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Schregel I, Papp M, Sipeki N, Kovats PJ, Taubert R, Engel B, Campos-Murguia A, Dalekos GN, Gatselis N, Zachou K, Milkiewicz P, Janik MK, Raszeja-Wyszomirska J, Ytting H, Braun F, Casar C, Sebode M, Lohse AW, Schramm C. Unmet needs in autoimmune hepatitis: Results of the prospective multicentre European Reference Network Registry (R-LIVER). Liver Int 2024; 44:2687-2699. [PMID: 39037185 DOI: 10.1111/liv.16035] [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: 10/29/2023] [Revised: 06/04/2024] [Accepted: 06/26/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND AND AIMS The European Reference Network on Hepatological Diseases (ERN RARE-LIVER) launched the prospective, multicentre, quality-controlled R-LIVER registry on rare liver diseases. The aim of this study was to assess the presentation and outcome of autoimmune hepatitis (AIH) after 1 year of treatment. METHODS Data were prospectively collected at the time of diagnosis and after 6 and 12 months follow-up. Complete biochemical response (CBR) was defined as normalization of alanine aminotransferase (ALT) and immunoglobulin G (IgG) serum levels. RESULTS A total of 231 patients from six European centres were included in the analysis. After 6 months of treatment 50% (106/212), and after 12 months 63% (131/210) of patients reached CBR with only 27% (56/211) achieving a steroid-free CBR within the first year. Overall, 16 different treatment regimens were administered. Change of treatment, mostly due to intolerance, occurred in 30.4% within the first 6 months. In multivariate analysis, younger age at diagnosis (odds ratio [OR] = 1.03 [95% confidence interval (CI) 1.01-1.05]; p = .007), severe fibrosis (OR .38 [95% .16-.89], p = .026) and change of treatment within the first 6 months (OR .40 [95% CI .2-.86]; p = .018) were associated with a lesser chance of ALT normalization at 12 months follow-up. CONCLUSION The landscape of AIH treatment in Europe is highly heterogeneous, even between expert centres. The results from this first European multicentre prospective registry reveal several unmet needs, highlighted by the overall low rates of CBR and the frequent failure to withdraw corticosteroids.
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Affiliation(s)
- Ida Schregel
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Maria Papp
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary, Germany
| | - Nora Sipeki
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary, Germany
| | - Patricia J Kovats
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Hungary, Germany
- Faculty of Medicine, Kálmán Laki Doctoral School, University of Debrecen, Hungary, Germany
| | - Richard Taubert
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bastian Engel
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Alejandro Campos-Murguia
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - George N Dalekos
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Nikolaos Gatselis
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Kalliopi Zachou
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece
| | - Piotr Milkiewicz
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
- Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland
| | - Maciej K Janik
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Joanna Raszeja-Wyszomirska
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Hepatology, Transplantology and Internal Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Henriette Ytting
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Department of Clinical Medicine, Hvidovre University Hospital of Copenhagen, Copenhagen, Denmark
| | - Felix Braun
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Christian Casar
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Marcial Sebode
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- European Reference Network (ERN) RARE-LIVER, Hamburg, Germany
- Martin Zeitz Center for Rare Diseases, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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Tadokoro T, Nomura T, Fujita K, Manabe T, Takuma K, Nakahara M, Oura K, Mimura S, Tani J, Morishita A, Kobara H, Ono M, Masaki T. Management of hepatocellular carcinoma, an important cause of death in Japanese autoimmune hepatitis patients. BMC Gastroenterol 2024; 24:123. [PMID: 38561671 PMCID: PMC10986071 DOI: 10.1186/s12876-024-03204-z] [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: 01/27/2024] [Accepted: 03/11/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established. AIM To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies. METHODS We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment. RESULTS In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p < 0.0001) and cumulative cancer rates were high. Multidisciplinary therapy other than immune checkpoint inhibitors was administered as treatment for HCC. Two of the three patients who used molecular-targeted drugs discontinued the treatment because of adverse events. CONCLUSION HCC is an important cause of death in patients with AIH. Currently available drug therapies are limited and early detection is desirable. TRIAL REGISTRATION This trial was retrospectively registered in the Ethics Committee of Kagawa University School of Medicine under the identifier 2019 - 238, registered on 4 Feb 2020.
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Affiliation(s)
- Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
- Gastroenterology and Hepatology, HITO Medical Center, 788-1 Kamibun-cho, Shikokutyuou, Ehime, 799-0121, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Takushi Manabe
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Kei Takuma
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Mai Nakahara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Masafumi Ono
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
- Division of Innovative Medicine for Hepatobiliary and Pancreatology, Faculty of Medicine, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
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Roth L, Michl P, Rosendahl J. [Sex-specific differences in gastroenterological diseases]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2023; 64:736-743. [PMID: 36884055 DOI: 10.1007/s00108-023-01491-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/31/2023] [Indexed: 03/09/2023]
Abstract
Diseases of the gastrointestinal tract present with substantial sex differences that have a potential impact on patient outcome. This fact is not sufficiently addressed either in basic research or in clinical studies. For example, most animal studies utilize male animals. Despite differences in incidence, sex may affect complication rates, prognosis, or therapeutic response. The incidence of gastrointestinal cancers is frequently higher in males, but this observation cannot solely rely on a distinct risk behaviour. Here, differences in immune response and p53 signalling may be factors responsible for this finding. Nevertheless, taking sex differences into account and improving our understanding of relevant mechanisms is crucial and will most likely have a substantial impact on disease outcome. This overview aims to highlight sex differences in the context of various gastroenterological diseases, primarily to enhance awareness. Attention to sex-specific differences is essential to improve individualized treatment.
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Affiliation(s)
- Laura Roth
- Universitätsklinik und Poliklinik für Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Deutschland.
- Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
| | - Patrick Michl
- Universitätsklinik und Poliklinik für Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Deutschland
- Klinik für Innere Medizin IV, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - Jonas Rosendahl
- Universitätsklinik und Poliklinik für Innere Medizin I, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle (Saale), Deutschland.
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KASL clinical practice guidelines for management of autoimmune hepatitis 2022. Clin Mol Hepatol 2023; 29:542-592. [PMID: 37137334 PMCID: PMC10366804 DOI: 10.3350/cmh.2023.0087] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 03/27/2023] [Accepted: 04/03/2023] [Indexed: 05/05/2023] Open
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Biewenga M, Verhelst X, Baven-Pronk M, Putter H, van den Berg A, Colle I, Schouten J, Sermon F, Van Steenkiste C, van Vlierberghe H, van der Meer A, van Hoek B. Aminotransferases During Treatment Predict Long-Term Survival in Patients With Autoimmune Hepatitis Type 1: A Landmark Analysis. Clin Gastroenterol Hepatol 2022; 20:1776-1783.e4. [PMID: 34022454 DOI: 10.1016/j.cgh.2021.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 04/27/2021] [Accepted: 05/07/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Biochemical remission, important treatment goal in autoimmune hepatitis (AIH), has been associated with better long-term survival. The aim of this study was to determine the independent prognostic value of aminotransferases and immunoglobulin G (IgG) during treatment on long-term transplant-free survival in AIH. METHODS In a multicenter cohort alanine aminotransferase, aspartate aminotransferase (AST), and IgG were collected at diagnosis and 6, 12, 24, and 36 months after start of therapy and related to long-term outcome using Kaplan-Meier survival and Cox regression analysis with landmark analysis at these time points, excluding patients with follow-up ending before each landmark. RESULTS A total of 301 AIH patients with a median follow-up of 99 (range, 7-438) months were included. During follow-up, 15 patients required liver transplantation and 33 patients died. Higher AST at 12 months was associated with worse survival (hazard ratio [HR], 1.86; P < .001), while IgG was not associated with survival (HR, 1.30; P = .53). In multivariate analysis AST at 12 months (HR, 2.13; P < .001) was predictive for survival independent of age, AST at diagnosis and cirrhosis. Multivariate analysis for AST yielded similar results at 6 months (HR, 2.61; P = .001), 24 months (HR, 2.93; P = .003), and 36 months (HR, 3.03; P = .010). There was a trend toward a worse survival in patients with mildly elevated aminotransferases (1-1.5× upper limit of normal) compared with patients with normal aminotransferases (P = .097). CONCLUSIONS Low aminotransferases during treatment are associated with a better long-term survival in autoimmune hepatitis. IgG was not associated with survival in first 12 months of treatment. Normalization of aminotransferases should be the treatment goal for autoimmune hepatitis to improve long-term survival.
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Affiliation(s)
- Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | - Xavier Verhelst
- Department of Gastroenterology and Hepatology, UZ Ghent, member of European Reference Network RARE-LIVER, Ghent, Belgium
| | - Martine Baven-Pronk
- Department of Gastroenterology and Hepatology, Green Heart Hospital, Gouda, the Netherlands
| | - Hein Putter
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Aad van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, member of European Reference Network RARE-LIVER, Groningen, the Netherlands
| | - Isabelle Colle
- Department of Gastroenterology and Hepatology, ASZ Aalst, Aalst, Belgium
| | - Jeoffrey Schouten
- Department of Gastroenterology and Hepatology, AZ Nikolaas, Sint-Niklaas, Belgium
| | - Filip Sermon
- Department of Gastroenterology and Hepatology, OLV Aalst, Aalst, Belgium
| | - Christophe Van Steenkiste
- Department of Gastroenterology and Hepatology, AZ Maria Middelares Ghent, Ghent, Belgium; Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | - Hans van Vlierberghe
- Department of Gastroenterology and Hepatology, UZ Ghent, member of European Reference Network RARE-LIVER, Ghent, Belgium
| | - Adriaan van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
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Scandolara TB, Pacholak LM, Tavares IM, Kern R, Garcia-Velazquez L, Panis C. Cross talks between autoimmunity and cancer. TRANSLATIONAL AUTOIMMUNITY 2022:15-49. [DOI: 10.1016/b978-0-323-85415-3.00005-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Increased Cancer Risk in Autoimmune Hepatitis: A Danish Nationwide Cohort Study. Am J Gastroenterol 2022; 117:129-137. [PMID: 34622808 DOI: 10.14309/ajg.0000000000001525] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 09/09/2021] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease and as such may increase the risk of cancer. We examined cancer risks in a nationwide cohort of patients with AIH. METHODS This study was based on nationwide Danish healthcare registries. We identified all persons diagnosed with AIH between 1994 and 2018. We included 1805 patients with AIH and 16,617 age- and sex-matched population controls. We estimated cumulative risks of cancers and risk ratios (RRs) between patients and controls. Within the cohort of patients with AIH, we examined the impact of immunosuppressive treatment (IST) and cirrhosis on cancer risks. RESULTS The 10-year risk of any cancer was 13.6% (95% confidence interval [CI] 11.7-15.6) in patients with AIH with an RR of 1.5 (95% CI 1.3-1.7) compared with controls. Patients with AIH had a 10-year risk of 0.5% (95% CI 0.2-1.1) for hepatocellular carcinoma. The 10-year risk was 1.6% (95% CI 1.0-2.5) for colorectal cancer (RR: 2.1 [95% CI 1.3-3.5]) and 4.0% (95% CI 3.0-5.3) for nonmelanoma skin cancer (RR: 1.8 [95% CI 1.3-2.5]). Among patients with AIH, the risk of cancer was higher for those with cirrhosis (hazard ratio: 1.3 [95% CI 1.0-1.7]), and it also increased 1.05-fold (95% CI 1.0-1.1) for every year the patient was on IST. DISCUSSION AIH was associated with a 1.5-fold increased 10-year risk of cancer compared with age- and sex-matched controls. Among patients with AIH, the risk of cancer was higher for those with cirrhosis, and it also increased slightly with longer duration of IST.
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Biewenga M, Verhelst XPDMJ, Baven-Pronk MAMC, Putter H, van den Berg AP, van Nieuwkerk KCMJ, van Buuren HR, Bouma G, de Boer YS, Simoen C, Colle I, Schouten J, Sermon F, van Steenkiste C, van Vlierberghe H, van der Meer AJ, Nevens F, van Hoek B. Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1. United European Gastroenterol J 2021; 9:662-671. [PMID: 34165262 PMCID: PMC8281048 DOI: 10.1002/ueg2.12112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/26/2021] [Accepted: 03/28/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients. OBJECTIVE The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis. METHODS The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort. RESULTS In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844]). CONCLUSIONS A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated.
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Affiliation(s)
- Maaike Biewenga
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
| | | | | | - Hein Putter
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands
| | - Aad P van den Berg
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands
| | - Karin C M J van Nieuwkerk
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands
| | - Henk R van Buuren
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands
| | - Ynte S de Boer
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location VUmc, Amsterdam, the Netherlands
| | - Cedric Simoen
- Department of Gastroenterology and Hepatology, UZ Ghent, Ghent, Belgium
| | - Isabelle Colle
- Department of Gastroenterology and Hepatology, ASZ Aalst, Aalst, Belgium
| | - Jeoffrey Schouten
- Department of Gastroenterology and Hepatology, AZ Nikolaas, Sint-Niklaas, Belgium
| | - Filip Sermon
- Department of Gastroenterology and Hepatology, OLV Aalst, Aalst, Belgium
| | - Christophe van Steenkiste
- Department of Gastroenterology and Hepatology, AZ Maria Middelares Ghent, Ghent, Belgium.,Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium
| | | | | | - Frederik Nevens
- Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Bart van Hoek
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
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Wang G, Tanaka A, Zhao H, Jia J, Ma X, Harada K, Wang FS, Wei L, Wang Q, Sun Y, Hong Y, Rao H, Efe C, Lau G, Payawal D, Gani R, Lindor K, Jafri W, Omata M, Sarin SK. The Asian Pacific Association for the Study of the Liver clinical practice guidance: the diagnosis and management of patients with autoimmune hepatitis. Hepatol Int 2021; 15:223-257. [PMID: 33942203 PMCID: PMC8144150 DOI: 10.1007/s12072-021-10170-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/27/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Guiqiang Wang
- Peking University First Hospital, Beijing, China. .,Peking University International Hospital, Beijing, China.
| | | | - Hong Zhao
- Peking University First Hospital, Beijing, China.,Peking University International Hospital, Beijing, China
| | - Jidong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine Kanazawa, Kanazawa, Japan
| | - Fu-Sheng Wang
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Qixia Wang
- Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ying Sun
- Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Yuan Hong
- Peking University First Hospital, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Beijing, China
| | - Cumali Efe
- Department of Gastroenterology, Harran University, Şanlıurfa, Turkey
| | - George Lau
- Humanity and Health Medical Group, Hong Kong Special Administrative Region, China
| | - Diana Payawal
- Department of Hepatology, Cardinal Santos Medical Center, Manila, Philippines
| | - Rino Gani
- Department of Internal Medicine, Cipto Mangunkusumo Hospital, University of Indonesia, Jakarta, Indonesia
| | - Keith Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | | | - Masao Omata
- Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-City, Yamanashi, Japan.,The University of Tokyo, Tokyo, Japan
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Rigopoulou EI, Dalekos GN. Current Trends and Characteristics of Hepatocellular Carcinoma in Patients with Autoimmune Liver Diseases. Cancers (Basel) 2021; 13:1023. [PMID: 33804480 PMCID: PMC7957658 DOI: 10.3390/cancers13051023] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the commonest among liver cancers, is one of the leading causes of mortality among malignancies worldwide. Several reports demonstrate autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) to confer increased risk of hepatobiliary malignancies, albeit at lower frequencies compared to other liver diseases. Several parameters have been recognized as risk factors for HCC development in AIH and PBC, including demographics such as older age and male sex, clinical features, the most decisive being cirrhosis and other co-existing factors, such as alcohol consumption. Moreover, biochemical activity and treatment response have been increasingly recognized as prognostic factors for HCC development in AIH and PBC. As available treatment modalities are effective only when HCC diagnosis is established early, surveillance has been proven essential for HCC prognosis. Considering that the risk for HCC is not uniform between and within disease groups, refinement of screening strategies according to prevailing demographic, clinical, and molecular risk factors is mandated in AILDs patients, as personalized HCC risk prediction will offer significant advantage in patients at high and/or medium risk. Furthermore, future investigations should draw attention to whether modification of immunosuppression could benefit AIH patients after HCC diagnosis.
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Affiliation(s)
| | - George N. Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, 41110 Larissa, Greece;
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11
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Higuchi T, Oka S, Furukawa H, Tohma S, Yatsuhashi H, Migita K. Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response. Hum Genomics 2021; 15:6. [PMID: 33509297 PMCID: PMC7841991 DOI: 10.1186/s40246-020-00301-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/15/2020] [Indexed: 01/10/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.
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Affiliation(s)
- Takashi Higuchi
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.,Department of Nephrology, Ushiku Aiwa General Hospital, 896 Shishiko-cho, Ushiku, 300-1296, Japan.,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan
| | - Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan.,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan.,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan. .,Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan. .,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan.
| | - Shigeto Tohma
- Department of Rheumatology, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose, 204-8585, Japan.,Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18-1 Sakuradai, Minami-ku, Sagamihara, 252-0392, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, 856-8562, Japan.,Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan
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12
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Migita K, Nakamura M, Aiba Y, Kozuru H, Abiru S, Komori A, Fujita Y, Temmoku J, Asano T, Sato S, Furuya M, Naganuma A, Yoshizawa K, Shimada M, Ario K, Mannami T, Kohno H, Kaneyoshi T, Komura T, Ohira H, Yatsuhashi H. Association of soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) and mac-2 binding protein glycosylation isomer (M2BPGi) in patients with autoimmune hepatitis. PLoS One 2020; 15:e0238540. [PMID: 33347507 PMCID: PMC7751864 DOI: 10.1371/journal.pone.0238540] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Accepted: 08/18/2020] [Indexed: 12/23/2022] Open
Abstract
Background Autoimmune hepatitis (AIH) is a disorder of unknown etiology in which immune-mediated liver injury progress to cirrhosis or hepatocellular carcinoma (HCC). The aim of the present study was to determine whether circulating soluble TIM3 (sTIM3) is elevated in patients with AIH patients and whether sTIM-3 levels are associated with clinical parameters of AIH. Methods We enrolled 123 Japanese patients with AIH who were identified from the National Hospital Organization–AIH-liver–network database, as well as 32 patients with chronic hepatitis C (CHC), 30 patients with primary biliary cholangitis (PBC) and healthy control subjects. Serum sTIM-3 concentrations were quantified by ELISA. Results Serum levels of sTIM-3 were significantly higher in AIH patients (median 4865 pg/ml; [interquartile range (IQR); 3122–7471]) compared to those in CHC (1026 pg/ml [IQR: 806–1283] p<0.001), PBC (2395 pg/ml [IQR: 2012–3422] p<0.001) or healthy controls (1285 pg/ml [IQR: 1098–1812] p<0.001). In AIH group, serum sTIM-3 were correlated with alanine aminotransferase (ALT), or total bilirubin (TB) and negatively correlated with serum levels of albumin (Alb). Serum levels of sTIM-3 were also strongly correlated with Mac-2 binding protein glycosylation isomer (M2BPGi) levels, but did not correlate with the histological grade of liver fibrosis. Steroid treatment of AIH patients significantly reduced serum sTIM-3 levels (2147±623pg/ml versus 1321±378pg/ml, p<0.001). Conclusions Circulating sTIM-3 levels were elevated in AIH patients and are associated with AIH disease activity and AIH-related liver damage. These findings indicate that serum sTIM-3 correlated with disease status of AIH and could be useful biomarkers to detect autoimmune-mediated liver injury. Our data suggest a possible link between the TIM-3/GAL-9 pathway and AIH severity or phenotype, and further investigations of the TIM-3 pathway and AIH pathophysiology is warranted.
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Affiliation(s)
- Kiyoshi Migita
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
- Department of Rheumatology, Fukushima Medical University, Fukushima, Japan
- * E-mail:
| | - Minoru Nakamura
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
| | - Hideko Kozuru
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
| | - Seigo Abiru
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
| | - Atsumasa Komori
- Clinical Research Center, Nagasaki Medical Center, Nagasaki, Japan
| | - Yuya Fujita
- Department of Rheumatology, Fukushima Medical University, Fukushima, Japan
| | - Junpei Temmoku
- Department of Rheumatology, Fukushima Medical University, Fukushima, Japan
| | - Tomoyuki Asano
- Department of Rheumatology, Fukushima Medical University, Fukushima, Japan
| | - Shuzo Sato
- Department of Rheumatology, Fukushima Medical University, Fukushima, Japan
| | - Makiko Furuya
- Department of Rheumatology, Fukushima Medical University, Fukushima, Japan
| | - Atsushi Naganuma
- National Hospital Organization, Takasaki Medical Center, Takasaki, Japan
| | - Kaname Yoshizawa
- National Hospital Organization, Shinsyu-Ueda Medical Center, Ueda, Nagano, Japan
| | - Masaaki Shimada
- National Hospital Organization, Nagoya Medical Center, Nagoya, Aichi, Japan
| | - Keisuke Ario
- National Hospital Organization, Ureshino Medical Center, Ureshino, Saga, Japan
| | - Tomohiko Mannami
- National Hospital Organization, Okayama Medical Center, Okayama, Okayama, Japan
| | - Hiroshi Kohno
- National Hospital Organization, Kure Medical Center, Kure, Hiroshima, Japan
| | - Toshihiko Kaneyoshi
- National Hospital Organization, Fukuyama Medical Center, Kanazawa, Ishikawa, Japan
| | - Takuya Komura
- National Hospital Organization, Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
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13
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Grønbaek L, Otete H, Ban L, Crooks C, Card T, Jepsen P, West J. Incidence, prevalence and mortality of autoimmune hepatitis in England 1997-2015. A population-based cohort study. Liver Int 2020; 40:1634-1644. [PMID: 32304617 DOI: 10.1111/liv.14480] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 04/06/2020] [Accepted: 04/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS There are few population-based studies of the incidence and mortality of autoimmune hepatitis. The burden of the disease and how it has changed over time have not been fully explored. We conducted a population-based cohort study on the incidence and mortality of autoimmune hepatitis in England, 1997-2015. METHODS From the Clinical Practice Research Datalink we included 882 patients diagnosed with autoimmune hepatitis in England, 1997-2015. The patients were followed through 2015, and we calculated the sex- and age-standardized incidence and prevalence of autoimmune hepatitis. We examined variation in incidence by sex, age, calendar year, geographical region and socioeconomic status, and incidence rate ratios were calculated with Poisson regression. We calculated all-cause and cause-specific mortality. RESULTS The overall standardized incidence rate of autoimmune hepatitis was 2.08 (95% confidence interval 1.94-2.22) per 100,000 population per year, higher in women, higher in older age and independent of region and socioeconomic status. From 1997 to 2015 the incidence doubled from 1.27 (95% confidence interval 0.51-2.02) to 2.56 (95% confidence interval 1.79-3.33) per 100,000 population per year. The 10-year cumulative all-cause mortality was 31.9% (95% confidence interval 27.6-36.5), and the 10-year cumulative liver-related mortality, including hepatocellular carcinoma was ~10.5%. CONCLUSIONS This population-based study showed that the incidence of autoimmune hepatitis doubled over an eighteen-year period. The incidence was particularly high in older women and was similar across all regions of England and independent of socioeconomic status. Patients with autoimmune hepatitis had a high mortality.
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Affiliation(s)
- Lisbet Grønbaek
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.,Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,Department of Medicine, Regional Hospital Horsens, Horsens, Denmark
| | - Harmony Otete
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,School of Medicine and Dentistry, University of Central Lancashire, Preston, United Kingdom
| | - Lu Ban
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Colin Crooks
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom.,Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Timothy Card
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom
| | - Peter Jepsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N, Denmark.,Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark.,Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Joe West
- Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom.,National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, United Kingdom
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14
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Dakhoul L, Jones KR, Gawrieh S, Ghabril M, McShane C, Vuppalanchi R, Vilar-Gomez E, Nephew L, Chalasani N, Lammert C. Older Age and Disease Duration Are Highly Associated with Hepatocellular Carcinoma in Patients with Autoimmune Hepatitis. Dig Dis Sci 2019; 64:1705-1710. [PMID: 30617453 PMCID: PMC6525055 DOI: 10.1007/s10620-018-5441-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 12/18/2018] [Indexed: 01/03/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is rare in patients with autoimmune hepatitis (AIH). However, the overall burden of AIH cirrhosis in causing HCC and patients' risk factors are not well understood. AIMS To characterize the proportion of HCC linked to AIH at a large academic health center, and to identify variables associated with HCC in patients with AIH in a case-control study design. METHODS Over a 14.5-year period, medical records of all patients with HCC were reviewed. Cases are AIH patients identified from the cohort, and controls are patients with AIH without HCC. Three controls were randomly chosen from the Genetic Repository of Autoimmune Liver Disease and Coexisting Exposures database for each eligible case. RESULTS Out of 1250 eligible patients, 20 were linked to AIH (1.6%). Their median age was 64 years, 40% men and 100% Caucasian. Ten percent of AIH patients did not have evidence of cirrhosis at HCC diagnosis. The proportion of HCCs due to AIH decreased during the time intervals of the study. Compared to controls, cases were more likely men (40.0% vs. 18%, p = 0.049), with longer AIH duration (median 16 years vs. 5 years, p = 0.004). Prolonged AIH duration (OR 1.68, p = 0.006) and older age (OR 1.15, p = 0.049) were risk factors for HCC. CONCLUSIONS AIH is a rare cause (1.6%) for HCC in Midwestern USA with a decreasing trend over 14.5 years. Ten percent of AIH-HCC patients did not have cirrhosis at time of HCC diagnosis. Patients with prolonged duration of the disease and older age are at high risk to develop HCC.
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Affiliation(s)
- Lara Dakhoul
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Keaton R Jones
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Chelsey McShane
- Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Eduardo Vilar-Gomez
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.
| | - Craig Lammert
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.
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15
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Higuchi T, Oka S, Furukawa H, Nakamura M, Komori A, Abiru S, Hashimoto S, Shimada M, Yoshizawa K, Kouno H, Naganuma A, Ario K, Kaneyoshi T, Yamashita H, Takahashi H, Makita F, Yatsuhashi H, Ohira H, Migita K. Role of deleterious single nucleotide variants in the coding regions of TNFAIP3 for Japanese autoimmune hepatitis with cirrhosis. Sci Rep 2019; 9:7925. [PMID: 31138864 PMCID: PMC6538649 DOI: 10.1038/s41598-019-44524-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 05/17/2019] [Indexed: 12/17/2022] Open
Abstract
Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis. TNFAIP3 gene encodes A20, an inhibitor of nuclear factor-κB pathway, and is a susceptibility gene for autoimmune diseases. We investigated deleterious variants in the coding regions of TNFAIP3 gene of Japanese AIH patients or those with cirrhosis. The deleterious variants in the coding regions of TNFAIP3 gene were analyzed by the cycle sequencing method and the frequencies of deleterious TNFAIP3 alleles of AIH or AIH with cirrhosis were compared with those of Japanese controls. The deleterious alleles in TNFAIP3 were not associated with AIH. A significant association was shown for the deleterious alleles in TNFAIP3 (P = 0.0180, odds ratio (OR) 4.28, 95% confidence interval (CI) 1.53-11.95) with AIH with cirrhosis at presentation. The serum IgM levels in AIH patients with deleterious alleles in TNFAIP3 were tended to be lower than those without (P = 0.0152, Q = 0.1216). The frequency of deleterious alleles in TNFAIP3 was higher in the AIH subset without the DRB1 risk alleles than that with (P = 0.0052, OR 5.10, 95%CI 1.55-16.74). The deleterious alleles in TNFAIP3were associated with AIH with cirrhosis.
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Affiliation(s)
- Takashi Higuchi
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan
| | - Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, 305-8575, Tsukuba, Japan.
| | - Minoru Nakamura
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Seigo Abiru
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Satoru Hashimoto
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Masaaki Shimada
- National Hospital Organization, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, 460-0001, Nagoya, Japan
| | - Kaname Yoshizawa
- Department of Gastroenterology, National Hospital Organization, Shinshu Ueda Medical Center, 1-27-21 Midorigaoka, 386-8610, Ueda, Japan
| | - Hiroshi Kouno
- National Hospital Organization, Kure Medical Center, 3-1 Aoyama-cho, 737-0023, Kure, Japan
| | - Atsushi Naganuma
- National Hospital Organization, Takasaki General Medical Center, 36 Takamatsu-cho, 370-0829, Takasaki, Japan
| | - Keisuke Ario
- National Hospital Organization, Ureshino Medical Center, 2436 Shimojuku, 843-0393, Ureshino, Japan
| | - Toshihiko Kaneyoshi
- National Hospital Organization, Fukuyama Medical Center, 4-14-17 Okinogami-cho, 720-8520, Fukuyama, Japan
| | - Haruhiro Yamashita
- National Hospital Organization, Okayama Medical Center, 1711-1 Tamasu, Kita-ku, 701-1192, Okayama, Japan
| | - Hironao Takahashi
- National Hospital Organization, Higashinagoya National Hospital, 5-101 Umemorizaka, Meito-ku, 465-8620, Nagoya, Japan
| | - Fujio Makita
- National Hospital Organization, Shibukawa Medical Center, 383 Shiroi, 377-0280, Shibukawa, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, 960-1295, Fukushima, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, 856-8562, Omura, Japan.,Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, 960-1295, Fukushima, Japan
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16
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Valean S, Acalovschi M, Dumitrascu DL, Ciobanu L, Nagy G, Chira R. Hepatocellular carcinoma in patients with autoimmune hepatitis - a systematic review of the literature published between 1989-2016. Med Pharm Rep 2019; 92:99-105. [PMID: 31086834 PMCID: PMC6510357 DOI: 10.15386/mpr-1228] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/28/2018] [Accepted: 01/25/2019] [Indexed: 12/24/2022] Open
Abstract
Background and aims Liver cancer is one of the most common cause of deaths from cancer. Hepatocellular carcinoma (HCC) was reported at a frequency of 7% of patients with autoimmune hepatitis (AIH) - related cirrhosis in 1988. We aimed to provide a systematic literature review on the frequency of HCC in patients with AIH, after the discovery of hepatitis C virus (HCV), in order to avoid any possible confounding etiology. Methods A literature search of the PubMed database between 1989–2016 was performed, using the relevant keywords “hepatocellular carcinoma” and “autoimmune hepatitis”. We followed the PRISMA statement guidelines during the preparation of this review. Results Eleven studies (n=8,460 patients with AIH) were retained for the final analysis. HCC was diagnosed in 0–12.3% of the AIH patients included in these studies. The overall occurrence of HCC in patients with AIH was estimated in two studies, at 5.1% and 6.2%, respectively. In patients with AIH and cirrhosis, the percentage of HCC varied between 0.2%–12.3%. The proportion of HCC in patients with AIH without cirrhosis was estimated at 1.03%. The percentage of cirrhosis in AIH patients varied from 18.7% to 83.3% in Japan, and from 12% to 50.2% in the other areas. The mean follow-up of the patients with AIH was of 10 years. Conclusions The development of HCC in patients with AIH appeared to be similar before and after the discovery of HCV, and it was mainly associated to cirrhosis. The number of patients developing cirrhosis in relation with AIH was impressive. The long evolution of AIH to cirrhosis and, eventually, to HCC, has been be suggested.
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Affiliation(s)
- Simona Valean
- Medical Clinic no. 1, Department of Gastroenterology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Monica Acalovschi
- Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Dan L Dumitrascu
- Medical Clinic no. 2, Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lidia Ciobanu
- Octavian Fodor Regional Institute of Gastroenterology and Hepatology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Georgiana Nagy
- Medical Clinic no. 1, Department of Gastroenterology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Romeo Chira
- Medical Clinic no. 1, Department of Gastroenterology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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17
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Tarao K, Nozaki A, Ikeda T, Sato A, Komatsu H, Komatsu T, Taguri M, Tanaka K. Real impact of liver cirrhosis on the development of hepatocellular carcinoma in various liver diseases-meta-analytic assessment. Cancer Med 2019; 8:1054-1065. [PMID: 30791221 PMCID: PMC6434205 DOI: 10.1002/cam4.1998] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/27/2018] [Accepted: 01/06/2019] [Indexed: 12/12/2022] Open
Abstract
Background It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. Methods The PubMed database was examined (1989‐2017) for studies published in English language regarding the prospective follow‐up results for the development of HCC in various liver diseases. A meta‐analysis was performed for each liver disease. Results The annual incidence (%) of HCC in the non‐cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non‐cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73‐fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07‐fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88‐fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79‐fold), and (e) NASH (0.03%→1.35%, 45.00‐fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow‐up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. Conclusions When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.
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Affiliation(s)
- Kazuo Tarao
- Tarao's Gastroenterological Clinic, Yokohama, Japan
| | - Akito Nozaki
- Gastroenterological Center, Medical Center, Yokohama City University, Yokohama, Japan
| | - Takaaki Ikeda
- Gastroenterology Department, Yokosuka General Hospital Uwamachi, Yokosuka, Japan
| | - Akira Sato
- Division of Gastroenterology, Department of Internal Medicine, St. Marianna University, Yokohama City Seibu Hospital, Yokohama, Japan
| | - Hirokazu Komatsu
- Department of Gastroenterology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan
| | - Tatsuji Komatsu
- Department Clinical Research, National Hospital Organization, Yokohama Medical Center, Yokohama, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University, Yokohama, Japan
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Dalekos GN, Koskinas J, Papatheodoridis GV. Hellenic Association for the Study of the Liver Clinical Practice Guidelines: Autoimmune hepatitis. Ann Gastroenterol 2019; 32:1-23. [PMID: 30598587 PMCID: PMC6302199 DOI: 10.20524/aog.2018.0330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a relatively rare acute or chronic liver disease of unknown etiology characterized by large heterogeneity. Its distribution is global, covering all ages, both sexes and all ethnic groups. The aim of the present Clinical Practice Guidelines (CPG) of the Hellenic Association for the Study of the Liver was to provide updated guidance and help to gastroenterologists, hepatologists, internists and general practitioners for AIH diagnosis and management. AIH diagnosis is based on clinicopathological characteristics: namely, polyclonal hypergammaglobulinemia, particularly of immunoglobulin G (IgG), circulating autoantibodies, interface hepatitis on liver histology, absence of viral hepatitis, and a favorable response to immunosuppression. Clinical manifestations at disease onset are variable, ranging from asymptomatic to the acute/severe form. Aminotransferase and bilirubin levels vary, while the presence of hepatitis at the histological level is a prerequisite for diagnosis. Autoantibodies are the hallmark for AIH diagnosis; therefore, the CPG describe the appropriate serological algorithm for their detection. AIH therapy should aim to achieve complete biochemical (normalization of IgG and aminotransferases) and histological remission. All patients who have active disease, even those with cirrhosis, should be treated with individualized and response-guided induction therapy using prednisolone in combination with azathioprine or mycophenolate mofetil as first-line therapy. Immunosuppression should be given for at least 3 years and for at least 2 years after the achievement of complete biochemical response, while a liver biopsy should be recommended before treatment discontinuation. Current CPG are also provided for several specific conditions and difficult-to-treat patients.
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Affiliation(s)
- George N. Dalekos
- Institute of Internal Medicine and Hepatology, Larissa (George N. Dalekos)
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa (George N. Dalekos)
| | - John Koskinas
- Second Department of Internal Medicine, National and Kapodistrian University of Athens, “Hippokratio” General Hospital of Athens, Athens (John Koskinas)
| | - George V. Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, “Laiko” General Hospital of Athens, Athens (George V. Papatheodoridis), Greece
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19
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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] [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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Wang QX, Yan L, Ma X. Autoimmune Hepatitis in the Asia-Pacific Area. J Clin Transl Hepatol 2018; 6:48-56. [PMID: 29577032 PMCID: PMC5862999 DOI: 10.14218/jcth.2017.00032] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/23/2017] [Accepted: 10/26/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis has been considered as a relatively rare immunological liver disease, especially in the Asia-Pacific area. Although the diagnosis criteria and immunosuppressive treatment regimens have been established, there are still some challenges. According to the different presentations, the personalized management of patients who suffer from this disease, including those with chronic or acute severe onset, the autoantibody-negative phenotype and cirrhosis are necessarily descriptive. Each subgroup of patients should receive an individualized therapy. Here, we review the recent studies of autoimmune hepatitis, mainly focusing on the epidemiology and genetics, personalized diagnostics, individualized treatment strategies, special subgroups and outcomes. Most of the research in the literature is based on Japanese and Chinese populations.
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Affiliation(s)
- Qi-Xia 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, Shanghai, 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, Shanghai, 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, Shanghai, China
- *Correspondence to: Xiong Ma, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China. Tel: +86-21-63200874, Fax: +86-21-63266027, E-mail:
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21
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Association of a single nucleotide polymorphism in TNIP1 with type-1 autoimmune hepatitis in the Japanese population. J Hum Genet 2018; 63:739-744. [PMID: 29559739 DOI: 10.1038/s10038-018-0440-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 02/02/2018] [Accepted: 02/22/2018] [Indexed: 12/20/2022]
Abstract
Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03-1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12-1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.
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22
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Arinaga-Hino T, Ide T, Miyajima I, Ogata K, Kuwahara R, Amano K, Kawaguchi T, Nakamura T, Kawaguchi T, Koga H, Yonemoto K, Torimura T. Risk of malignancies in autoimmune hepatitis type 1 patients with a long-term follow-up in Japan. Hepatol Res 2018; 48:E222-E231. [PMID: 28841782 DOI: 10.1111/hepr.12973] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 08/18/2017] [Accepted: 08/21/2017] [Indexed: 02/08/2023]
Abstract
AIM The risk of malignancies in autoimmune diseases is high and is regarded to be due to immunological abnormalities, the use of immunosuppressive agents, and/or chronic inflammation. The aim of this study was to investigate the incidence and risk of malignancies in patients with autoimmune hepatitis (AIH) type 1 in Japan. METHODS Two hundred and fifty-six patients diagnosed with AIH were enrolled. A person-year calculation was carried out for AIH patients, and the numbers of expected events were clarified using data from "The Monitoring of Cancer Incidence in Japan Project" in order to examine the standard incident rate (SIR) of each type of malignancy. Biochemical data regarding carcinogenesis and its background factors were also examined. RESULTS Twenty-seven patients (10.5%) developed malignancies; 11 (4.3%) with hepatobiliary cancer and 16 (6.3%) with extrahepatic malignancies. The overall SIR for malignancies in AIH was significantly high at 2.04 (95% confidence interval [CI], 1.34-2.96), and was high among female patients at 2.49 (95% CI, 1.60-3.71). The SIR for hepatobiliary cancer was 14.14 (95% CI, 7.05-25.30), and was markedly high for female patients at 21.83 (95% CI, 10.45-40.16). The SIR for oral/pharyngeal cancer was significantly high for female patients at 14.61 (95% CI, 1.64-52.77). The risk factors for hepatobiliary cancer at the diagnosis of AIH were low levels of alanine aminotransferase (P = 0.0226), low platelet counts (P < 0.0001), and cirrhosis (P = 0.0004). The risk factor for extrahepatic malignancy was relapse of AIH (P = 0.0485). CONCLUSION The risk of malignancies was generally high among AIH patients. Those with the risk factors of malignancies should be carefully followed up.
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Affiliation(s)
- Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Ichiro Miyajima
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Kei Ogata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Reiichiro Kuwahara
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Keisuke Amano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toshihiro Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Koji Yonemoto
- The Biostatistics Center, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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23
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Oka S, Furukawa H, Yasunami M, Kawasaki A, Nakamura H, Nakamura M, Komori A, Abiru S, Nagaoka S, Hashimoto S, Naganuma A, Naeshiro N, Yoshizawa K, Yamashita H, Ario K, Ohta H, Sakai H, Yabuuchi I, Takahashi A, Abe K, Yatsuhashi H, Tohma S, Ohira H, Tsuchiya N, Migita K. HLA-DRB1 and DQB1 alleles in Japanese type 1 autoimmune hepatitis: The predisposing role of the DR4/DR8 heterozygous genotype. PLoS One 2017; 12:e0187325. [PMID: 29088299 PMCID: PMC5663488 DOI: 10.1371/journal.pone.0187325] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/17/2017] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Autoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH. METHODS HLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed. RESULTS The predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62-5.43), DRB1*04:05 (P = 1.89×10-21, Pc = 5.86×10-20, OR 3.41, 95% CI 2.65-4.38), and DQB1*04:01 (P = 4.66×10-18, Pc = 6.99×10-17, OR 3.89, 95% CI 2.84-5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32-0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10-9, OR 3.52, 95% CI 2.34-5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45-424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10-6, OR 10.64, 95% CI 3.19-35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without. CONCLUSIONS The important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.
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Affiliation(s)
- Shomi Oka
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18–1 Sakuradai, Minami-ku, Sagamihara, Japan
| | - Hiroshi Furukawa
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18–1 Sakuradai, Minami-ku, Sagamihara, Japan
- * E-mail:
| | - Michio Yasunami
- Department of Medical Genomics, Life Science Institute, Saga-ken Medical Centre Koseikan, 400 Kasemachi-Nakabaru, Saga, Japan
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Japan
| | - Aya Kawasaki
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
| | - Hitomi Nakamura
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, Japan
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, Japan
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Atsumasa Komori
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Seigo Abiru
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Shinya Nagaoka
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Satoru Hashimoto
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Atsushi Naganuma
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Noriaki Naeshiro
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Kaname Yoshizawa
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Haruhiro Yamashita
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Keisuke Ario
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Hajime Ohta
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Hironori Sakai
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Iwao Yabuuchi
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Atsushi Takahashi
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
| | - Kazumichi Abe
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
| | - Shigeto Tohma
- Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, 18–1 Sakuradai, Minami-ku, Sagamihara, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
| | - Naoyuki Tsuchiya
- Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Japan
| | - Kiyoshi Migita
- Clinical Research Center, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- NHO-AIH study group, National Hospital Organization Nagasaki Medical Center, 2-1001-1 Kubara, Omura, Japan
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Japan
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Population-based prevalence, incidence, and disease burden of autoimmune hepatitis in South Korea. PLoS One 2017; 12:e0182391. [PMID: 28771543 PMCID: PMC5542613 DOI: 10.1371/journal.pone.0182391] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/17/2017] [Indexed: 12/18/2022] Open
Abstract
Background and aim Little is known about population-based epidemiology and disease burden of autoimmune hepatitis (AIH). The aim of this study was to investigate the prevalence, incidence, comorbidity and direct medical cost of AIH in South Korea. Methods The data was from the nationwide, population-based National Health Insurance Service claims database and the Rare Intractable Disease registration program. Age and gender-specific prevalence rates were calculated, and data on comorbidity, diagnostic tests, prescribed drugs, and medical costs were retrieved for patients registered under the disease code K75.4 (AIH) from 2009 to 2013. Results A total of 4,085 patients with AIH were identified between 2009 and 2013 with a female-to-male ratio of 6.4. The age-adjusted prevalence rate was 4.82/100,000 persons and gender adjusted prevalence rates were 8.35 in females and 1.30 in males. The age-adjusted calculated incidence rate was 1.07/100,000 persons (gender-adjusted 1.83 in females and 0.31 in males). Ascites, variceal bleeding, and hepatocellular carcinoma were found in 1.4%, 1.3%, and 2.2% of the patients, respectively. Forty-six patients (1.1%) underwent liver transplantation during the study period. Case-fatality was 2.18%. Corticosteroid and azathioprine were prescribed in 44.1% and 38.0% of prevalent patients with AIH in 2013, respectively. The nationwide total direct medical cost was less than 4.0 million USD, and the average cost for each patient was 1,174 USD in 2013. Conclusion This is the first report on the nationwide epidemiology of AIH in Korea, and it showed a lower prevalence than that of Western countries with considerable disease burden.
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25
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Tansel A, Katz LH, El-Serag HB, Thrift AP, Parepally M, Shakhatreh MH, Kanwal F. Incidence and Determinants of Hepatocellular Carcinoma in Autoimmune Hepatitis: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2017; 15:1207-1217.e4. [PMID: 28215616 PMCID: PMC5522646 DOI: 10.1016/j.cgh.2017.02.006] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 01/31/2017] [Accepted: 02/06/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk factors among patients with AIH. METHODS We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I2 statistic. RESULTS A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I2 = 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I2 = 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis. CONCLUSIONS Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis.
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Affiliation(s)
- Aylin Tansel
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
| | - Lior H Katz
- The Department of Gastroenterology, Sheba Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Hashomer, Israel
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Aaron P Thrift
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Mayur Parepally
- Division of Gastroenterology and Nutrition, Department of Medicine, Loyola University Medical Center, Chicago, Illinois
| | - Mohammad H Shakhatreh
- Section of Gastroenterology and Hepatology, Virginia Tech Carilion School of Medicine and Research Institute, Roanoke, Virginia
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas; Section of Gastroenterology and Hepatology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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van Gerven NMF, de Boer YS, Mulder CJJ, van Nieuwkerk CMJ, Bouma G. Auto immune hepatitis. World J Gastroenterol 2016; 22:4651-4661. [PMID: 27217697 PMCID: PMC4870072 DOI: 10.3748/wjg.v22.i19.4651] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/29/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
To provide an update of the latest trends in epidemiology, clinical course, diagnostics, complications and treatment of auto immune hepatitis (AIH). A search of the MEDLINE database was performed using the search terms: “auto immune hepatitis”, “clinical presentation”, “symptoms”, “signs”, “diagnosis”, “auto antibodies”, “laboratory values”, “serology”, “histopathology”, “histology”, “genetics”, “HLA genes”, “non-HLA genes”, “environment”, “epidemiology”, “prevalence”, “incidence”, “demographics”, “complications”, “HCC”, “PBC”, “PSC”, “corticosteroid”, “therapy”, “treatment”, “alternative treatment”. English-language full-text articles and abstracts were considered. Articles included reviews, meta-analysis, prospective retrospective studies. No publication date restrictions were applied. AIH is an immune meditated progressive inflammatory liver disease that predominantly affects middle-aged females but may affect people of all ages. The clinical spectrum of AIH is wide, ranging from absent or mild symptoms to fulminant hepatic failure. The aetiology of AIH is still unknown, but is believed to occur as the consequence of an aberrant immune response towards an un-known trigger in a genetically susceptible host. In the absence of a gold standard, diagnosis is based on the combination of clinical, biochemical and histopathological criteria. Immunosuppressive treatment has been the cornerstone of treatment since the earliest description of the disease in 1950 by Waldenström. Such treatment is often successful at inducing remission and generally leads to normal life expectancy. Nevertheless, there remain significant areas of unmet aetiological a clinical needs including fundamental insight in disease pathogenesis, optimal therapy, duration of treatment and treatment alternatives in those patients unresponsive to standard treatment regimens.
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Maeda Y, Migita K, Higuchi O, Mukaino A, Furukawa H, Komori A, Nakamura M, Hashimoto S, Nagaoka S, Abiru S, Yatsuhashi H, Matsuo H, Kawakami A, Yasunami M, Nakane S. Association between Anti-Ganglionic Nicotinic Acetylcholine Receptor (gAChR) Antibodies and HLA-DRB1 Alleles in the Japanese Population. PLoS One 2016; 11:e0146048. [PMID: 26807576 PMCID: PMC4726510 DOI: 10.1371/journal.pone.0146048] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 11/24/2015] [Indexed: 11/25/2022] Open
Abstract
Background/Aims Anti-ganglionic nicotinic acetylcholine receptor (gAChR) antibodies are observed in autoimmune diseases, as well as in patients with autoimmune autonomic ganglionopathy. However, the genetic background of anti-gAChR antibodies is unclear. Here, we investigated HLA alleles in autoimmune hepatitis (AIH) patients with or without anti-gAChR antibodies. Methodology/Principal Findings Genomic DNA from 260 patients with type-1 autoimmune hepatitis (AIH) were genotyped for HLA-A, B, DRB1, and DQB1 loci. Anti-gAChR antibodies in the sera form AIH patients were measured using the luciferase immunoprecipitation system, and examined allelic association in patients with or without anti-gAChR antibodies. Methodology/ Methods We detected anti-α3 or -β4 gAChR antibodies in 11.5% (30/260) of patients with AIH. Among AIH patients there was no significant association between HLA-A, B DQB1 alleles and the positivity for anti-gAChR antibodies. Whereas the HLA-DRB1*0403 allele showed a significantly increased frequency in AIH patients with anti-gAChR antibodies compared with those without anti-gAChR antibodies. Conclusions/Significance The frequency of the HLA-DRB1*0403 allele differed among Japanese patients with AIH according to the presence or absence of anti-gAChR antibodies. Our findings suggest that particular HLA class II molecules might control the development of anti-gAChR antibodies in the autoimmune response to gAChR.
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Affiliation(s)
- Yasuhiro Maeda
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan.,Department of Neuroimmunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kiyoshi Migita
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Osamu Higuchi
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan
| | - Akihiro Mukaino
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan
| | - Hiroshi Furukawa
- Department of Molecular and Genetic Epidemiology, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Atsumasa Komori
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
| | - Satoru Hashimoto
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Shinya Nagaoka
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Seigo Abiru
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hidenori Matsuo
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Kawatana, Nagasaki, Japan
| | - Atsushi Kawakami
- First Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan
| | - Michio Yasunami
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Nagasaki, Japan
| | - Shunya Nakane
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
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28
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Migita K, Jiuchi Y, Furukawa H, Nakamura M, Komori A, Yasunami M, Kozuru H, Abiru S, Yamasaki K, Nagaoka S, Hashimoto S, Bekki S, Yoshizawa K, Shimada M, Kouno H, Kamitsukasa H, Komatsu T, Hijioka T, Nakamuta M, Naganuma A, Yamashita H, Nishimura H, Ohta H, Nakamura Y, Ario K, Oohara Y, Sugi K, Tomizawa M, Sato T, Takahashi H, Muro T, Makita F, Mita E, Sakai H, Yatsuhashi H. Lack of association between the CARD10 rs6000782 polymorphism and type 1 autoimmune hepatitis in a Japanese population. BMC Res Notes 2015; 8:777. [PMID: 26652023 PMCID: PMC4677039 DOI: 10.1186/s13104-015-1733-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 11/23/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Previous genome-wide association studies have evaluated the impact of common genetic variants and identified several non-HLA risk loci associated with autoimmune liver diseases. More recent genome-wide association studies and replication analyses reported an association between variants of the CARD10 polymorphism rs6000782 and risk of type 1 autoimmune hepatitis (AIH). In this case-control study, we genotyped 326 Japanese AIH patients and 214 control subjects. RESULTS Genomic DNA from 540 individuals of Japanese origin, including 326 patients with type-1 AIH and 214 healthy controls, was analyzed for two single nucleotide polymorphisms (SNPs) in the CARD10 gene. We selected CARD10 rs6000782 SNPs and genotyped these using PCR-RFLP method and direct sequencing. The Chi square test revealed that the rs6000782 variant alle (c) was not associated with the susceptibility for AIH in a Japanese population [p = 0.376, odds ratio (OR) 1.271, 95 % confidence interval (CI) 0.747-2.161] in an allele model. Our data also showed that CARD10 rs6000782 variants were not associated with AIH or with the clinical parameters of AIH. CONCLUSIONS In this study we examined an association between rs6000782 SNPs in the CARD10 gene and type-1 AIH. Results showed no significant association of rs62000782 with type-1 AIH in a Japanese population. This study demonstrated no association between CARD10 rs6000782 variants and AIH in a Japanese population.
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Affiliation(s)
- Kiyoshi Migita
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan. .,Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura, 856-8652, Japan.
| | - Yuka Jiuchi
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hiroshi Furukawa
- Department of Rheumatology, NHO Sagamihara Hospital, Minamikusakuradai 18-1, Sagamihara, Kanagawa, 252-0392, Japan.
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-12-4, Ngasaki, Nagasaki, 852-8523, Japan.
| | - Atsumasa Komori
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Michio Yasunami
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Ngasaki, Nagasaki, 852-8523, Japan.
| | - Hideko Kozuru
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Seigo Abiru
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Kazumi Yamasaki
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Shinya Nagaoka
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Satoru Hashimoto
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Shigemune Bekki
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Kaname Yoshizawa
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Masaaki Shimada
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hiroshi Kouno
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hiroshi Kamitsukasa
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Tatsuji Komatsu
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Taizo Hijioka
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Makoto Nakamuta
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Atsushi Naganuma
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Haruhiro Yamashita
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hideo Nishimura
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hajime Ohta
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Yoko Nakamura
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Keisuke Ario
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Yukio Oohara
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Kazuhiro Sugi
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Minoru Tomizawa
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Takeaki Sato
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hironao Takahashi
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Toyokichi Muro
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Fujio Makita
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Eiji Mita
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hironori Sakai
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
| | - Hiroshi Yatsuhashi
- NHO-AIH study group, Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
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Circulating microRNA Profiles in Patients with Type-1 Autoimmune Hepatitis. PLoS One 2015; 10:e0136908. [PMID: 26575387 PMCID: PMC4648542 DOI: 10.1371/journal.pone.0136908] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 08/09/2015] [Indexed: 02/07/2023] Open
Abstract
Recent studies have demonstrated that micro (mi)RNA molecules can be detected in the circulation and can serve as potential biomarkers of various diseases. This study used microarray analysis to identify aberrantly expressed circulating miRNAs in patients with type 1 autoimmune hepatitis (AIH) compared with healthy controls. Patients with well-documented and untreated AIH were selected from the National Hospital Organization (NHO)-AIH-liver-network database. They underwent blood sampling and liver biopsy with inflammation grading and fibrosis staging before receiving treatment. To further confirm the microarray data, circulating expression levels of miR-21 and miR-122 were quantified by real-time quantitative polymerase chain reaction in 46 AIH patients, 40 patients with chronic hepatitis C (CHC), and 13 healthy controls. Consistent with the microarray data, serum levels of miR-21 were significantly elevated in AIH patients compared with CHC patients and healthy controls. miR-21 and miR-122 serum levels correlated with alanine aminotransferase levels. Circulating levels of miR-21 and miR-122 were significantly reduced in AIH patients with liver cirrhosis, and were inversely correlated with increased stages of fibrosis. By contrast, levels of circulating miR-21 showed a significant correlation with the histological grades of inflammation in AIH. We postulate that aberrantly expressed serum miRNAs are potential biomarkers of AIH and could be implicated in AIH pathogenesis. Alternations of miR-21 and miR-122 serum levels could reflect their putative roles in the mediation of inflammatory processes in AIH.
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30
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Affiliation(s)
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- EASL office, 7 Rue Daubin, CH 1203 Geneva, Switzerland,
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31
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Yang F, Wang Q, Bian Z, Ren LL, Jia J, Ma X. Autoimmune hepatitis: East meets west. J Gastroenterol Hepatol 2015; 30:1230-6. [PMID: 25765710 DOI: 10.1111/jgh.12952] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2015] [Indexed: 01/10/2023]
Abstract
Autoimmune hepatitis (AIH) is an inflammatory liver disease with diverse clinical spectrum, which predominantly affects females. This review provides detailed comparisons of epidemiology, genetic predispositions, clinical features, risk factors of hepatocellular carcinoma, and mortality in AIH patients between eastern and western countries. AIH prevalence and incidence are lower in Asia-Pacific area than in Europe and America. European and American patients seem to have more severe disease, characterized with human leukocyte antigen-DR3 haplotype, younger age, more AIH-induced "cirrhosis" at diagnosis, higher elevated serum immunoglobulin G levels, and positive rate of antisoluble liver antigen/liver pancreatitis. The overall AIH diagnostic accuracy of revised original criteria and simplified scoring system are similar in European/American populations and Asian. Cirrhosis at presentation and non-response to immunosuppressive therapy within 1 year are the most important predictors for poor prognosis of AIH patients.
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Affiliation(s)
- Fan Yang
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Qixia Wang
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Zhaolian Bian
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Lin-Lin Ren
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
| | - Jidong Jia
- Liver Research Center & Clinical Epidemiology and EBM Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiong Ma
- State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
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Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21:60-83. [PMID: 25574080 PMCID: PMC4284362 DOI: 10.3748/wjg.v21.i1.60] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
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Bouomrani S, Kilani I, Nouma H, Slama A, Beji M. [Non fibrolamellar hepatocellular carcinoma on a healthy liver]. Pan Afr Med J 2014; 18:155. [PMID: 25419293 PMCID: PMC4236843 DOI: 10.11604/pamj.2014.18.155.2762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 12/21/2013] [Indexed: 01/10/2023] Open
Abstract
Le carcinome hépatocellulaire (CHC) survient le plus souvent sur foie de cirrhose. Sa survenue sur un foie sain est exceptionnelle et pose un véritable défit diagnostique pour le clinicien. Nous rapportons l'observation d'un patient de 53 ans, sans antécédents pathologiques notables qui fût admis pour exploration d'une douleur de l'hypochondre droit évoluant depuis quelques mois avec une exacerbation récente, associée à un amaigrissement important et une altération de l’état général. L'examen clinique notait une hépatomégalie ferme et douloureuse. L’échographie abdominale montrait une masse hétérogène du secteur latéral droit du foie faisant 10 cm de grand axe. La TDM abdominale montrait une masse tissulaire, hétérogène, à vascularisation artérielle importante, mesurant 10 cm de diamètre et occupant le secteur latéral droit du foie. Cette tumeur comprime la branche portale droite sans signes d'extension. Il n'y avait pas d'adénopathie ni d’épanchement intra abdominal. La ponction biopsique écho-guidée avait conclu à un CHC non fibrolamellaire. Le bilan biologique, en particulier les transaminases, le taux de prothrombine, l’électrophorèse des protéines sanguine et l'alpha foeto-protéine, était sans anomalies. Les sérologies de l'hépatites virales B et C ainsi que la recherche des auto anticorps spécifiques des hépatites auto immunes et le bilan cuprique étaient aussi négatives. Vue l’âge, le stade avancé de la tumeur et l'altération de l’état général la conduite thérapeutique était de s'abstenir.
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Affiliation(s)
- Salem Bouomrani
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
| | - Ichrak Kilani
- Service de Gastroentérologie, Hôpital Militaire de Gabès 6000, Tunisie
| | - Hanène Nouma
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
| | - Alaeddine Slama
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
| | - Maher Beji
- Service de Médecine Interne, Hôpital Militaire de Gabes 6000, Tunisie
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34
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Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M. Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. PLoS One 2014; 9:e100565. [PMID: 24956105 PMCID: PMC4067340 DOI: 10.1371/journal.pone.0100565] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 05/25/2014] [Indexed: 12/31/2022] Open
Abstract
Although we earlier demonstrated that the human leukocyte antigen (HLA) DRB1*04:05 allele was associated with susceptibility to autoimmune hepatitis (AIH) in Japan, the precise relationship of HLA haplotype and the role of amino acid alignment with disease susceptibility and progression has not been fully clarified. We reinvestigated HLA class I A, B, and C and HLA class II DRB1, DQB1, and DPB1 alleles and haplotypes in a larger new cohort of 156 Japanese patients with type 1 AIH and compared them with the published data of 210 healthy subjects. The DRB1*04:05-DQB1*04:01 haplotype was significantly associated with AIH susceptibility (30% vs. 11%, P = 1.2×10−10; odds ratio [OR] = 3.51) and correlated with elevated serum IgG (3042 vs. 2606 mg/dL, P = 0.041) and anti-smooth muscle antigen positivity (77% vs. 34%, P = 0.000006). No associations with HLA-DPB1 alleles were found. The HLA A*24:02 and C*01:02 alleles were associated with disease susceptibility (corrected P = 0.0053 and 0.036, respectively), but this likely constituents of a long ranged haplotype including DRB1*04:05-DQB1*04:01 haplotype. Conversely, the DRB1*15:01-DQB1*06:02 haplotype was associated with protection from both disease onset (5% vs. 13%, P = 0.00057; OR = 0.38) and the development of hepatocellular carcinoma (25% vs. 5%, P = 0.017; OR = 6.81). The frequency of the DRB1*08:03-DQB1*06:01 haplotype was significantly higher in patients who developed hepatic failure (22% vs. 6%, P = 0.034; OR = 4.38). In conclusion, this study established the role of HLA haplotypes in determining AIH susceptibility and progression in the Japanese population. Additional sequencing of the entire HLA region is required to more precisely identify the genetic components of AIH.
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Affiliation(s)
- Takeji Umemura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Kaname Yoshizawa
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan; Department of Gastroenterology, NHO Ueda Medical Center, Ueda, Japan
| | - Takefumi Kimura
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Satoru Joshita
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Michiharu Komatsu
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akihiro Matsumoto
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Eiji Tanaka
- Department of Medicine, Division of Hepatology and Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masao Ota
- Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan
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Castro FA, Liu X, Försti A, Ji J, Sundquist J, Sundquist K, Koshiol J, Hemminki K. Increased risk of hepatobiliary cancers after hospitalization for autoimmune disease. Clin Gastroenterol Hepatol 2014; 12:1038-45.e7. [PMID: 24246767 DOI: 10.1016/j.cgh.2013.11.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 10/23/2013] [Accepted: 11/04/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Some autoimmune diseases are associated with increased risk of liver cancer. However, there has been no comprehensive evaluation of autoimmune diseases among patients who develop different subtypes of hepatobiliary cancer. We examined the association between autoimmune diseases and cancers of the liver and biliary tract in the Swedish population. METHODS We analyzed data from national datasets at the Center for Primary Health Care Research (Lund University, Sweden). Data on patients with autoimmune disorders were retrieved from the Swedish Hospital Discharge Register, from 1964 through 2008; 33 diseases were evaluated. Hepatobiliary cancer cases were retrieved from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) and hazard ratios for incident cancers and deaths from hepatobiliary cancers. RESULTS Among 402,462 patients with autoimmune disorders, 582 were diagnosed with primary liver cancer, 330 with gallbladder cancer, 115 with extrahepatic bile duct cancer, and 43 with ampulla of Vater cancers. We identified 14 autoimmune conditions that were significantly associated with increased risk of primary liver cancer (overall SIR [any autoimmune disease], 2.1; 95% confidence interval [CI], 2.0-2.3), 5 conditions associated with gallbladder cancer (overall SIR, 1.3; 95% CI, 1.1-1.4), and 3 associated with extrahepatic bile duct cancer (overall SIR, 1.6; 95% CI, 1.3-1.9). The autoimmune disorders with the strongest association with primary liver cancer were primary biliary cirrhosis (SIR, 39.5; 95% CI, 28.2-53.8) and autoimmune hepatitis (SIR, 29.0; 95% CI, 9.1-68.2); ulcerative colitis was strongly associated with extrahepatic bile duct cancer (SIR, 5.6; 95% CI, 3.6-8.4). Celiac disease, Crohn's disease, systemic sclerosis, and ulcerative colitis were associated with at least 2 types of cancer. Increased hazard ratios were observed only for patients with biliary tract cancer who had been hospitalized for autoimmune conditions. CONCLUSIONS In a study of the Swedish population, we identified an increased risk of hepatobiliary cancers among individuals diagnosed with autoimmune disease. Associations among different cancer types indicate that shared immunomodulatory mechanisms determine susceptibility to hepatobiliary cancer.
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Affiliation(s)
- Felipe A Castro
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
| | - Xiangdong Liu
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Asta Försti
- Center for Primary Health Care Research, Lund University, Malmö, Sweden; Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Jianguang Ji
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden; Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden; Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, California
| | - Jill Koshiol
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Kari Hemminki
- Center for Primary Health Care Research, Lund University, Malmö, Sweden; Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
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Autoimmune hepatitis in Denmark: incidence, prevalence, prognosis, and causes of death. A nationwide registry-based cohort study. J Hepatol 2014; 60:612-7. [PMID: 24326217 DOI: 10.1016/j.jhep.2013.10.020] [Citation(s) in RCA: 236] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 10/10/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Population-based studies of the clinical course of autoimmune hepatitis are scarce. We conducted a nationwide study of incidence, prevalence, prognosis, and causes of death of autoimmune hepatitis in Denmark. METHODS From nationwide healthcare registries we identified all Danish citizens diagnosed with autoimmune hepatitis in 1994-2012 and their liver biopsy data. We followed patients through January 2013 and examined age-standardized incidence and prevalence, mortality, prognostic factors, risk of hepatocellular carcinoma, and causes of death. We used Cox regression to compare patients' mortality relative to a gender- and age-matched general population sample. RESULTS We included 1721 autoimmune hepatitis patients. The incidence rate was 1.68 (95% confidence interval 1.60 to 1.76) per 100,000 population per year, and it doubled during the study period. Of the 1318 patients who were biopsied at diagnosis, 28.3% had cirrhosis. The 10-year cumulative risk of hepatocellular carcinoma was 0.7% (95% confidence interval 0.3 to 1.5). Male gender and cirrhosis were associated with high mortality and development of hepatocellular carcinoma. In the first year after diagnosis, patients with autoimmune hepatitis had six-fold higher mortality than the general population; later, their mortality remained two-fold higher. Their 10-year cumulative mortality was 26.4% (95% confidence interval 23.7 to 29.1). 38.6% of deaths were liver-related including 3.6% from hepatocellular carcinoma. CONCLUSIONS This nationwide population-based study of autoimmune hepatitis showed that the incidence increased during 1994-2012, and that the disease remains associated with a high mortality, particularly in the first year after diagnosis. Male gender and cirrhosis were adverse prognostic factors.
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Zachou K, Muratori P, Koukoulis GK, Granito A, Gatselis N, Fabbri A, Dalekos GN, Muratori L. Review article: autoimmune hepatitis -- current management and challenges. Aliment Pharmacol Ther 2013; 38:887-913. [PMID: 24010812 DOI: 10.1111/apt.12470] [Citation(s) in RCA: 113] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Revised: 03/22/2013] [Accepted: 08/12/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. AIM To review recent advancements in understanding aetiopathogenesis, clinical, serological and histological features, diagnostic criteria and treatment strategies of AIH. METHODS Published studies on AIH extracted mainly from PubMed during the last 15 years. RESULTS Autoimmune hepatitis has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations are variable ranging from no symptoms to severe acute hepatitis and only seldom to fulminant hepatic failure. Autoimmune attack is perpetuated, possibly via molecular mimicry mechanisms, and favoured by the impaired control of regulatory T-cells. A typical laboratory finding is hypergammaglobulinaemia with selective elevation of IgG, although in 15-25% of patients - particularly children, elderly and acute cases - IgG levels are normal. Liver histology and autoantibodies, although not pathognomonic, still remain the hallmark for diagnosis. Immunosuppressive treatment is mandatory and life-saving; however, to meet strict response criteria, the conventional therapy with prednisolone with or without azathioprine is far from ideal. CONCLUSIONS Autoimmune hepatitis remains a major diagnostic and therapeutic challenge. The clinician, the hepato-pathologist and the laboratory personnel need to become more familiar with different expressions of the disease, interpretation of liver histology and autoimmune serology. According to the strict definition of treatment response issued by the 2010 AASLD guidelines, many patients are nonresponders to conventional treatment. Newer immunosuppressive agents targeting pathogenetic mechanisms can improve patient management, which needs to be tailored on a case-by-case basis.
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Affiliation(s)
- K Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, Medical School, Thessaly University, Larissa, Greece
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38
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Migita K, Nakamura M, Abiru S, Jiuchi Y, Nagaoka S, Komori A, Hashimoto S, Bekki S, Yamasaki K, Komatsu T, Shimada M, Kouno H, Hijioka T, Kohjima M, Nakamuta M, Kato M, Yoshizawa K, Ohta H, Nakamura Y, Takezaki E, Nishimura H, Sato T, Ario K, Hirashima N, Oohara Y, Naganuma A, Muro T, Sakai H, Mita E, Sugi K, Yamashita H, Makita F, Yatsuhashi H, Ishibashi H, Yasunami M. Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population. PLoS One 2013; 8:e71382. [PMID: 23990947 PMCID: PMC3750035 DOI: 10.1371/journal.pone.0071382] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 07/02/2013] [Indexed: 01/31/2023] Open
Abstract
Background/Aims Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study. Methodology/Principal Findings Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23–2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13–1.99; P = 0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies). Conclusions/Significance This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.
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Affiliation(s)
- Kiyoshi Migita
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
- * E-mail:
| | - Minoru Nakamura
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Seigo Abiru
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Yuka Jiuchi
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Shinya Nagaoka
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Atsumasa Komori
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Satoru Hashimoto
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Shigemune Bekki
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Kazumi Yamasaki
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Tatsuji Komatsu
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Masaaki Shimada
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hiroshi Kouno
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Taizo Hijioka
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Motoyuki Kohjima
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Makoto Nakamuta
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Michio Kato
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Kaname Yoshizawa
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hajime Ohta
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Yoko Nakamura
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Eiichi Takezaki
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hideo Nishimura
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Takeaki Sato
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Keisuke Ario
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Noboru Hirashima
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Yukio Oohara
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Atsushi Naganuma
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Toyokichi Muro
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Hironori Sakai
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Eiji Mita
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Kazuhiro Sugi
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | | | - Fujio Makita
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | | | - Hiromi Ishibashi
- NHO-AIH Study Group, Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Michio Yasunami
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan
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Nishikawa H, Osaki Y. Non-B, non-C hepatocellular carcinoma (Review). Int J Oncol 2013; 43:1333-42. [PMID: 23969900 DOI: 10.3892/ijo.2013.2061] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 07/16/2013] [Indexed: 11/06/2022] Open
Abstract
Although most hepatocellular carcinoma (HCC) is related to viral infection, there is a substantial population of HCC patients (5-20%) who are negative for both markers of hepatitis B virus and hepatitis C virus infection [non-B, non-C (NBNC) hepatitis] in Japan and the incidence of NBNC-HCC has recently tended to increase. The most common cause of liver disease in developed countries is non‑alcoholic fatty liver disease (NAFLD), which includes non‑alcoholic steatohepatitis (NASH) and its related complications. Increased body mass index and diabetes mellitus are associated with developing NAFLD and NASH, which is a severe form of NAFLD. Furthermore, increasing clinical evidence supports the fact that NAFLD and NASH can progress to liver cirrhosis and even HCC. A detailed understanding of the epidemiology, etiology, molecular mechanism, clinical features and prognosis of NBNC-HCC could improve our screening and therapy of this disease. In this review, we primarily focus on clinical aspects of NBNC-HCC and refer to our current knowledge of this cancer.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Tennoji-ku, Osaka 543-0027, Japan
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Matsumura H, Nirei K, Nakamura H, Higuchi T, Arakawa Y, Ogawa M, Tanaka N, Moriyama M. Histopathology of type C liver disease for determining hepatocellular carcinoma risk factors. World J Gastroenterol 2013; 19:4887-4896. [PMID: 23946593 PMCID: PMC3740418 DOI: 10.3748/wjg.v19.i30.4887] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 03/11/2013] [Accepted: 06/20/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the histopathological findings of type C liver disease to determine risk factors for development of hepatocellular carcinoma (HCC).
METHODS: We studied 232 patients, who underwent liver biopsy for type C chronic liver disease between 1992 and 2009, with sustained virological response (SVR) after interferon therapy. The patients were divided into two groups according to the F stage 0 + 1 + 2 group (n = 182) and F3 + 4 group (n = 50). We prospectively observed and compared the incidence of HCC of the patients with SVR in the F0 + 1 + 2 and F3 + 4 groups. Then, the background factors and liver histopathological findings, including the degree of fibrosis, F stage, inflammation, necrosis, bile duct obstruction, fat deposition, and degree of irregular regeneration (IR) of hepatocytes, were correlated with the risk of developing HCC.
RESULTS: HCC developed in three of 182 (1.6%) patients in the F0 + 1 + 2 group, and four of 50 (8.0%) in the F3 + 4 group. The cumulative incidence of HCC in the former group was found to be significantly lower than in the F3 + 4 group (log rank test P = 0.0224). The presence of atypical hepatocytes among IR of hepatocytes in the F3 + 4 group resulted in a higher cumulative incidence of HCC, and was significantly correlated with risk of HCC development (RR = 20.748, 95%CI: 1.335-322.5, P = 0.0303).
CONCLUSION: Atypical hepatocytes among the histopathological findings of type C liver disease may be an important risk factor for HCC development along with progression of liver fibrosis.
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Hepatocellular carcinoma and other malignancies in autoimmune hepatitis. Dig Dis Sci 2013; 58:1459-76. [PMID: 23306849 DOI: 10.1007/s10620-012-2525-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2012] [Accepted: 12/03/2012] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma and extrahepatic malignancies can complicate the course of autoimmune hepatitis, and these occurrences may increase in frequency as the survival of patients with cirrhosis is extended and the prospect of new nonstandard immune-modifying intervention is realized. The frequency of hepatocellular carcinoma in patients with autoimmune hepatitis and cirrhosis is 1-9 %, and annual occurrence in patients with cirrhosis is 1.1-1.9 %. The standardized incidence ratio for hepatocellular carcinoma in autoimmune hepatitis is 23.3 (95 % confidence interval (CI) 7.5-54.3) in Sweden, and the standardized mortality ratio for hepatobiliary cancer is 42.3 (95 % CI 20.3-77.9) in New Zealand. The principal risk factor is long-standing cirrhosis, and patients at risk are characterized mainly by cirrhosis for ≥ 10 years, manifestations of portal hypertension, persistent liver inflammation, and immunosuppressive therapy for ≥ 3 years. Multiple molecular disturbances, including the accumulation of senescent hepatocytes because of telomere shortening, step-wise accumulation of chromosomal injuries, and aberrations in transcription factors and genes, may contribute to the risk. Extraheptic malignancies of diverse cell types occur in 5 % in an unpredictable fashion. The standardized incidence ratio is 2.7 (95 % CI 1.8-3.9) in New Zealand, and non-melanoma skin cancers are most common. Outcomes are related to the nature and stage of the tumor at diagnosis. Surveillance recommendations have not been promulgated, but hepatic ultrasonography every six months in patients with cirrhosis is a consideration. Routine health screening measures for other malignancies should be applied diligently.
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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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