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Appell ML, Hindorf U, Almer S, Haglund S. Response to azathioprine treatment in autoimmune hepatitis is dependent on glutathione transferase genotypes. Dig Liver Dis 2025; 57:885-892. [PMID: 39863504 DOI: 10.1016/j.dld.2024.12.026] [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: 06/25/2024] [Revised: 11/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Azathioprine (AZA) is part of the standard treatment for autoimmune hepatitis (AIH). The first step in the complex bioconversion of AZA to active metabolites is mediated by glutathione transferases (GSTs). AIMS Elucidate the association between GSTM1 and GSTT1 copy number variation (CNV), genetic variation in GSTA2, GSTP1, and inosine-triphosphate-pyrophosphatase, and the response to AZA in AIH. METHODS Genotyping was performed in AIH patients (n = 131) on AZA, and in a Swedish background population (n = 283). Thiopurine metabolites in blood erythrocytes were determined by high performance liquid chromatography. RESULTS GSTM1 and GSTT1 CNV were associated with treatment response to AZA. Gene deletion of GSTM1-but not of GSTT1-was associated with the liver transaminase levels. None of the studied genetic variants were associated with the thiopurine metabolite concentrations, suggesting non-enzymatic mechanisms of GSTM1 and GSTT1 in the context of AZA efficacy in AIH. The prevalence of GSTM1 and GSTT1 CNV genotypes was similar in AIH and in the background population. CONCLUSION This study shows the effects of GSTM1 and GSTT1 CNV on AZA efficacy in AIH, not previously described. It also elaborates on the impact of the definition of treatment response, on the importance of the various GSTs studied. Furthermore, the GSTM1 and GSTT1 CNV frequencies previously reported in European populations were confirmed.
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Affiliation(s)
- Malin Lindqvist Appell
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
| | - Ulf Hindorf
- Department of Gastroenterology and Nutrition, University Hospital Lund, Lund, Sweden.
| | - Sven Almer
- Centre for Digestive Health, Department of Gastroenterology, Dermatology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.
| | - Sofie Haglund
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Department of Laboratory Medicine, Region Jönköping County, Jönköping, Sweden.
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Komori A, Kugiyama Y. Hard-to-treat autoimmune hepatitis and primary biliary cholangitis: The dawn of a new era of pharmacological treatment. Clin Mol Hepatol 2025; 31:90-104. [PMID: 39523716 PMCID: PMC11791546 DOI: 10.3350/cmh.2024.0821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/04/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
Patients with hard-to-treat autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC) are defined a posteriori as those who do not show a sufficient response or are intolerant to pharmacological treatments, thus not achieving biochemical surrogate endpoints that are associated with long-term liver-related-event-free survival. The absence of a recently harmonized definition of 'complete biochemical response within 6 months (CBR≤6M)', which is defined as the normalization of serum transaminase and IgG levels below the upper limit of normal at ≤6 months after treatment initiation, is regarded as hard-to-treat AIH. The implementation of CBR≤6M, in turn, has been facilitating clinical trials, e.g., between azathioprine and mycophenolate mofetil, to reconsider appropriate first-line steroid sparing agents, leading to a reduction in the number of hard-to-treat AIH cases. Regarding PBC, one of the disseminated definitions of hard-to-treat patients is the absence of POISE criteria, which are evaluated at 12 months with serum alkaline phosphatase and bilirubin levels, after the introduction of ursodeoxycholic acid. Hard-to-treat PBC not meeting the POISE criteria has very recently been the target population for the U.S. FDA-approved second-line drugs, elafibranor and seladelpar. In future pharmacological treatment of AIH and PBC, the primary objective for AIH is likely to focus on lowering the number of hard-to-treat patients with personalized steroid sparing treatment regimens. A challenging goal in PBC treatment is the further optimization of treatment surrogate endpoints, even to the stricter alkaline phosphatase normalization, with which an indication of second- or later-line drugs might be expanded, but could ultimately lengthen patients' long-term survival.
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Affiliation(s)
- Atsumasa Komori
- Clinical Research Center, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
- Hepatology Unit, NHO Nagasaki Medical Center, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
| | - Yuki Kugiyama
- Hepatology Unit, NHO Nagasaki Medical Center, Nagasaki University Graduate School of Biomedical Sciences, Omura, Nagasaki, Japan
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Chen W, Noel G, Amin M, Chen F. The utility of the mHAI scoring system in pediatric autoimmune hepatitis diagnosis and its association with treatment response. Ann Diagn Pathol 2024; 73:152381. [PMID: 39418718 DOI: 10.1016/j.anndiagpath.2024.152381] [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: 08/25/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/19/2024]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory autoimmune disease with either acute or chronic presentation. Previous scoring systems have primarily focused on chronic hepatitis, but none have been validated in an acute setting of pediatric patients. This study aimed to: 1) summarize the clinicopathologic characteristics of pediatric AIH patients; 2) assess if the modified Hepatic Activity Index (mHAI) can be used in both acute and chronic presentations of pediatric AIH; 3) evaluate the association of initial mHAI scores with treatment response at various endpoints. Thirty-one pediatric AIH patients were categorized into acute and chronic presentation groups. Biopsies were reviewed using the mHAI grading and staging system. AIH treatment endpoints were analyzed: 4 weeks (response vs. non-response), 6 months (complete vs. insufficient response), and approximately 12 months (histological remission vs. non-remission). Patients with acute AIH had higher mean mHAI scores and more prominent interface activity. Those achieving complete response at 6 months had significantly higher mean mHAI scores compared to those with an insufficient response. Notably, patients demonstrating fibrosis reversal at the 1-year follow-up often had higher initial mHAI scores. The mHAI can be used to evaluate acute and chronic presentations of pediatric AIH. Acute pediatric AIH has a higher mHAI score with more severe activity. The patients with a higher mHAI have a greater likelihood of achieving a complete response to treatment at 6 months and subsequent improvement in fibrosis status.
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Affiliation(s)
- Wei Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
| | - Gillian Noel
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
| | - Mansi Amin
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
| | - Fengming Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
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Plagiannakos CG, Hirschfield GM, Lytvyak E, Roberts SB, Ismail M, Gulamhusein AF, Selzner N, Qumosani KM, Worobetz L, Hercun J, Vincent C, Flemming JA, Swain MG, Cheung A, Chen T, Grbic D, Peltekain K, Mason AL, Montano-Loza AJ, Hansen BE. Treatment response and clinical event-free survival in autoimmune hepatitis: A Canadian multicentre cohort study. J Hepatol 2024; 81:227-237. [PMID: 38527524 DOI: 10.1016/j.jhep.2024.03.021] [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: 05/13/2023] [Revised: 03/11/2024] [Accepted: 03/13/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND & AIMS Treatment outcomes for people living with autoimmune hepatitis (AIH) are limited by a lack of specific therapies, as well as limited well-validated prognostic tools and clinical trial endpoints. We sought to identify predictors of outcome for people living with AIH. METHODS We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. RESULTS In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12 months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and IgG values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased the risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. CONCLUSION In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. IMPACT AND IMPLICATIONS Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, and uses continuous measurements over follow-up. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side effects.
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Affiliation(s)
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada.
| | - Ellina Lytvyak
- Division of Preventive Medicine, Department of Medicine, University of Alberta, Edmonton, Canada
| | - Surain B Roberts
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada
| | - Marwa Ismail
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Aliya F Gulamhusein
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada; Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Canada
| | - Nazia Selzner
- Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | | | - Lawrence Worobetz
- Department of Medicine, University of Saskatchewan, Saskatoon, Canada
| | - Julian Hercun
- Liver Unit, Department of Medicine, Centre Hospitalier De l'Université De Montréal, Montréal, Canada
| | - Catherine Vincent
- Liver Unit, Department of Medicine, Centre Hospitalier De l'Université De Montréal, Montréal, Canada
| | | | - Mark G Swain
- Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Canada
| | - Angela Cheung
- Department of Medicine, University of Ottawa, Ottawa, Canada
| | - Tianyan Chen
- Department of Medicine, McGill University Health Centre, Montréal, Canada
| | | | - Kevork Peltekain
- Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Andrew L Mason
- Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
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Hatoum S, Rockey DC. Long-term outcomes of patients with autoimmune hepatitis induced cirrhosis after immunosuppressive treatment. Eur J Gastroenterol Hepatol 2024; 36:742-749. [PMID: 38555597 PMCID: PMC11058017 DOI: 10.1097/meg.0000000000002714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
INTRODUCTION Autoimmune hepatitis is an immune-mediated liver disease that results in hepatic inflammation and subsequent fibrosis. We aimed to assess the natural history of autoimmune hepatitis in patients who had cirrhosis at the time of diagnosis. METHODS We examined consecutive patients with autoimmune hepatitis (based on the revised International Autoimmune Hepatitis Group criteria) and cirrhosis who had long-term follow-up between 2012 and 2018. Complete clinical data, including longitudinal data, was obtained for each patient to determine clinical and biochemical outcomes. Decompensating events were defined as complications of portal hypertension. RESULTS Thirty-four patients presenting with autoimmune hepatitis induced cirrhosis (age 50, 17-81; 71% women) were followed for an average of 8 years post-diagnosis. Fourteen (41%) patients had a decompensating event at diagnosis. All patients were begun on treatment; index decompensating events resolved in all patients. Twenty-six (76%) patients had normalization of transaminases; in this group, 4 (15%) patients developed one or more new decompensating events and 1 patient (4%) died. Of the 8 (24%) patients who did not have transaminase normalization, 6 (75%) developed one or more new decompensating events and 5 (62%) died or underwent liver transplant. There was a significant association between achieving normalization of transaminases and protection from developing a decompensating event ( P = 0.003) and liver transplant or death ( P = 0.001). CONCLUSION Most patients with autoimmune hepatitis with cirrhosis at presentation achieved normalization of transaminases with treatment and rarely developed further decompensating events. We speculate that some of these patients had stabilization or reversal of portal hypertension.
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Affiliation(s)
- Sara Hatoum
- Digestive Disease Research Center, Medical University of South Carolina, Charleston, South Carolina, USA
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Altamimi E, Al Omari D, Obeidat H, Barham K. Retrospective, single-center analysis of autoimmune hepatitis in Jordanian children: clinical features, treatments, and outcomes. BMC Pediatr 2024; 24:102. [PMID: 38331749 PMCID: PMC10851525 DOI: 10.1186/s12887-024-04590-9] [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: 11/30/2023] [Accepted: 01/24/2024] [Indexed: 02/10/2024] Open
Abstract
OBJECTIVES This study describes clinical, biochemical, and histological features and long-term outcomes in pediatric patients diagnosed with autoimmune hepatitis (AIH) at King Abdullah University Hospital, Jordan. DESIGN Retrospective, single-center study. SETTING King Abdullah University Hospital, Jordan. PARTICIPANTS Inclusion of all pediatric patients with AIH diagnosed at our hospital from 2015 to 2023. Exclusion criteria was patients aged over 18 at time of diagnosis and those diagnosed elsewhere. OUTCOME MEASURES Understanding clinical, biochemical, and histological AIH features in children, evaluating treatment responses, and reporting short- and long-term complications, including mortality. RESULTS Sixteen pediatric cases were diagnosed, with an average age of 9.84 ± 4.13 years. Females comprised 75% of patients, and 31.3% presented with acute liver failure. Jaundice was the most common symptom, and hepatosplenomegaly was observed in 18% of cases. Most patients had elevated transaminase levels, along with positive anti-smooth muscle antibody (ASMA) and antinuclear antibodies (ANA). Common hematological abnormalities included anemia (56.3%) and thrombocytopenia (37.5%). All patients underwent liver biopsy, with interface hepatitis present in 81.3% of cases. Treatment mainly involved prednisone and azathioprine. Three patients died, one discontinued therapy, two patients were lost to follow-up, and 10 remained on treatment. CONCLUSION Autoimmune hepatitis affects Jordanian children, primarily female children. Jaundice is the most common presenting symptoms. Only Type I AIH occurred in our cohort. Although of good response to conventional treatment with steroids and immunosuppression, mortality reached 18.8%.
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Affiliation(s)
- Eyad Altamimi
- Pediatric and Neonatology Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan.
| | - Dana Al Omari
- Pediatric and Neonatology Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Hanadi Obeidat
- Pediatric and Neonatology Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Kamleh Barham
- Pediatric and Neonatology Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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Zhang Z, Wang J, Wang H, Li Y, Zhu L, Chen Y, Liu J, Liu Y, Chen Y, Yin S, Tong X, Yan X, Yang Y, Zhu C, Li J, Qiu Y, Huang R, Wu C. Develop and validate a novel online AIHI-nomogram to predict severe liver inflammation in patients with autoimmune hepatitis. Ann Hepatol 2023; 28:101134. [PMID: 37442347 DOI: 10.1016/j.aohep.2023.101134] [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: 01/07/2023] [Revised: 04/11/2023] [Accepted: 06/01/2023] [Indexed: 07/15/2023]
Abstract
INTRODUCTION AND OBJECTIVES Assessment of liver inflammation plays a vital role in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate a nomogram to predict severe liver inflammation in AIH patients. PATIENTS AND METHODS AIH patients who underwent liver biopsy were included and randomly divided into a training set and a validation set. Independent predictors of severe liver inflammation were selected by the least absolute shrinkage and selection operator regression from the training set and used to conduct a nomogram. Receiver characteristic curves (ROC), calibration curves, and decision curve analysis (DCA) were adopted to evaluate the performance of nomogram. RESULTS Of the 213 patients, female patients accounted for 83.1% and the median age was 53.0 years. The albumin, gamma-glutamyl transpeptidase, total bilirubin, red cell distribution width, prothrombin time, and platelets were independent predictors of severe inflammation. An online AIHI-nomogram was established and was available at https://ndth-zzy.shinyapps.io/AIHI-nomogram/. The calibration curve revealed that the AIHI-nomogram had a good agreement with actual observation in the training and validation sets. The area under the ROCs of AIHI-nomogram were 0.795 in the training set and 0.759 in the validation set, showing significantly better performance than alanine aminotransferase and immunoglobulin G in the training and validation sets, as well in AIH patients with normal ALT in the training set. DCA indicated that the AIHI-nomogram was clinically useful. CONCLUSIONS This novel AIHI-nomogram provided an excellent prediction of severe liver inflammation in AIH patients and could be used for the better management of AIH.
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Affiliation(s)
- Zhiyi Zhang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China
| | - Huali Wang
- Department of General Practice, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yiguang Li
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, China
| | - Li Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yun Chen
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China; Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yongfeng Yang
- Department of Hepatology, Nanjing Second Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuanwang Qiu
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, Jiangsu, China.
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China; Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, China; Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, China.
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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] [Grants] [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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Li Y, Yan L, Wang R, Wang Q, You Z, Li B, Zhang J, Huang B, Chen Y, Li Y, Lian M, Tang R, Qiu D, Gershwin ME, Xiao X, Miao Q, Ma X. Serum Immunoglobulin G Levels Predict Biochemical and Histological Remission of Autoimmune Hepatitis Type 1: A Single-Center Experience and Literature Review. Clin Rev Allergy Immunol 2021; 62:292-300. [PMID: 33512642 DOI: 10.1007/s12016-021-08833-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2021] [Indexed: 12/17/2022]
Abstract
Autoimmune hepatitis (AIH) is characterized by interface hepatitis, elevated serum alanine aminotransferase and aspartate aminotransferase levels, circulating autoantibodies, and elevated predominantly immunoglobulin G (IgG) levels. The goal in the treatment of autoimmune hepatitis (AIH) is complete disease remission. Here we took advantage of a large cohort of AIH patients to clarify predictors associated with biochemical and histological remission. Of 705 patients with complete follow-up, 569 (80.7%) patients achieved complete biochemical remission. Lower IgG levels (17.8 vs. 25 g/L, p < 0.001) and less liver cirrhosis (19.3% vs. 33.1%, p < 0.001) at diagnosis were observed in these patients. They also had lower serum IgG levels (13 vs. 18.9 g/L, p < 0.001) after 3 months of treatment. Histological remission was achieved in 69.4% of 160 patients with complete biochemical remission after 3 years of treatment. Patients with histological remission had lower IgG levels (16.2 vs. 20.1 g/L, p = 0.006) and Ishak fibrosis scores (3.4 vs. 4.1, p = 0.010) at diagnosis, and they appeared to achieve biochemical remission more rapidly (1 vs. 3 months, p < 0.001). Of note, patients with histological remission had higher frequency of fibrosis regression than those with persisting histological activity (87.5% vs. 60%, p = 0.004). In conclusion, lower serum IgG levels, less fibrosis in liver histology at diagnosis, and rapid response to immunosuppressive therapy are reliable predictors of biochemical and histological remission. Our study underscores the importance of early diagnosis and appropriate treatment.
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Affiliation(s)
- You Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Li Yan
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.,Department of Hepatobiliary Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qixia Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Zhengrui You
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Jun Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Bingyuan Huang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Yikang Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Dekai Qiu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiao Xiao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Qi Miao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
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10
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Arase Y, Matsumoto K, Anzai K, Tsuruya K, Sugiyama S, Yoshihara S, Hirose S, Uojima H, Hidaka H, Nakazawa T, Deguchi R, Kojima S, Takashimizu S, Shiraishi K, Shirai T, Kagawa T. Clinicopathological Features of Autoimmune Hepatitis with IgG4-Positive Plasma Cell Infiltration. Dig Dis 2020; 39:225-233. [PMID: 32731217 PMCID: PMC8117379 DOI: 10.1159/000510562] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/29/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND We aimed to elucidate the characteristics and prognosis of autoimmune hepatitis (AIH) patients with immunoglobulin (Ig) G4-positive plasma cell infiltration. METHODS We enrolled 84 AIH patients. The number of IgG- and IgG4-positive plasma cells was immunohistochemically counted per high-power field in the portal area. Patients with 3 or more IgG4-positive plasma cells on average and a ratio of IgG4 to IgG-positive plasma cells ≥5% were defined as IgG4-associated AIH (IgG4-AIH), and their clinicopathological characteristics and prognosis were compared to those of the remaining classical-AIH patients. RESULTS Ten (11.9%) and 74 patients (88.1%) were categorized as IgG4-AIH and classical-AIH patients, respectively. The median age of the IgG4-AIH patients was 67 years, the majority was female (80.0%), and the distribution was similar to that of the classical-AIH patients. The IgG4-AIH patients exhibited significantly more severe phenotypes in portal inflammation, interface hepatitis, fibrosis, and rosette formation. All clinical laboratory data were similar except for serum IgG4 levels, which were higher in IgG4-AIH patients (168.5 vs. 22.9 mg/dL, p = 0.014). During a median follow-up period of 139 months, the relapse rate was significantly lower in the IgG4-AIH group than in the classical-AIH group (11.1 vs. 49.2%; p = 0.048). Twelve (16.2%) and 6 (8.1%) classical-AIH patients underwent liver-related events and liver-related deaths, respectively. In contrast, none of the IgG4-AIH patients progressed to severe liver disease. CONCLUSIONS The IgG4-AIH patients had more severe inflammation and advanced fibrosis in the liver. However, their prognosis was not poor compared to that of classical-AIH patients. IgG4-AIH may have a phenotype distinct from classical-AIH.
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Affiliation(s)
- Yoshitaka Arase
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan,
| | - Koshi Matsumoto
- Department of Pathology, Ebina General Hospital, Ebina, Japan
| | - Kazuya Anzai
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Kota Tsuruya
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Satoru Sugiyama
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Shihou Yoshihara
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Shunji Hirose
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Haruki Uojima
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Takahide Nakazawa
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Ryuzo Deguchi
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Seiichiro Kojima
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Shinji Takashimizu
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Koichi Shiraishi
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Takayuki Shirai
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
| | - Tatehiro Kagawa
- Department of Gastroenterology and Hepatology, Tokai University School of Medicine, Isehara, Japan
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11
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Murillo Perez CF, Harms MH, Lindor KD, van Buuren HR, Hirschfield GM, Corpechot C, van der Meer AJ, Feld JJ, Gulamhusein A, Lammers WJ, Ponsioen CY, Carbone M, Mason AL, Mayo MJ, Invernizzi P, Battezzati PM, Floreani A, Lleo A, Nevens F, Kowdley KV, Bruns T, Dalekos GN, Gatselis NK, Thorburn D, Trivedi PJ, Verhelst X, Parés A, Janssen HLA, Hansen BE. Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase. Am J Gastroenterol 2020; 115:1066-1074. [PMID: 32618657 DOI: 10.14309/ajg.0000000000000557] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.
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Affiliation(s)
- Carla F Murillo Perez
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Maren H Harms
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Keith D Lindor
- College of Health Solutions, Arizona State University, Phoenix, Arizona
| | - Henk R van Buuren
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Christophe Corpechot
- Centre de Re[Combining Acute Accent]fe[Combining Acute Accent]rence des Maladies Inflammatoires des VoiesBiliaires, Ho[Combining Circumflex Accent]pital Saint-Antoine, Paris, France
| | - Adriaan J van der Meer
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Aliya Gulamhusein
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Willem J Lammers
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands
| | - Marco Carbone
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Andrew L Mason
- Divison of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Marlyn J Mayo
- Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
| | - Pier Maria Battezzati
- Department of Health Sciences, Universita[Combining Grave Accent] degli Studi di Milano, Milan, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Humanitas Clinical Research Center IRCSS, Humanitas University, Rozzano (Milan), Italy
| | - Frederik Nevens
- Department of Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Kris V Kowdley
- Liver Care Network, Swedish Medical Center, Seattle, Washington
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece
| | - Douglas Thorburn
- The Sheila Sherlock Liver Centre, The Royal Free Hospital, London, United Kingdom
| | - Palak J Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre and Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Albert Parés
- Liver Unit, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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12
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Red blood cell distribution width for predicting significant liver inflammation in patients with autoimmune hepatitis. Eur J Gastroenterol Hepatol 2019; 31:1527-1532. [PMID: 31107736 DOI: 10.1097/meg.0000000000001447] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Red blood cell distribution width (RDW) was reported to be associated with the severity of liver diseases. We aimed to investigate the association between RDW and severity of liver inflammation in autoimmune hepatitis (AIH). PATIENTS AND METHODS Ninety-two consecutive AIH patients who underwent liver biopsy during 2016-2017 were included. Liver histology was evaluated using the Scheuer scoring system. Logistic regression analysis was used to analyze the risk factors for significant inflammation. The diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve. RESULTS The RDW level was higher in AIH patients with significant inflammation (14.6%, interquartile range: 13.2-16.3%) than in patients with mild inflammation (13.2%, interquartile range: 12.6-13.8%). The RDW level was correlated positively with the grades of liver inflammation (r=0.356, P < 0.001). The area under the receiver operating characteristic curve of RDW in predicting significant inflammation was 0.739 (95% confidential interval: 0.634-0.843, P < 0.001), with 67.80% sensitivity and 75.76% specificity. The diagnostic performance of RDW for significant inflammation was better than alanine aminotransferase (P = 0.003) and immunoglobulin G (P = 0.049). RDW (odds ratio = 1.702, P = 0.001) was identified as an independent predictor for significant inflammation by logistic multivariable analysis. CONCLUSION The RDW level was correlated positively with the severity of liver inflammation in AIH patients. RDW can be a promising indicator for predicting significant liver inflammation in AIH.
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13
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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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14
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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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15
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Migita K, Horai Y, Kozuru H, Koga T, Abiru S, Yamasaki K, Komori A, Fujita Y, Asano T, Sato S, Suzuki E, Matsuoka N, Kobayashi H, Watanabe H, Naganuma A, Naeshiro N, Yoshizawa K, Ohta H, Sakai H, Shimada M, Nishimura H, Tomizawa M, Ario K, Yamashita H, Kamitsukasa H, Kohno H, Nakamura M, Furukawa H, Takahashi A, Kawakami A, Ohira H, Yastuhashi H. Serum cytokine profiles and Mac-2 binding protein glycosylation isomer (M2BPGi) level in patients with autoimmune hepatitis. Medicine (Baltimore) 2018; 97:e13450. [PMID: 30557999 PMCID: PMC6320116 DOI: 10.1097/md.0000000000013450] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH).We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array.Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (sICAM-1) and interferon-γ-inducible protein 10 (IP-10) were most downregulated by steroid therapy in AIH patients. We measured serum sICAM-1 and IP-10 by ELISA and found the levels were significantly higher in AIH patients (n = 77) compared with chronic viral hepatitis C patients (n = 32). Furthermore, there was a positive correlation between sICAM-1 or IP-10 and alanine aminotransferase, total bilirubin, and circulating M2BPGi levels. M2BPGi levels were increased in AIH patients with high stages of liver fibrosis. Additionally, M2BPGi levels were correlated with the histological grade of inflammation in AIH. Circulating M2BPGi levels were significantly reduced by steroid treatment in AIH patients.sICAM-1 and IP-10 are useful markers to assess immune-mediated hepatitis activity in AIH and they correlate with circulating M2BPGi. Serum M2BPGi levels increased in untreated AIH patients with active hepatitis and were decreased by steroid therapy. M2BPGi reflects autoimmune-mediated hepatic inflammation as well as liver fibrosis.
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Affiliation(s)
- Kiyoshi Migita
- Department of Rheumatology, Fukushima Medical University, Fukushima
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | - Yoshiro Horai
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | - Hideko Kozuru
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | - Tomohiro Koga
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
| | - Seigo Abiru
- Clinical Research Center, Nagasaki Medical Center, Nagasaki
| | | | | | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Eiji Suzuki
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Naoki Matsuoka
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Hiroko Kobayashi
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Hiroshi Watanabe
- Department of Rheumatology, Fukushima Medical University, Fukushima
| | - Atsushi Naganuma
- National Hospital Organization, Takasaki Medical Center, Takasaki
| | - Noriaki Naeshiro
- National Hospital Organization, Higashihiroshima Medical center, Higashihiroshima, Hiroshima
| | - Kaname Yoshizawa
- National Hospital Organization, Shinsyu-Ueda Medical Center, Ueda, Nagano
| | - Hajime Ohta
- National Hospital Organization, Kanazawa Medical Center, Kanazawa, Ishikawa
| | - Hironori Sakai
- National Hospital Organization, Beppu Medical Center, Beppu, Oita
| | - Masaaki Shimada
- National Hospital Organization, Nagoya Medical Center, Naka-ku, Nagoya, Aichi
| | - Hideo Nishimura
- National Hospital Organization, Asahikawa Medical Center, Asahikawa, Hokkaido
| | - Minoru Tomizawa
- National Hospital Organization, Shimoshizu Hospital, Yotsukaido, Chiba
| | - Keisuke Ario
- National Hospital Organization, Ureshino Medical Center, Ureshino, Saga
| | - Haruhiro Yamashita
- National Hospital Organization, Okayama Medical Center, Okayama, Okayama
| | | | - Hiroshi Kohno
- National Hospital Organization, Kure Medical Center, Kure, Hiroshima
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba
| | - Atsushi Takahashi
- Department of Gastroenterology, Fukushima Medical University, Fukushima
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima
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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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Clinical and Pathological Characteristics of Autoimmune Hepatitis with Acute Presentation. Can J Gastroenterol Hepatol 2018; 2018:3513206. [PMID: 29744332 PMCID: PMC5878912 DOI: 10.1155/2018/3513206] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 12/27/2017] [Accepted: 01/08/2018] [Indexed: 02/05/2023] Open
Abstract
Aim. To study the differences between acute presentation-autoimmune hepatitis (A-AIH) and chronic autoimmune hepatitis (C-AIH). Methods. Through long-term follow-up, 80 patients were included in our study by using the revised international autoimmune hepatitis group (IAIHG) score and were divided into acute and chronic groups for comparison. Results. No significant difference was found in the gender, age, IAIHG score (pretreatment/posttreatment), definite diagnosis rate, extrahepatic autoimmune disease, onset time, or treatment before biopsy between the acute and chronic groups. In terms of clinical symptoms, A-AIH patients were more prone to jaundice, anorexia, yellow urine, and detesting oil than C-AIH patients, but melena only occurred in chronic group (P < 0.05). The acute group exhibited more severe injury upon histological evaluation, with lobular inflammation and bile duct injury, especially central necrosis of the lobule, more pronounced in this group (P < 0.05). Conclusion. A-AIH had manifestations of acute hepatitis and presented cholestasis. Serum indicators could preliminarily distinguish A-AIH and C-AIH. Histologically, the primary manifestation of A-AIH was lobular inflammation, which was usually accompanied by lobular central necrosis. For the diagnosis of A-AIH, more attention should be paid to long-term follow-up. This study was registered at ClinicalTrials.gov (identifier: NCT02994537).
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Carbone M, Cristoferi L, Cortesi PA, Rota M, Ciaccio A, Okolicsanyi S, Gemma M, Scalone L, Cesana G, Fabris L, Colledan M, Fagiuoli S, Ideo G, Belli LS, Munari LM, Mantovani L, Strazzabosco M. Optimising the clinical strategy for autoimmune liver diseases: Principles of value-based medicine. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1415-1422. [PMID: 28844954 DOI: 10.1016/j.bbadis.2017.08.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 08/14/2017] [Accepted: 08/16/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis represent the three major autoimmune liver diseases (AILDs). Their management is highly specialized, requires a multidisciplinary approach and often relies on expensive, orphan drugs. Unfortunately, their treatment is often unsatisfactory, and the care pathway heterogeneous across different centers. Disease-specific clinical outcome indicators (COIs) able to evaluate the whole cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. Aim of our study was to generate a set of COIs for the three AILDs. We then prospectively validated these indicators based on a series of consecutive patients recruited at three tertiary clinical centers in Lombardy, Italy. METHODS In phase I using a Delphi method and a RAND 9-point appropriateness scale a set of COIs was generated. In phase II the indicators were applied in a real-life dataset. RESULTS Two-hundred fourteen patients were enrolled and followed-up for a median time of 54months and the above COIs were recorded using a web-based electronic medical record program. The COIs were easy to collect in the clinical practice environment and their values compared well with the available natural history studies. CONCLUSIONS We have generated a comprehensive set of COIs which sequentially capture different clinical outcome of the three AILDs explored. These indicators represent a critical tool to implement a value-based approach to patients with these conditions, to monitor, compare and improve quality through benchmarking of clinical performance and to assess the significance of novel drugs and technologies. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Laura Cristoferi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Paolo Angelo Cortesi
- Research Centre on Public Health (CESP), University of Milan-Bicocca, Milan, Italy
| | - Matteo Rota
- International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Antonio Ciaccio
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Stefano Okolicsanyi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Marta Gemma
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy
| | - Luciana Scalone
- Research Centre on Public Health (CESP), University of Milan-Bicocca, Milan, Italy
| | - Giancarlo Cesana
- Research Centre on Public Health (CESP), University of Milan-Bicocca, Milan, Italy
| | - Luca Fabris
- International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy; Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Molecular Medicine, University of Padua School of Medicine, Padua, Italy
| | - Michele Colledan
- Department of Surgery, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Stefano Fagiuoli
- Department of Gastroenterology, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | | | - Luca Saverio Belli
- International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy; Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milan, Italy
| | - Luca Maria Munari
- Department of Hepatology and Gastroenterology, Liver Unit, Niguarda Hospital, Milan, Italy
| | - Lorenzo Mantovani
- Research Centre on Public Health (CESP), University of Milan-Bicocca, Milan, Italy
| | - Mario Strazzabosco
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy; International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy; Liver Center & Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
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Shibuki T, Otsuka T, Isoda H, Araki N, Kubotsu Y, Kawaguchi Y, Nakashita S, Yoshioka W, Kawazoe S, Kawasoe H, Ide Y, Mizuta T, Liver Diseases Sasld SSGO. Seropositivity and Titers of Anti-Smooth Muscle Actin Antibody Are Associated with Relapse of Type 1 Autoimmune Hepatitis. Med Sci Monit 2017; 23:4028-4033. [PMID: 28822993 PMCID: PMC5574375 DOI: 10.12659/msm.902576] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background It is important to avoid relapse in autoimmune hepatitis (AIH) because repeated multiple relapses have been associated with a worse prognosis. However, risk factors for relapse before initiation of treatment are not fully understood. The aim of this study was to find predictive markers for relapse of type 1 AIH. Material/Methods We reviewed the records of 53 patients diagnosed with type 1 AIH based on the revised scoring system proposed by the International Autoimmune Hepatitis Group (IAIHG) between 2009 and 2014 at 4 hospitals belonging to the Saga Study Group of Liver Diseases (SASLD). We analyzed the differences in background characteristics between patients with or without relapse. Results All patients achieved remission after treatment, and 9 (17%) subsequently relapsed. The relapsed patients were significantly younger and had a higher positive rate of anti-smooth muscle antibody (ASMA) than the non-relapsed patients (100% vs. 25%, P=0.0012). Moreover, relapse rate increased with titer of ASMA, while titer of antinuclear antibody was not associated with relapse rate. Conclusions ASMA is a useful predictive marker for relapse of type 1 AIH during or after withdrawal of medical therapy. More careful attention should be paid to immunosuppressive therapy in patients with high titers of ASMA.
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Affiliation(s)
- Taro Shibuki
- Department of Internal Medicine, Imari Arita Kyoritsu Hospital, Saga, Japan
| | - Taiga Otsuka
- Hepatology Division, Saga University Hospital, Saga city, Japan
| | - Hiroshi Isoda
- Hepatology Division, Saga University Hospital, Saga, Japan
| | - Norimasa Araki
- Hepatology Division, Saga University Hospital, Saga, Japan
| | | | - Yasunori Kawaguchi
- Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Center Koseikan, Saga, Japan
| | - Shunya Nakashita
- Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Center Koseikan, Saga, Japan
| | - Wataru Yoshioka
- Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Center Koseikan, Saga, Japan
| | - Seiji Kawazoe
- Department of Hepatobiliary and Pancreatology, Saga-Ken Medical Center Koseikan, Saga, Japan
| | - Hiroaki Kawasoe
- Department of Internal Medicine, Imari Arita Kyoritsu Hospital, Saga, Japan
| | - Yasushi Ide
- Department of Internal Medicine, Karatsu Red Cross Hospital, Saga, Japan
| | - Toshihiko Mizuta
- Department of Internal Medicine, Imari Arita Kyoritsu Hospital, Saga, Japan
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Zachou K, Gatselis NK, Arvaniti P, Gabeta S, Rigopoulou EI, Koukoulis GK, Dalekos GN. A real-world study focused on the long-term efficacy of mycophenolate mofetil as first-line treatment of autoimmune hepatitis. Aliment Pharmacol Ther 2016; 43:1035-47. [PMID: 26991238 DOI: 10.1111/apt.13584] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 10/20/2015] [Accepted: 02/18/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Front-line therapy with mycophenolate mofetil (MMF) in autoimmune hepatitis (AIH) has shown high on-treatment remission rates. AIM To study prospectively in a real-world fashion the long-term outcome of a large group of consecutive treatment-naïve AIH patients. METHODS Between 2000 and 2014, 158 patients were recruited but only 131 were eligible for treatment (109 MMF/prednisolone; 22 prednisolone ± azathioprine). Long-term data on outcome after drug withdrawal were evaluated. Patients stopped treatment after having achieved complete response (normal transaminases and IgG) for at least the last 2 years. RESULTS At diagnosis, 31.6% of patients had cirrhosis and 72.8% insidious presentation. A total of 102 of 109 (93.6%) responded initially to MMF within 2 (1-18) months. A total of 78 of 109 (71.6%) had complete response on treatment and 61 of 78 (78.2%) maintained remission off prednisolone. MMF-treated patients had increased probability of complete response compared to those receiving azathioprine (P = 0.03). Independent predictors of complete response were lower ALT at 6 months (P = 0.001) and acute presentation (P = 0.03). So far, treatment withdrawal was feasible in 40/109 patients and 30 (75%) are still in remission after 24 (2-129) months. Remission maintenance was associated with longer MMF treatment (P = 0.005), higher baseline ALT (P < 0.02), lower IgG on 6 months (P = 0.004) and histological improvement. CONCLUSIONS Mycophenolate mofetil proved to be an efficient first-line treatment for AIH, achieving so far the highest rates of remission maintenance off treatment (75%) ever published for at least a median of 2 years, although the remission criteria used were strict. However, the risk of potential bias and overestimation of intervention benefits from MMF cannot be completely excluded as this is a real world and not a randomised controlled trial.
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Affiliation(s)
- K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - N K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - P Arvaniti
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - S Gabeta
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - E I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
| | - G K Koukoulis
- Department of Pathology, Medical School, University of Thessaly, Larissa, Greece
| | - G N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece
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Kirstein MM, Metzler F, Geiger E, Heinrich E, Hallensleben M, Manns MP, Vogel A. Prediction of short- and long-term outcome in patients with autoimmune hepatitis. Hepatology 2015; 62:1524-35. [PMID: 26178791 DOI: 10.1002/hep.27983] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 07/09/2015] [Indexed: 12/22/2022]
Abstract
UNLABELLED Autoimmune hepatitis (AIH) is a chronic inflammatory disease characterized by a loss of tolerance toward the hepatocellular epithelium. Liver transplantation (LT) represents the ultimate therapeutic option for a fulminant course or end-stage liver disease. The aim of this study was to elucidate the clinical, serological, and genetic features of remission, relapse, and overall and LT-free survival. Between 2000 and 2014, 354 AIH patients from Hannover Medical School were included. Clinical, laboratory, and histological reports were analyzed. DRB1 allele analyses were performed in 264 AIH and 399 non-AIH patients. Cox's regression analysis was performed to identify factors significantly associated with survival. Patients diagnosed in childhood were at higher risk for relapses (P=0.003), requirement for LTs (P=0.014, log rank), and had a reduced life expectancy (P<0.001, log rank). Detection of soluble liver antigen/liver pancreas antigen (SLA/LP) antibodies was significantly associated with reduced overall and LT-free survival (P=0.037; P=0.021). Cirrhosis, which was evident in 25% at first diagnosis, was found to be a predictor of poor survival and requirement for LT (P=0.003; P=0.009). DRB1*04:01-positive phenotype was associated with a higher rate of complete remissions and with a lower frequency of cirrhosis and LTs. There were no significant differences for subsequent relapses or survival in patients achieving either partial or complete remission. CONCLUSION Diagnosis<18 years, histological cirrhosis at first diagnosis and SLA/LP antibodies are major risk factors for a poor short- and long-term outcome. These patients are in need of high surveillance. Separating patients with positive SLA/LP antibodies into a third group may be reconsidered. DRB1*04:01 positivity has been identified in association with a favorable clinical outcome.
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Affiliation(s)
- Martha M Kirstein
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Frauke Metzler
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Elena Geiger
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Eyk Heinrich
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | | | - Michael P Manns
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
| | - Arndt Vogel
- Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
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Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis. Am J Gastroenterol 2015; 110:993-9. [PMID: 26010310 DOI: 10.1038/ajg.2015.139] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 03/31/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Biochemical remission is widely considered a satisfactory treatment end point in autoimmune hepatitis (AIH). The significance of persisting histological activity despite biochemical remission is unknown. We aimed to assess the frequency and prognostic significance of persisting histological inflammation in patients with AIH who had achieved biochemical remission with treatment. METHODS We studied 120 patients (median age at diagnosis 57 years; 81% female) with AIH by International Criteria (59% definite), who received immunosuppressive treatment and underwent a follow-up liver biopsy after at least 6 months of sustained biochemical remission (defined as normal serum ALT and globulin). RESULTS Fifty-five patients (46%) had persisting histological activity (Ishak histological activity index (HAI) ≥4). These patients had higher serum ALT (24 vs. 18 IU/l, P=0.003) and AST (27 vs. 23 IU/l, P=0.03) at the time of follow-up biopsy, compared with patients who achieved histological remission (HAI ≤3). They had less frequent regression of fibrosis on follow-up biopsy compared with those achieving histological remission (32 vs. 60%, P=0.004) and had excess mortality (standardized mortality ratio 1.4 vs. 0.7, P<0.05). The excess mortality was due to liver disease. On multivariate analysis, persisting histological activity was independently associated with all-cause death/transplantation (HR 3.1 (95% CI 1.2-8.1); P=0.02); an association with liver-related death/transplantation fell short of significance (HR 9.7 (95% CI 0.84-111.6; P=0.07). CONCLUSIONS Persisting histological activity, despite biochemical remission, is frequent in patients with treated AIH and is associated with lower rates of fibrosis regression and reduced long-term survival.
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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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Miyake Y, Yamamoto K, Matsushita H, Abe M, Takahashi A, Umemura T, Tanaka A, Nakamuta M, Nakamoto Y, Ueno Y, Saibara T, Takikawa H, Yoshizawa K, Ohira H, Zeniya M, Onji M, Tsubouchi H. Multicenter validation study of anti-programmed cell death-1 antibody as a serological marker for type 1 autoimmune hepatitis. Hepatol Res 2014; 44:1299-307. [PMID: 24506172 DOI: 10.1111/hepr.12305] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/06/2014] [Accepted: 01/20/2014] [Indexed: 02/08/2023]
Abstract
AIM Recently, serum levels of anti-programmed cell death-1 (anti-PD-1) antibodies have been reported to be useful for the discrimination of type 1 autoimmune hepatitis (AIH) from drug-induced liver injury (DILI) and to be associated with clinical features of type 1 AIH. This multicenter study aimed to validate the usefulness of serum anti-PD-1 antibody as a serological marker for type 1 AIH. METHODS Serum samples before the initiation of corticosteroid treatment were obtained from 71 type 1 AIH patients and 37 DILI patients. Serum levels of anti-PD-1 antibodies were measured by indirect enzyme-linked immunosorbent assay. RESULTS Serum levels of anti-PD-1 antibodies were higher in type 1 AIH patients than in DILI patients (P < 0.001). The receiver-operator curve analysis showed that serum levels of anti-PD-1 antibodies were useful for the discrimination of type 1 AIH from DILI (area under the curve, 0.80). On the other hand, the multivariate Cox proportional hazard model showed that positivity for serum anti-PD-1 antibody, probable diagnosis based on the revised scoring system proposed by the International Autoimmune Hepatitis Group, and prothrombin activity of less than 60% were associated with the later normalization of serum transaminase levels. During the clinical course, the disease relapsed more frequently in patients positive for serum anti-PD-1 antibody (36% vs 11%). CONCLUSION This study suggests that serum anti-PD-1 antibody is useful for the diagnosis of type 1 AIH as an auxiliary diagnostic marker, and that serum levels of anti-PD-1 antibodies reflect clinical features of type 1 AIH.
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Affiliation(s)
- Yasuhiro Miyake
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Ehime
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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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Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20:2515-32. [PMID: 24627588 PMCID: PMC3949261 DOI: 10.3748/wjg.v20.i10.2515] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
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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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Liu Z, Que S, Xu J, Peng T. Alanine aminotransferase-old biomarker and new concept: a review. Int J Med Sci 2014; 11:925-35. [PMID: 25013373 PMCID: PMC4081315 DOI: 10.7150/ijms.8951] [Citation(s) in RCA: 172] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Accepted: 06/12/2014] [Indexed: 02/06/2023] Open
Abstract
Measurement of serum alanine aminotransferase (ALT) is a common, readily available, and inexpensive laboratory assay in clinical practice. ALT activity is not only measured to detect liver disease, but also to monitor overall health. ALT activity is influenced by various factors, including viral hepatitis, alcohol consumption, and medication. Recently, the impact of metabolic abnormalities on ALT variation has raised concern due to the worldwide obesity epidemic. The normal ranges for ALT have been updated and validated considering the metabolic covariates in the various ethnic districts. The interaction between metabolic and demographic factors on ALT variation has also been discussed in previous studies. In addition, an extremely low ALT value might reflect the process of aging, and frailty in older adults has been raised as another clinically significant feature of this enzyme, to be followed with additional epidemiologic investigation. Timely updated, comprehensive, and systematic introduction of ALT activity is necessary to aid clinicians make better use of this enzyme.
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Affiliation(s)
- Zhengtao Liu
- 1. Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Shuping Que
- 2. Department of Pediatrics, Women and children's hospital of Guangxi, Nanning, 530005, Guangxi province, China
| | - Jing Xu
- 1. Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Tao Peng
- 1. Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
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Matsumoto K, Miyake Y, Matsushita H, Ohnishi A, Ikeda F, Shiraha H, Takaki A, Nouso K, Yamamoto K. Anti-programmed cell death-1 antibody as a new serological marker for type 1 autoimmune hepatitis. J Gastroenterol Hepatol 2014; 29:110-5. [PMID: 23869988 DOI: 10.1111/jgh.12340] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/02/2013] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIM Recently, the association of the dysfunction of programmed cell death (PD)-1 expressed on activated lymphocytes with the pathogenesis of autoimmune hepatitis (AIH) has been speculated. This study aimed to investigate the association of serum anti-PD-1 antibodies with clinical characteristics of type 1 AIH. METHODS Serum samples before the initiation of prednisolone treatment were obtained from 52 type 1 AIH patients, 24 patients with drug-induced liver injury (DILI), 30 patients with acute viral hepatitis (AVH), 11 patients with primary sclerosing cholangitis (PSC), and 62 healthy volunteers. Titers of serum anti-PD-1 antibodies were measured by indirect enzyme-linked immunosorbent assay. The cutoff level was represented by a mean absorbance + 2 standard deviations in healthy volunteers. RESULTS Prevalence of serum anti-PD-1 antibodies was 63% in type 1 AIH patients, 8% in DILI patients, 13% in AVH patients, 18% in PSC patients, and 3% in healthy volunteers. In type 1 AIH patients, titers of serum anti-PD-1 antibodies were correlated with serum levels of bilirubin (r = 0.31, P = 0.030) and alanine aminotransferase (r = 0.31, P = 0.027) but not serum immunoglobulin G levels. Positivity for serum anti-PD-1 antibodies was associated with the later normalization of serum alanine aminotransferase levels after the initiation of prednisolone and the disease relapse. CONCLUSIONS Serum anti-PD-1 antibodies would be useful for the discrimination of type 1 AIH from DILI, AVH, and PSC as an auxiliary diagnostic marker. Furthermore, anti-PD-1 antibodies may be associated with clinical characteristics of type 1 AIH.
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Affiliation(s)
- Kazuyuki Matsumoto
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Abstract
Autoimmune hepatitis is a disease of the hepatic parenchyma that can present in acute or chronic forms. In common with many autoimmune diseases, autoimmune hepatitis is associated with non-organ-specific antibodies in the context of hepatic autoimmunity. This dichotomy has made definition of a unifying hypothesis in the pathophysiology of the disease difficult, although data from the past 8 years have drawn attention to the role of regulatory T cells. Several triggers have been identified, and the disease arises in genetically susceptible individuals. Clinical and biochemical remission is achievable in up to 85% of cases. For the remaining patients, alternative immunosuppression strategies are an option. Liver transplantation provides an excellent outcome for patients with acute liver failure or complications of end-stage liver disease, including hepatocellular carcinoma. Variant or overlapping syndromes are worthy of consideration when unexpected disease features arise.
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Affiliation(s)
- Michael A Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, Denmark Hill, London, UK.
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Gutkowski K, Hartleb M, Kacperek-Hartleb T, Kajor M, Mazur W, Zych W, Walewska-Zielecka B, Habior A, Sobolewski M. Laboratory-based scoring system for prediction of hepatic inflammatory activity in patients with autoimmune hepatitis. Liver Int 2013; 33:1370-7. [PMID: 23651331 DOI: 10.1111/liv.12198] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 04/13/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS In autoimmune hepatitis (AIH), inflammation is closely related to fibrosis. Although transaminase levels are commonly used to assess hepatic inflammation, they may not relate directly to the histology. We developed a noninvasive diagnostic score as an alternative to liver biopsy to help optimize treatment for AIH and monitor disease progress. METHODS Eighty-two participants with type 1 AIH who had undergone liver biopsy were included (44 in training and 38 in validation sets). Liver histology was assessed according to the histologic activity index (HAI; score 0-18) and Ishak's histologic fibrosis index (HFI; score 0-6). High inflammation was defined as HAI>4, and advanced fibrosis was defined as HFI>2. Routine laboratory test findings and stepwise linear regression were used to develop the best models predicting HAI and HFI. The best cut-off value to predict high inflammation and advanced fibrosis for these formulas was then calculated based on receiver-operating characteristic analysis. RESULTS The cut-off value for a model predicting high inflammation was ≥3.57 (AUROC = 0.93; 95% CI: 0.86-1.00), with 100% sensitivity and 85% specificity. High inflammation was confirmed with an 81% positive predictive value and excluded with a 100% negative predictive value. In the validation set, the sensitivity, specificity, positive predictive value and negative predictive values were 100, 56, 88 and 100% respectively. The diagnostic yield of the fibrosis score was unsatisfactory. CONCLUSIONS The noninvasive inflammatory score based on four routine laboratory parameters discriminated patients with and without significant hepatic inflammation and may facilitate follow-up of type 1 AIH patients.
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Affiliation(s)
- Krzysztof Gutkowski
- Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland
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Fabbri A, Lenzi M. Non-invasive markers of inflammation in autoimmune hepatitis. Liver Int 2013; 33:1295-7. [PMID: 24011359 DOI: 10.1111/liv.12251] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 06/12/2013] [Indexed: 12/20/2022]
Affiliation(s)
- Angela Fabbri
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38:343-64. [PMID: 23808490 DOI: 10.1111/apt.12381] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 05/30/2013] [Accepted: 06/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Kriese S, Heneghan MA. Current concepts in the diagnosis and management of autoimmune hepatitis. Frontline Gastroenterol 2013; 4:2-11. [PMID: 28839695 PMCID: PMC5369782 DOI: 10.1136/flgastro-2012-100208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 07/06/2012] [Accepted: 07/08/2012] [Indexed: 02/04/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a progressive necroinflammatory liver disease associated with significant morbidity and mortality. Mainly affecting females, AIH has a varied clinical presentation from minor symptomatology to acute liver failure. The diagnosis should be considered in anyone with abnormal liver function tests. Diagnostic features include biochemical evidence of transaminitis, elevated IgG and positive autoantibodies. Liver biopsy may show interface hepatitis with portal-based plasma cell infiltrates. A clinical and pathological spectrum of disease exists with other autoimmune liver disease in rare cases. AIH responds promptly to immunosuppression therapy, including corticosteroids (prednis(ol)one or budesonide) with azathioprine. Treatment failure can be addressed with several second-line immunosuppressive agents. Liver transplantation remains a successful salvage therapy for acute autoimmune liver failure or treatment failure in chronic AIH complicated by synthetic dysfunction, portal hypertension or hepatocellular carcinoma.
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Affiliation(s)
- Stephen Kriese
- Institute of Liver Studies, King's College London Medical School at King's College Hospital, London, UK
| | - Michael A Heneghan
- Institute of Liver Studies, King's College London Medical School at King's College Hospital, London, UK
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Selvarajah V, Montano-Loza AJ, Czaja AJ. Systematic review: managing suboptimal treatment responses in autoimmune hepatitis with conventional and nonstandard drugs. Aliment Pharmacol Ther 2012; 36:691-707. [PMID: 22973822 DOI: 10.1111/apt.12042] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 07/17/2012] [Accepted: 08/21/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Corticosteroid treatment for autoimmune hepatitis has been shown by randomised controlled clinical trials to ameliorate symptoms, normalise liver tests, improve histological findings and extend survival. Nevertheless, suboptimal responses to corticosteroid treatment still occur. AIM To describe the current definitions, frequencies, clinical relevance and treatment options for suboptimal responses, and to discuss alternative medications that have been used off-label for these occurrences. METHODS Literature search was made for full-text papers published in English using the keyword 'autoimmune hepatitis'. Authors' personal experience and investigational studies also helped to identify important contributions to the literature. RESULTS Suboptimal responses to standard therapy include treatment failure (7%), incomplete response (14%), drug toxicity (13%) and relapse after drug withdrawal (50-86%). The probability of a suboptimal response prior to treatment is higher in young patients and in patients with a severe presentation, jaundice, high MELD score at diagnosis, multilobular necrosis or cirrhosis, antibodies to soluble liver antigen, or inability to improve by clinical indices within two weeks or by MELD score within 7 days of conventional corticosteroid treatment. Management strategies have been developed for the adverse responses and nonstandard drugs, including mycophenolate mofetil, budesonide, ciclosporin, tacrolimus, sirolimus and rituximab, are emerging as rescue therapies or alternative frontline agents. CONCLUSIONS Once diagnosed, the suboptimal response should be treated by a highly individualised and well-monitored regimen, preferentially using first-line therapy. Nonstandard drugs warrant consideration as salvage or second-line therapies.
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Affiliation(s)
- V Selvarajah
- Division of Gastroenterology & Liver Unit, University of Alberta Hospital, Edmonton, AB, Canada
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Abstract
Prednisone and prednisolone are the mainstays of treatment for autoimmune hepatitis. Prednisone is converted in the liver to the active metabolite, prednisolone. The principal therapeutic action of prednisolone is to suppress cytokine gene expression and to inhibit the differentiation and proliferation of activated lymphocytes. It also has anti-inflammatory effects that include decreased production of adhesion molecules, increased apoptosis of lymphocytes and decreased hepatic collagen deposition. Advanced liver disease does not sufficiently suppress hepatic conversion of prednisone to warrant the preferential use of prednisolone. Budesonide combined with azathioprine has been more effective and safer than the conventional prednisone-based regimen when given for 6 months to treatment-naive patients. It is emerging as a frontline treatment, especially for noncirrhotic patients with uncomplicated 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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Yoshizawa K, Matsumoto A, Ichijo T, Umemura T, Joshita S, Komatsu M, Tanaka N, Tanaka E, Ota M, Katsuyama Y, Kiyosawa K, Abe M, Onji M. Long-term outcome of Japanese patients with type 1 autoimmune hepatitis. Hepatology 2012; 56:668-676. [PMID: 22334246 DOI: 10.1002/hep.25658] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Accepted: 02/07/2012] [Indexed: 12/18/2022]
Abstract
UNLABELLED The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. CONCLUSION Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.
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Affiliation(s)
- Kaname Yoshizawa
- Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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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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Migita K, Watanabe Y, Jiuchi Y, Nakamura Y, Saito A, Yagura M, Ohta H, Shimada M, Mita E, Hijioka T, Yamashita H, Takezaki E, Muro T, Sakai H, Nakamuta M, Abiru S, Komori A, Ito M, Yatsuhashi H, Nakamura M, Ishibashi H. Hepatocellular carcinoma and survival in patients with autoimmune hepatitis (Japanese National Hospital Organization-autoimmune hepatitis prospective study). Liver Int 2012; 32:837-44. [PMID: 22221966 DOI: 10.1111/j.1478-3231.2011.02734.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 11/30/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS Although the outcome of autoimmune hepatitis (AIH) is generally good, the natural course and likelihood of progression to cirrhosis or hepatocellular carcinoma (HCC) remain undefined, and may vary by region and population structure. Our aims were to evaluate risk factors that contribute to poor outcome and particularly development of HCC in a prospective multicentric cohort study of AIH. METHODS The study group comprised 193 Japanese patients with AIH who were prospectively followed up at annual intervals between 1995 and 2008. The mean follow-up period was 8.0 ± 4.5 years. RESULTS Twenty-one (10.9%) patients had cirrhosis at presentation and a further 15 (7.8%) developed cirrhosis during the follow-up period. Survival rates were 94.2% at 10 years and 89.3% at 15 years. HCC was diagnosed in seven of the 193 patients. The presence of cirrhosis at presentation was a risk factor for HCC according to a Cox proportional hazard model, and the HCC-free survival rate was significantly lower in those with cirrhosis compared to those without cirrhosis according to Kaplan-Meier analysis. CONCLUSIONS Although the outcome of AIH is as good if not better among Japanese than for other populations, there was an increased risk of HCC in these patients. Cirrhosis at presentation was predictive of development of HCC in AIH in Japan.
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Affiliation(s)
- Kiyoshi Migita
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.
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Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver that occurs worldwide with a low and probably underestimated prevalence. Although it typically affects young and middle-aged women, it can occur in both sexes and across all age groups. AIH runs a fluctuating course, but can present as severe and even fulminant hepatic failure or at a stage of advanced fibrosis or cirrhosis. Prognosis of severe AIH is poor if untreated. The pathogenesis is complex, combining environmental factors (external chemical or infectious triggers) and host genetic susceptibility. The diagnosis is based, after exclusion of other etiologies of chronic liver disease, on a combination of different elements, including the presence of elevated transaminases, elevated immunoglobulin G (IgG) levels, the presence and pattern of typical autoantibodies, and a liver biopsy showing interface hepatitis and other characteristic features. No single test can be used to make the diagnosis. Response to treatment can also help to establish the diagnosis. Simplified criteria can be used to make a bedside diagnosis with relatively high accuracy. Treatment consists of corticosteroids or other immunosuppressive regimens according to the severity of the disease, the response to the treatment, and the tolerance to therapy, with liver transplantation as an ultimate remedy in treatment-resistant cases with liver decompensation.
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Affiliation(s)
- Sven Francque
- Antwerp University Hospital, Department of Gastroenterology Hepatology, Antwerp, Belgium ; Antwerp University, Faculty of Medicine and Health Sciences, Laboratory of Experimental Medicine and Paediatrics, Antwerp, Belgium
| | - Luisa Vonghia
- Antwerp University Hospital, Department of Gastroenterology Hepatology, Antwerp, Belgium ; Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari, Italy
| | - Albert Ramon
- Antwerp University Hospital, Department of Gastroenterology Hepatology, Antwerp, Belgium ; Institute and Laboratory for Genetic Diseases and Molecular Biology, Cologne, Germany
| | - Peter Michielsen
- Antwerp University Hospital, Department of Gastroenterology Hepatology, Antwerp, Belgium ; Antwerp University, Faculty of Medicine and Health Sciences, Laboratory of Experimental Medicine and Paediatrics, Antwerp, Belgium
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Zachou K, Gatselis N, Papadamou G, Rigopoulou EI, Dalekos GN. Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naïve patients. J Hepatol 2011; 55:636-646. [PMID: 21238519 DOI: 10.1016/j.jhep.2010.12.032] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2010] [Revised: 11/30/2010] [Accepted: 12/03/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Standard therapy for autoimmune hepatitis (AIH) is corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to conventional treatment. Therefore, we evaluated prospectively the efficacy and safety of mycophenolate mofetil (MMF) in inducing and/or maintaining remission in treatment-naïve AIH patients. METHODS Fifty-nine treatment-naïve patients with well defined AIH were treated with prednisolone plus 1.5-2g/d of MMF. Patients were candidates for MMF withdrawal after at least 4 years. Treatment outcomes were defined according to the International Autoimmune Hepatitis Group report. RESULTS Treatment duration with MMF was 26months (range 3-92). Eighty-eight percent (52/59) of patients responded initially clinically and biochemically (normalization of transaminases and γ-globulins) most of them within 3months. The remaining 7 patients (12%) had partial response. In total, 59.3% (35/59) of patients had complete response (CR) with 37% (22/59) of them having achieved CR off prednisolone, while 28.8% (17/59) had initial CR with relapses. No patient was non-responder. Prednisolone withdrew in 57.6% (34/59) of patients in 8months. The only independent predictor of treatment outcome, was γ-GT (baseline γ-GT, p=0.008 and γ-GT on month 24, p<0.05). Severe side effects leading to MMF discontinuation occurred in only 3.4% (2/59) of patients. Six patients (2 according to protocol and 4 for personal reasons), stopped treatment with MMF, but 3 relapsed. CONCLUSIONS MMF seems safe and effective as first-line therapy in inducing and maintaining remission in treatment-naive patients with AIH, having a significant and rapid steroid sparing effect as attested by the fact that so far, 37% (22/59) of AIH patients achieved CR off prednisolone.
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Affiliation(s)
- Kalliopi Zachou
- Department of Medicine and Research Lab of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece; Institute of Biomedical Research and Technology, Centre for Research and Technology-Thessaly (CE.RE.TE.TH), Larissa, Greece
| | - Nikolaos Gatselis
- Department of Medicine and Research Lab of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece
| | - Georgia Papadamou
- Department of Medicine and Research Lab of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece
| | - Eirini I Rigopoulou
- Department of Medicine and Research Lab of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece
| | - George N Dalekos
- Department of Medicine and Research Lab of Internal Medicine, Medical School, University of Thessaly, Larissa, Thessaly, Greece; Institute of Biomedical Research and Technology, Centre for Research and Technology-Thessaly (CE.RE.TE.TH), Larissa, Greece.
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Hoeroldt B, McFarlane E, Dube A, Basumani P, Karajeh M, Campbell MJ, Gleeson D. Long-term outcomes of patients with autoimmune hepatitis managed at a nontransplant center. Gastroenterology 2011; 140:1980-9. [PMID: 21396370 DOI: 10.1053/j.gastro.2011.02.065] [Citation(s) in RCA: 156] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2010] [Revised: 02/02/2011] [Accepted: 02/25/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The long-term outcomes of patients treated for autoimmune hepatitis (AIH) are considered to be good. However, follow-up data beyond 10 years are limited and confined to tertiary referral centers. We assessed long-term outcomes and determinants of outcome in patients with AIH from a nontransplant center. METHODS We studied 245 patients (204 women; median age, 56 years; range, 2.5-87 years) with AIH (167 definite by International AIH Group criteria) managed at a single nontransplant center from 1971 to 2007. RESULTS 229 patients (93%) achieved normal serum levels of alanine aminotransferase within 12 months after treatment. After a median follow-up period of 9.4 years (range, 0.01-36 years), 11 patients received liver transplants (2 subsequently died). Seventy other patients died (30 from liver disease), 15 were censored (moved away, defaulted, or developed primary biliary cirrhosis), and 149 were still being followed up on December 31, 2007. Survival rates from all-cause death or transplantation were 82%±3% and 48%±5% after 10 and 20 years, respectively, and from liver-related death or transplantation were 91%±2% and 70%±5%, respectively. The standardized mortality ratio was 1.63 for all-cause death (95% confidence interval [CI], 1.25-2.02), 1.86 also considering liver transplant as "death" (95% CI, 1.49-2.26), and 0.91 for non-liver-related death (95% CI, 0.62-1.19). By Cox regression analysis, liver decompensation, cirrhosis at any time, failure to normalize levels of alanine aminotransferase within 12 months, and >4 relapses per decade were significantly associated with liver-related death or transplant. CONCLUSIONS Despite a good initial response to immunosuppression, long-term mortality of patients with AIH is greater than that of the general population.
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Affiliation(s)
- Barbara Hoeroldt
- Department of Gastroenterology, Rotherham General Hospital, Rotherham, England
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Evaluation of risk factors for the development of cirrhosis in autoimmune hepatitis: Japanese NHO-AIH prospective study. J Gastroenterol 2011; 46 Suppl 1:56-62. [PMID: 21042923 DOI: 10.1007/s00535-010-0337-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2010] [Accepted: 09/28/2010] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis (AIH) is a chronic and progressive liver disease characterized by histological interface hepatitis and circulating autoantibodies. Our aims were to evaluate risk factors that contribute to the outcome and, particularly, the development of liver cirrhosis in a prospective multicenter cohort study of AIH. One hundred and seventy-four patients were enrolled. Histologically 21 (12.1%) had cirrhosis at the initial observation and the remaining 153 showed chronic or acute hepatitis at presentation. Among the latter 153 patients, 14 developed cirrhosis during the follow-up period (mean 8.0 years). Demographic, clinical, and laboratory indices associated with the development of cirrhosis were identified. Patients who developed cirrhosis differed in mean levels of alanine aminotransferase (ALT; 158 ± 182 vs. 441 ± 423 IU/ml) and platelet counts (14.7 ± 5.5 vs. 19.4 ± 6.9 × 10(4)/μl) at presentation and received lower doses of corticosteroid (13.9 ± 15.8 vs. 31.8 ± 85.5 mg/day). In a multivariate analysis, an independent predictor for progression to cirrhosis was an older age of onset (≥ 60 years). AIH patients with cirrhosis, or those who developed cirrhosis, had a worse survival. AIH patients with an older age of onset were likely to develop cirrhosis, and careful observation and aggressive treatments are necessary for such patients.
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Muratori L, Muratori P, Granito A, Pappas G, Cassani F, Lenzi M. Current topics in autoimmune hepatitis. Dig Liver Dis 2010; 42:757-764. [PMID: 20615766 DOI: 10.1016/j.dld.2010.05.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 05/23/2010] [Accepted: 05/31/2010] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis.
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MESH Headings
- Animals
- Autoantibodies/immunology
- Autoantigens/immunology
- Biomarkers/blood
- Budesonide/therapeutic use
- Cholangitis, Sclerosing/complications
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/therapy
- Cyclosporine/therapeutic use
- Glucocorticoids/therapeutic use
- Hepatitis, Autoimmune/complications
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/therapy
- Humans
- Hypergammaglobulinemia
- Immunity, Cellular
- Immunoglobulin G/blood
- Immunosuppressive Agents/therapeutic use
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Transplantation/adverse effects
- Mice
- Mycophenolic Acid/analogs & derivatives
- Mycophenolic Acid/therapeutic use
- Rats
- Transaminases/blood
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Affiliation(s)
- Luigi Muratori
- Department of Clinical Medicine, Alma Mater Studiorum - University of Bologna, Policlinico Sant'Orsola-Malpighi, Padiglione 11, Bologna, Italy.
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Czaja AJ. Late relapse of type 1 autoimmune hepatitis after corticosteroid withdrawal. Dig Dis Sci 2010; 55:1761-9. [PMID: 20428945 DOI: 10.1007/s10620-010-1243-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Accepted: 04/06/2010] [Indexed: 01/03/2023]
Abstract
BACKGROUND Relapse of autoimmune hepatitis after corticosteroid withdrawal is common, but the outer limit for this occurrence and the appropriate post-treatment surveillance strategy are uncertain. AIMS The purpose of this study was to determine the frequency and nature of relapses that occur long after drug withdrawal and to propose a long-term surveillance strategy. METHODS The intervals between drug withdrawal and relapse were determined retrospectively in 84 patients with autoimmune hepatitis. RESULTS Relapses occurred in 8 patients (10%) after 49-265 months of observation (mean, 110 +/- 27 months; median, 76 months), and these occurrences were separated from earlier exacerbations by at least 21 months. Treatment continued until normal liver tests and tissue had been accomplished in 14 of the 84 patients (17%), and 13 relapsed within 2-12 months. Only one of the 8 patients with late exacerbations had achieved normal liver tests and tissue immediately prior to drug withdrawal. The patients with late relapses were indistinguishable from patients with early exacerbations, and they all responded to corticosteroid-based therapy during 30 +/- 10 months of observation. CONCLUSIONS Autoimmune hepatitis can relapse as long as 22 years after drug withdrawal, and all late relapses responded to the resumption of corticosteroid therapy. These patients may be outliers of a typical relapse pattern or constitute a bimodal distribution of relapse that reflects different pathogenic mechanisms. The risk of relapse cannot be discounted by treatment to normal liver tests and tissue prior to drug withdrawal or protracted quiescence of the disease after termination of treatment. The unpredictable propensity for relapse warrants regular life-long surveillance.
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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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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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Miyake Y, Iwasaki Y, Kobashi H, Yasunaka T, Ikeda F, Takaki A, Okamoto R, Takaguchi K, Ikeda H, Makino Y, Ando M, Sakaguchi K, Yamamoto K. Efficacy of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis. Hepatol Int 2009; 3:556-562. [PMID: 19847577 PMCID: PMC2790591 DOI: 10.1007/s12072-009-9155-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Revised: 08/12/2009] [Accepted: 09/29/2009] [Indexed: 12/12/2022]
Abstract
PURPOSE This study aimed to investigate the efficacy of ursodeoxycholic acid (UDCA) for Japanese patients with autoimmune hepatitis (AIH). METHODS One hundred forty-seven patients were investigated. RESULTS As initial treatment, 25 patients received UDCA (300-600 mg/day) monotherapy (UDCA group), 40 received a combination of prednisolone (PSL) (≥20 mg/day) and UDCA (combination group), 68 received PSL monotherapy (PSL group), and 14 received other treatments. During the follow-up, in the UDCA group, PSL was added to 8 of 12 patients failing to achieve the normalization of serum transaminase levels with UDCA monotherapy. Cumulative incidence of the normalization of serum transaminase levels was 64% in the UDCA group, 95% in the combination group, and 94% in the PSL group (log-rank test, P = 0.0001). UDCA group required longest periods until the normalization of serum transaminase levels. Eleven patients, who achieved persistent normalization of serum transaminase levels with UDCA monotherapy, did not reach liver failure or develop hepatocellular carcinoma for 49.7 (range = 13.4-137.3) months. Meanwhile, during the taper of PSL, doses of PSL at the initial relapse were lower in patients treated with PSL and UDCA than in those treated with PSL monotherapy, and initial relapse occurred earlier in patients treated with PSL monotherapy. CONCLUSIONS UDCA monotherapy is effective for some Japanese AIH patients; however, UDCA monotherapy for patients with either high-grade inflammatory activity or poor residual capacity of liver function is not recommended because they may reach liver failure before achievement of remission. Meanwhile, additional use of UDCA during the taper of corticosteroids may be effective for the prevention of early relapse.
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Affiliation(s)
- Yasuhiro Miyake
- Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yoshiaki Iwasaki
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558 Japan
| | - Haruhiko Kobashi
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558 Japan
| | - Tetsuya Yasunaka
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558 Japan
| | - Fusao Ikeda
- Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Akinobu Takaki
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558 Japan
| | - Ryoichi Okamoto
- Department of Internal Medicine, Hiroshima City Hospital, Hiroshima, Japan
| | - Kouichi Takaguchi
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Hiroshi Ikeda
- Department of Gastroenterology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Yasuhiro Makino
- Department of Gastroenterology, Iwakuni Clinical Center, Iwakuni, Japan
| | - Masaharu Ando
- Department of Gastroenterology, Mitoyo General Hospital, Kanonji, Japan
| | - Kohsaku Sakaguchi
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558 Japan
| | - Kazuhide Yamamoto
- Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, 700-8558 Japan
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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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