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1
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Zhu L, Hua X, Zhan L. Refining the Understanding of Autoimmune Liver Disease Mortality. Liver Int 2025; 45:e70044. [PMID: 39976305 DOI: 10.1111/liv.70044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Accepted: 02/10/2025] [Indexed: 02/21/2025]
Abstract
The comprehensive population-based cohort study of autoimmune liver disease (AILD) mortality by Lasyte et al. provides valuable epidemiological insights. Several methodological perspectives merit consideration, including public database limitations, temporal mortality trends and the role of chronic kidney disease as an unmeasured covariate in mortality risk assessment. These methodological elements further enhance the interpretation of this robust AILD mortality analysis.
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Affiliation(s)
- Lingyun Zhu
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
- Department of Intensive Rehabilitation, The First Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Xingshi Hua
- Liaoning University of Traditional Chinese Medicine Affiliated Second Hospital, Shenyang, China
| | - Libin Zhan
- Liaoning University of Traditional Chinese Medicine, Shenyang, China
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2
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Wu L, Zhang L, Huang M, Wu Y, Jin S, Zhang Y, Gan X, Yu T, Yu G, Zhang J, Wang X. Mesenchymal Stem Cell-Derived Exosomes: Emerging as a Promising Cell-Free Therapeutic Strategy for Autoimmune Hepatitis. Biomolecules 2024; 14:1353. [PMID: 39595530 PMCID: PMC11592114 DOI: 10.3390/biom14111353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated liver disease that currently faces limited treatment options. In its advanced stages, AIH can progress to liver fibrosis and cirrhosis. Recent research has increasingly focused on cell-free therapies, particularly the use of mesenchymal stem cell (MSC)-derived exosomes (Exos), which have shown promise in treating autoimmune diseases, including AIH. MSC-Exos, as microvesicles with low immunogenicity, high safety, and permeability, can deliver RNA, DNA, proteins, lipids, and various drugs for disease treatment, showing promising clinical application prospects. This review provides a comprehensive summary of the current research on MSC-Exos in the treatment of autoimmune hepatitis (AIH) and explores the underlying molecular mechanisms involved. It highlights the significant regulatory effects of MSC-Exos on immune cells and their ability to modify the microenvironment, demonstrating anti-inflammatory and anti-fibrotic properties while promoting liver regeneration. Additionally, this review also discusses potential challenges and future strategies for advancing Exo-based therapies in the treatment of AIH.
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Affiliation(s)
- Liwen Wu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Longze Zhang
- Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University, Zunyi 563003, China
| | - Minglei Huang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yan Wu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Sikan Jin
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yaqi Zhang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Xinyun Gan
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Ting Yu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Guang Yu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Jidong Zhang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Xianyao Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
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3
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Reau NS, Lammert CS, Weinberg EM. Autoimmune hepatitis: Current and future therapies. Hepatol Commun 2024; 8:e0458. [PMID: 38836863 PMCID: PMC11155538 DOI: 10.1097/hc9.0000000000000458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 04/09/2024] [Indexed: 06/06/2024] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that can lead to cirrhosis and liver failure. AIH can present in all ages, races, and ethnicities, but it predominantly affects women. As a heterogeneous disease, AIH presents variably in different patients, making diagnosis and treatment a challenge. Currently, the standard treatment for AIH comprises immunosuppressants; however, their long-term use is associated with adverse effects. The pathogenesis of AIH is complex, involving T cells, macrophages, and plasma cells that invade the periportal parenchyma and lead to an inflammatory cascade that can result in liver damage. Due to the complexity of AIH pathogenesis, treatment targets several inflammatory pathways. However, unlike other autoimmune diseases in which targeted treatments have been approved, there has been little progress made in advancing the treatment paradigm for AIH. Major obstacles to progress include challenges in conducting clinical trials, particularly patient recruitment and ensuring a diverse range of backgrounds; poorly defined outcomes to assess treatment response and improved quality of life; and a lack of study designs that account for the stage of disease and variations in treatment. A focus on individualized and steroid-free treatment approaches is needed to improve AIH prognosis and minimize steroid-associated adverse effects.
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Affiliation(s)
- Nancy S. Reau
- Section of Hepatology, Hepatology Services, Rush University Medical Center, Chicago, Illinois, USA
| | - Craig S. Lammert
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ethan M. Weinberg
- Division of Gastroenterology & Hepatology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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4
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Beehler MK, Kearns SA, Crouse ZJ. Mycophenolate mofetil as a treatment for presumed idiopathic chronic hepatitis in dogs: Six cases (2010-2022). Vet Med Sci 2023; 9:2527-2533. [PMID: 37659075 PMCID: PMC10650243 DOI: 10.1002/vms3.1261] [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: 05/29/2023] [Revised: 07/17/2023] [Accepted: 08/18/2023] [Indexed: 09/04/2023] Open
Abstract
OBJECTIVES The objectives of this study were to describe the clinical findings, treatment and outcomes of six dogs with presumed idiopathic chronic hepatitis treated with mycophenolate mofetil (MMF). MATERIALS AND METHODS Medical records were retrospectively searched to identify dogs in which idiopathic chronic hepatitis was diagnosed on histopathology between January 2010 and June 2022 that were treated with MMF for at least two weeks with >2 follow-up examinations. Data recorded from each dog included signalment, clinical signs, diagnostic test results and treatment. RESULTS Six dogs were treated with MMF at a median initial dosage of 9.6 mg/kg PO q 12 h. Reported adverse effects from MMF included decreased appetite, vomiting and diarrhoea. In all six dogs, MMF was used successfully long term for the treatment of idiopathic chronic hepatitis as determined by 46% or greater improvement of alanine aminotransferase (ALT) between 4 and 18 weeks of starting MMF. Three dogs were also temporarily treated for 4-6 months on a tapering dose of prednisone. In two dogs, ALT remained within the reference interval, and in one dog, it was very mildly elevated when on MMF alone. In all six dogs, owners reported that the medication was well tolerated. CLINICAL SIGNIFICANCE To the authors' knowledge, this is the first report describing the use of MMF with and without a tapering dose of prednisone for the treatment of idiopathic chronic hepatitis in six dogs. Based on the outcomes of the dogs in this report, MMF can be effective for the long-term treatment of idiopathic chronic hepatitis as measured by reduction in ALT and improvement of clinical signs.
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Affiliation(s)
- Michelle K. Beehler
- Department of Internal MedicineAngell Animal Medical CenterBostonMassachusettsUSA
| | - Shawn A. Kearns
- Department of Internal MedicineAngell Animal Medical CenterBostonMassachusettsUSA
| | - Zachary J. Crouse
- Department of Internal MedicineAngell Animal Medical CenterBostonMassachusettsUSA
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5
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Zhang Y, Zhang D, Chen L, Zhou J, Ren B, Chen H. The progress of autoimmune hepatitis research and future challenges. Open Med (Wars) 2023; 18:20230823. [PMID: 38025543 PMCID: PMC10655690 DOI: 10.1515/med-2023-0823] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/24/2023] [Accepted: 09/28/2023] [Indexed: 12/01/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease with various immune system manifestations, showing a global trend of increased prevalence. AIH is diagnosed through histological abnormalities, clinical manifestations, and biochemical indicators. The biochemical markers involve interfacial hepatitis, transaminase abnormalities, positive autoantibodies, etc. Although AIH pathogenesis is unclear, gene mutations and immunological factors could be the leading factors. AIH usually presents as a chronic liver disease and sometimes as acute hepatitis, making it challenging to distinguish it from drug-related hepatitis due to similar clinical symptoms. Normalizing transaminases and serum IgG levels is essential in assessing the remission status of AIH treatment. Glucocorticoids and azathioprine are the first-line AIH treatment, with lifelong maintenance therapy in some patients. The quality of life and survival can be improved after appropriate treatment. However, certain limitations jeopardize the quality of treatment, including long treatment cycles, side effects, poor patient compliance, and inability to inhibit liver fibrosis and cirrhosis. Accurate AIH animal models will help us understand the pathophysiology of the disease while providing fresh perspectives for avoiding and treating AIH. This review will help us understand AIH better, from the cellular and molecular causes to the clinical features, and will provide insight into new therapy techniques with fewer side effects.
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Affiliation(s)
- Yang Zhang
- Graduate Department of Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dehe Zhang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ling Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jing Zhou
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Binbin Ren
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Haijun Chen
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Pellicano R, Ferro A, Cicerchia F, Mattivi S, Fagoonee S, Durazzo M. Autoimmune Hepatitis and Fibrosis. J Clin Med 2023; 12:1979. [PMID: 36902767 PMCID: PMC10004701 DOI: 10.3390/jcm12051979] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/16/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic immune-inflammatory disease of the liver, generally considered a rare condition. The clinical manifestation is extremely varied and can range from paucisymptomatic forms to severe hepatitis. Chronic liver damage causes activation of hepatic and inflammatory cells leading to inflammation and oxidative stress through the production of mediators. This results in increased collagen production and extracellular matrix deposition leading to fibrosis and even cirrhosis. The gold standard for the diagnosis of fibrosis is liver biopsy; however, there are serum biomarkers, scoring systems, and radiological methods useful for diagnosis and staging. The goal of AIH treatment is to suppress fibrotic and inflammatory activities in the liver to prevent disease progression and achieve complete remission. Therapy involves the use of classic steroidal anti-inflammatory drugs and immunosuppressants, but in recent years scientific research has focused on several new alternative drugs for AIH that will be discussed in the review.
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Affiliation(s)
- Rinaldo Pellicano
- Unit of Gastroenterology, Città della Salute e della Scienza Hospital, C.so Bramante 88, 10126 Turin, Italy
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| | - Francesca Cicerchia
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| | - Simone Mattivi
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
| | - Sharmila Fagoonee
- Institute for Biostructure and Bioimaging, National Research Council, Molecular Biotechnology Centre, 10126 Turin, Italy
| | - Marilena Durazzo
- Department of Medical Sciences, University of Turin, C.so A.M. Dogliotti 14, 10126 Turin, Italy
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Kelly C, Zen Y, Heneghan MA. Post-Transplant Immunosuppression in Autoimmune Liver Disease. J Clin Exp Hepatol 2023; 13:350-359. [PMID: 36950491 PMCID: PMC10025678 DOI: 10.1016/j.jceh.2022.07.002] [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: 04/06/2022] [Revised: 06/10/2022] [Accepted: 07/04/2022] [Indexed: 02/17/2023] Open
Abstract
Autoimmune liver diseases (AILDs) are a group of conditions where immune-mediated liver damage can lead to the need for transplantation. Collectively, they account for almost a quarter of all liver transplants. Outcomes in terms of graft and patient survival for all liver transplants have improved markedly over decades with improvements in patient selection, surgical techniques and longer-term care and this is also seen in patients with AILDs. The current five- and ten-year survival rates post-transplant in autoimmune disease are excellent, at 88% and 78%, respectively. A key factor in maintaining good outcomes post liver transplant for these autoimmune conditions is the immunosuppression strategy. These patients have increased the rates of rejection, and autoimmune conditions can all recur in the graft ranging from 12 to 60% depending on the population studied. Immunosuppressive regimens are centred on calcineurin inhibitors, often combined with low dose corticosteroids, with or without the addition of antimetabolite therapy. There is no clear evidence-based immunosuppressive regimen for these conditions, and a tailored approach balancing the individuals' immunological profile against the risks of immunosuppression is often used. There are disease-specific considerations to optimised graft function including the role of ursodeoxycholic acid in both primary biliary cholangitis and primary sclerosing cholangitis and the role and timing of colectomy in primary sclerosing cholangitis in inflammatory bowel disease patients. However, unmet needs still exist in the management of AILDs post liver transplantation particularly in building the evidence base for optimal immunosuppression as well as mitigating the risk of recurrent disease.
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Key Words
- AIH, Autoimmune hepatitis
- AILD, Autoimmune liver disease
- CNI, Calcineurin inhibitors
- IBD, Inflammatory bowel disease
- LT, Liver transplantation
- PBC, Primary biliary cholangitis
- PSC, Primary sclerosing cholangitis
- autoimmune liver disease
- immunosuppression
- rAIH, Recurrent autoimmune hepatitis
- rPBC, Recurrent primary biliary cholangitis
- rPSC, Recurrent primary sclerosing cholangitis
- transplantation
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Affiliation(s)
- Claire Kelly
- Institute of Liver Studies, Kings College Hospital, London, UK
| | - Yoh Zen
- Institute of Liver Studies, Kings College Hospital, London, UK
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Kadokawa Y, Inoue S, Tatsumi A, Uchida M, Fujita K, Takagi M, Inoue T, Ohe S, Nakai Y, Otsuka T, Abe Y, Nakabori T, Isei T, Kumagai T, Nishimura K, Ohkawa K. Efficacy and safety of mycophenolate mofetil in treating immune-related hepatitis induced by immune checkpoint inhibitor use: A retrospective study. JGH Open 2023; 7:87-97. [PMID: 36852148 PMCID: PMC9958334 DOI: 10.1002/jgh3.12868] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Revised: 12/17/2022] [Accepted: 01/12/2023] [Indexed: 02/16/2023]
Abstract
Background and Aim To investigate the outcomes in eight Japanese patients with cancer treated with mycophenolate mofetil (MMF) and corticosteroids for immune checkpoint inhibitor treatment-induced severe immune-related hepatitis (ir-hepatitis) and the efficacy and safety of MMF. Methods We retrospectively examined patient background, treatment course, as well as examination and imaging data using electronic medical records. Results The ratio of male to female patients was 7:1, and the median age was 60 years (27-72 years). There were five and two cases of kidney cancer and malignant melanoma, respectively, and one case of lung cancer. The median number of days until MMF administration in addition to systemic corticosteroid therapy after the onset of ir-hepatitis was 14.5 (2-42). The patients were categorized as four "good responders" who showed an improvement in the liver function tests following MMF treatment and four "poor responders" who did not. Furthermore, the time from the onset of ir-hepatitis to initial MMF administration was significantly shorter in good responders (median 3 days, range 2-15 days) than in poor responders (median 25.5 days, range 14-42 days) (P = 0.042). No significant intergroup difference was observed in other clinical factors. No serious adverse events caused by MMF were observed in any case. Conclusions According to these findings, early recognition of corticosteroid refractoriness and the use of MMF may be beneficial in patients with ir-hepatitis.
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Affiliation(s)
- Yukio Kadokawa
- Department of PharmacyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Satoko Inoue
- Department of PharmacyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Akitoshi Tatsumi
- Faculty of Pharmaceutical SciencesKobe Gakuin UniversityKobeJapan
| | - Mayako Uchida
- Faculty of Pharmaceutical SciencesDoshisha Women's College of Liberal ArtsKyotoJapan
| | - Keiko Fujita
- Department of PharmacyOsaka General Medical Center, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Mari Takagi
- Department of PharmacyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Takako Inoue
- Department of Respiratory MedicineOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Shuichi Ohe
- Department of Dermatologic OncologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Yasutomo Nakai
- Department of UrologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Tomoyuki Otsuka
- Department of Medical OncologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Yutaro Abe
- Department of Hepatobiliary and Pancreatic OncologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Tasuku Nakabori
- Department of Hepatobiliary and Pancreatic OncologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Taiki Isei
- Department of Dermatologic OncologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Toru Kumagai
- Department of Respiratory MedicineOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Kazuo Nishimura
- Department of UrologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
| | - Kazuyoshi Ohkawa
- Department of Hepatobiliary and Pancreatic OncologyOsaka International Cancer Institute, Osaka Prefectural Hospital OrganizationOsakaJapan
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9
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Dong B, Chen Y, Lyu G, Yang X. Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis-4 Index for Detecting Liver Fibrosis in Patients With Autoimmune Hepatitis: A Meta-Analysis. Front Immunol 2022; 13:892454. [PMID: 35663945 PMCID: PMC9157437 DOI: 10.3389/fimmu.2022.892454] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 04/21/2022] [Indexed: 11/13/2022] Open
Abstract
Background Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are the two most widely studied noninvasive markers of liver fibrosis. We aimed to assess the diagnostic accuracy of APRI and FIB-4 for liver fibrosis in patients with autoimmune hepatitis (AIH) using liver biopsy as the reference standard. Methods PubMed, EMBASE, Cochrane Library and Web of Science databases were searched for studies (published as of May 1st, 2021) that assessed the diagnostic performance of APRI and FIB-4 for liver fibrosis in AIH. The summary area under receiver operating characteristics curve (AUROC), sensitivity, specificity, diagnostic odds ratios were used to assess the diagnostic accuracy of APRI and FIB-4 for detecting liver fibrosis. Results Fourteen studies (including 1015 patients) were selected with 13 studies each evaluating the use of APRI and FIB-4 for detecting different stages of fibrosis in AIH. For prediction of significant fibrosis, advanced fibrosis, and cirrhosis, the summary AUROC value was 0.66 [95% confidence interval (CI): 0.61-0.70], 0.71 (95% CI: 0.67-0.75), and 0.75 (95% CI: 0.71-0.79) for APRI, and the summary AUROC value was 0.75 (95% CI: 0.71-0.79), 0.73 (95% CI: 0.69-0.77) and 0.79 (95% CI: 0.75-0.82) for FIB-4, respectively. The summary sensitivity and specificity for diagnosis of significant fibrosis, advanced fibrosis, and cirrhosis were 90% and 36%, 78% and 55%, and 77% and 61% for APRI, and 70% and 70%, 65% and 70%, and 78% and 65% for FIB-4, respectively. Conclusions APRI and FIB-4 showed suboptimal diagnostic performance for identifying liver fibrosis in AIH with mediocre sensitivity and specificity.
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Affiliation(s)
- Bingtian Dong
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Yuping Chen
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Guorong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.,Department of Clinical Medicine, Quanzhou Medical College, Quanzhou, China
| | - Xiaocen Yang
- Department of Ultrasound, Chenggong Hospital, Xiamen University, Xiamen, China
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10
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Jiang R, Tang J, Zhang X, He Y, Yu Z, Chen S, Xia J, Lin J, Ou Q. CCN1 Promotes Inflammation by Inducing IL-6 Production via α6β1/PI3K/Akt/NF-κB Pathway in Autoimmune Hepatitis. Front Immunol 2022; 13:810671. [PMID: 35547732 PMCID: PMC9084230 DOI: 10.3389/fimmu.2022.810671] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 03/25/2022] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. CCN1, an extracellular matrix-associated protein, is associated with carcinoma, inflammation, liver fibrosis, and even autoimmune diseases. However, the role that CCN1 plays in AIH has remained undetermined. In this study, expression of CCN1 in liver was detected by real-time PCR, western blot and immunohistochemistry (IHC). CCN1 level in serum was detected by ELISA. Diagnostic value of CCN1 was determined by receiver operating characteristic (ROC) curve analysis. CCN1 conditional knockout (CCN1fl/flCre+) mice were generated by mating CCN1fl/fl C57BL/6J and CAG-Cre-ERT C57BL/6J mice. Autoimmune hepatitis mice model was induced by concanavalin A (ConA). IKKα/β, IκBα, NF-κB p65 and Akt phosphorylation were determined by western blot. NF-κB p65 nuclear translocation was examined by immunofluorescence. Here, we found that CCN1 was over-expressed in hepatocytes of AIH patients. CCN1 level also increased in serum of AIH patients compared to healthy controls (HC). ROC curve analysis results showed that serum CCN1 was able to distinguish AIH patients from HD. In ConA induced hepatitis mice model, CCN1 conditional knockout (CCN1fl/flCre+) attenuated inflammation by reducing ALT/AST level and IL-6 expression. In vitro, CCN1 treatment dramatically induced IL-6 production in LO2 cells. Moreover, the production of IL-6 was attenuated by CCN1 knockdown. Furthermore, we showed that CCN1 could activate IL-6 production via the PI3K/Akt/NF-κB signaling pathway by binding to α6β1 receptor. In summary, our results reveal a novel role of CCN1 in promoting inflammation by upregulation of IL-6 production in AIH. Our study also suggests that targeting of CCN1 may represent a novel strategy in AIH treatment.
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Affiliation(s)
- Renquan Jiang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jifeng Tang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Xuehao Zhang
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yujue He
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Ziqing Yu
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Shuhui Chen
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jinfang Xia
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jinpiao Lin
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qishui Ou
- Department of Laboratory Medicine, Gene Diagnosis Research Center, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.,Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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11
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Losurdo G, Gravina AG, Maroni L, Gabrieletto EM, Ianiro G, Ferrarese A. Future challenges in gastroenterology and hepatology, between innovations and unmet needs: A SIGE Young Editorial Board's perspective. Dig Liver Dis 2022; 54:583-597. [PMID: 34509394 DOI: 10.1016/j.dld.2021.08.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/09/2021] [Accepted: 08/12/2021] [Indexed: 02/08/2023]
Abstract
Gastroenterology, Digestive Endoscopy and Hepatology have faced significant improvements in terms of diagnosis and therapy in the last decades. However, many fields still remain poorly explored, and many questions unanswered. Moreover, basic-science, as well as translational and clinical discoveries, together with technology advancement will determine further steps toward a better, refined care for many gastroenterological disorders in the future. Therefore, the Young Investigators of the Italian Society of Gastroenterology (SIGE) joined together, offering a perspective on major future innovations in some hot clinical topics in Gastroenterology, Endoscopy, and Hepatology, as well as the current pitfalls and the grey zones.
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Affiliation(s)
- Giuseppe Losurdo
- Gastroenterology Unit, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari; PhD Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari.
| | - Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Maroni
- Department of Gastroenterology, Marche Polytechnic University, Ancona, Italy
| | | | - Gianluca Ianiro
- Digestive Disease Center, Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alberto Ferrarese
- Gastroenterology and Hepatology, Azienda Ospedaliera Universitaria Integrata, Ospedale Borgo Trento, Verona, Italy
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12
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Pape S, Snijders RJALM, Gevers TJG, Chazouilleres O, Dalekos GN, Hirschfield GM, Lenzi M, Trauner M, Manns MP, Vierling JM, Montano-Loza AJ, Lohse AW, Schramm C, Drenth JPH, Heneghan MA. Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group. J Hepatol 2022; 76:841-849. [PMID: 35066089 DOI: 10.1016/j.jhep.2021.12.041] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 11/18/2021] [Accepted: 12/11/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Autoimmune hepatitis (AIH) has been well characterised and codified through the development of diagnostic criteria. These criteria have been adapted and simplified and are widely used in clinical practice. However, there is a need to update and precisely define the criteria for both treatment response and treatment. METHODS A systematic review was performed and a modified Delphi consensus process was used to identify and redefine the response criteria in autoimmune hepatitis. RESULTS The consensus process initiated by the International Autoimmune Hepatitis Group proposes that the term 'complete biochemical response' defined as 'normalization of serum transaminases and IgG below the upper limit of normal' be adopted to include a time point at 6 months after initiation of treatment. An insufficient response by 6 months was a failure to meet the above definition. Non-response was defined as '<50% decrease of serum transaminases within 4 weeks after initiation of treatment'. Remission is defined as liver histology with a Hepatitis Activity Index <4/18. Intolerance to treatment was agreed to stand for 'any adverse event possibly related to treatment leading to potential drug discontinuation'. CONCLUSIONS These definitions provide a simple and reproducible framework to define treatment response and non-response, irrespective of the therapeutic intervention. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable inter-study comparisons. Future prospective database studies are needed to validate these endpoints. LAY SUMMARY Consensus among international experts on response criteria and endpoints in autoimmune hepatitis is lacking. A consensus on endpoints is urgently required to set a global standard for the reporting of study results and to enable the comparison of results between clinical trials. Therefore, the International Autoimmune Hepatitis Group (IAIHG) herein presents a statement on 5 agreed response criteria and endpoints: complete biochemical response, insufficient response, non-response, remission, and intolerance to treatment, which can be used to guide future reporting.
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Affiliation(s)
- Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Romée J A L M Snijders
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Tom J G Gevers
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht 6229HX, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Oliver Chazouilleres
- Hepatology Department, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Saint-Antoine Hospital Assistance Publique-Hôpitaux de Paris, Paris, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly Medical School, Larissa, Greece
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada
| | - Marco Lenzi
- Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi, University of Bologna, Bologna, Italy
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Hepatology, University of Alberta Hospital, Edmonton, Canada
| | - Ansgar W Lohse
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Christoph Schramm
- 1(st) Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands; European Reference Network on Hepatological Diseases (ERN RARE-LIVER)
| | - Michael A Heneghan
- Institute of Liver Studies, King's College Hospital, London, United Kingdom; European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
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13
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New agents for immunosuppression. Best Pract Res Clin Gastroenterol 2021; 54-55:101763. [PMID: 34874846 DOI: 10.1016/j.bpg.2021.101763] [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: 07/19/2021] [Revised: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 01/31/2023]
Abstract
The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.
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14
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Snijders RJALM, Milkiewicz P, Schramm C, Gevers TJG. Health-related quality of life in autoimmune hepatitis. World J Hepatol 2021; 13:1642-1652. [PMID: 34904034 PMCID: PMC8637685 DOI: 10.4254/wjh.v13.i11.1642] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/15/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a severe chronic autoimmune disease and has a significant impact on the patient's quality of life, in particular regarding psychological problems such as anxiety and depression. Consistent evidence on which patient-related, disease-related or physician-related factors cause health-related quality of life (HRQoL) impairment in patients with AIH is lacking. Current studies on HRQoL in AIH are mainly single-centered, comprising small numbers of patients, and difficult to compare because of the use of different questionnaires, patient populations, and cutoff values. Literature in the pediatric field is sparse, but suggests that children/adolescents with AIH have a lower HRQoL. Knowledge of HRQoL and cohesive factors in AIH are important to improve healthcare for AIH patients, for example by developing an AIH-specific chronic healthcare model. By recognizing the importance of quality of life beyond the concept of biochemical and histological remission, clinicians allow us to seek enhancements and possible interventions in the management of AIH, aiming at improved health.
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Affiliation(s)
- Romée JALM Snijders
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen 6525GA, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw 02-091, Poland
- Translational Medicine Group, Pomeranian Medical University, Szczecin 70-204, Poland
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Christoph Schramm
- First Department of Medicine, University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany
- Martin Zeitz Center for Rare Diseases and Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg Eppendorf, Hamburg 20246, Germany
- European Reference Network RARE-LIVER, Hamburg, Germany
| | - Tom JG Gevers
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen 6525GA, The Netherlands
- Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht 6229HX, The Netherlands
- European Reference Network RARE-LIVER, Hamburg, Germany.
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15
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Fujita K, Oura K, Tadokoro T, Nakahara M, Tani J, Morishita A, Kobara H, Tsutsui K, Himoto T, Masaki T. Prognosis of probable autoimmune hepatitis patients: a single-center study in Japan. Intern Emerg Med 2021; 16:2155-2162. [PMID: 33783693 DOI: 10.1007/s11739-021-02720-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/18/2021] [Indexed: 10/21/2022]
Abstract
Autoimmune hepatitis (AIH) is an idiopathic inflammatory liver disease with genetic susceptibility and unknown environmental triggers. The gold standard for diagnosis, International Autoimmune Hepatitis Group (IAIHG) scoring system, classifies AIH as definite or probable. Conventional research on probable AIH has focused on the Caucasian population and there is little data pertaining to the Asian population. This study aimed to assess and compare the prognosis of Japanese patients with probable and definite AIH. In the current study, patients with probable and definite AIH diagnosed based on IAIHG scores between 1987 and 2018 were enrolled. As a result, 72 patients with definite AIH and 49 patients with probable AIH were evaluated. Univariate analysis revealed age, fibrosis stage 4, and the fibrosis-4 index were prognostic factors for overall survival. Multivariate analysis indicated that age and liver cirrhosis significantly affected the overall survival. When the cut off albumin-bilirubin score was set appropriately, cirrhosis was differentially diagnosed using albumin-bilirubin score with 100% sensitivity and 70.5% specificity. Classification of probable or definite disease did not alter overall survival with statistical significance. In conclusion, our findings suggest that probable AIH should be managed as definite AIH is managed in Japanese population. The albumin-bilirubin score helps identify liver cirrhosis and is a prognostic biomarker for overall survival.
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Affiliation(s)
- Koji Fujita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan.
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Kunihiko Tsutsui
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1 Hara, Mure, Takamatsu, Kagawa, 761-0123, Japan.
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan
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16
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The role of diffusion tensor imaging of the liver in children with autoimmune hepatitis. Pol J Radiol 2021; 86:e461-e467. [PMID: 34567291 PMCID: PMC8449556 DOI: 10.5114/pjr.2021.108171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 04/15/2021] [Indexed: 12/04/2022] Open
Abstract
Purpose To evaluate the role of diffusion tensor imaging (DTI) of the liver in children with autoimmune hepatitis (AIH). Material and methods A prospective study was done on 42 children with AIH (30 girls and 12 boys, with a mean age of 13 years) and 20 age- and sex-matched healthy control children. They underwent DTI of the liver and laboratory tests. Liver biopsy was done for the patients. The mean diffusivity (MD) and fractional anisotropy (FA) of the liver were calculated and correlated with the pathological results. Results The mean MD and FA of the liver in children with AIH were 1.42 ± 0.06 × 10-3 mm2/s and 0.37 ± 0.11; and in the control children they were 1.55 ± 0.07 × 10-3 mm2/s and 0.25 ± 0.03, respectively. The MD and FA were significantly different in the children with AIH compared to the control children (p = 0.001). The cutoff MD and FA used to differentiate patients from controls were 1.50 × 10-3 mm2/s, 0.31 with AUC of 0.919 and 0.813, sensitivity of 97.6% and 66.7%, a specificity of 80% and 70%, an accuracy of 94.2% and 67.3%, PPV of 95.3 and 90.3, and NPV of 88.9 and 33.3, respectively. There was significantly lower MD and higher FA of the liver in children with AIH type I (n = 31) than type II (n = 11) (p = 0.001), and patients with (n = 9) and without (n = 33) overlap syndrome (p = 0.005). Conclusions We concluded that DTI parameters can help to diagnose AIH, detect its phenotyping, and give clues as to the presence of associated overlap syndrome.
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17
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Therapeutic drug monitoring of immunosuppressive drugs in hepatology and gastroenterology. Best Pract Res Clin Gastroenterol 2021; 54-55:101756. [PMID: 34874840 DOI: 10.1016/j.bpg.2021.101756] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 06/11/2021] [Indexed: 01/31/2023]
Abstract
Immunosuppressive drugs have been key to the success of liver transplantation and are essential components of the treatment of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). For many but not all immunosuppressants, therapeutic drug monitoring (TDM) is recommended to guide therapy. In this article, the rationale and evidence for TDM of tacrolimus, mycophenolic acid, the mammalian target of rapamycin inhibitors, and azathioprine in liver transplantation, IBD, and AIH is reviewed. New developments, including algorithm-based/computer-assisted immunosuppressant dosing, measurement of immunosuppressants in alternative matrices for whole blood, and pharmacodynamic monitoring of these agents is discussed. It is expected that these novel techniques will be incorporate into the standard TDM in the next few years.
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18
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Hirasawa Y, Yoshimura K, Matsui H, Kubota Y, Ishida H, Arai J, Sakaki M, Oguro N, Shida M, Taniguchi M, Hamada K, Ariizumi H, Ishiguro T, Ohkuma R, Sambe T, Horiike A, Imamura CK, Shiozawa E, Wada S, Tsurutani J, Iwamoto S, Uchida N, Kiuchi Y, Tate G, Kobayashi S, Tsunoda T. A case report on severe nivolumab-induced adverse events similar to primary sclerosing cholangitis refractory to immunosuppressive therapy. Medicine (Baltimore) 2021; 100:e25774. [PMID: 34114983 PMCID: PMC8202549 DOI: 10.1097/md.0000000000025774] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/15/2021] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death. PATIENTS CONCERNS The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses. DIAGNOSIS A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct. INTERVENTIONS Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered. OUTCOMES The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death. CONCLUSION This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.
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Affiliation(s)
- Yuya Hirasawa
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Kiyoshi Yoshimura
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
- Department of Clinical Immuno-Oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
| | - Hiroto Matsui
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Yutaro Kubota
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Hiroo Ishida
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Jun Arai
- Division of Gastroenterology, Department of Medicine
| | | | - Nao Oguro
- Division of Rheumatology, Department of Medicine
| | - Midori Shida
- Department of Clinical Immuno-Oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
| | - Makoto Taniguchi
- Department of Clinical Immuno-Oncology, Clinical Research Institute of Clinical Pharmacology and Therapeutics, Showa University
| | - Kazuyuki Hamada
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Hirotsugu Ariizumi
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Tomoyuki Ishiguro
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Ryotaro Ohkuma
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Takehiko Sambe
- Division of Clinical Pharmacology, Department of Pharmacology, Showa University School of Medicine
| | - Atsushi Horiike
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
| | - Chiyo K. Imamura
- Advanced Cancer Translational Research Institute, Showa University
| | - Eisuke Shiozawa
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine
| | - Satoshi Wada
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
- Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University
| | - Junji Tsurutani
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
- Advanced Cancer Translational Research Institute, Showa University
| | - Sanju Iwamoto
- Division of Physiology and Pathology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy
| | - Naoki Uchida
- Division of Clinical Pharmacology, Department of Pharmacology, Showa University School of Medicine
| | - Yuji Kiuchi
- Division of Medical Pharmacology, Department of Pharmacology, Showa University School of Medicine
| | - Genshu Tate
- Department of Pathology and Laboratory Medicine, Showa University School of Medicine
| | - Shinichi Kobayashi
- Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan
| | - Takuya Tsunoda
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine
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19
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Wang H, Banerjee N, Liang Y, Wang G, Hoffman KL, Khan MF. Gut microbiome-host interactions in driving environmental pollutant trichloroethene-mediated autoimmunity. Toxicol Appl Pharmacol 2021; 424:115597. [PMID: 34051218 DOI: 10.1016/j.taap.2021.115597] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/18/2021] [Accepted: 05/24/2021] [Indexed: 12/15/2022]
Abstract
Trichloroethene (TCE), a widely used industrial solvent, is associated with the development of autoimmune diseases (ADs), including systemic lupus erythematosus and autoimmune hepatitis. Increasing evidence support a linkage between altered gut microbiome composition and the onset of ADs. However, it is not clear how gut microbiome contributes to TCE-mediated autoimmunity, and initial triggers for microbiome-host interactions leading to systemic autoimmune responses remain unknown. To achieve this, female MRL+/+ mice were treated with 0.5 mg/ml TCE for 52 weeks and fecal samples were subjected to 16S rRNA sequencing to determine the microbiome composition. TCE exposure resulted in distinct bacterial community revealed by β-diversity analysis. Notably, we observed reduction in Lactobacillaceae, Rikenellaceae and Bifidobacteriaceae families, and enrichment of Akkermansiaceae and Lachnospiraceae families after TCE exposure. We also observed significantly increased colonic oxidative stress and inflammatory markers (CD14 and IL-1β), and decreased tight junction proteins (ZO-2, occludin and claudin-3). These changes were associated with increases in serum antinuclear and anti-smooth muscle antibodies and cytokines (IL-6 and IL-12), together with increased PD1 + CD4+ T cells in TCE-exposed spleen and liver tissues. Importantly, fecal microbiota transplantation (FMT) using feces from TCE-treated mice to antibiotics-treated mice induced increased anti-dsDNA antibodies and hepatic CD4+ T cell infiltration in the recipient mice. Our studies thus delineate how imbalance in gut microbiome and mucosal redox status together with gut inflammatory response and permeability changes could be the key factors in contributing to TCE-mediated ADs. Furthermore, FMT studies provide a solid support to a causal role of microbiome in TCE-mediated autoimmunity.
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Affiliation(s)
- Hui Wang
- Department of Pathology, University of Texas Medical Branch, TX, United States of America
| | - Nivedita Banerjee
- Department of Pathology, University of Texas Medical Branch, TX, United States of America
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, TX, United States of America
| | - Gangduo Wang
- Department of Pathology, University of Texas Medical Branch, TX, United States of America
| | - Kristi L Hoffman
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, United States of America
| | - M Firoze Khan
- Department of Pathology, University of Texas Medical Branch, TX, United States of America.
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20
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Abstract
Autoimmune liver diseases are characterized by immune-mediated inflammation and eventual destruction of the hepatocytes and the biliary epithelial cells. They can progress to irreversible liver damage requiring liver transplantation. The post-liver transplant goals of treatment include improving the recipient’s survival, preventing liver graft-failure, and decreasing the recurrence of the disease. The keystone in post-liver transplant management for autoimmune liver diseases relies on identifying which would be the most appropriate immunosuppressive maintenance therapy. The combination of a steroid and a calcineurin inhibitor is the current immunosuppressive regimen of choice for autoimmune hepatitis. A gradual withdrawal of glucocorticoids is also recommended. On the other hand, ursodeoxycholic acid should be initiated soon after liver transplant to prevent recurrence and improve graft and patient survival in primary biliary cholangitis recipients. Unlike the previously mentioned autoimmune diseases, there are not immunosuppressive or disease-modifying agents available for patients with primary sclerosing cholangitis. However, colectomy and annual colonoscopy are key components during the post-liver transplant period.
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21
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Aghabi YO, Yasin A, Kennedy JI, Davies SP, Butler AE, Stamataki Z. Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer. Front Immunol 2021; 12:662134. [PMID: 33953725 PMCID: PMC8089374 DOI: 10.3389/fimmu.2021.662134] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.
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Affiliation(s)
| | | | | | | | | | - Zania Stamataki
- College of Medical and Dental Sciences, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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22
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Scurt FG, Bose K, Canbay A, Mertens PR, Chatzikyrkou C. [Chronic kidney injury in patients with liver diseases - Reappraising pathophysiology and treatment options]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:560-579. [PMID: 33728618 DOI: 10.1055/a-1402-1502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Acute and chronic kidney disease concurs commonly with liver disease and is associated with a wide array of complications including dialysis dependency and increased mortality. Patients with liver disease or liver cirrhosis show a higher prevalence of chronic kidney disease. This is attributed to concomitant comorbidities, such as metabolic syndrome, chronic inflammation, hypercoagulability, hyperfibrinolysis, diabetes mellitus and dyslipidaemias. But chronic progressive kidney disease is not always due to hepatorenal syndrome. Beyond that, other diseases or disease entities should be considered. Among them are diabetic nephropathy, secondary IgA nephropathy, hepatitis C -associated membranoproliferative Glomerulonephritis (MPGN) and hepatitis B-associated membranous nephropathy.Coexisting diseases, similar underlying pathophysiologic mechanisms, or simultaneously concurring pathophysiological processes and overlapping clinical manifestations, impede the etiologic diagnosis and corresponding treatment of chronic kidney disease in the setting of chronic liver disease. In this review, we focus on common and rare pathologies, which can lead to chronic kidney disease in this particular patient group and try to summarize the most recent therapeutic modalities.
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Affiliation(s)
- Florian Gunnar Scurt
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany
| | - Katrin Bose
- Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany.,Universitätsklinik für Gastroenterologie, Hepatologie und Infektiologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland
| | - Ali Canbay
- Ruhr-Universität Bochum, Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Deutschland
| | - Peter R Mertens
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany
| | - Christos Chatzikyrkou
- Klinik für Nieren- und Hochdruckerkrankungen, Diabetologie und Endokrinologie, Medizinische Fakultät der Otto-von-Guericke-Universität, Magdeburg, Deutschland.,Health Campus Immunology, Infectiology and Inflammation, Otto von Guericke University, Magdeburg, Germany
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23
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Yu K, Yang J, Xie W, Wu F, Wang M, Li N. Integrated bioinformatic analysis revealed biological processes and immune cells implicated in autoimmune hepatitis. J Cell Physiol 2021; 236:5411-5420. [PMID: 33595095 DOI: 10.1002/jcp.30246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 12/12/2020] [Accepted: 12/15/2020] [Indexed: 12/23/2022]
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease for which the pathogenesis remains incompletely understood. The current study aimed to reveal key biological processes and immune cells implicated in AIH by integrated bioinformatic analysis. The global gene expression in livers from wild-type BALB/c mice, mice with Tgfb1 deficiency, and mice with both Tgfb1 and Ifng deficiency was assessed by microarray data analysis. Differentially expressed genes were identified and subjected to functional enrichment analysis. AIH mice with Tgfb1 deletion showed significantly enhanced immune responses but impaired metabolic processes, whereas increased T cell activation and cytokine production, but weakened organic acid and lipid metabolic processes were observed in mice with deletion of both Tgfb1 and Ifng. In addition, infiltration of immune cells was evaluated by CIBERSORT. Increased infiltration of T cells, macrophages, and natural killer cells, and decreased infiltration of neutrophils, eosinophils, plasma cells, and B cells were observed in AIH mice. In conclusion, we identified potential biological processes and immune cells that contributed to AIH; further investigations are needed to confirm these findings and thus provide a potential novel therapeutic target for AIH treatment.
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Affiliation(s)
- Kangkang Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingshu Yang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Wentao Xie
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Feizhen Wu
- Key Laboratory of Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Mei Wang
- Department of Geriatrics, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ning Li
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
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24
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Identification and characterization of dynamically regulated hepatitis-related genes in a concanavalin A-induced liver injury model. Aging (Albany NY) 2020; 12:23187-23199. [PMID: 33221747 PMCID: PMC7746381 DOI: 10.18632/aging.104089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/31/2020] [Indexed: 12/11/2022]
Abstract
Background: Concanavalin A (ConA)-induced liver damage of mice is a well-established murine model mimicking the human autoimmune hepatitis (AIH). However, the pathogenic genes of the liver injury remain to be revealed. Methods: Using time-series liver transcriptome, top dynamic genes were inferred from a set of segmented regression models, and cross-checked by weighted correlation network analysis (WGCNA). AIH murine models created by ConA were used to verify the in vivo effect of these genes. Results: We identified 115 top dynamic genes, of which most were overlapped with the hub genes determined by WGCNA. The expression of several top dynamic genes including Cd63, Saa3, Slc10a1, Nrxn1, Ugt2a3, were verified in vivo. Further, Cluster determinant 63 (Cd63) knockdown in mice treated with ConA showed significantly less liver pathology and inflammation as well as higher survival rates than the corresponding controls. Conclusion: We have identified the top dynamic genes related to the process of acute liver injury, and highlighted a targeted strategy for Cd63 might have utility for the protection of hepatocellular damage.
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25
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Wu R, Liu Y, Yan R, Liu X, Duan L. Assessment of EN-RAGE, sRAGE and EN-RAGE/sRAGE as potential biomarkers in patients with autoimmune hepatitis. J Transl Med 2020; 18:384. [PMID: 33036620 PMCID: PMC7547460 DOI: 10.1186/s12967-020-02556-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/27/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a liver disease characterized by the autoimmune-induced injury of hepatocytes which can lead to cirrhosis and hepatic failure. The diagnosis and disease management of AIH patients remain challenging due to the diversity of clinical phenotypes and the presence of confounders such as alcohol and viruses. Recently, EN-RAGE and sRAGEs have been implicated in inflammatory-immune response. Nonetheless, their natural behaviour and relationship to disease activity as well as clinical predictive values in AIH development or therapy-induced remission have not been reported. METHODS Sixty-seven AIH patients and thirty gender- and age-matched healthy controls (HC) were enrolled. The serum concentrations of EN-RAGE, sRAGE and their ratio (EN-RAGE/sRAGE) in these subjects were measured by ELISA. Besides, the correlations of three parameters with clinical features and therapeutic response were analyzed, respectively. Furthermore, their potential predictive values for monitoring the AIH progression and therapeutic response were also evaluated. RESULTS Higher serum EN-RAGE, lower sRAGE and higher EN-RAGE/sRAGE value were observed in AIH patients. EN-RAGE and sRAGE as well as EN-RAGE/sRAGE were correlated with liver necroinflammation parameters, cirrhosis occurrence and therapeutic response. In addition, we identified that EN-RAGE/sRAGE, EN-RAGE and sRAGE had valuable predicting power for AIH patients, AIH patients with normal ALT and cirrhosis incidence, respectively. More importantly, EN-RAGE/sRAGE also exerted predicting power for the remission in AIH patients. CONCLUSIONS AIH patients rendered distinct patterns of serum EN-RAGE, sRAGE or EN-RAGE/sRAGE compared to healthy controls. Moreover, these three parameters exhibited potentials as novel biomarkers for AIH diagnosis and prognosis evaluation.
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Affiliation(s)
- Rui Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, No.1 You Yi Road, Yuan Jia Gang, Yu Zhong District, Chongqing, China
| | - Yan Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, No.1 You Yi Road, Yuan Jia Gang, Yu Zhong District, Chongqing, China
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ruyu Yan
- Department of Rheumatology and Immunology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoyu Liu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - Liang Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, No.74 linjiang Road, Yu Zhong District, Chongqing, China
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26
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Wang H, Feng X, Yan W, Tian D. Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients. Front Immunol 2020; 11:575572. [PMID: 33117375 PMCID: PMC7575771 DOI: 10.3389/fimmu.2020.575572] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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27
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Liu Y, Chen H, Hao J, Li Z, Hou T, Hao H. Microarray-based transcriptional profiling of a mouse model of autoimmune hepatitis. FEBS Open Bio 2020; 10:2040-2054. [PMID: 32808463 PMCID: PMC7530384 DOI: 10.1002/2211-5463.12953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/03/2020] [Accepted: 08/13/2020] [Indexed: 12/23/2022] Open
Abstract
Long noncoding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that do not typically code for a protein. lncRNAs have regulatory roles in many physiological processes, and their dysregulation can contribute to cancer, cardiovascular and neurodegenerative diseases, as well as the onset of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. However, lncRNA expression changes in autoimmune hepatitis (AIH), a form of inflammation induced by immunological tolerance disorders, are poorly understood. Here, for the first time to our knowledge, we used microarrays to profile 1161 differentially expressed lncRNAs (DELs; 608 up- and 553 down-regulated) and 11 512 differentially expressed mRNAs (DEMs; 5189 up- and 6323 down- regulated) in a concanavalin A-induced AIH mouse model. We used quantitative real-time PCR to confirm the expression of eight DELs and DEMs, and analyzed the coexpression relationship between them. Potential biological functions of screened DELs and DEMs were predicted with Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. DEL-DEM interaction networks were also constructed. Our study revealed the roles of DELs and DEMs in the pathogenesis of AIH. We also provided potential candidate biomarkers that may have potential for future development into possible diagnostics or as a treatment for this disorder.
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Affiliation(s)
- Yang Liu
- College of Basic Medical SciencesShanxi University of Chinese MedicineJinzhongChina
- Basic Laboratory of Integrated Traditional Chinese and Western MedicineShanxi University of Chinese MedicineJinzhongChina
| | - Hao Chen
- College of Basic Medical SciencesShanxi University of Chinese MedicineJinzhongChina
- Basic Laboratory of Integrated Traditional Chinese and Western MedicineShanxi University of Chinese MedicineJinzhongChina
| | - Jian‐heng Hao
- College of Basic Medical SciencesShanxi University of Chinese MedicineJinzhongChina
- Basic Laboratory of Integrated Traditional Chinese and Western MedicineShanxi University of Chinese MedicineJinzhongChina
| | - Zhen‐cheng Li
- College of Basic Medical SciencesShanxi University of Chinese MedicineJinzhongChina
- Basic Laboratory of Integrated Traditional Chinese and Western MedicineShanxi University of Chinese MedicineJinzhongChina
| | - Tiezheng Hou
- College of Basic Medical SciencesShanxi University of Chinese MedicineJinzhongChina
- Basic Laboratory of Integrated Traditional Chinese and Western MedicineShanxi University of Chinese MedicineJinzhongChina
| | - Hui‐qin Hao
- College of Basic Medical SciencesShanxi University of Chinese MedicineJinzhongChina
- Basic Laboratory of Integrated Traditional Chinese and Western MedicineShanxi University of Chinese MedicineJinzhongChina
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28
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Trivella JP, Martin P, Carrion AF. Novel targeted therapies for the management of liver fibrosis. Expert Opin Emerg Drugs 2020; 25:59-70. [PMID: 32098512 DOI: 10.1080/14728214.2020.1735350] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 02/24/2020] [Indexed: 12/11/2022]
Abstract
Introduction: Prolonged liver injury results in tissue damage and replacement by extracellular matrix and fibrosis. Cirrhosis represents a leading cause of mortality worldwide and imposes a major financial burden on health-care systems. Fortunately, fibrogenesis has proven to be reversible if halted early, encouraging the development of novel anti-fibrotic agents that may accelerate histological restoration. Preclinical data have elucidated numerous potential therapeutic targets and many anti-fibrotic agents are currently at various stages of clinical research.Areas covered: The present review summarizes recent clinical data regarding anti-fibrotic drugs including monoclonal antibodies, targeted conjugates, and small molecule agents.Expert opinion: Although undeniable progress has been made in the development of anti-fibrotic agents in recent years, most data currently available are derived from preclinical and early clinical studies. The efficacy and safety of these agents will need to be corroborated by larger clinical trials, some of which are ongoing with results expected in the upcoming years. Combination therapy with agents targeting different pathways of fibrogenesis will also be of great interest for the future and will need to be explored in clinical trials.
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Affiliation(s)
- Juan P Trivella
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Paul Martin
- Division of Gastroenterology and Hepatology, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Andres F Carrion
- Division of Gastroenterology and Hepatology, University of Miami, Miller School of Medicine, Miami, FL, USA
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29
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Golbabapour S, Bagheri-Lankarani K, Ghavami S, Geramizadeh B. Autoimmune Hepatitis and Stellate Cells: An Insight into the Role of Autophagy. Curr Med Chem 2020; 27:6073-6095. [PMID: 30947648 DOI: 10.2174/0929867326666190402120231] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 03/11/2019] [Accepted: 03/15/2019] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis is a necroinflammatory process of liver, featuring interface hepatitis by T cells, macrophages and plasma cells that invade to periportal parenchyma. In this process, a variety of cytokines are secreted and liver tissues undergo fibrogenesis, resulting in the apoptosis of hepatocytes. Autophagy is a complementary mechanism for restraining intracellular pathogens to which the innate immune system does not provide efficient endocytosis. Hepatocytes with their particular regenerative features are normally in a quiescent state, and, autophagy controls the accumulation of excess products, therefore the liver serves as a basic model for the study of autophagy. Impairment of autophagy in the liver causes the accumulation of damaged organelles, misfolded proteins and exceeded lipids in hepatocytes as seen in metabolic diseases. In this review, we introduce autoimmune hepatitis in association with autophagy signaling. We also discuss some genes and proteins of autophagy, their regulatory roles in the activation of hepatic stellate cells and the importance of lipophagy and tyrosine kinase in hepatic fibrogenesis. In order to provide a comprehensive overview of the regulatory role of autophagy in autoimmune hepatitis, the pathway analysis of autophagy in autoimmune hepatitis is also included in this article.
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Affiliation(s)
- Shahram Golbabapour
- Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Queen
Elizabeth Hospital, Birmingham, B15 2WB, UK
| | - Kamran Bagheri-Lankarani
- Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeid Ghavami
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
- Department of Human Anatomy and Cell Science, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada
| | - Bita Geramizadeh
- Department of Pathology, Medical school of Shiraz University, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Centre, Shiraz University of medical Sciences, Shiraz, Iran
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30
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Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. J Immunol Res 2019; 2019:9437043. [PMID: 31886312 PMCID: PMC6899271 DOI: 10.1155/2019/9437043] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/15/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
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