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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [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: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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2
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Chung SW, Kim YJ, Lim J, Choi J, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Kim S, Choi WM. Risk of Extrahepatic Malignancies in Patients With Autoimmune Hepatitis: A Nationwide Cohort Study. Am J Gastroenterol 2024:00000434-990000000-01495. [PMID: 39718241 DOI: 10.14309/ajg.0000000000003261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
INTRODUCTION Nationwide, population-based data on the risk of extrahepatic malignancy in patients with autoimmune hepatitis (AIH) in Asian countries are scarce. This study aimed to examine the risk of developing extrahepatic malignancies in a nationwide cohort of patients with AIH. METHODS Using claims data from the Korean National Health Insurance Service database, patients diagnosed with AIH between 2007 and 2019 (n = 7,382) were matched in a 1:8 ratio with an age- and sex-matched control population (n = 58,320). We compared the incidence rates and hazard ratios (HRs) of overall and specific extrahepatic malignancies between the 2 groups, while also examining the impact of immunosuppressant use. RESULTS During a median follow-up period of 5.2 years, a total of 3,713 extrahepatic malignancies developed. The incidence rate of extrahepatic malignancy in patients with AIH (990.8 cases per 100,000 person-years) was comparable with that in the matched controls (937.6 cases per 100,000 person-years), with an HR of 0.93 (95% confidence interval (CI), 0.81-1.07; P = 0.30). However, a significantly higher risk of hematologic malignancies, particularly lymphoma or myeloma (HR, 2.66; 95% CI, 1.70-4.17; P < 0.001), was observed. The use of glucocorticoids (HR, 0.74; 95% CI, 0.31-1.75; P = 0.50) or azathioprine (HR, 2.12; 95% CI, 0.90-5.02; P = 0.09) had no impact on the risk of lymphoma or myeloma in patients with AIH. DISCUSSION In this nationwide, population-based cohort, AIH was not associated with an increased risk of overall extrahepatic malignancy compared with age- and sex-matched controls. However, AIH itself increased the risk of lymphoma or myeloma, independent of immunosuppressant use.
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Affiliation(s)
- Sung Won Chung
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ye-Jee Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jihye Lim
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Yeouido St. Mary Hospital, Catholic University College of Medicine, Seoul, Republic of Korea
| | - Jonggi Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sehee Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Evans S, Hofmann A. Autoimmune Biliary Diseases: A Review of Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Immunoglobulin G4-Related Sclerosing Cholangitis, and Autoimmune Hepatitis. Surg Clin North Am 2024; 104:1249-1261. [PMID: 39448126 DOI: 10.1016/j.suc.2024.04.010] [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] [Indexed: 10/26/2024]
Abstract
Autoimmune and immune-mediated biliary diseases represent a small proportion of biliary disorders, but owing to their progressive nature, lead to end-stage liver disease, necessitating liver transplantation for definitive management.
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Affiliation(s)
- Suzanne Evans
- Department of Pediatric and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, C3.163, Cincinnati, OH 45229, USA.
| | - Alana Hofmann
- Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way, MSB 1464, Cincinnati, OH 45267, USA
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Mercado LA, Gil-Lopez F, Chirila RM, Harnois DM. Autoimmune Hepatitis: A Diagnostic and Therapeutic Overview. Diagnostics (Basel) 2024; 14:382. [PMID: 38396421 PMCID: PMC10887775 DOI: 10.3390/diagnostics14040382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/02/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its clinical presentation can be very broad, from having an asymptomatic and silent course to presenting as acute hepatitis, cirrhosis, and acute liver failure potentially requiring liver transplantation. The diagnosis is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (increased aspartate aminotransferase, alanine aminotransferase, and serum IgG concentration), and the presence of one or more characteristic autoantibodies. The large heterogeneity of these clinical, biochemical, and histological findings can sometimes make a timely and proper diagnosis a difficult task. Treatment seeks to achieve remission of the disease and prevent further progression of liver disease. First-line therapy includes high-dose corticosteroids, which are later tapered to decrease side effects, and azathioprine. In the presence of azathioprine intolerance or a poor response to the standard of care, second-line therapy needs to be considered, including mycophenolate mofetil. AIH remains a diagnostic and therapeutic challenge, and a further understanding of the pathophysiological pathways of the disease and the implementation of randomized controlled trials are needed.
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Affiliation(s)
- Lydia A. Mercado
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Fernando Gil-Lopez
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Razvan M. Chirila
- Department of General Internal Medicine, Mayo Clinic Florida, Jacksonville, FL 32224, USA;
| | - Denise M. Harnois
- Department of Liver Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
- Department of Gastroenterology and Hepatology, Mayo Clinic Florida, Jacksonville, FL 32224, USA
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5
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Abstract
The goal of autoimmune hepatitis treatment is to achieve clinical and biochemical remission, which is associated with significantly improved outcomes. Induction treatment with corticosteroids and the subsequent addition of steroid-sparing therapy with gradual tapering of corticosteroids remains the standard of care. Several alternatives to azathioprine and second-line agents, such as mycophenolate mofetil, tacrolimus, cyclosporine, sirolimus, or rituximab, have been evaluated in those with intolerance or inadequate response to standard-of-care therapy. Treatment withdrawal is achievable in less than 20% of patients after 2 years of sustained remission. Liver transplantation should be considered in those with progressive liver disease or those with complications such as hepatocellular carcinoma.
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Affiliation(s)
- Aparna Goel
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94043, USA.
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University, Palo Alto, CA 94043, USA
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6
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KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
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7
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Autoimmune Hepatitis and Fibrosis. J Clin Med 2023; 12:jcm12051979. [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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8
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Gerussi A, Halliday N, Carbone M, Invernizzi P, Thorburn D. Open challenges in the management of autoimmune hepatitis. Minerva Gastroenterol (Torino) 2023; 69:61-83. [PMID: 33267568 DOI: 10.23736/s2724-5895.20.02805-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.
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Affiliation(s)
- Alessio Gerussi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy - .,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy - .,Ancient DNA Lab Dan David Center for Human Evolution and Biohistory Research, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel -
| | - Neil Halliday
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milano-Bicocca, Monza, Monza-Brianza, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Monza-Brianza, Italy
| | - Douglas Thorburn
- Institute for Liver and Digestive Health, University College London, London, UK
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9
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Kim JK. [Treatment of Autoimmune Hepatitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 81:72-85. [PMID: 36824035 DOI: 10.4166/kjg.2023.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/13/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.
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Affiliation(s)
- Ja Kyung Kim
- Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
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10
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Abe K, Suzuki R, Fujita M, Hayashi M, Takahashi A, Ohira H. Circulating extracellular vesicle-encapsulated microRNA-557 induces a proinflammatory immune response and serves as a diagnostic or relapse marker in autoimmune hepatitis. Hepatol Res 2022; 52:1034-1049. [PMID: 35962993 DOI: 10.1111/hepr.13829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 12/12/2022]
Abstract
AIM This study investigated serum microRNAs (miRNAs/miRs) in autoimmune hepatitis (AIH) and the relationship of these molecules with diagnostic and relapse markers. METHODS Initially, extracellular vesicle-encapsulated miRNAs (EV-miRNAs) in serum with altered expression in AIH relative to healthy control (HC) samples were identified using microarray analysis. To validate the microarray results, the expression levels of selected EV-miRNAs were determined. RESULTS Among the 2569 mature miRNAs evaluated in the microarray, EV-miR-557 discriminated patients with AIH from healthy controls (HCs). Validation by digital polymerase chain reaction indicated that serum EV-miR-557 levels were higher in patients with AIH (7.75 copies/μl) than in patients with non-alcoholic steatohepatitis (1.60 copies/μl; p < 0.001), patients with primary biliary cholangitis (2.16 copies/μl; p < 0.005), and HCs (1.86 copies/μl; p < 0.005). The area under the receiver operating characteristic curve values for the probability of AIH using serum EV-miR-557 between the AIH and non-alcoholic steatohepatitis, AIH and primary biliary cholangitis, and AIH and HC groups were 0.81, 0.78, and 0.79, respectively. In addition, serum EV-miR-557 levels >7.69 copies/μl were associated with a significantly higher risk of relapse in patients with AIH (7-year incidence rate: 11.1 vs. 35.4%, log-rank test, p < 0.05). Interestingly, gene expression analysis revealed that increased miR-557 expression following transient transfection of peripheral blood mononuclear cells with a miR-557 mimic resulted in enhanced expression of proinflammatory cytokine-related genes such as interleukin-6, interferon-γ, and tumor necrosis factor. Moreover, miR-557 induced significant tumor necrosis factor-α production (mean: 313.5 vs. 10 642.3 pg/ml, p < 0.05). CONCLUSION EV-miR-557 may play an important role as a potential biomarker of AIH and may be a promising therapeutic target for AIH.
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Affiliation(s)
- Kazumichi Abe
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Rei Suzuki
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Masashi Fujita
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Manabu Hayashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
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11
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Ohira H, Takahashi A, Zeniya M, Abe M, Arinaga-Hino T, Joshita S, Takaki A, Nakamoto N, Kang JH, Suzuki Y, Sogo T, Inui A, Koike K, Harada K, Nakamoto Y, Kondo Y, Genda T, Tsuneyama K, Matsui T, Tanaka A. Clinical practice guidelines for autoimmune hepatitis. Hepatol Res 2022; 52:571-585. [PMID: 35533021 DOI: 10.1111/hepr.13776] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/22/2022] [Accepted: 04/28/2022] [Indexed: 02/08/2023]
Affiliation(s)
- Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mikio Zeniya
- Akasaka Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
| | | | - Satoru Joshita
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuhiro Nakamoto
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jong-Hon Kang
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | | | - Tsuyosi Sogo
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology and Hepatology, The Third Hospital of Jikei University School of Medicine, Tokyo, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yasuteru Kondo
- Department of Hepatology, Sendai Kousei Hospital, Sendai, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Izunokuni, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Takushima, Japan
| | - Tsuyoshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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12
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van den Brand FF, Snijders RJALM, de Boer YS, Verwer BJ, van Nieuwkerk CMJ, Bloemena E, Kuiken SD, Drenth JPH, Bouma G. Drug withdrawal in patients with autoimmune hepatitis in long-term histological remission: A prospective observational study. Eur J Intern Med 2021; 90:30-36. [PMID: 33865679 DOI: 10.1016/j.ejim.2021.03.024] [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: 09/23/2020] [Revised: 02/24/2021] [Accepted: 03/15/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Recommendations for drug withdrawal in patients with autoimmune hepatitis (AIH) in longstanding remission are conflicting and rely on retrospective data. We prospectively investigated the predictive value of histological normalisation for successful treatment withdrawal in AIH patients. METHODS Non-cirrhotic patients with established AIH and complete biochemical remission (normalisation of serum alanine aminotransferase [ALT] or aspartate aminotransferase [AST] and immunoglobulin G [IgG]) of at least 2 years were biopsied. Immunosuppressive therapy was only withdrawn in patients with histological normalisation (histological activity index [HAI] ≤3) with a minimum follow-up of 12 months. RESULTS A total of 17 patients in biochemical remission for at least 2 years were included. Persistent histological inflammatory activity (HAI >3) precluded drug withdrawal in five patients. These had higher values of ALT (25 vs. 16 U/L; p = 0.01) and AST (26 vs. 22 U/L; p = 0.01) compared with patients in histological remission. Immunosuppressive medication was withdrawn in 12 patients; eight (67%, C.I. 40-93% p = 0.4) remained in remission during a median follow-up of 62 months (range: 13-75 months); and four (33%, C.I. 7-60% p = 0.4) required reinstitution of therapy after 1, 6, 11, and 40 months, all without clinical signs of disease progression or hepatic decompensation. No predictors of relapse were identified. CONCLUSION Two-thirds of the patients who prove to have histological normalisation after at least 2 years of biochemical remission achieve treatment-free remission. Although patient numbers were small and results should be interpreted with caution, these findings support a liver biopsy prior to drug withdrawal.
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Affiliation(s)
- Floris F van den Brand
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, de Boelelaan 1117, Amsterdam, the Netherlands.
| | - Romée J A L M Snijders
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, de Boelelaan 1117, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, the Netherlands
| | - Ynto S de Boer
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, de Boelelaan 1117, Amsterdam, the Netherlands
| | - Bart J Verwer
- Department of Gastroenterology and Hepatology, Spaarne Hospital, Haarlem, the Netherlands
| | - Carin M J van Nieuwkerk
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, de Boelelaan 1117, Amsterdam, the Netherlands
| | - Elisabeth Bloemena
- Amsterdam UMC, Vrije Universiteit Amsterdam, Pathology, Amsterdam, the Netherlands
| | - Sjoerd D Kuiken
- Department of Gastroenterology and Hepatology, OLVG, Amsterdam, the Netherlands
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, the Netherlands
| | - Gerd Bouma
- Amsterdam UMC, Vrije Universiteit Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology and Metabolism, de Boelelaan 1117, Amsterdam, the Netherlands
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13
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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: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [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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14
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Interest in Immunosuppression Withdrawal among Liver Transplant and Autoimmune Hepatitis Patients. GASTROENTEROLOGY INSIGHTS 2021. [DOI: 10.3390/gastroent12020013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Immunosuppression withdrawal (ISW) is considered in liver transplant recipients (LTRs) and autoimmune hepatitis patients (AIHPs). Immunosuppressive therapy (IST) can be burdensome both financially and due to its side effect profile, making ISW an important intervention to consider. Data on patient interest in ISW would be helpful to providers in ISW decision-making. We conducted independent single-center surveys of LTR and AIHP attitudes on IST and withdrawal interest. Of 325 LTRs screened, 120 completed the survey (50% female, mean age 58 ± 14 years, mean time since transplant 8 ± 10.5 years and 79.5% Caucasian). Of 100 AIHPs screened, 45 completed the survey (77.8% female, mean age 54 ± 2 and 82.2% Caucasian). A higher percentage of AIHPs expressed concern with their IST and were interested in ISW compared with LTRs. However, over a third of LTRs were interested in ISW, particularly those with knowledge of this potential intervention. LTRs who discussed ISW with a physician were more likely to desire withdrawal (p = 0.02; OR = 2.781 (95% CI = 1.125, 6.872)). As patient interest in ISW is of growing interest, investigators should continue to assess patient-reported desires and outcomes and pursue strategies to achieve immunological tolerance.
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15
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Kakisaka K, Suzuki Y, Kowata S, Ito S, Takikawa Y. Acute Liver Injury Due to T-cell Infiltration into the Liver as an Initial Clinical Finding of Adult T-cell Leukemia/Lymphoma. Intern Med 2021; 60:2431-2436. [PMID: 34334592 PMCID: PMC8381176 DOI: 10.2169/internalmedicine.6793-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Acute liver injury (ALI) has been rarely reported as a clinical finding of adult T-cell leukemia/lymphoma (ATLL). A 74-year-old Japanese female patient who was histologically diagnosed as having autoimmune hepatitis (AIH) one year earlier, showed elevations in her aminotransferase and total bilirubin levels, and this was considered to be an exacerbation of AIH. Liver biopsy revealed interface hepatitis. Because atypical lymphocytes and human T-cell leukemia virus 1 immunoglobulin G antibody were positive, the patient was diagnosed to have ATLL. The biopsy revealed CD4+ and CD8+, but not CD20+ lymphocytes. Thus, the ALI in the patient was due to T-cell infiltration into the liver, and not due to an exacerbation of AIH.
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Affiliation(s)
- Keisuke Kakisaka
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yuji Suzuki
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
| | - Shugo Kowata
- Division of Hematology and malignancy, Department of Internal Medicine, Iwate Medical University, Japan
| | - Shigeki Ito
- Division of Hematology and malignancy, Department of Internal Medicine, Iwate Medical University, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Japan
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16
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Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology 2020; 72:671-722. [PMID: 31863477 DOI: 10.1002/hep.31065] [Citation(s) in RCA: 520] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Cara L Mack
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - David Adams
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - David N Assis
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT
| | - Nanda Kerkar
- Golisano Children's Hospital at Strong, University of Rochester Medical Center, New York, NY
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- Division of Digestive and Liver Diseases, University of Texas SW Medical Center, Dallas, TX
| | - John M Vierling
- Medicine and Surgery, Baylor College of Medicine, Houston, TX
| | | | - Mohammad H Murad
- Mayo Knowledge and Encounter Research Unit, Mayo Clinic College of Medicine, Rochester, MN
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
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17
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Vierling JM, Kerkar N, Czaja AJ, Mack CL, Adams D, Assis DN, Manns MP, Mayo MJ, Nayfeh T, Majzoub AMM, Alzuabi MA, Ding J, Haffar S, Murad MH, Alsawas M. Immunosuppressive Treatment Regimens in Autoimmune Hepatitis: Systematic Reviews and Meta-Analyses Supporting American Association for the Study of Liver Diseases Guidelines. Hepatology 2020; 72:753-769. [PMID: 32500593 DOI: 10.1002/hep.31407] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/30/2020] [Accepted: 05/26/2020] [Indexed: 12/13/2022]
Affiliation(s)
- John M Vierling
- Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Nanda Kerkar
- Department of Pediatrics, University of Rochester School of Medicine, Rochester, NY, USA
| | - Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Cara L Mack
- Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA
| | - David Adams
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - David N Assis
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Marlyn J Mayo
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tarek Nayfeh
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | | | - Muayad A Alzuabi
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Jingyi Ding
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Samir Haffar
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - M Hassan Murad
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
| | - Mouaz Alsawas
- Mayo Clinic Evidence-Based Practice Research Program, Rochester, MN, USA
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18
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Czaja AJ. Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis. Aliment Pharmacol Ther 2020; 51:1286-1304. [PMID: 32363674 DOI: 10.1111/apt.15743] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. AIMS To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. METHODS English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. RESULTS Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. CONCLUSIONS The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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19
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Prognostic factors for remission, relapse, and treatment complications in type 1 autoimmune hepatitis. Heliyon 2020; 6:e03767. [PMID: 32382677 PMCID: PMC7203077 DOI: 10.1016/j.heliyon.2020.e03767] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/22/2020] [Accepted: 04/06/2020] [Indexed: 02/07/2023] Open
Abstract
Background and aim Autoimmune hepatitis (AIH) is a rare chronic form of hepatitis, the prognosis for which has not been definitively established. The current study aimed to define the prognostic factors for remission and compare the median time to remission, complications, and relapse rate between type 1 AIH patients treated with prednisolone monotherapy and those treated using prednisolone in combination with azathioprine. Materials and methods The data of 86 patients diagnosed with type 1 AIH between January 1998 and January 2018 were retrospectively reviewed. Clinical, serological, and histological parameters were obtained. Cox-proportional hazard and logistic regression analyses were applied to the data. Results The prognostic factors related to complete remission were absence of liver cirrhosis, hypertension, and azathioprine exposure. The median time to complete remission of the prednisolone group (92 days; 95%CI; 65–264 days) was significantly shorter (P = 0.01) than that of the combination group (336 days; 95%CI; 161–562 days); however, the prednisolone group had higher rates of treatment complications—including skin and soft tissue infections (P = 0.010) and cushingoid appearance (P = 0.011)—than the combination group. The prednisolone group also had a higher relapse rate (odds ratio 6.13, 95% CI 1.72–21.80, P = 0.005). Conclusions The absence of liver cirrhosis and hypertension at the time of diagnosis and no azathioprine exposure during the treatment period were favorable prognostic factors for complete remission. The prednisolone group had a significantly shorter median time to complete remission but higher rates of treatment complications and a higher relapse rate than the combination group.
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20
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Hartl J, Miquel R, Zachou K, Wong GW, Asghar A, Pape S, Sebode M, Peiseler M, Zenouzi R, Ehlken H, Krech T, Weiler-Normann C, Drenth JPH, Oo YH, Dalekos GN, Heneghan M, Schramm C, Lohse AW. Features and outcome of AIH patients without elevation of IgG. JHEP Rep 2020; 2:100094. [PMID: 32280942 PMCID: PMC7139106 DOI: 10.1016/j.jhepr.2020.100094] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/28/2020] [Accepted: 01/31/2020] [Indexed: 12/27/2022] Open
Abstract
Background & Aims High IgG levels are considered a hallmark of autoimmune hepatitis (AIH). A subgroup of patients with AIH has IgG within the normal range despite evidence of clinical disease activity. The clinical significance of this biomarker has not been explored. Methods In a European multicentre study we compared biochemical, clinical and histological features from patients with AIH and normal IgG-values at diagnosis to an age- and sex-matched control group of patients with typical AIH presenting with elevated IgG. Data were assessed at diagnosis, after 12 months of therapy and at last follow-up. Results Out of 1,318 patients with AIH, 130 (10%) had normal IgG at presentation. Histological and biochemical parameters at diagnosis, as well as treatment response, showed no difference between groups. Stable remission off treatment was achieved more commonly in the normal IgG group than in the typical AIH group (24 vs. 8%; p = 0.0012). Patients of the control group not only had higher IgG levels (29.5 ± 5.8 vs. 12.5 ± 3.2 g/L; p <0.0001), but also a higher IgG/IgA ratio (9.3 ± 6.9 vs. 5.4 ± 2.4; p <0.0001) at diagnosis. The IgG/IgA ratio only declined in patients with typical AIH and was no longer different between groups after 12 months (6.3 ± 4.3 vs. 5.5 ± 2.2; p = 0.1), indicating a selective increase of IgG in typical AIH and its suppression by immunosuppression. Autoantibody titres were higher in the typical AIH group, but not when controlled for IgG levels. Conclusions Compared to AIH with typical biochemical features, patients with normal IgG levels at diagnosis (i) show similar biochemical, serological and histological features and comparable treatment response, (ii) appear to lack the selective elevation of serum IgG levels observed in typical active AIH disease, (iii) may represent a subgroup with a higher chance of successful drug withdrawal. Lay summary A characteristic feature of autoimmune hepatitis (AIH) is an elevation of immunoglobulin G (IgG), which is therefore used as a major diagnostic criterion, as well as to monitor treatment response. Nevertheless, normal IgG does not preclude the diagnosis of AIH. Therefore, we herein assessed the features of patients with AIH and normal IgG in a large multicentre study. This study demonstrates that about 10% of all patients with AIH have normal IgG; these patients are indistinguishable from other patients with AIH with respect to biochemical markers, liver histology, disease severity and treatment response, but might represent a subgroup with a higher chance of remission after drug withdrawal.
Patients with AIH and normal IgG comprise around 10% of all patients with AIH. These patients are indistinguishable from patients with typical AIH by biochemical markers or liver histology. They have no selective IgG elevation, with lower IgG and IgA levels than patients with typical AIH. These patients might represent a subgroup in whom there is a high chance of successful drug withdrawal.
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Key Words
- AIH, autoimmune hepatitis
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AMA, anti-mitochondrial antibody
- ANA, anti-nuclear antibody
- AST, aspartate aminotransferase
- Anti-SLA/LP, anti-soluble liver antigen and anti-liver-pancreas antibodies
- INR, international normalized ratio
- LKM, liver kidney microsomal antigen
- SMA, smooth muscle antibody
- autoimmune hepatitis
- drug withdrawal
- hypergammaglobulinemia
- immunoglobulin G
- immunoglobulins
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Affiliation(s)
- Johannes Hartl
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Rosa Miquel
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Kalliopi Zachou
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Guan-Wee Wong
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Asma Asghar
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom
| | - Simon Pape
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands.,European Reference Network on Hepatological Diseases
| | - Marcial Sebode
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Moritz Peiseler
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Roman Zenouzi
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Hanno Ehlken
- Department of Interdisciplinary Endoscopy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Till Krech
- Department of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Christina Weiler-Normann
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Joost P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, the Netherlands.,European Reference Network on Hepatological Diseases
| | - Ye H Oo
- Centre for Liver and Gastroenterology Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom.,Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, United Kingdom.,European Reference Network on Hepatological Diseases
| | - George Nikolaos Dalekos
- Institute of Internal Medicine and Hepatology, Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa, Greece
| | - Michael Heneghan
- Institute of Liver Studies, King's College Hospital, London, United Kingdom
| | - Christoph Schramm
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
| | - Ansgar Wilhelm Lohse
- First Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,Martin Zeitz Centre for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.,European Reference Network on Hepatological Diseases
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21
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Chang C, Tanaka A, Bowlus C, Gershwin ME. The use of biologics in the treatment of autoimmune liver disease. Expert Opin Investig Drugs 2020; 29:385-398. [PMID: 32102572 DOI: 10.1080/13543784.2020.1733527] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and juvenile autoimmune hepatitis (JAIH). The pathophysiologic features of each disease vary, but generally include presence of autoantibodies, cytokine abnormalities, and/or T and B cell autoreactivity.Areas covered: This article compares conventional therapy with newer biologics available for treatment of autoimmune liver diseases. Conventional therapy involves the use of immunosuppressive agents, or other treatment modalities for specific autoimmune liver diseases such as ursodeoxycholic acid and fibrates for PBC. Biologics were developed to target the production of autoantibodies by B cells, the presence of proinflammatory cytokines, adhesion molecules or T and B cell activation.Expert opinion: Despite the promise of biologics being able to target specific cellular and humoral pathways, results have been generally poor, and safety has not been as expected. Cases of autoimmune hepatitis have also developed with the use of these biologicals. Reasons for the lack of success of biologics in treating autoimmune liver disease has led to a reevaluation of our understanding of underlying pathogenesis, demonstrating that while our knowledge of the immunity has improved over the past two decades, it is far from complete.
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Affiliation(s)
- Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.,Division of Pediatric Immunology and Allergy, Joe DiMaggio Children's Hospital, Hollywood, FL, USA
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Christopher Bowlus
- Division of Gastroenterology, University of California at Davis, Davis, CA, USA
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
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22
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Alsayed MAL, Elbeah SM, El-Desoky MM, Elziny SM, Megahed A. Polymorphism in Macrophage Migration Inhibitory Factor -173GC in Pediatric Patients with Autoimmune Hepatitis. Pediatr Gastroenterol Hepatol Nutr 2020; 23:63-71. [PMID: 31988876 PMCID: PMC6966214 DOI: 10.5223/pghn.2020.23.1.63] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 09/13/2019] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Autoimmune hepatitis (AIH) is a chronic disease that may lead to cirrhosis. The immunopathogenesis of AIH is not fully understood and it mainly involves T-cell mediated mechanism. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that promotes T cell response and its polymorphism may serve as a severity marker of AIH. No previous study has considered investigating MIF polymorphism in children with AIH. METHODS Forty-two children with definite diagnosis of AIH were enrolled along with 100 age and sex matched controls. All participants were tested for polymorphism at -173GC (rs755622) of MIF gene. All patients received the standard protocol of steroid plus azathioprine to achieve remission. Liver biopsy was performed at time of diagnosis for all patients and only 18 of them underwent a second biopsy after treatment. RESULTS No statistically significant differences in the frequency of the genotypes GG and GC or in allele distribution were found in both patient and control groups (p=0.590, 0.640 respectively). Initial alanine aminotransferase (ALT) levels at the time of presentation was significantly higher in the GC group than GG group (p=0.020). GC genotype significantly correlated with disease relapse (r=0.41, p=0.007). Regression of necroinflammation and the fibrosis score in the second liver biopsy was statistically significant in the GG group (p<0.0001, p=0.010 respectively). CONCLUSION MIF -173GC polymorphism is associated with clinically significant markers of pediatric AIH, including increased initial serum ALT levels, may help predict necroinflammatory/fibrosis regression effectively, following immunosuppressive treatment.
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Affiliation(s)
- Mona Abdel Latif Alsayed
- Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children's Hospital, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Shymaa Mohsen Elbeah
- Biochemistry Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Manal M El-Desoky
- Biochemistry Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Shereen Magdy Elziny
- Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children's Hospital, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Megahed
- Pediatric Gastroenterology and Hepatology Unit, Mansoura University Children's Hospital, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
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23
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Tu H, Chen D, Cai C, Du Q, Lin H, Pan T, Sheng L, Xu Y, Teng T, Tu J, Lin Z, Wang X, Wang R, Xu L, Chen Y. microRNA-143-3p attenuated development of hepatic fibrosis in autoimmune hepatitis through regulation of TAK1 phosphorylation. J Cell Mol Med 2020; 24:1256-1267. [PMID: 31808606 PMCID: PMC6991639 DOI: 10.1111/jcmm.14750] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/12/2019] [Accepted: 09/24/2019] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA-143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir-143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1-mediated miRNA-143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA-143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA-143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis.
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Affiliation(s)
- Hanxiao Tu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Dazhi Chen
- Department of GastroenterologyThe First Hospital of Peking UniversityBeiJingChina
| | - Chao Cai
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Qianjing Du
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Hongwei Lin
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Tongtong Pan
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Lina Sheng
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
- Department of Infectious DiseasesThe Affiliated Yiwu Central Hospital of Wenzhou Medical UniversityYiwuChina
| | - Yuedong Xu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Teng Teng
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Jingjing Tu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Zhuo Lin
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Xiaodong Wang
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Rui Wang
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
| | - Lanman Xu
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
- Department of Infectious Diseases and Liver DiseasesNingbo Medical Center Lihuili HospitalNingboChina
- Department of Infectious Diseases and Liver DiseasesThe Affiliated Lihuili Hospital of Ningbo UniversityNingboChina
| | - Yongping Chen
- Department of Infectious DiseasesWenzhou Key Laboratory of HepatologyThe First Affiliated Hospital of Wenzhou Medical UniversityHepatology Institute of Wenzhou Medical UniversityWenzhouChina
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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: 78] [Impact Index Per Article: 13.0] [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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Takahashi A, Ohira H. Autoimmune hepatitis, fatty liver, and Fukushima. Fukushima J Med Sci 2019; 65:25-29. [PMID: 31270280 DOI: 10.5387/fms.2019-13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The use of direct antiviral agents (DAAs) for hepatitis C virus has led to a paradigm shift from viral hepatitis to non-viral disease. Autoimmune hepatitis (AIH) remains to be an issue in liver disease after the DAAs era. Moreover, fatty liver had been increasing in incidence and has attracted attention because of its risk for hepatocellular carcinoma. In 2011, the Great East Japan Earthquake, with the associated tsunami and accident at Fukushima Daiichi Nuclear Power Plant, has changed the lifestyle of residents in Fukushima prefecture. In this manuscript, we outlined the recent topics about AIH, fatty liver, and Fukushima.
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Affiliation(s)
- Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University School of Medicine
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine
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Choi J, Choi GH, Lee D, Shim JH, Lim YS, Lee HC, Chung YH, Lee YS, Kim KM. Long-term clinical outcomes in patients with autoimmune hepatitis according to treatment response in Asian country. Liver Int 2019; 39:985-994. [PMID: 30821090 DOI: 10.1111/liv.14082] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/15/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long-term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain. METHODS A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (<1year) and late CBR (≥1year) by the timing of remission. Liver-related adverse outcomes including liver-related death, liver transplantation and hepatocellular carcinoma were evaluated. RESULTS With immunosuppressive treatment, 222 (76.3%) patients achieved CBR (early CBR: 168 and late CBR: 54). BR was achieved in 55 (18.9%) patients and 14 (4.8%) patients remained non-remission. With a median follow-up duration of 6.6 years, the risk of liver-related mortality was the lowest in patients with CBR, followed by patients with late CBR, BR and non-response. The cumulative risk of liver-related adverse outcomes was the highest in patients with non-response (8.51/100 person-years [PYs]), followed by BR (1.95/100 PYs), late CBR (1.89/100 PYs) and early CBR (0.75/100 PYs). By multivariable analysis, age, cirrhosis and treatment responses were independently associated with liver-related adverse outcomes. CONCLUSIONS Patients with CBR within 1 year after treatment initiation had the lowest risk of liver-related adverse outcomes. Patients with late CBR and those with only BR had a comparable risk of long-term outcomes.
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Affiliation(s)
- Jonggi Choi
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gwang Hyeon Choi
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Hwa Chung
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung-Sang Lee
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Harrison L, Gleeson D. Stopping immunosuppressive treatment in autoimmune hepatitis (AIH): Is it justified (and in whom and when)? Liver Int 2019; 39:610-620. [PMID: 30667576 DOI: 10.1111/liv.14051] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/07/2019] [Accepted: 01/10/2019] [Indexed: 02/13/2023]
Abstract
BACKGROUND Initial treatment of autoimmune hepatitis (AIH) with prednisolone ± azathioprine is based on randomised controlled trials. Many patients receive long-term immunosuppressive treatment to prevent disease relapse; this strategy has a weaker evidence base. AIM To consider whether immunosuppressive treatment (IST) withdrawal in AIH is justified and to develop a rationale for patient selection. METHODS We reviewed published papers between 1972 and 2018, which addressed the outcomes of IST withdrawal and/or complications of IST in AIH. RESULTS (1) AIH relapse rates after withdrawal of IST vary between 25% and 100%. There is heterogeneity in these studies regarding relapse definition, IST duration prior to withdrawal and criteria for biochemical and histological remission prior to withdrawal. (2) Factors associated with relapse following IST withdrawal include: (a) absence of an identifiable initial disease trigger, (b) presence of other autoimmune diseases, (c) longer time to biochemical remission and (d) elevated serum transaminases on treatment withdrawal. Reports of associations between relapse and age, IST duration and failure of histological remission have been inconsistent. (3) Continued IST reduces risk of AIH relapse over at least 5 years. However, there is no evidence that routine (as opposed to selective) long-term IST improves disease outcome. (4) Patients with AIH have an increased risk of extrahepatic cancer, notably non-melanoma skin cancer, to which long-term IST may contribute. Long-term corticosteroid therapy is associated with weight gain, low-trauma fractures, diabetes and possibly vascular disease. CONCLUSIONS While further studies are needed, evidence supports a strategy of IST withdrawal in some patients with AIH who have achieved remission.
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Affiliation(s)
- Laura Harrison
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospital's NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, The University of Sheffield, Medical School, Sheffield, UK
| | - Dermot Gleeson
- Liver Unit, Northern General Hospital, Sheffield Teaching Hospital's NHS Foundation Trust, Sheffield, UK
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Abe K, Takahashi A, Fujita M, Hayashi M, Okai K, Nozawa Y, Ohira H. Interleukin-33/ST2-Mediated Inflammation Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis. Hepatol Commun 2019; 3:670-684. [PMID: 31061955 PMCID: PMC6492473 DOI: 10.1002/hep4.1326] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/22/2019] [Indexed: 12/11/2022] Open
Abstract
Interleukin (IL)‐33 was recently described as a new member of the IL‐1 family; members of this family have proinflammatory activity. IL‐33 and its soluble receptor ST2 (sST2) have been implicated in the pathogenesis of autoimmune diseases. This study investigated serum IL‐33 and sST2 in type I autoimmune hepatitis (AIH) and the relationship of these molecules with clinical and pathologic parameters. Subjects included 65 patients with AIH who were diagnosed in our hospital. The control population included 17 healthy individuals and 36 patients with primary biliary cholangitis (PBC). Mean age at AIH diagnosis was 55.5 years, and the male‐to‐female ratio was 6:59. Serum IL‐33 and sST2 levels were significantly higher in patients with AIH than in those with PBC or controls. Importantly, immunohistochemistry revealed high IL‐33 expression in liver sections from patients with AIH. In particular, serum IL‐33 and sST2 levels were significantly higher in acute‐onset AIH than in chronic‐onset AIH. Serum IL‐33 levels were positively correlated with serum total bilirubin (TB), alanine aminotransferase (ALT), and necroinflammatory activity in AIH. We performed multivariate logistic regression analysis and found serum IL‐33 levels to be independent factors for severe activity. Serum sST2 levels were positively correlated with serum TB and ALT and negatively correlated with serum albumin and prothrombin time in AIH. In particular, serum sST2 levels were significantly higher in severe symptoms of AIH. Serum IL‐33 and sST2 levels in patients with AIH responsive to treatment with prednisolone were significantly decreased after treatment. Interestingly, serum IL‐33 level was associated with a significantly increased risk of relapse. Conclusion: IL‐33/ST2 may play an important role in the pathogenesis and severity of AIH and may be a promising target for AIH therapy. This study aimed to investigate serum IL‐33 and sST2 in type I autoimmune hepatitis (AIH) patients and its relationship with clinical and pathological parameters. Multivariate analysis was performed, and serum IL‐33 levels were independent factors for severe activity and relapse. Our findings suggest that IL‐33/ST2 may play an important role in the pathogenesis and severity of AIH and may present a promising target for AIH therapy.
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Affiliation(s)
- Kazumichi Abe
- Department of Gastroenterology Fukushima Medical University School of Medicine Fukushima Japan
| | - Atsushi Takahashi
- Department of Gastroenterology Fukushima Medical University School of Medicine Fukushima Japan
| | - Masashi Fujita
- Department of Gastroenterology Fukushima Medical University School of Medicine Fukushima Japan
| | - Manabu Hayashi
- Department of Gastroenterology Fukushima Medical University School of Medicine Fukushima Japan
| | - Ken Okai
- Department of Gastroenterology Fukushima Medical University School of Medicine Fukushima Japan
| | - Yoshihiro Nozawa
- Department of Pathology Shirakawa Kousei General Hospital Shirakawa Japan
| | - Hiromasa Ohira
- Department of Gastroenterology Fukushima Medical University School of Medicine Fukushima Japan
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Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
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Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
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Sciveres M, Nastasio S, Maggiore G. Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis. Front Pediatr 2019; 7:382. [PMID: 31616649 PMCID: PMC6763601 DOI: 10.3389/fped.2019.00382] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Juvenile autoimmune hepatitis (JAIH) is a rare, chronic, inflammatory disease of the liver characterized by a complex interaction between genetic, immunological, and environmental factors leading to loss of immunotolerance to hepatic antigens. It affects both children and adolescents, most commonly females, and its clinical manifestations are quite variable. JAIH is progressive in nature and if left untreated may lead to cirrhosis and terminal liver failure. Although JAIH was first described almost 50 years ago, there have been few significant advances in the clinical management of these patients, both in terms of available diagnostic tools and therapeutic options. Aminotransferase activity, class G immunoglobulins and autoantibodies are the biomarkers used to diagnose AIH and monitor treatment response alongside clinical and histological findings. Despite their utility and cost-effectiveness, these biomarkers are neither an accurate expression of AIH pathogenic mechanism nor a precise measure of treatment response. Current standard of care is mainly based on the administration of steroids and azathioprine. This combination of drugs has been proven effective in inducing remission of disease in the majority of patients dramatically improving their survival; however, it not only fails to restore tolerance to hepatic autoantigens, but it also does not halt disease progression in some patients, it is often needed life-long and finally, it has deleterious side-effects. The ideal therapy should be enough selective to contrast immune-mediated live damage while preserving or potentiating the ability to develop permanent tolerance vs. pathogenic autoantigens. By reviewing the state of the art literature, this article highlights novel diagnostic and therapeutic strategies for managing pediatric AIH with a special focus on new strategies of immunotherapy. These promising tools could improve the diagnostic algorithm, more accurately predict disease prognosis, and provide targeted, individualized treatment.
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Affiliation(s)
- Marco Sciveres
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy
| | - Silvia Nastasio
- Division of Gastroenterology, Hepatology, and Nutrition, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Giuseppe Maggiore
- Pediatric Hepatology and Liver Transplantation, ISMETT-University of Pittsburgh Medical Center Italy, Palermo, Italy.,Section of Pediatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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31
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Lowe D, John S. Autoimmune hepatitis: Appraisal of current treatment guidelines. World J Hepatol 2018; 10:911-923. [PMID: 30631396 PMCID: PMC6323516 DOI: 10.4254/wjh.v10.i12.911] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis affects patients of all ages and gender, across all geographic regions. Although still rare, its incidence and prevalence are increasing. Genetic predisposition conveyed by human leucocyte antigen is a strong risk factor for the disease and may be responsible in part for the wide variation in presentation in different geographic regions. Our understanding of the underlying pathogenic mechanisms is evolving and may lead to development of more targeted immunotherapies. Diagnosis is based on elevated levels of serum aminotransferases, gamma globulins, autoantibodies and characteristic findings on histology. Exclusion of other causes of chronic hepatitis is important. Although undiagnosed disease is associated with poor outcomes, it is readily treatable with timely immunosuppressive therapy in the majority of patients. International guidelines are available to guide management but there exists a disparity in the standard treatment regimens. This minireview aims to review the available guidelines and summarize the key recommendations involved in management of this complex autoimmune disease.
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Affiliation(s)
- Dhruv Lowe
- Division of Gastroenterology and Hepatology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13202, United States
| | - Savio John
- Division of Gastroenterology and Hepatology, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, NY 13202, United States
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32
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Aljumah AA, Al Jarallah B, Albenmousa A, Al Khathlan A, Al Zanbagi A, Al Quaiz M, Al-Judaibi B, Nabrawi K, Al Hamoudi W, Alghamdi M, Fallatah H. The Saudi association for the study of liver diseases and transplantation clinical practice guidelines for management of autoimmune hepatitis. Saudi J Gastroenterol 2018; 24:S1-S20. [PMID: 30264737 PMCID: PMC6305081 DOI: 10.4103/sjg.sjg_159_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Abdulrahman A. Aljumah
- Division of Hepatology, Hepatobiliary Sciences and Organ Transplant Center, King Abdulaziz Medical City and King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Badr Al Jarallah
- Department of Medicine, Division of Gastroenterology, Al Qassim University, Al Qassim, Saudi Arabia
| | - Ali Albenmousa
- Department of Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Abdullah Al Khathlan
- Department of Medicine, Division of Gastroenterology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Adnan Al Zanbagi
- Department of Medicine, Division of Gastroenterology, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Mohammed Al Quaiz
- Department of Medicine, Section of Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Bandar Al-Judaibi
- Department of Medicine, University of Rochester, Rochester City, New York State, USA
| | - Khalid Nabrawi
- Department of Internal Medicine, Aseer Central Hospital, Abha, Saudi Arabia
| | - Waleed Al Hamoudi
- Department of Medicine, Division of Gastroenterology, King Saud University, Riyadh, Saudi Arabia
| | - Mohammed Alghamdi
- Department of Internal Medicine, King Fahad Military Medical City, Dhahran, Saudi Arabia
| | - Hind Fallatah
- Department of Medicine, Division of Gastroenterology and Hepatology, King Abdulaziz University, Jeddah, Saudi Arabia
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Wong LL, Fisher HF, Stocken DD, Rice S, Khanna A, Heneghan MA, Oo YH, Mells G, Kendrick S, Dyson JK, Jones DEJ. The Impact of Autoimmune Hepatitis and Its Treatment on Health Utility. Hepatology 2018; 68:1487-1497. [PMID: 29663477 PMCID: PMC6585808 DOI: 10.1002/hep.30031] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/22/2018] [Accepted: 04/10/2018] [Indexed: 12/17/2022]
Abstract
Patient reporting suggests that the physical and psychological effects of autoimmune hepatitis (AIH) can be substantial. However, health-related quality of life (HRQOL) in patients with AIH remains incompletely characterized, and health utility remains to be explored. Treatment for AIH often includes the use of corticosteroids, which are agents that can be associated with significant adverse effects. Here we explore the impact of AIH and its treatments on patient-reported HRQOL and health utility in a large cohort of prevalent cases from the United Kingdom Autoimmune Hepatitis (UK-AIH) national study. Data were collected from 990 adult participants with a clinical diagnosis of AIH using validated HRQOL tools including the European Quality-of-Life 5-Dimension 5-Level (EQ-5D-5L) and clinical data forms. The EQ-5D-5L dimension scores were compared with UK population norms and with a disease control cohort with primary biliary cholangitis (PBC). Within the AIH cohort, regression analysis was used to explore associations between HRQOL and demographic and clinical variables with a particular focus on the impact of AIH therapies including corticosteroid use. HRQOL, measured by the EQ-5D-5L utility index, is shown to be significantly impaired in our cohort of AIH patients compared with population norms. Within the AIH cohort, corticosteroid use was found to be significantly associated with impaired HRQOL, even when controlling for biochemical disease activity status. CONCLUSION Our data show evidence of HRQOL impairment in a large cohort of AIH patients compared with the general population. Furthermore, corticosteroid use is strongly associated with decreased HRQOL, independent of remission status. This highlights the need for better corticosteroid-free therapy approaches and it emphasizes the need for future novel therapeutic trials in AIH. (Hepatology 2018; 00:000-000).
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Affiliation(s)
- Lin Lee Wong
- Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUnited Kingdom
- Liver Unit, Freeman HospitalThe Newcastle upon Tyne NHS Foundation TrustNewcastle upon TyneUnited Kingdom
| | - Holly F Fisher
- Institute of Health and SocietyNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Deborah D Stocken
- Leeds Institute of Clinical Trials ResearchUniversity of LeedsLeedsUnited Kingdom
| | - Stephen Rice
- Institute of Health and SocietyNewcastle UniversityNewcastle upon TyneUnited Kingdom
| | - Amardeep Khanna
- Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUnited Kingdom
- Liver Unit, Freeman HospitalThe Newcastle upon Tyne NHS Foundation TrustNewcastle upon TyneUnited Kingdom
| | | | - Ye Htun Oo
- Centre for Liver Research and NIHR BRCUniversity of Birmingham and Liver Unit, University Hospital Birmingham NHS Foundation TrustUnited Kingdom
| | - George Mells
- Academic Department of Medical GeneticsUniversity of Cambridge and Addenbrooke’s HospitalCambridge Biomedical CampusUnited Kingdom
| | - Stuart Kendrick
- GlaxoSmithKline (GSK)Research and DevelopmentHertfordshireUnited Kingdom
| | - Jessica Katharine Dyson
- Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUnited Kingdom
- Liver Unit, Freeman HospitalThe Newcastle upon Tyne NHS Foundation TrustNewcastle upon TyneUnited Kingdom
| | - David E. J. Jones
- Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUnited Kingdom
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Clinical features of autoimmune hepatitis with acute presentation: a Japanese nationwide survey. J Gastroenterol 2018; 53:1079-1088. [PMID: 29476251 DOI: 10.1007/s00535-018-1444-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/15/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is characterized by progressive inflammation and necrosis of hepatocytes and eventually leads to a variety of phenotypes, including acute liver dysfunction, chronic progressive liver disease, and fulminant hepatic failure. Although the precise mechanisms of AIH are unknown, environmental factors may trigger disease onset in genetically predisposed individuals. Patients with the recently established entity of AIH with acute presentation often display atypical clinical features that mimic those of acute hepatitis forms even though AIH is categorized as a chronic liver disease. The aim of this study was to identify the precise clinical features of AIH with acute presentation. METHODS Eighty-six AIH patients with acute presentation were retrospectively enrolled from facilities across Japan and analyzed for clinical features, histopathological findings, and disease outcomes. RESULTS Seventy-five patients were female and 11 were male. Patient age ranged from adolescent to over 80 years old, with a median age of 55 years. Median alanine transaminase (ALT) was 776 U/L and median immunoglobulin G (IgG) was 1671 mg/dL. There were no significant differences between genders in terms of ALT (P = 0.27) or IgG (P = 0.51). The number of patients without and with histopathological fibrosis was 29 and 57, respectively. The patients with fibrosis were significantly older than those without (P = 0.015), but no other differences in clinical or histopathological findings were observed. Moreover, antinuclear antibody (ANA)-positive (defined as × 40, N = 63) and -negative (N = 23) patients showed no significant differences in clinical or histopathological findings or disease outcomes. Twenty-five patients experienced disease relapse and two patients died during the study period. ALP ≥ 500 U/L [odds ratio (OR) 3.20; 95% confidence interval (CI) 1.12-9.10; P < 0.030] and GGT ≥ 200 U/L (OR 2.98; 95% CI 1.01-8.77; P = 0.047) were identified as independent risk factors of disease relapse. CONCLUSIONS AIH with acute presentation is a newly recognized disease entity for which diagnostic hallmarks, such as ALT, fibrosis, and ANA, are needed. Further investigation is also required on the mechanisms of this disorder. Clinicians should be mindful of disease relapse during patient care.
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Rizvi S, Gawrieh S. Autoimmune Hepatitis in the Elderly: Diagnosis and Pharmacologic Management. Drugs Aging 2018; 35:589-602. [PMID: 29971609 DOI: 10.1007/s40266-018-0556-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune hepatitis (AIH) may present as acute or chronic hepatitis in the elderly. Advanced hepatic fibrosis and cirrhosis are common on first presentation in this population. In this review, we discuss the presentation, approach to diagnosis and management of AIH in the elderly. As polypharmacy is common in the elderly, careful medication use history is essential for detecting drug-induced AIH-like hepatitis. Steroid-sparing or minimizing therapeutic regimens are preferred to treat AIH in the elderly. For the purpose of induction, budesonide or lower dose prednisone in combination with azathioprine (AZA) regimens are preferred over high-dose prednisone monotherapy due to the higher risk of side effects of the later in the elderly. The goal of maintenance therapy should be to achieve full biochemical and histologic remission. Bone density monitoring and interventions to prevent steroid-related bone disease should be implemented throughout the course of the disease. Liver transplantation should be considered in the elderly patient with liver failure or early hepatocellular carcinoma if there are no significant comorbidities or compromise in functional status.
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Affiliation(s)
- Syed Rizvi
- Gastroenterology and Hepatology Division, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI, 53226, USA.
| | - Samer Gawrieh
- Gastroenterology and Hepatology Division, Indiana University School of Medicine, 702 Rotary Cir, Indianapolis, IN, 46202-5175, USA.
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Guirguis J, Alonso Y, Lopez R, Carey W. Well-controlled autoimmune hepatitis treatment withdrawal may be safely accomplished without liver-biopsy guidance. Gastroenterol Rep (Oxf) 2018; 6:284-290. [PMID: 30430017 PMCID: PMC6225821 DOI: 10.1093/gastro/goy020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 02/26/2018] [Accepted: 05/08/2018] [Indexed: 12/25/2022] Open
Abstract
Background Autoimmune hepatitis may flare up after treatment withdrawal, especially in those who had not achieved histological remission but had normal liver enzymes. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) Guidelines recommend performing liver biopsy before treatment withdrawal. The aim of the study is to define the outcome of treatment withdrawal in adults with well-controlled disease for 2 years with and without liver-biopsy guidance. Methods A retrospective observational study was conducted on biopsy-proven autoimmune hepatitis patients who were treated for 2 years and with persistently normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or nearly so for 6 months prior to treatment withdrawal. Exclusions were: juvenile onset autoimmune hepatitis and prior treatment or use of agents other than corticosteroids and azathioprine. The primary endpoint was to define freedom from flare-ups for 1 year after treatment withdrawal. Results Thirty-four consecutive subjects meeting study criteria were identified. Treatment withdrawal was accomplished in 24 subjects without liver-biopsy guidance and 10 had pre-treatment withdrawal liver biopsy. Demographics, immunosuppressive usage, pre-treatment cirrhosis and pre-treatment liver enzymes were similar between the two groups, and 25% had an enzyme flare-up within 12 months after treatment withdrawal, which was similar in the two groups (20.8 vs 30.0%, P = 0.57). Conclusions Adults with autoimmune hepatitis and excellent response to therapy for 2 years are candidates for treatment withdrawal without the need for liver biopsy.
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Affiliation(s)
- John Guirguis
- Department of Internal Medicine, Blake Medical Center, Bradenton, FL, USA
| | - Yilien Alonso
- Department of Gastroenterology, Ochsner Health System, New Orleans, LA, USA
| | - Rocio Lopez
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - William Carey
- Digestive Disease Institute, Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
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Baseline IL-2 and the AIH score can predict the response to standard therapy in paediatric autoimmune hepatitis. Sci Rep 2018; 8:419. [PMID: 29323192 PMCID: PMC5764983 DOI: 10.1038/s41598-017-18818-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 12/18/2017] [Indexed: 12/23/2022] Open
Abstract
Although autoimmune hepatitis (AIH) can be treated with corticosteroid-based first-line therapy, incomplete remission is associated with progressive liver fibrosis. So far accepted predictors of the subsequent treatment response of AIH patients are lacking. Therefore, we analysed baseline parameters, including iron homeostasis and cytokine levels, in 60 children with paediatric AIH (pAIH). In contrast to adults, elevated serum markers indicating iron overload were not commonly found in children. Therefore, ferritin was not predictive of the treatment response in pAIH. Although baseline immunoglobulins were lower in pAIH children with subsequent complete biochemical remission (BR) upon standard first-line therapy, only lower AIH scores (≤16 points) could predict BR upon standard therapy in our training and validation cohorts. Additionally, higher baseline IL-2 and MCP-1/CCL2 levels were associated with BR in a sub-cohort. A combined score of IL-2 level and a simplified AIH score predicted treatment response more precisely than both parameter alone in this sub-cohort. In conclusion, the baseline AIH score could be validated as a predictor of treatment response in pAIH. Additionally, low baseline IL-2 may help identify children who need salvage therapy. This could be important because the use of low-dose IL-2 therapies is being tested in various autoimmune diseases.
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Czaja AJ. Review article: next-generation transformative advances in the pathogenesis and management of autoimmune hepatitis. Aliment Pharmacol Ther 2017; 46:920-937. [PMID: 28901565 DOI: 10.1111/apt.14324] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 08/01/2017] [Accepted: 08/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Advances in autoimmune hepatitis that transform current concepts of pathogenesis and management can be anticipated as products of ongoing investigations driven by unmet clinical needs and an evolving biotechnology. AIM To describe the advances that are likely to become transformative in autoimmune hepatitis, based on the direction of current investigations. METHODS Pertinent abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and a secondary bibliography was developed. The discovery process was repeated, and a tertiary bibliography was identified. The number of abstracts reviewed was 2830, and the number of full-length articles reviewed exceeded 150. RESULTS Risk-laden allelic variants outside the major histocompatibility complex (rs3184504, r36000782) are being identified by genome-wide association studies, and their gene products are potential therapeutic targets. Epigenetic changes associated with environmental cues can enhance the transcriptional activity of genes, and chromatin re-structuring and antagonists of noncoding molecules of ribonucleic acid are feasible interventions. The intestinal microbiome is a discovery field for microbial products and activated immune cells that may translocate to the periphery and respond to manipulation. Epidemiological studies and controlled interview-based surveys may implicate environmental and xenobiotic factors that warrant evidence-based changes in lifestyle, and site-directed molecular and cellular interventions promise to change the paradigm of treatment from one of blanket immunosuppression. CONCLUSIONS Advances in genetics, epigenetics, pathophysiology, epidemiology, and site-directed molecular and cellular interventions constitute the next generation of transformative advances in autoimmune hepatitis.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis. PLoS One 2017; 12:e0179074. [PMID: 28594937 PMCID: PMC5464635 DOI: 10.1371/journal.pone.0179074] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 05/23/2017] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25–34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87–24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635–0.863) and internal validation cohort (AUC = 0.741; CI 0.558–0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.
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Joshi D, Gupta N, Samyn M, Deheragoda M, Dobbels F, Heneghan MA. The management of childhood liver diseases in adulthood. J Hepatol 2017; 66:631-644. [PMID: 27914924 DOI: 10.1016/j.jhep.2016.11.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 11/20/2016] [Accepted: 11/21/2016] [Indexed: 12/12/2022]
Abstract
An increasing number of patients with childhood liver disease survive into adulthood. These young adults are now entering adult services and require ongoing management. Aetiologies can be divided into liver diseases that develop in young adults which present to adult hepatologists i.e., biliary atresia and Alagille syndrome or liver diseases that occur in children/adolescents and adults i.e., autoimmune hepatitis or Wilson's disease. To successfully manage these young adults, a dynamic and responsive transition service is essential. In this review, we aim to describe the successful components of a transition service highlighting the importance of self-management support and a multi-disciplinary approach. We will also review some of the liver specific aetiologies which are unique to young adults, offering an update on pathogenesis, management and outcomes.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK.
| | - Nitika Gupta
- Division of Paediatric Gastroenterology, Emory University School of Medicine, Atlanta, USA
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital, London, UK
| | | | - Fabienne Dobbels
- Academic Centre for Nursing and Midwifery, Katholieke Universiteit Leuven, Belgium
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van Gerven NMF, de Boer YS, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Auto immune hepatitis. World J Gastroenterol 2016; 22:4651-4661. [PMID: 27217697 PMCID: PMC4870072 DOI: 10.3748/wjg.v22.i19.4651] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: “auto immune hepatitis”, “clinical presentation”, “symptoms”, “signs”, “diagnosis”, “auto antibodies”, “laboratory values”, “serology”, “histopathology”, “histology”, “genetics”, “HLA genes”, “non-HLA genes”, “environment”, “epidemiology”, “prevalence”, “incidence”, “demographics”, “complications”, “HCC”, “PBC”, “PSC”, “corticosteroid”, “therapy”, “treatment”, “alternative treatment”. English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.
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Czaja AJ. Diagnosis and Management of Autoimmune Hepatitis: Current Status and Future Directions. Gut Liver 2016; 10:177-203. [PMID: 26934884 PMCID: PMC4780448 DOI: 10.5009/gnl15352] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is characterized by autoantibodies, hypergammaglobulinemia, and interface hepatitis on histological examination. The features lack diagnostic specificity, and other diseases that may resemble autoimmune hepatitis must be excluded. The clinical presentation may be acute, acute severe (fulminant), or asymptomatic; conventional autoantibodies may be absent; centrilobular necrosis and bile duct changes may be present; and the disease may occur after liver transplantation or with features that suggest overlapping disorders. The diagnostic criteria have been codified, and diagnostic scoring systems can support clinical judgment. Nonstandard autoantibodies, including antibodies to actin, α-actinin, soluble liver antigen, perinuclear antineutrophil antigen, asialoglycoprotein receptor, and liver cytosol type 1, are tools that can support the diagnosis, especially in patients with atypical features. Prednisone or prednisolone in combination with azathioprine is the preferred treatment, and strategies using these medications in various doses can ameliorate treatment failure, incomplete response, drug intolerance, and relapse after drug withdrawal. Budesonide, mycophenolate mofetil, and calcineurin inhibitors can be considered in selected patients as frontline or salvage therapies. Molecular (recombinant proteins and monoclonal antibodies), cellular (adoptive transfer and antigenic manipulation), and pharmacological (antioxidants, antifibrotics, and antiapoptotic agents) interventions constitute future directions in management. The evolving knowledge of the pathogenic pathways and the advances in technology promise new management algorithms.
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Affiliation(s)
- Albert J. Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN,
USA
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Bittencourt PL, Cançado ELR, Couto CA, Levy C, Porta G, Silva AEB, Terrabuio DRB, Carvalho Filho RJD, Chaves DM, Miura IK, Codes L, Faria LC, Evangelista AS, Farias AQ, Gonçalves LL, Harriz M, Lopes Neto EPA, Luz GO, Oliveira P, Oliveira EMGD, Schiavon JLN, Seva-Pereira T, Parise ER, Parise ER. Brazilian society of hepatology recommendations for the diagnosis and management of autoimmune diseases of the liver. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52 Suppl 1:15-46. [DOI: 10.1590/s0004-28032015000500002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
ABSTRACT In order to draw evidence-based recommendations concerning the management of autoimmune diseases of the liver, the Brazilian Society of Hepatology has sponsored a single-topic meeting in October 18th, 2014 at São Paulo. An organizing committee comprised of seven investigators was previously elected by the Governing Board to organize the scientific agenda as well as to select twenty panelists to make a systematic review of the literature and to present topics related to the diagnosis and treatment of autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and their overlap syndromes. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of those recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present paper is the final version of the reviewed manuscript organized in topics, followed by the recommendations of the Brazilian Society of Hepatology.
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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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45
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Takahashi A, Ohira H, Abe K, Miyake Y, Abe M, Yamamoto K, Suzuki Y, Onji M, Tsubouchi H. Rapid corticosteroid tapering: Important risk factor for type 1 autoimmune hepatitis relapse in Japan. Hepatol Res 2015; 45:638-44. [PMID: 25070037 DOI: 10.1111/hepr.12397] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 07/19/2014] [Accepted: 07/24/2014] [Indexed: 12/12/2022]
Abstract
AIM Patients with autoimmune hepatitis (AIH) sometimes relapse after immunosuppressive therapies are discontinued or sometimes even while they are still being administrated. Furthermore, relapse often occurs in the absence of AIH relapse risk factors. This study aimed to identify the frequency of relapse and to analyze the risk factors associated with relapse in type 1 AIH patients. METHODS Clinical characteristics and therapeutic processes were assessed in 129 type 1 AIH patients. RESULTS Relapse was identified in 39 (30.2%) type 1 AIH patients after alanine aminotransferase (ALT) level normalization. ALT levels significantly increased when corticosteroid treatment was initiated in relapsed patients compared with that in patients with sustained remission. The reduction dose and rate of corticosteroid taper were significantly increased in relapsed patients compared with those in sustained remission patients. Moreover, positive correlations were identified between the reduction dose/taper rate and initial corticosteroid dose, and ALT levels, total bilirubin levels and hepatitis activity. Multivariate logistic regression analysis identified the corticosteroid reduction rate as significantly associated with AIH relapse. CONCLUSION Corticosteroid reduction taper rate until ALT normalization is an important AIH relapse risk factor.
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Affiliation(s)
- Atsushi Takahashi
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Yasuhiro Miyake
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Morikazu Onji
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
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Abstract
Autoimmune hepatitis is characterized by increased serum aminotransferase levels, autoantibodies, hypergammaglobulinemia, and interface hepatitis. Presentation can be acute, severe (fulminant), asymptomatic, or chronic. Diagnosis requires multiple findings and exclusion of similar diseases. Treatment with prednisone or prednisolone with azathioprine is recommended. Budesonide with azathioprine has normalized laboratory test with few side effects, but histologic resolution, durability of response, and target population are uncertain. Progressive worsening, incomplete improvement, drug intolerance, and relapse after drug withdrawal are suboptimal outcomes. Calcineurin inhibitors and mycophenolate mofetil are salvage agents in small series and liver transplantation is effective for liver failure.
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Abstract
INTRODUCTION Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions. AREAS COVERED PubMed searches from 1970 - 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects. EXPERT OPINION Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, From the Division of Gastroenterology and Hepatology , 200 First Street S.W, Rochester, MN 55905 , USA +1 507 284 2691 ; +1 507 284 0538 ;
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Challenges in the diagnosis and management of autoimmune hepatitis. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2014; 27:531-9. [PMID: 24078938 DOI: 10.1155/2013/981086] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Autoimmune hepatitis has diverse clinical phenotypes and outcomes that challenge current diagnostic criteria and management algorithms. OBJECTIVES To highlight the major difficulties in diagnosis and management, describe the efforts to ease them and encourage further progress in problem solving. METHODS The MEDLINE database was reviewed for published experiences from 1984 to 2013. RESULTS Acute or acute severe (fulminant) hepatitis, asymptomatic mild disease, and histological findings of centrilobular necrosis or bile duct injury can confound diagnosis and treatment. Continuation of conventional therapy until normal liver test results and liver tissue reduces the frequency of relapse, but does not prevent its occurrence. Problematic patients can be identified using mathematical models, clinical phenotype, serological markers and the speed of improvement after treatment; however, their recognition and treatment are inconsistent. Mycophenolate mofetil can rescue patients with azathioprine intolerance but is less effective for refractory disease. Budesonide in combination with azathioprine can be used frontline, but is effective primarily in noncirrhotic, uncomplicated disease. Molecular and cellular interventions are feasible but largely unevaluated. DISCUSSION Resolution of the current challenges requires revision of diagnostic criteria, characterization of biological markers that reflect pathogenic pathways, development of dynamic indexes based on changes in disease behaviour, and introduction of new pharmacological, molecular and cellular interventions that have undergone rigorous evaluation. CONCLUSION These challenges reflect important remediable deficiencies in current management.
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Czaja AJ. Review article: permanent drug withdrawal is desirable and achievable for autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:1043-58. [PMID: 24628539 DOI: 10.1111/apt.12701] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 02/09/2014] [Accepted: 02/23/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis can be rendered treatment-free, but the difficulty, frequency and risks associated with the pursuit of this outcome are unclear. AIM To describe the frequency that autoimmune hepatitis can be rendered treatment-free, identify the features that characterise these patients, examine the pathogenic pathways that may sustain or terminate the disease and indicate management protocols that can obtain this result. METHODS Studies cited in Pub Med from 1972-2014 for autoimmune hepatitis, treatment, relapse, remission and outcome were selected. RESULTS The frequency of a treatment-free state varies from 19% to 40% in patients observed for ≥3 years after drug withdrawal. Complete laboratory resolution and reversion to normal liver tissue prior to drug withdrawal favours this response. The development of cirrhosis during therapy may increase treatment-dependence. Persistent liver damage and the generation of neo-antigens during the apoptosis of hepatocytes may perpetuate the disease. Genetic and age-related effects on the vigour of the immune response may also contribute. Reversion to normal liver tissue is achieved in only 22% of patients during conventional corticosteroid therapy, and the emerging pharmacological and biological interventions may improve this frequency. A management strategy designed to achieve a treatment-free state accommodates all candidates for this outcome, and it can be modified to a long-term maintenance strategy as warranted by the clinical response. CONCLUSIONS Permanent drug withdrawal is a treatment outcome that is desirable and achievable in patients with autoimmune hepatitis. Normalisation of liver tests and liver tissue during treatment enhances this occurrence.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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Deneau M, Book LS, Guthery SL, Jensen MK. Outcome after discontinuation of immunosuppression in children with autoimmune hepatitis: a population-based study. J Pediatr 2014; 164:714-719.e2. [PMID: 24423432 DOI: 10.1016/j.jpeds.2013.12.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 10/29/2013] [Accepted: 12/05/2013] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To assess sustained immunosuppression-free remission (SIFR) in children with autoimmune hepatitis (AIH). STUDY DESIGN We retrospectively reviewed all children with AIH in the region between 1986 and 2011 using a population-based methodology. RESULTS We identified 56 children with AIH (62.5% females; median age, 11.1 years [IQR, 5.7-14.4 years], followed for a median of 5.6 years [IQR, 2.8-8.6 years]). Liver disease was characterized by type II AIH in 8.9%, cirrhosis in 14.0%, and primary sclerosing cholangitis in 21.4%. Coexisting nonhepatic immune-mediated diseases occurred in 37.5%. Biochemical remission on immunosuppressive therapy was achieved in 76.4% of all patients with AIH at a median of 1.2 years (IQR, 0.4-3.6 years); 23.1% of these patients experienced a subsequent relapse. Discontinuation of all immunosuppressive medications was attempted in 16 patients and was successful in 14 patients (87.5%) with type 1 AIH (median age at discontinuation, 8.9 years [IQR, 3.5-17.9 years], treated for a median of 2.0 years [IQR, 1.3-3.5 years] after diagnosis), with SIFR occurring at a median of 3.4 years (IQR, 2.6-5.8 years) of follow-up. Excluding patients with inflammatory bowel disease who received immunosuppressive therapy independent of their liver disease, the probability of achieving SIFR within 5 years of diagnosis of AIH was 41.6% (95% CI, 25.3%-62.9%). Baseline patient characteristics associated with an inability to achieve biochemical remission on immunosuppression or SIFR were elevated international normalized ratio, positive antineutrophil cytoplasmic antibody titer, cirrhosis, and a nonhepatic autoimmune disorder. CONCLUSION We found a high rate of successful discontinuation of all immunosuppressive medications in carefully selected patients with AIH in a population-based cohort. SIFR is an achievable goal for children with AIH, particularly those with type I disease in stable biochemical remission on immunosuppressive therapy.
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Affiliation(s)
- Mark Deneau
- Section of Pediatric Gastroenterology, Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba, Canada.
| | - Linda S Book
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah, Salt Lake City, UT
| | - Stephen L Guthery
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah, Salt Lake City, UT
| | - M Kyle Jensen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Utah, Salt Lake City, UT
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