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Tanaka A, Harada K. Acute presentation of autoimmune hepatitis -from acute hepatitis to ALF and ACLF. Hepatol Int 2024; 18:1385-1395. [PMID: 39127981 DOI: 10.1007/s12072-024-10714-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/15/2024] [Indexed: 08/12/2024]
Abstract
Acute presentation of autoimmune hepatitis (AIH) occurs in 22-43% of all AIH cases, and is not a rare condition. Rather than constituting a single disease entity, it represents a clinical spectrum characterized by considerable variability in severity and the presence of preexisting chronic AIH. This spectrum ranges from acute AIH and acute severe AIH to AIH presenting as acute liver failure (ALF) or as acute-on-chronic liver failure (ACLF), contingent upon factors such as coagulopathy, hepatic encephalopathy, and underlying liver disease. Diagnosing acute presentation of AIH can be particularly challenging due to the frequent absence of classical serologic signatures such as autoantibodies and elevated IgG levels. Histopathological examination remains essential for diagnosis, typically necessitating percutaneous or transjugular liver biopsy. Corticosteroids (CS) are recommended for the management of acute AIH and acute severe AIH with coagulopathy. However, the therapeutic response to CS should be meticulously monitored. If a poor response is anticipated, liver transplantation (LT) should be promptly considered. For AIH presenting as ALF with encephalopathy or ACLF with advanced underlying liver disease, LT is generally advised. Nonetheless, there is potential for a trial of CS therapy in cases of ALF with low MELD scores or ACLF without encephalopathy. This review provides an overview of the latest findings concerning the definition, diagnosis, and management of acute presentation of AIH.
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Affiliation(s)
- Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan.
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University School of Medical Sciences, Kanazawa, Japan
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Fawzy A, Sutton H, Vandriel SM, Sonnenberg M, Kamath BM. Outcomes and management in paediatric autoimmune hepatitis presenting as acute liver failure: Individual patient data meta-analysis. Liver Int 2024; 44:1797-1807. [PMID: 38700362 DOI: 10.1111/liv.15943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 03/16/2024] [Accepted: 04/08/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND AND AIMS Autoimmune hepatitis (AIH) in children presenting in acute liver failure (ALF) can be fatal and often requires liver transplantation (LTx). This individual patient data meta-analysis (IPD) aims to examine management and outcomes of this population, given the lack of large cohort studies on paediatric AIH first presenting as ALF (AIH-ALF). METHODS A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses of IPD statement using PubMed and Excerpta Medica dataBASE, and included English studies published between 2000 and 2020. The study included patients under 21 years of age, diagnosed with type 1 or 2 AIH and presenting with ALF. Data extracted included clinical and biochemical characteristics, interventions, and outcomes. RESULTS Three hundred and thirty eligible patients from 61 studies were identified, with an additional five patients from our institution. The majority were female (66.8%), with a median age of 10. Overall, 59.7% achieved native liver survival (NLS), 35% underwent LTx, and 5% died before LTx. The use of corticosteroids with non-steroid immunomodulators increased the likelihood of NLS by 2.5-fold compared to corticosteroids alone. AIH-1 was associated with 3.3-fold odds for NLS, compared to AIH-2. However, on multivariate analysis, only AIH-1 was identified as an independent predictor for NLS (OR 3.8 [95% CI 1.03-14.2], p = .04). CONCLUSION While corticosteroids and non-steroid immunomodulators treatment may offer enhanced probability of achieving NLS, treatment regimens for AIH-ALF may need to consider patient-specific factors, especially AIH type. This highlights the potential for NLS in AIH-ALF and suggest a need to identify biomarkers which predict the need for combination immunosuppression to avoid LTx.
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Affiliation(s)
- Aly Fawzy
- Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Harry Sutton
- Division of Gastroenterology Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
| | - Shannon M Vandriel
- Division of Gastroenterology Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
| | - Mikayla Sonnenberg
- Division of Gastroenterology Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
| | - Binita M Kamath
- Division of Gastroenterology Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
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Slooter CD, van den Brand FF, Lleo A, Colapietro F, Lenzi M, Muratori P, Kerkar N, Dalekos GN, Zachou K, Lucena MI, Robles-Díaz M, Di Zeo-Sánchez DE, Andrade RJ, Montano-Loza AJ, Lytvyak E, Lissenberg-Witte BI, Maisonneuve P, Bouma G, Macedo G, Liberal R, de Boer YS. Lack of complete biochemical response in autoimmune hepatitis leads to adverse outcome: First report of the IAIHG retrospective registry. Hepatology 2024; 79:538-550. [PMID: 37676683 DOI: 10.1097/hep.0000000000000589] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 08/02/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND AND AIMS The International Autoimmune Hepatitis Group retrospective registry (IAIHG-RR) is a web-based platform with subjects enrolled with a clinical diagnosis of autoimmune hepatitis (AIH). As prognostic factor studies with enough power are scarce, this study aimed to ascertain data quality and identify prognostic factors in the IAIHG-RR cohort. METHODS This retrospective, observational, multicenter study included all patients with a clinical diagnosis of AIH from the IAIHG-RR. The quality assessment consisted of external validation of completeness and consistency for 29 predefined variables. Cox regression was used to identify risk factors for liver-related death and liver transplantation (LT). RESULTS This analysis included 2559 patients across 7 countries. In 1700 patients, follow-up was available, with a completeness of individual data of 90% (range: 30-100). During a median follow-up period of 10 (range: 0-49) years, there were 229 deaths, of which 116 were liver-related, and 143 patients underwent LT. Non-White ethnicity (HR 4.1 95% CI: 2.3-7.1), cirrhosis (HR 3.5 95% CI: 2.3-5.5), variant syndrome with primary sclerosing cholangitis (PSC) (HR 3.1 95% CI: 1.6-6.2), and lack of complete biochemical response within 6 months (HR 5.7 95% CI: 3.4-9.6) were independent prognostic factors. CONCLUSIONS The IAIHG-RR represents the world's largest AIH cohort with moderate-to-good data quality and a relevant number of liver-related events. The registry is a suitable platform for patient selection in future studies. Lack of complete biochemical response to treatment, non-White ethnicity, cirrhosis, and PSC-AIH were associated with liver-related death and LT.
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Affiliation(s)
- Charlotte D Slooter
- Department of Gastroenterology and Hepatology, Amsterdam UMC, AGEM Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Floris F van den Brand
- Department of Gastroenterology and Hepatology, Amsterdam UMC, AGEM Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Francesca Colapietro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Marco Lenzi
- Department of Clinical Medicine, University of Bologna, Bologna, Italy
| | - Paolo Muratori
- Department of Sciences for the Quality of Life, University of Bologna, Bologna, Italy
| | - Nanda Kerkar
- Department of Gastroenterology, Hepatology and Nutrition, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, USA
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN-RARE LIVER), General University Hospital of Larissa, Larissa, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Expertise Center of Greece in Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN-RARE LIVER), General University Hospital of Larissa, Larissa, Greece
| | - M Isabel Lucena
- Liver Unit, Gastroenterology Service and Department of Medicine, Vírgen de Victoria University Hospital, University of Málaga, Malaga, Spain
| | - Mercedes Robles-Díaz
- Liver Unit, Gastroenterology Service and Department of Medicine, Vírgen de Victoria University Hospital, University of Málaga, Malaga, Spain
| | - Daniel E Di Zeo-Sánchez
- Liver Unit, Gastroenterology Service and Department of Medicine, Vírgen de Victoria University Hospital, University of Málaga, Malaga, Spain
| | - Raúl J Andrade
- Liver Unit, Gastroenterology Service and Department of Medicine, Vírgen de Victoria University Hospital, University of Málaga, Malaga, Spain
| | - Aldo J Montano-Loza
- Department of Gastroenterology and Hepatology, University of Alberta Hospital, Edmonton, Canada
| | - Ellina Lytvyak
- Department of Gastroenterology and Hepatology, University of Alberta Hospital, Edmonton, Canada
| | - Birgit I Lissenberg-Witte
- Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam UMC, AGEM Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar São João, Porto, Portugal
| | - Rodrigo Liberal
- Department of Gastroenterology and Hepatology, Centro Hospitalar São João, Porto, Portugal
| | - Ynto S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam UMC, AGEM Institute, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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Hsu SJ, Chao YC, Lin XH, Liu HH, Zhang Y, Hong WF, Chen MP, Xu X, Zhang L, Ren ZG, Du SS, Chen RX. Antinuclear antibody (ANA) status predicts immune-related adverse events in liver cancer patients undergoing anti-PD-1 therapy. Clin Exp Immunol 2023; 212:239-248. [PMID: 36966354 PMCID: PMC10243869 DOI: 10.1093/cei/uxad036] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 12/31/2022] [Accepted: 03/25/2023] [Indexed: 03/27/2023] Open
Abstract
Immune-related adverse events (irAEs) clinically resemble autoimmune diseases, indicating autoantibodies could be potential biomarkers for the prediction of irAEs. This study aimed to assess the predictive value of peripheral blood antinuclear antibody (ANA) status for irAEs, considering the time and severity of irAEs, as well as treatment outcome in liver cancer patients administered anti-PD-1 therapy. Ninety-three patients with advanced primary liver cancer administered anti-PD-1 treatment were analyzed retrospectively. They were divided into the ANA positive (ANA+, titer ≥ 1:100) and negative (ANA-, titer < 1:100) groups. Development of irAEs, progression-free survival (PFS), and overall survival (OS) were assessed. Compared with ANA- patients, ANA+ cases were more prone to develop irAEs (43.3% vs. 19.2%, P = 0.031). With the increase of ANA titers, the frequency of irAEs increased. The time interval between anti-PD-1 therapy and the onset of irAEs was significantly shorter in ANA+ patients compared with the ANA- group (median, 1.7 months vs. 5.0 months, P = 0.022). Moreover, the time between anti-PD-1 therapy and irAE occurrence decreased with increasing ANA titer. In addition, PFS and OS were decreased in ANA+ patients compared with the ANA- group (median PFS, 2.8 months vs. 4.2 months, P = 0.043; median OS, 21.1 months vs. not reached, P = 0.041). IrAEs occur at higher frequency in ANA+ liver cancer patients undergoing anti-PD-1 therapy. ANA titer could help predict irAE development and treatment outcome in these patients.
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Affiliation(s)
- Shu-Jung Hsu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yen-Cheng Chao
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xia-Hui Lin
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hua-Hua Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yang Zhang
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei-Feng Hong
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mao-Pei Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lan Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shi-Suo Du
- Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Rong-Xin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Khedr MA, Salem TA, Boghdadi GM, Elharoun AS, El-Shahaway AA, Atallah HR, Sira MM. Seronegative autoimmune hepatitis in children : A real diagnostic challenge. Wien Klin Wochenschr 2022; 134:195-201. [PMID: 34283299 DOI: 10.1007/s00508-021-01907-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 06/11/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Classical autoimmune hepatitis (AIH) is characterized by the presence of conventional autoantibodies (anti-smooth muscle, antinuclear and anti-liver-kidney-microsomal antibodies). The absence of such autoantibodies in some patients does not preclude AIH diagnosis or the need for its treatment. This group of patients was termed seronegative AIH. Whether non-conventional autoantibodies can identify this group of patients is still elusive. We aimed to study the prevalence of seronegativity of conventional autoantibodies and the occurrence of non-conventional autoantibodies in children with AIH. METHODS In this study, 55 children with AIH were investigated for non-conventional autoantibodies (anti-neutrophil cytoplasmic antibodies, antibodies to soluble liver antigen, anti-tissue transglutaminase and antiplatelet antibodies). All the patients received immunosuppressive therapy and were assessed for treatment response. RESULTS Of the patients 44 had classical AIH (type 1, 70.09%, type 2, 9.09%) and 20% were seronegative. The four studied non-conventional autoantibodies occurred in four patients, one for each. All non-conventional autoantibodies were exclusively associated with type 1 AIH. The clinical profile, ultrasonographic findings, liver biochemistry and histopathological findings were comparable in the classical and seronegative AIH. The majority of patients with classical (72.7%) and seronegative (54.5%) AIH were treatment responders. CONCLUSION Seronegative AIH represents a substantial percentage of pediatric patients diagnosed with AIH. They were even negative for non-conventional autoantibodies. Furthermore, apart from autoantibodies, seronegative AIH is almost indistinguishable from the classical AIH and the majority of patients were treatment responders. This favorable response to immunosuppression deserves sustainable efforts for considering such a diagnosis and start therapy to halt disease progression is worthwhile.
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Affiliation(s)
- Mohammed A Khedr
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, 32511, Shebin El-koom, Menoufia, Egypt
| | - Tahany A Salem
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, 32511, Shebin El-koom, Menoufia, Egypt.
| | - Ghada M Boghdadi
- Department of Immunology Research Laboratories, Microbiology and Immunology, Faculty of Medicine, Zagazig University, 44519, El-Sharkiya, Egypt
| | - Ahmed S Elharoun
- Department of Microbiology and Immunology, Faculty of Medicine, Menoufia University, Shebin El-koom, Menoufia, Egypt
| | - Allia A El-Shahaway
- Department of Immunology Research Laboratories, Microbiology and Immunology, Faculty of Medicine, Zagazig University, 44519, El-Sharkiya, Egypt
| | - Hany R Atallah
- Department of Pediatrics, Ahmed Maher Teaching Hospital, Ministry of Health, Cairo, Egypt
| | - Mostafa M Sira
- Department of Pediatric Hepatology, Gastroenterology and Nutrition, National Liver Institute, Menoufia University, 32511, Shebin El-koom, Menoufia, Egypt
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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: 548] [Impact Index Per Article: 109.6] [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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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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Tarao K, Nozaki A, Ikeda T, Sato A, Komatsu H, Komatsu T, Taguri M, Tanaka K. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment. Cancer Med 2019; 8:1054-1065. [PMID: 30791221 PMCID: PMC6434205 DOI: 10.1002/cam4.1998] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/27/2018] [Accepted: 01/06/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. METHODS The PubMed database was examined (1989-2017) for studies published in English language regarding the prospective follow-up results for the development of HCC in various liver diseases. A meta-analysis was performed for each liver disease. RESULTS The annual incidence (%) of HCC in the non-cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non-cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73-fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07-fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88-fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79-fold), and (e) NASH (0.03%→1.35%, 45.00-fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow-up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. CONCLUSIONS When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.
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Affiliation(s)
- Kazuo Tarao
- Tarao’s Gastroenterological ClinicYokohamaJapan
| | - Akito Nozaki
- Gastroenterological Center, Medical CenterYokohama City UniversityYokohamaJapan
| | - Takaaki Ikeda
- Gastroenterology DepartmentYokosuka General Hospital UwamachiYokosukaJapan
| | - Akira Sato
- Division of Gastroenterology, Department of Internal MedicineSt. Marianna University, Yokohama City Seibu HospitalYokohamaJapan
| | - Hirokazu Komatsu
- Department of GastroenterologyYokohama Municipal Citizen’s HospitalYokohamaJapan
| | - Tatsuji Komatsu
- Department Clinical ResearchNational Hospital Organization, Yokohama Medical CenterYokohamaJapan
| | - Masataka Taguri
- Department of Data ScienceYokohama City UniversityYokohamaJapan
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Pericleous M, Kelly C, Ala A, De Lusignan S. The role of the chronic care model in promoting the management of the patient with rare liver disease. Expert Rev Gastroenterol Hepatol 2018; 12:829-841. [PMID: 29976101 DOI: 10.1080/17474124.2018.1497483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
INTRODUCTION The chronic care model (CCM) provides a holistic approach for managing chronic illnesses. Patients with rare liver diseases (RLD) have complex needs, impaired quality of life and often life-threatening complications. Most RLD meet the criteria for a long-term chronic condition and should be viewed through the prism of CCM. We aimed to ascertain whether the CCM has been considered for the frequently-encountered RLD. METHODS MEDLINE®/PubMed®/Cochrane/EMBASE were searched to identify publications relating to the use of the CCM for the management of six RLD. We identified 33 articles eligible for inclusion. RESULTS Six, eleven, one, thirteen, two and zero studies, discussed individual components of the CCM for autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cirrhosis (PSC), Wilsons disease (WD), alpha-1 antitrypsin deficiency (A1AD) and lysosomal acid lipase deficiency (LALd) respectively. We have not identified studies using the full CCM for any of the aforementioned RLD. DISCUSSION Unlike in common chronic conditions e.g. diabetes, there has been limited consideration of the use of CCM (or its components) for the management of RLD. This may reflect a reluctance of the clinical community to view these diseases as chronic or lack of healthcare policy investment in rare diseases in general.
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Affiliation(s)
- Marinos Pericleous
- a Department of Gastroenterology and Hepatology , Royal Surrey County Hospital NHS Foundation Trust , Guildford , UK.,b Department of Clinical and experimental medicine , University of Surrey , Guildford , UK
| | - Claire Kelly
- a Department of Gastroenterology and Hepatology , Royal Surrey County Hospital NHS Foundation Trust , Guildford , UK.,b Department of Clinical and experimental medicine , University of Surrey , Guildford , UK
| | - Aftab Ala
- a Department of Gastroenterology and Hepatology , Royal Surrey County Hospital NHS Foundation Trust , Guildford , UK.,b Department of Clinical and experimental medicine , University of Surrey , Guildford , UK
| | - Simon De Lusignan
- b Department of Clinical and experimental medicine , University of Surrey , Guildford , UK
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10
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Saxena V, Terrault NA. Recurrent Primary Disease After Liver Transplantation. ZAKIM AND BOYER'S HEPATOLOGY 2018:784-815.e14. [DOI: 10.1016/b978-0-323-37591-7.00053-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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11
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Tansel A, Katz LH, El-Serag HB, Thrift AP, Parepally M, Shakhatreh MH, Kanwal F. Incidence and Determinants of Hepatocellular Carcinoma in Autoimmune Hepatitis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2017; 15:1207-1217.e4. [PMID: 28215616 PMCID: PMC5522646 DOI: 10.1016/j.cgh.2017.02.006] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 01/31/2017] [Accepted: 02/06/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk factors among patients with AIH. METHODS We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I2 statistic. RESULTS A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I2 = 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I2 = 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis. CONCLUSIONS Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis.
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Affiliation(s)
- Aylin Tansel
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
| | - Lior H Katz
- The Department of Gastroenterology, Sheba Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Aaron P Thrift
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Mayur Parepally
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Medical Center, Chicago, Illinois
| | - Mohammad H Shakhatreh
- Section of Gastroenterology and Hepatology, Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, Virginia
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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12
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Zizzo AN, Valentino PL, Shah PS, Kamath BM. Second-line Agents in Pediatric Patients With Autoimmune Hepatitis: A Systematic Review and Meta-analysis. J Pediatr Gastroenterol Nutr 2017; 65:6-15. [PMID: 28644343 DOI: 10.1097/mpg.0000000000001530] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population. METHODS Electronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed. RESULTS Fifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54%-100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size. CONCLUSIONS Cyclosporine had the highest response rate at 6 months in children with standard-treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate.
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Affiliation(s)
- Andréanne N Zizzo
- *The Hospital for Sick Children †University of Toronto, Toronto, Ontario, Canada ‡Yale University School of Medicine, New Haven, CT §Mount Sinai Hospital, Toronto ||London Health Sciences Centre, Western University, London, Ontario, Canada
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Li YN, Ma H, Zhou L, Zhang J, Guo LP, Li SQ, Qian YQ, Wang BM. Autoimmune Hepatitis-related Cirrhosis: Clinical Features and Effectiveness of Immunosuppressive Treatment in Chinese Patients. Chin Med J (Engl) 2016; 129:2434-2440. [PMID: 27748335 PMCID: PMC5072255 DOI: 10.4103/0366-6999.191760] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background: The long-term outcomes of patients with autoimmune hepatitis (AIH) given the immunosuppressive treatment are considered to be preferable. However, little is known about the response of AIH patients with cirrhosis to immunosuppressive treatment. We assessed the effects of immunosuppressive therapy in Chinese AIH patients with cirrhosis from a tertiary hospital. Methods: Patients with a clinical diagnosis of AIH January 2000 and December 2015 were retrospectively reviewed. Two-hundred and fourteen patients who were followed up and satisfied the simplified AIH criteria were included in the study. Among these patients, 87 presented with cirrhosis when initially diagnosed for AIH. Immunosuppressive treatments were employed in 57 AIH patients who did not present with cirrhosis and 39 patients who presented with cirrhosis. Initial responses to immunosuppressive treatment of patients with and without cirrhosis were analyzed. Independent risk factors were assessed for predicting the prognosis of patients. The t-test and Cox regression statistical analysis were used. Results: In total, 96 AIH patients including 39 with cirrhosis and 57 without cirrhosis underwent immunosuppressive therapy. The overall complete remission after initial immunosuppressive treatment was achieved in 81/96 patients (84.4%), whereas 9/96 (9.4%) achieved incomplete response, and 6/96 (6.3%) occurred treatment failure. Compared to noncirrhotic patients, patients who presented with cirrhosis responded to treatment to a comparable extent regarding complete response (noncirrhosis 50/57 [87.7%] vs. cirrhosis 31/39 [79.5%], P = 0.275), incomplete remission (noncirrhosis 4/57 [7.0%] vs. cirrhosis 5/39 [12.8%], P = 0.338), and treatment failure (noncirrhosis 3/57 [5.3%] vs. cirrhosis 3/39 [7.7%], P = 0.629). Importantly, the remission rate was comparable (54/57 [94.7%] and 36/39 [92.3%], P = 0.629) for noncirrhotic and cirrhotic patients after immunosuppressive therapy. Compared to patients who maintained remission (n = 19) after drug withdrawal, patients who experienced relapse (n = 17) had significantly higher levels of serum immunoglobulin G at entry (15.0 ± 6.5 g/L vs. 22.3 ± 5.8 g/L, t = 2.814, P = 0.004). Moreover, cirrhosis at presentation significantly increased the risk of disease exacerbation (hazard ratio [HR]: 4.603; P = 0.002). The treatment of immunosuppressant (HR: 0.058; P = 0.005) and the level of aspartate aminotransferase at presentation (HR: 1.002; P = 0.017) also increased the risk of disease progression. Conclusions: The efficacy of initial immunosuppressive treatment in AIH patients with cirrhosis is comparable to that in those without cirrhosis. Cirrhotic patients not treated by immunosuppressants have poor long-term outcomes.
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Affiliation(s)
- Yan-Ni Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300054, China
| | - Huan Ma
- Department of Gastroenterology and Hepatology, Hebei Medical University Third Hospital, Hebei Medical University, Shijiazhuang, Heibei 050051, China
| | - Lu Zhou
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300054, China
| | - Jie Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300054, China
| | - Li-Ping Guo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300054, China
| | - Shu-Qian Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300054, China
| | - Yi-Qi Qian
- Department of Preventive Medicine, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Bang-Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin 300054, China
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14
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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: 101] [Impact Index Per Article: 11.2] [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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15
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Muratori P, Lalanne C, Barbato E, Fabbri A, Cassani F, Lenzi M, Muratori L. Features and Progression of Asymptomatic Autoimmune Hepatitis in Italy. Clin Gastroenterol Hepatol 2016; 14:139-146. [PMID: 26192146 DOI: 10.1016/j.cgh.2015.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 06/23/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Patients with autoimmune hepatitis (AIH) can present with symptoms ranging from those that are insidious and nonspecific to acute hepatitis with jaundice. However, some patients have no symptoms at diagnosis and are identified incidentally. We investigated disease progression and outcomes of these 2 groups of patients. METHODS We performed a retrospective study to compare clinical, immunologic, and histologic features and outcomes of patients with asymptomatic vs. symptomatic AIH. We analyzed data collected from 305 patients (90 asymptomatic and 215 with symptoms), diagnosed with AIH from 1994 and 2013, at the Center for the Study and Treatment of the Autoimmune Diseases of the Liver and Biliary System in Bologna, Italy. RESULTS At diagnosis, patients with asymptomatic AIH had significantly lower mean levels of alanine aminotransferase (7.0- ± 8.0-fold the upper limit of normal) than patients with symptomatic disease (23.0- ± 18.0-fold the upper limit of normal; P < .001), and lower mean levels of bilirubin (1.4 ± 1.4 mg/dL vs. 8.6 ± 10.4 mg/dL; P < .001). Asymptomatic patients also had significantly lower histologic grades (7.0 ± 2.5) than symptomatic patients (9.0 ± 2.9; P < .001). However, larger proportions of asymptomatic patients had anti-liver/kidney microsomal antibodies type 1 (26.8% vs. 13.1%; P < .006), and associated autoimmune thyroid (26.7% vs. 12.6%; P = .003) or skin (8.9% vs. 2.3%; P = .010) disorders. Age at onset, sex, response to therapy, disease progression, genetic factors, and other autoantibody markers did not differ between patients with asymptomatic vs. symptomatic disease. CONCLUSIONS Patients with asymptomatic vs. symptomatic AIH have similar courses of disease progression and responses to immunosuppressive agents, and therefore should receive the same treatment. Patients affected by thyroid or dermatologic autoimmune disorders are at increased risk of developing subclinical liver disease, and should be assessed routinely for AIH.
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Affiliation(s)
- Paolo Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | - Claudine Lalanne
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | - Erica Barbato
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | - Angela Fabbri
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | - Fabio Cassani
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Policlinico di Sant'Orsola, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marco Lenzi
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy
| | - Luigi Muratori
- Centro per lo Studio e la Cura delle Malattie Autoimmuni del Fegato e delle Vie Biliari, Policlinico di Sant'Orsola, Bologna, Italy; Dipartimento di Scienze Mediche e Chirurgiche, Alma Mater Studiorum-Università di Bologna, Bologna, Italy.
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16
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Faisal N, Renner EL. Recurrence of autoimmune liver diseases after liver transplantation. World J Hepatol 2015; 7:2896-905. [PMID: 26689244 PMCID: PMC4678376 DOI: 10.4254/wjh.v7.i29.2896] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 11/07/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT.
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Affiliation(s)
- Nabiha Faisal
- Nabiha Faisal, Eberhard L Renner, Liver Transplant Program/Multiorgan Transplant Program, University Health Network/Toronto General Hospital, University of Toronto, Toronto, ON M5G 2N2, Canada
| | - Eberhard L Renner
- Nabiha Faisal, Eberhard L Renner, Liver Transplant Program/Multiorgan Transplant Program, University Health Network/Toronto General Hospital, University of Toronto, Toronto, ON M5G 2N2, Canada
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Abstract
Liver transplantation (LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), but not for primary sclerosing cholangitis (PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease (AIH, PBC, PSC) following LT.
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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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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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Czaja AJ. Review article: The prevention and reversal of hepatic fibrosis in autoimmune hepatitis. Aliment Pharmacol Ther 2014; 39:385-406. [PMID: 24387318 DOI: 10.1111/apt.12592] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 11/29/2013] [Accepted: 12/05/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunosuppressive treatment of autoimmune hepatitis can prevent or reverse hepatic fibrosis, but these anti-fibrotic effects are inconsistent secondary gains. AIM To describe the anti-fibrotic effects of current therapies for autoimmune hepatitis, discuss the pathogenic mechanisms of hepatic fibrosis that might be targeted by anti-fibrotic interventions, indicate the non-invasive diagnostic tests of hepatic fibrosis that must be validated in autoimmune hepatitis and to suggest promising treatment opportunities. METHODS Studies cited in PubMed from 1972 to 2013 for autoimmune hepatitis, hepatic fibrosis, cirrhosis, anti-fibrotic therapy and non-invasive tests of hepatic fibrosis were selected. RESULTS Hepatic fibrosis improves in 53-57% of corticosteroid-treated patients with autoimmune hepatitis; progressive fibrosis slows or is prevented in 79%; and cirrhosis may be reversed. Progressive hepatic fibrosis is associated with liver inflammation, and the inability to fully suppress inflammatory activity within 12 months is associated with progression to cirrhosis (54%) and death or need for liver transplantation (15%). Liver tissue examination remains the gold standard for assessing hepatic fibrosis, but laboratory and radiological tests may be useful non-invasive methods to measure the fibrotic response. Severe liver inflammation can confound radiological assessments, and the preferred non-invasive test in autoimmune hepatitis is uncertain. Individualised treatment adjustments and adjunctive anti-fibrotic therapies are poised for study in this disease. CONCLUSIONS The prevention and reversal of hepatic fibrosis are achievable objectives in autoimmune hepatitis. Strategies that evaluate individualised therapies adjusted to the rapidity and completeness of the inflammatory response, and the use of adjunctive anti-fibrotic interventions, must be evaluated.
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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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Peng M, Li Y, Zhang M, Jiang Y, Xu Y, Tian Y, Peng F, Gong G. Clinical features in different age groups of patients with autoimmune hepatitis. Exp Ther Med 2013; 7:145-148. [PMID: 24348780 PMCID: PMC3860875 DOI: 10.3892/etm.2013.1363] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 10/17/2013] [Indexed: 12/12/2022] Open
Abstract
The Chinese population are at an increased risk of autoimmune hepatitis (AIH). The aims of this study were to determine the demographic and clinical features of AIH in China. A total of 83 patients with AIH diagnosed by the revised scoring system were re-analyzed, and the clinical presentations among the different ages were compared. The patients were classified according to age at presentation. AIH occurred in patients aged ≤30 years (9.6%), 31–39 years (10.8%), 40–49 years (16.9%), 50–59 years (31.3%) and ≥60 years (31.3%). There were no differences in the form of the clinical presentation, concurrent autoimmune diseases, cirrhosis distribution and autoantibodies among the groups. However, patients aged ≥60 years presented with higher levels of alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GT) compared with patients aged ≤30 years (P=0.034, P=0.043, respectively), and patients aged 31–39 years had a significantly lower immunoglobulin G (IgG) level compared with those aged 50–59 years (P=0.049) and those aged ≥60 years (P=0.012). By contrast, patients aged ≤30 years had a significantly higher total bilirubin (TBIL) level compared with those aged 31–39 years (P=0.007), 50–59 years (P=0.002) and ≥60 years (P=0.013). A substantial portion of patients with AIH were aged >60 years, indicating a poor liver-associated outcome under current management strategies. Elderly patients appeared to be more asymptomatic compared with the younger patients.
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Affiliation(s)
- Milin Peng
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yi Li
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Min Zhang
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yongfang Jiang
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yuan Xu
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yi Tian
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Feng Peng
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Guozhong Gong
- Center of Liver Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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Liberal R, Zen Y, Mieli-Vergani G, Vergani D. Liver transplantation and autoimmune liver diseases. Liver Transpl 2013; 19:1065-77. [PMID: 23873751 DOI: 10.1002/lt.23704] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2013] [Accepted: 06/23/2013] [Indexed: 12/16/2022]
Abstract
Liver transplantation (LT) is an effective treatment for patients with end-stage autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Indications for LT for these diseases do not differ substantially from those used for other acute or chronic liver diseases. Despite the good outcomes reported, the recurrence of autoimmune liver disease is relatively common in the allograft. In addition, it has become apparent that autoimmunity and autoimmune liver disease can arise de novo after transplantation for nonautoimmune liver disorders. An awareness of the existence of recurrent autoimmune liver diseases and de novo autoimmune hepatitis after LT has important clinical implications because their management differs from the standard antirejection treatment and is similar to the management of classic autoimmune liver diseases in the native liver.
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Affiliation(s)
- Rodrigo Liberal
- Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, United Kingdom; Faculty of Medicine, University of Porto, Porto, Portugal
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Ngu JH, Gearry RB, Frampton CM, Stedman CAM. Predictors of poor outcome in patients w ith autoimmune hepatitis: a population-based study. Hepatology 2013; 57:2399-406. [PMID: 23359353 DOI: 10.1002/hep.26290] [Citation(s) in RCA: 79] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2012] [Accepted: 01/16/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) can lead to cirrhosis, hepatic failure, and death. We aimed to identify predictors of advanced liver fibrosis at presentation, predictors of incomplete response to initial immunosuppression, and predictors of poor liver-related outcomes in the population-based AIH cohort from Canterbury, New Zealand. Cases diagnosed after 1980 that fulfilled standard diagnostic criteria were included. Cases were censored at death or liver transplantation and had a median follow-up of 9 years. Analyses were performed with Cox proportional hazards regression and logistic binary regression. The times to event outcomes were summarized using Kaplan-Meier curves. A total of 133 AIH patients were included. Predictors for advanced liver fibrosis at diagnosis were age at presentation of ≤20 years or >60 years (P = 0.02), serum albumin <36 g/L (P < 0.01), platelet <150 U/L (P < 0.01), and International Normalized Ratio (INR) >1.2 (P < 0.01). The only independent predictor for incomplete normalization of alanine aminotransferase (ALT) at 6 months was age at presentation ≤20 years. Independent predictors of poor liver-related outcomes were incomplete normalization of ALT at 6 months (P < 0.01), serum albumin <36 g/L (P < 0.01), and age at presentation of ≤20 years or >60 years (P = 0.01). Kaplan-Meier estimates showed that 10-year adverse liver event-free survival was 80% for age at presentation ≤20 years and >60 years, and 93% and 100% for age at presentation between 21-40 years and 41-60 years, respectively. CONCLUSION Incomplete normalization of ALT at 6 months, low serum albumin concentration at diagnosis, and age at presentation of ≤20 years or >60 years were significant independent predictors of liver-related death or requirement for liver transplantation. Histological cirrhosis at diagnosis was not associated with poor prognosis and did not influence the response to initial immunosuppressive treatment. (HEPATOLOGY 2013;57:2399-2406).
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Affiliation(s)
- Jing Hieng Ngu
- Department of Gastroenterology, Christchurch Hospital, Christchurch, Canterbury, New Zealand
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Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an autoimmune liver disease: immunological aspects and clinical overview. Autoimmune Dis 2012; 2012:312817. [PMID: 23304455 PMCID: PMC3530748 DOI: 10.1155/2012/312817] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 09/09/2012] [Accepted: 10/12/2012] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a unique form of immune-mediated disease that attacks the liver through a variety of immune mechanisms. The outcomes of AIH are either acute liver disease, which can be fatal, or, more commonly, chronic progressive liver disease, which can lead to decompensated liver cirrhosis if left untreated. AIH has characteristic immunological, and pathological, features that are important for the establishment of the diagnosis. More importantly, most patients with AIH have a favorable response to treatment with prednisolone and azathioprine, although some patients with refractory AIH or more aggressive disease require more potent immune-suppressant agents, such as cyclosporine or Mycophenolate Mofetil. In this paper, we discuss the immunological, pathological and clinical features of AIH, as well as the standard and alternative treatments for AIH.
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Affiliation(s)
- Hind I. Fallatah
- Medical Department, Arab Board and Saudi Board of Internal Medicine, MACP, King Abdul Aziz University Hospital, P.O. Box 9714, Jeddah 21423, Saudi Arabia
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27
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Advances in the current treatment of autoimmune hepatitis. Dig Dis Sci 2012; 57:1996-2010. [PMID: 22476586 DOI: 10.1007/s10620-012-2151-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Accepted: 03/16/2012] [Indexed: 12/17/2022]
Abstract
Current treatment strategies for autoimmune hepatitis are complicated by frequent relapse after drug withdrawal, medication intolerance, and refractory disease. The objective of this review is to describe advances that have improved treatment outcomes by defining the optimum objectives of initial therapy, managing relapse more effectively, identifying problematic patients early, and incorporating the new pharmacological interventions that have emerged as frontline and salvage therapies. Initial corticosteroid treatment should be continued until serum aminotransferase, γ-globulin, and immunoglobulin G levels are normal, and maintenance of this improvement for 3-8 months before liver tissue assessment. Improvement to normal liver tissue is the ideal histological result that justifies drug withdrawal, but it is achievable in only 22 % of patients. Minimum portal hepatitis, inactive cirrhosis, or minimally active cirrhosis is the most common treatment end point. Relapse after drug withdrawal warrants institution of a long-term maintenance regimen, preferably with azathioprine. Mathematical models can identify problematic adult patients early, as also can clinical phenotype (age ≤ 30 years and HLA DRB1 03), rapidity of treatment response (≤ 24 months), presence of antibodies to soluble liver antigen, and non-white ethnicity. The calcineurin inhibitors (cyclosporine and tacrolimus) can be effective in steroid-refractory disease; mycophenolate mofetil can be corticosteroid-sparing and effective for azathioprine intolerance; budesonide combined with azathioprine can be effective for treatment-naïve, non-cirrhotic patients. Standard treatment regimens for autoimmune hepatitis can be upgraded without adjustments that require major new expertise.
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Abstract
Autoimmune hepatitis has a variable clinical phenotype, and the absence of conventional autoantibodies does not preclude its diagnosis or need for treatment. The goals of this review are to describe the frequency and nature of autoantibody-negative autoimmune hepatitis, indicate its outcome after corticosteroid treatment, and increase awareness of the diagnosis in patients with unexplained acute and chronic hepatitis. The frequency of presumed autoantibody-negative autoimmune hepatitis in patients with acute and acute severe presentations is ≤7%, and its frequency in patients with chronic presentations is 1-34%. Patients with acute presentations can have normal serum γ-globulin levels, centrilobular zone 3 necrosis, and low pre-treatment international diagnostic scores. Liver tissue examination is essential for the diagnosis, and hepatic steatosis can be a co-morbid feature. The comprehensive international scoring system can support but never override the clinical diagnosis pre-treatment, and non-standard serological markers should be sought if the clinical diagnosis is uncertain or the diagnostic score is low. A 3-month treatment trial with corticosteroids should be considered in all patients, regardless of the serological findings, and improvements have occurred in 67-87% of cases. Autoantibody-negative autoimmune hepatitis may be associated with an autoantibody outside the conventional battery; it may have a signature autoantibody that is still undiscovered, or its characteristic autoantibodies may have been suppressed or have a delayed expression. The pathogenic mechanisms are presumed to be identical to those of classical disease. Autoantibody-negative autoimmune hepatitis is an infrequent but treatable disease that must be considered in unexplained acute and chronic hepatitis.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Czaja AJ. Emerging opportunities for site-specific molecular and cellular interventions in autoimmune hepatitis. Dig Dis Sci 2010; 55:2712-26. [PMID: 20108036 DOI: 10.1007/s10620-009-1122-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2009] [Accepted: 12/28/2009] [Indexed: 02/08/2023]
Abstract
Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Abstract
Treatment decisions in autoimmune hepatitis are complicated by the diversity of its clinical presentations, uncertainties about its natural history, evolving opinions regarding treatment end points, varied nature of refractory disease, and plethora of alternative immunosuppressive agents. The goals of this article are to review the difficult treatment decisions and to provide the bases for making sound therapeutic judgments. The English literature on the treatment problems in autoimmune hepatitis were identified by Medline search up to October 2009 and 32 years of personal experience. Autoimmune hepatitis may have an acute severe presentation, mild inflammatory activity, lack autoantibodies, exhibit atypical histological changes (centrilobular zone 3 necrosis or bile duct injury), or have variant features reminiscent of another disease (overlap syndrome). Corticosteroid therapy must be instituted early, applied despite the absence of symptoms, or modified in an individualized fashion. Pursuit of normal liver tests and tissue is the ideal treatment end point, but this objective must be tempered against the risk of side effects. Relapse after treatment withdrawal requires long-term maintenance therapy, preferably with azathioprine. Treatment failure or an incomplete response warrants salvage therapy that can include conventional medications in modified dose or empirical therapies with calcineurin inhibitors or mycophenolate mofetil. Liver transplantation supersedes empirical drug therapy in decompensated patients. Elderly and pregnant patients warrant treatment modifications. Difficult treatment decisions in autoimmune hepatitis can be simplified by recognizing its diverse manifestations and individualizing treatment, pursuing realistic goals, applying appropriate salvage regimens, and identifying problematic patients early.
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31
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Kil JS, Lee JH, Han AR, Kang JY, Won HJ, Jung HY, Lim HM, Gwak GY, Choi MS, Koh KC, Paik SW, Yoo BC. Long-term treatment outcomes for autoimmune hepatitis in Korea. J Korean Med Sci 2010; 25:54-60. [PMID: 20052348 PMCID: PMC2800017 DOI: 10.3346/jkms.2010.25.1.54] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2009] [Accepted: 10/08/2009] [Indexed: 01/05/2023] Open
Abstract
Immunosuppressive therapy can improve clinical, biochemical and histological features and considerably prolong survival in patients with autoimmune hepatitis. Although ethnicity may affect disease severity and presentation, the long-term outcome of immunosuppression in Korean populations is unknown. This study was aimed to assess the efficacy of immunosuppressive therapy and determine the prognosis of autoimmune hepatitis in Korean populations. We reviewed the medical records of 86 patients diagnosed as having autoimmune hepatitis at the Samsung Medical Center between 1994 and 2008. Seventy-two (83.7%) patients reached remission after a median treatment duration of 3.5 months (range 1 to 44 months). Attempts to withdraw medications were made in 24 cases after the median treatment duration of 36 months (median 6 to 125 months). Thirteen of 24 (54.1%) patients relapsed after treatment withdrawal. Of the 86 patients, 6 (7.2%) experienced disease progression and the overall 5-and 10-yr progression-free survival rates were 91.2% and 85.5%, respectively. In conclusion, immunosuppressive therapy for autoimmune hepatitis results in a favorable rate of remission and excellent progression-free survival, but the relapse rate after treatment withdrawal is high. This suggests that long-term immunosuppressive therapy may be particularly important for treatment of Korean patients.
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Affiliation(s)
- Jae Sook Kil
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Joon Hyoek Lee
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - A-Reum Han
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Ja Young Kang
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Hye Jin Won
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Han Young Jung
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Hyun Min Lim
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
| | - Byung Chul Yoo
- Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea
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Greene MT, Whitington PF. Outcomes in pediatric autoimmune hepatitis. Curr Gastroenterol Rep 2009; 11:248-51. [PMID: 19463226 DOI: 10.1007/s11894-009-0038-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Autoimmune hepatitis (AIH) is a common cause of acute and chronic hepatitis in childhood. Once the diagnosis is established, treatment with cortico-steroid or corticosteroid and azathioprine is indicated. Most children with AIH respond to such therapy and experience remission from active disease. Eliminating drug therapy while maintaining remission is the ultimate goal of therapy. The optimal duration of therapy before drug elimination is unclear. Relapse rate is inversely related to therapy duration before drug withdrawal; thus, discontinuing immunosuppressive treatment is considered only after at least 1 to 2 years of complete remission. When applying a slow and systematic approach, many children with AIH can successfully be weaned off immunosuppression completely. Even patients presenting in acute liver failure may avoid liver transplantation with early medical therapy. In about 10% of patients, treatment fails, requiring alternative therapies and/or liver transplantation as liver disease progresses. Less than 10% of children with autoimmune hepatitis die during 10 years of follow-up.
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Affiliation(s)
- Maria T Greene
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Memorial Hospital, Chicago, IL 60614, USA.
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Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol 2009; 51:161-7. [PMID: 19446908 DOI: 10.1016/j.jhep.2009.02.026] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 02/03/2009] [Accepted: 02/23/2009] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIMS Corticosteroid therapy is effective in type 1 autoimmune hepatitis. This study determines if the rapidity of response affects outcome. METHODS The duration of treatment to improve clinical and laboratory indices was determined retrospectively in 146 patients and correlated with outcome. RESULTS Sixteen patients (11%) responded after < or =6 months, and 20 patients did so after 36 months (14%). The rapid responders were older than those who responded slowly (54+/-3 years versus 41+/-4 years, P=0.007), and they had a lower frequency of HLA DRB1 *03 (36% versus 76%, P=0.03). Patients aged > or =60 years responded within 6 months more commonly than adults aged <40 years (18% versus 2%, P=0.02), and most had responded within 24 months (94% versus 64%, P=0.003). Elderly patients who responded quickly had HLA DRB1 *04 more commonly than adults aged <40 years (75% versus 8%, P=0.0001). Progression to cirrhosis (18% versus 54%, P=0.03) and liver transplantation (2% versus 15%, P<0.05) was less common in the rapid responders. The frequencies of a sustained remission (19% versus 10%, P=0.6) and relapse after drug withdrawal (81% versus 90%, P=0.6) were similar between patients with an early and late response. CONCLUSIONS A rapid treatment response decreases progression to cirrhosis and liver transplantation, but it does not alter the frequency of sustained remission or relapse after drug withdrawal. Elderly patients respond more quickly to treatment than adults aged <40 years, and they are characterized by HLA DRB1 *04.
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Abstract
Corticosteroid therapy induces clinical, laboratory and histological improvements in 80% of patients with autoimmune hepatitis. Prednisone, alone or at a lower dose in combination with azathioprine, increases the 20-year life expectancy to 80% and prevents or reduces hepatic fibrosis in 79% of patients. The combination regimen is preferred and treatment should be considered in all patients with active disease. The duration of therapy is finite and the medication should be discontinued after resolution of all manifestations of inflammatory activity, including the histological changes. Relapse after drug withdrawal occurs in 50-79% of patients, and it should be treated with long-term azathioprine (2 mg/kg daily). Salvage therapies for individuals intolerant of or refractory to the conventional regimens include high-dose corticosteroids, with or without high-dose azathioprine, 6-mercaptopurine, mycophenolate mofetil, tacrolimus or ciclosporin. Liver transplantation should be considered in patients with hepatic failure unresponsive to corticosteroid treatment, decompensated cirrhosis with a Model for End-Stage Liver Disease score of at least 15 points, or hepatocellular carcinoma that meets transplantation criteria. Autoimmune hepatitis recurs after transplantation in at least 17% of patients, and it typically improves after adjustments in the immunosuppressive regimen. Future therapies are likely to include mesenchymal stem cell transplantation, adoptive transfer of T regulatory cells, and cytokine manipulation. The emergence of new treatments will require the development of a collaborative network of clinical and basic investigators, as the complexity and specificity of current management problems require solutions that exceed the capabilities of single institutions.
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Affiliation(s)
- Albert J Czaja
- Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Abstract
PURPOSE OF REVIEW To review studies that improve the diagnosis and treatment of autoimmune hepatitis and extend the understanding of its pathogenic mechanisms. RECENT FINDINGS A simplified diagnostic scoring system has high sensitivity and specificity. Biliary changes detected by MRI are of uncertain nature and significance. New candidate autoantigens have been identified by proteomic analyses. T regulatory cells suppress disease activity; their adoptive transfer is beneficial in animal models. Budesonide in combination with azathioprine is effective frontline therapy. Bone marrow-derived mesenchymal stem cell transplantation may emerge as salvage therapy. Screening for hepatocellular cancer is justified. Racial disparities in disease severity, mortality, and treatment remain unexplained. SUMMARY Diagnosis has been simplified and management strategies have been upgraded. Biliary changes have been recognized but are of uncertain nature and significance. New antigens and antibodies have been described. T-cell populations that modulate disease activity have been characterized, and adoptive transfer of T regulatory cells is possible. Budesonide in combination with azathioprine is effective frontline therapy, and therapeutic interventions that target critical pathogenic mechanisms are feasible.
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HLA class II association with autoimmune hepatitis in Latin America: A meta-analysis. Autoimmun Rev 2009; 8:325-31. [DOI: 10.1016/j.autrev.2008.11.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2008] [Accepted: 11/04/2008] [Indexed: 12/22/2022]
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