AIH patients or those with cirrhosis. The deleterious variants in the coding regions of TNFAIP3 gene were analyzed by the cycle sequencing method and the frequencies of deleterious TNFAIP3 alleles of AIH or AIH with cirrhosis were compared with those of Japanese controls. The deleterious alleles in TNFAIP3 were not associated with AIH. A significant association was shown for the deleterious alleles in TNFAIP3 (P = 0.0180, odds ratio (OR) 4.28, 95% confidence interval (CI) 1.53-11.95) with AIH with cirrhosis at presentation. The serum IgM levels in AIH patients with deleterious alleles in TNFAIP3 were tended to be lower than those without (P = 0.0152, Q = 0.1216). The frequency of deleterious alleles in TNFAIP3 was higher in the AIH subset without the DRB1 risk alleles than that with (P = 0.0052, OR 5.10, 95%CI 1.55-16.74). The deleterious alleles in TNFAIP3were associated with AIH with cirrhosis.
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Affiliation(s)
- Takashi Higuchi
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan
| | - Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan.
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Seigo Abiru
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Satoru Hashimoto
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Masaaki Shimada
- National Hospital Organization, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, 460-0001, Nagoya, Japan
| | - Kaname Yoshizawa
- Department of Gastroenterology, National Hospital Organization, Shinshu Ueda Medical Center, 1-27-21 Midorigaoka, 386-8610, Ueda, Japan
| | - Hiroshi Kouno
- National Hospital Organization, Kure Medical Center, 3-1 Aoyama-cho, 737-0023, Kure, Japan
| | - Atsushi Naganuma
- National Hospital Organization, Takasaki General Medical Center, 36 Takamatsu-cho, 370-0829, Takasaki, Japan
| | - Keisuke Ario
- National Hospital Organization, Ureshino Medical Center, 2436 Shimojuku, 843-0393, Ureshino, Japan
| | - Toshihiko Kaneyoshi
- National Hospital Organization, Fukuyama Medical Center, 4-14-17 Okinogami-cho, 720-8520, Fukuyama, Japan
| | - Haruhiro Yamashita
- National Hospital Organization, Okayama Medical Center, 1711-1 Tamasu, Kita-ku, 701-1192, Okayama, Japan
| | - Hironao Takahashi
- National Hospital Organization, Higashinagoya National Hospital, 5-101 Umemorizaka, Meito-ku, 465-8620, Nagoya, Japan
| | - Fujio Makita
- National Hospital Organization, Shibukawa Medical Center, 383 Shiroi, 377-0280, Shibukawa, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, 960-1295, Fukushima, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan.,Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, 960-1295, Fukushima, Japan
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Webb GJ, Hirschfield GM, Krawitt EL, Gershwin ME. Cellular and Molecular Mechanisms of Autoimmune Hepatitis. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2019; 13:247-292. [PMID: 29140756 DOI: 10.1146/annurev-pathol-020117-043534] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.
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Affiliation(s)
- G J Webb
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - G M Hirschfield
- National Institute for Health Research Liver Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; ,
| | - E L Krawitt
- Department of Medicine, University of Vermont, Burlington, Vermont 05405, USA; .,Department of Medicine, Dartmouth College, Hanover, New Hampshire 03755, USA
| | - M E Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, School of Medicine, University of California, Davis, California 95817, USA;
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Decreased health‐related quality of life in children and adolescents with autoimmune hepatitis. JORNAL DE PEDIATRIA (VERSÃO EM PORTUGUÊS) 2019. [DOI: 10.1016/j.jpedp.2018.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Bozzini AB, Neder L, Silva CA, Porta G. Decreased health-related quality of life in children and adolescents with autoimmune hepatitis. J Pediatr (Rio J) 2019; 95:87-93. [PMID: 29331407 DOI: 10.1016/j.jped.2017.10.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 10/16/2017] [Accepted: 10/30/2017] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE The objective of this study was to evaluate the health-related quality of life in children and adolescents with autoimmune hepatitis. METHODS A cross-sectional assessment with the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) was completed for 80 patients with autoimmune hepatitis and 45 healthy controls. Demographic data, prednisone dose, disease remission state, disease severity, and abdominal pain were also evaluated. RESULTS Based on the child self-reports, physical, emotional, school, and total scores were significantly lower in autoimmune hepatitis patients when compared with controls (p<0.05). Based on the parental reports, only the physical and total scores were significantly lower in autoimmune hepatitis patients versus controls (p<0.05). Further analysis in autoimmune hepatitis patients with abdominal pain in the last month revealed significantly lower physical, social, and total median scores (p<0.05). No differences were observed based on disease remission state or disease severity (p>0.05). Autoimmune hepatitis patients who received a prednisone dose below 0.16mg/kg/day at the time of the interview showed significantly higher physical scores than those who received a dose similar to or above 0.16mg/kg/day (87.5 [50-100] vs. 75 [15.63-100], p=0.006). CONCLUSIONS Reduced scores in the physical, emotional, and school domains were observed in pediatric autoimmune hepatitis patients compared to control patients. Abdominal pain and corticosteroid dose negatively influenced the health-related quality of life in children and adolescents with autoimmune hepatitis.
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Affiliation(s)
- Ana Beatriz Bozzini
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Pediatria, São Paulo, SP, Brazil.
| | - Luciana Neder
- Universidade Federal do Mato Grosso (UFMT), Departamento de Clínicas, Cuiabá, MT, Brazil
| | - Clovis A Silva
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Departamento de Pediatria, São Paulo, SP, Brazil
| | - Gilda Porta
- Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas, Programa de Pós-graduação Pediátrica, São Paulo, SP, Brazil
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Zachou K, Arvaniti P, Azariadis K, Lygoura V, Gatselis NK, Lyberopoulou A, Koukoulis GK, Dalekos GN. Prompt initiation of high-dose i.v. corticosteroids seems to prevent progression to liver failure in patients with original acute severe autoimmune hepatitis. Hepatol Res 2019; 49:96-104. [PMID: 30248210 DOI: 10.1111/hepr.13252] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Revised: 09/14/2018] [Accepted: 09/19/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Kalliopi Zachou
- Institute of Internal Medicine and Hepatology, Larissa, Greece.,Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Pinelopi Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Kalliopi Azariadis
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Vasiliki Lygoura
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Nikolaos K Gatselis
- Institute of Internal Medicine and Hepatology, Larissa, Greece.,Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Aggeliki Lyberopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - George K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, Larissa, Greece
| | - George N Dalekos
- Institute of Internal Medicine and Hepatology, Larissa, Greece.,Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
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Floreani A, Restrepo-Jiménez P, Secchi MF, De Martin S, Leung PS, Krawitt E, Bowlus CL, Gershwin ME, Anaya JM. Etiopathogenesis of autoimmune hepatitis. J Autoimmun 2018; 95:133-143. [DOI: 10.1016/j.jaut.2018.10.020] [Citation(s) in RCA: 75] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/18/2018] [Accepted: 10/22/2018] [Indexed: 12/13/2022]
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40
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Systematic review: diagnostic accuracy of non-invasive tests for staging liver fibrosis in autoimmune hepatitis. Hepatol Int 2018; 13:91-101. [PMID: 30443702 DOI: 10.1007/s12072-018-9907-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 10/22/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Non-invasive fibrosis assessment has been highly recommended in many liver diseases. However, comparative diagnostic accuracy of laboratory markers, ultrasound and magnetic resonance elastography (MRE) for fibrosis in autoimmune hepatitis (AIH) patients has not been established. METHODS Medline, Embase and Cochrane Library were searched. Primary outcome was significant fibrosis (SF), advanced fibrosis (AF) and cirrhosis, defined as Metavir stage F ≥ 2, F ≥ 3 and F = 4 according to liver biopsy. Hierarchical summary receiver operating characteristic curve (ROC) model was used to evaluate diagnostic accuracy of non-invasive methods. Summary area under ROC (AUROC) and diagnostic odds ratio (DOR) with 95% confidence interval (CI) were calculated. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess quality of evidence. RESULTS Overall, 16 studies with 861 patients were included, comparing aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index (FIB-4), aspartate aminotransferase/alanine aminotransferase ratio, transient elastography (TE), acoustic radiation force impulse, shear wave elastography and MRE versus liver biopsy. Among all non-invasive markers, TE had good performance for fibrosis staging. Summary AUROCs and DORs of TE were 0.90 (95% CI 0.87, 0.92) and 23.7, 0.91 (95% CI 0.89, 0.93) and 31.6, 0.89 (95% CI 0.86, 0.92) and 80.5 for staging SF, AF and cirrhosis, whereas APRI and FIB-4 showed poor performance for detecting AF (DOR, 4.6 and 4.7) and cirrhosis (DOR, 5.5 and 12.9). CONCLUSIONS TE performs well to stage liver fibrosis in patients with AIH, compared with other laboratory non-invasive indexes. Nevertheless, diagnostic accuracy of APRI and FIB-4 is poor.
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41
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Chaouali M, Fernandes V, Ghazouani E, Pereira L, Kochkar R. Association of STAT4, TGFβ1, SH2B3 and PTPN22 polymorphisms with autoimmune hepatitis. Exp Mol Pathol 2018; 105:279-284. [PMID: 30291855 DOI: 10.1016/j.yexmp.2018.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2018] [Revised: 09/09/2018] [Accepted: 10/01/2018] [Indexed: 12/19/2022]
Abstract
The physiopathology of autoimmune hepatitis (AIH) is complex and still not fully elucidated. The genes localized outside the histocompatibility complex involved in regulation and signal transduction of the immune system SH2B3, TGFβ1, STAT4 and PTPN22 could be associated to the susceptibility and hepatocyte lysis mechanism of this lethal autoimmune disorder. PATIENTS AND METHODS We investigated four polymorphic sites in SH2B3 (rs3184504), TGFβ1 (rs1800471), STAT4 (rs7574865) and PTPN22 (rs2476601) in 45 AIH patients and 150 healthy controls from Tunisia using real-time PCR. RESULTS Significant associations were found for SH2B3 T allele (OR = 1.861; p = 0.015, pc = 0.366) and PTPN22 A allele (OR = 7.070; p = 0.026; pc = 1.00) and AIH with opposite homozygous being protective against the disease (CC genotype with OR = 0.420, p = 0.025; GG genotype with OR = 0.136, p = 0.025, respectively). No statistically significant associations were found for the TGFβ1 and STAT4 polymorphisms with AIH susceptibility. CONCLUSION Our work enlarges information on non-HLA genes that are associated with AIH by focusing in a region of the world that was poorly molecularly characterized for this disease.
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Affiliation(s)
- Marwa Chaouali
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia; Laboratory of Mycology Pathologies and Biomarkers, El Manar University, Tunis 1092, Tunisia.
| | - Veronica Fernandes
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto 4200-135, Portugal
| | - Ezzedine Ghazouani
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
| | - Luisa Pereira
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto 4200-135, Portugal; Faculdade de Medicina da Universidade do Porto, Portugal
| | - Radhia Kochkar
- Department of Immunology, Military Hospital of Tunis, Montfleury 1008, Tunis, Tunisia
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Jin L, Fu X, Yao S, Yang J, Ning G, Zhang Z. Protective effects of protopanaxatriol on acute liver injury induced by concanavalin A. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:81-87. [PMID: 30269219 DOI: 10.1007/s00210-018-1567-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 09/19/2018] [Indexed: 10/28/2022]
Abstract
The purpose of this study was to explore the protective effect of protopanaxatriol (PPT) on acute liver injury induced by concanavalin A (ConA). In this study, mice were randomly separated into four groups. The first group received PBS (i.v.). The second group was given PPT (50 mg/kg body weight, i.p.) for 3 days before PBS (i.v.) injection. The third group received ConA (15 mg/kg body weight, i.v.). The fourth group was administered PPT (50 mg/kg body weight, i.p.) for 3 days before ConA (i.v.) injection. The serum levels of ALT and AST were detected after 20 h of ConA injection. The pathological changes of liver were observed by H/E staining. The expression of inflammatory factors was measured by ELISA and qRTPCR, and the changes of the signaling pathway were detected by western blot. Histopathological changes and blood transaminase elevation indicated significant liver injury after ConA injection. However, PPT pretreatment obviously reversed these changes. The ELISA and qRT-PCR results indicated that PPT preconditioning significantly inhibited the production of inflammatory factors. In addition, this inhibitory effect of PPT was mainly mediated by regulation of the nuclear factor-κB (NF-κB) signaling pathway. The active ingredient of ginseng, PPT, exerts an obvious protective effect on acute liver injury caused by ConA through inhibiting the inflammatory response.
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Affiliation(s)
- Lina Jin
- Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Xue Fu
- Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China
| | - Shuangshuang Yao
- Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China
| | - Jian Yang
- Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China
| | - Guang Ning
- Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China
| | - Zhiguo Zhang
- Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai Clinical Center for Endocrine and Metabolic Diseases, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, People's Republic of China.
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43
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Lian M, Selmi C, Gershwin ME, Ma X. Myeloid Cells and Chronic Liver Disease: a Comprehensive Review. Clin Rev Allergy Immunol 2018; 54:307-317. [PMID: 29313221 DOI: 10.1007/s12016-017-8664-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myeloid cells play a major role in the sensitization to liver injury, particularly in chronic inflammatory liver diseases with a biliary or hepatocellular origin, and the interplay between myeloid cells and the liver may explain the increased incidence of hepatic osteodystrophy. The myeloid cell-liver axis involves several mature myeloid cells as well as immature or progenitor cells with the complexity of the liver immune microenvironment aggravating the mist of cell differentiation. The unique positioning of the liver at the junction of the peripheral and portal circulation systems underlines the interaction of myeloid cells and hepatic cells and leads to immune tolerance breakdown. We herein discuss the scenarios of different chronic liver diseases closely modulated by myeloid cells and illustrate the numerous potential targets, the understanding of which will ultimately steer the development of solid immunotherapeutic regimens. Ultimately, we are convinced that an adequate modulation of the liver microenvironment to modify the functional and quantitative characteristics of myeloid cells will be a successful approach to treating chronic liver diseases of different etiologies.
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Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.,BIOMETRA Department, University of Milan, Milan, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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Renand A, Habes S, Mosnier JF, Aublé H, Judor JP, Vince N, Hulin P, Nedellec S, Métairie S, Archambeaud I, Brouard S, Gournay J, Conchon S. Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment. Hepatol Commun 2018; 2:968-981. [PMID: 30094407 PMCID: PMC6078209 DOI: 10.1002/hep4.1202] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 05/08/2018] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new‐onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood phenotypic analysis. Four blood lymphocyte populations were significantly altered in AIHn patients at diagnosis compared with healthy subjects. Levels of mucosal‐associated invariant T cells (MAIT), Type 1/Type 17 helper (Th1/ Th17) cells, clusters of differentiation (CD4) T cells, and invariant natural killer T cells were decreased, whereas MAIT granzyme B+ (GrB) cells were increased. A trend toward an increase of CD8+CD161+GrB+ cells was also observed. These alterations were not restored with standard immunosuppressive treatments. In the liver of AIHn patients, CD4, forkhead box P3 (Foxp3), and MAIT cell markers were enriched in the portal tract, and CD8, CD161, and GrB markers were enriched in the hepatic lobule. During remission, the hepatic lobule was clear of infiltrating T cells, but residual CD4 and MAIT cells were found in the portal tract, where Foxp3 was decreased, as previously described. In vitro, MAIT cells were functionally altered in AIH patients. Ex vivo MAIT cell activity (GrB) was linked to severe fibrosis. Conclusion: Our work proposes a global view of the lymphocyte alterations from diagnosis to remission phase in AIH patients. The absence of blood immune homeostasis restoration and the persistence of a CD4 infiltrate in the liver under standard immunosuppression could form the basis of the high risk of relapse observed in AIH. (Hepatology Communications 2018; 00:000‐000)
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Affiliation(s)
- Amédée Renand
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Institut de Transplantation Urologie Néphrologie CHU de Nantes Nantes France
| | - Sarah Habes
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Institut de Transplantation Urologie Néphrologie CHU de Nantes Nantes France.,Service Hépato-Gastro-entérologie et Assistance Nutritionnelle CHU Nantes Nantes France
| | - Jean-François Mosnier
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Service Anatomie et Cytologie Pathologiques CHU Nantes Nantes France
| | - Hélène Aublé
- Centre d'Investigation Clinique gastro-nutrition CHU Nantes Nantes France
| | - Jean-Paul Judor
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Institut de Transplantation Urologie Néphrologie CHU de Nantes Nantes France
| | - Nicolas Vince
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Institut de Transplantation Urologie Néphrologie CHU de Nantes Nantes France
| | - Philippe Hulin
- MicroPICell Imaging Core Facility, SFR Santé F. Bonamy UMS016, INSERM, CNRS Université de Nantes Nantes France
| | - Steven Nedellec
- MicroPICell Imaging Core Facility, SFR Santé F. Bonamy UMS016, INSERM, CNRS Université de Nantes Nantes France
| | - Sylvie Métairie
- Service Chirurgie Digestive et Endocrinienne CHU Nantes Nantes France
| | - Isabelle Archambeaud
- Service Hépato-Gastro-entérologie et Assistance Nutritionnelle CHU Nantes Nantes France.,Institut des Maladies de l'Appareil Digestif, IMAD CHU Nantes Nantes France
| | - Sophie Brouard
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Institut de Transplantation Urologie Néphrologie CHU de Nantes Nantes France
| | - Jérôme Gournay
- Service Hépato-Gastro-entérologie et Assistance Nutritionnelle CHU Nantes Nantes France.,Institut des Maladies de l'Appareil Digestif, IMAD CHU Nantes Nantes France
| | - Sophie Conchon
- Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM Université de Nantes Nantes France.,Institut de Transplantation Urologie Néphrologie CHU de Nantes Nantes France
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45
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Oka S, Higuchi T, Furukawa H, Nakamura M, Komori A, Abiru S, Nagaoka S, Hashimoto S, Naganuma A, Naeshiro N, Yoshizawa K, Shimada M, Nishimura H, Tomizawa M, Kikuchi M, Makita F, Yamashita H, Ario K, Yatsuhashi H, Tohma S, Kawasaki A, Tsuchiya N, Migita K. Association of a single nucleotide polymorphism in TNIP1 with type-1 autoimmune hepatitis in the Japanese population. J Hum Genet 2018; 63:739-744. [PMID: 29559739 DOI: 10.1038/s10038-018-0440-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 02/02/2018] [Accepted: 02/22/2018] [Indexed: 12/20/2022]
Abstract
Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03-1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12-1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.
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Affiliation(s)
- Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Takashi Higuchi
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan.
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Seigo Abiru
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Shinya Nagaoka
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Satoru Hashimoto
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Atsushi Naganuma
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Noriaki Naeshiro
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Kaname Yoshizawa
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Masaaki Shimada
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Hideo Nishimura
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Minoru Tomizawa
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Masahiro Kikuchi
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Fujio Makita
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Haruhiro Yamashita
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Keisuke Ario
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
| | - Shigeto Tohma
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Aya Kawasaki
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
| | - Naoyuki Tsuchiya
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan
- NHO-AIH Study Group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856‑8562, Japan
- Department of Rheumatology, School of Medicine, Fukushima Medical University, 1-Banchi Hikarigaoka, Fukushima, 960-1295, Japan
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Tanaka A, Leung PS, Young HA, Gershwin ME. Therapeutic and immunological interventions in primary biliary cholangitis: from mouse models to humans. Arch Med Sci 2018; 14:930-940. [PMID: 30002712 PMCID: PMC6040118 DOI: 10.5114/aoms.2017.70995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 04/15/2017] [Indexed: 12/12/2022] Open
Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Patrick S.C. Leung
- Division of Rheumatology Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
| | - Howard A. Young
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA
| | - M. Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, School of Medicine, University of California, Davis, CA, USA
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Takai S, Inoue J, Kogure T, Kakazu E, Ninomiya M, Iwata T, Umetsu T, Nakamura T, Sano A, Shimosegawa T. Acute-onset Autoimmune Hepatitis in a Young Woman with Type 1 Diabetes Mellitus. Intern Med 2018; 57:1591-1596. [PMID: 29321432 PMCID: PMC6028672 DOI: 10.2169/internalmedicine.9728-17] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Autoimmune hepatitis (AIH) and type 1 diabetes mellitus (T1DM) are thought to be induced by autoimmunity, but their coexistence has rarely been reported. We herein report a case in which a patient with T1DM developed acute-onset AIH. A 26-year-old woman, who had been diagnosed with T1DM in childhood, was transferred to our hospital because of acute liver failure of unknown etiology. The administration of corticosteroids including steroid pulse therapy was effective. Based on the histological finding of massive centrilobular necrosis and a good response to steroid therapy, we diagnosed the patient with acute-onset AIH. This case indicates that AIH can occur in young T1DM patients.
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Affiliation(s)
- Satoshi Takai
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Teruyuki Umetsu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Takuya Nakamura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Japan
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48
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Chaouali M, Azaiez MB, Tezeghdenti A, Lagha A, Yacoubi-Oueslati B, Ghazouani E, Abdallah HB, Kochkar R. Association of TNF-α-308 Polymorphism with Susceptibility to Autoimmune Hepatitis in Tunisians. Biochem Genet 2018; 56:650-662. [PMID: 29845365 DOI: 10.1007/s10528-018-9867-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 05/23/2018] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic hepatitis of unknown etiology and several proinflammatory cytokines are implicated in its pathogenesis. The association of TNF-α gene polymorphism with AIH onset is not fully elucidated especially in the Tunisian population. The aim of this study was to determine the association of TNF-α (-308 G > A) polymorphism with AIH susceptibility and with TNF-α expression or clinical manifestations of AIH. A total of 50 AIH patients and 150 controls were included. Evaluation of TNF-α polymorphism was performed by ARMS PCR method. A significantly higher frequence of the AA genotype was found in AIH patients compared to controls (34 vs. 8%, p = 0.00002, OR 5.88). The frequency of the A-allele was significantly higher in patients with AIH compared to controls (55 vs. 37.3%, p = 0.002, OR 2.05). The G-allele was significantly more frequent in healthy controls compared to AIH patients [43 vs. 61.3%, p = 0.001, OR 0.47 (0.3-0.75)]. There was a positive correlation between the A/A genotype and a higher serum expression of TNF-α. The TNF*A allele confer susceptibility to AIH in the Tunisian patients and is associated with increased production of TNF-α. Anti-TNF antibodies could be an alternative to the use of corticotherapy and may avoid the exacerbated immune response in AIH.
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Affiliation(s)
- Marwa Chaouali
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia.
- Laboratory of Mycology, Pathologies and Biomarkers, El Manar University, 1092, Tunis, Tunisia.
| | - Mouna Ben Azaiez
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Aymen Tezeghdenti
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Awatef Lagha
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Basma Yacoubi-Oueslati
- Laboratory of Mycology, Pathologies and Biomarkers, El Manar University, 1092, Tunis, Tunisia
| | - Ezzeddine Ghazouani
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Hatem Ben Abdallah
- Department of Gastroenterology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
| | - Radhia Kochkar
- Department of Immunology, Military Hospital of Tunis, Montfleury, 1008, Tunis, Tunisia
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49
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Chi G, Feng XX, Ru YX, Xiong T, Gao Y, Wang H, Luo ZL, Mo R, Guo F, He YP, Zhang GM, Tian DA, Feng ZH. TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression. Mol Immunol 2018; 99:171-181. [PMID: 29793131 DOI: 10.1016/j.molimm.2018.05.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 04/27/2018] [Accepted: 05/08/2018] [Indexed: 12/12/2022]
Abstract
Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver. The liver injury resulting from virus (adenovirus) or chemicals (CCl4) could induce an amplified (stronger/long-lasting) hepatic inflammation by releasing the ligands for TLR2/TLR4. The amplified inflammation resulted in the increase of multiple cytokines and chemokines in the liver. Among them, the sustained increase of IL-6/IL-12 resulted in the activation of STAT3 and STAT4 in hepatic CD4+CD25+ Treg cells, thus suppressing Foxp3 gene expression to reduce the suppressive function of Treg cells in the liver, but not those in the spleen. The increase of IL-12 and the impairment of Treg function promoted Th1 response in presence of self-mimicking antigen (human CYP2D6). Intriguingly, the amplified inflammation resulted in the increase of IL-4 and IL-25 in the liver. The moderate increase of IL-4 was sufficient for cooperating with IL-25 to initiate Th2 response, but inefficient in suppressing Th1 response, favoring the initiation of autoimmune response. Consequently, either adenovirus/CYP2D6 or CCl4/CYP2D6 could induce the autoimmune response and AIH in the mice, leading to hepatic fibrosis. The findings in this study suggest that the amplified non-AIH inflammation in the liver could be a driving force for the initiation of autoimmune response and AIH.
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Affiliation(s)
- Gang Chi
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Xin-Xia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China.
| | - Ying-Xia Ru
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Ting Xiong
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Yuan Gao
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Zhen-Long Luo
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Ran Mo
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Fang Guo
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Yong-Pei He
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Gui-Mei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - De-An Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China
| | - Zuo-Hua Feng
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, People's Republic of China.
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