New clinical classification and the criteria for predicting long-term outcome in primary biliary cirrhosis

2010 Fiscal Year Final Research Report

• Project/Area Number: 20590800
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Department of Clinical Research, National Hospital Organization Nagasaki Medical Center
• Principal Investigator: NAKAMURA Minoru Department of Clinical Research, National Hospital Organization Nagasaki Medical Center, 臨床研究センター, 客員研究員 (40217906)
• Co-Investigator(Kenkyū-buntansha): KOMORI Atumasa 独立行政法人国立病院機構長崎医療センター, 臨床研究センター, 室長 (50234901) ; ISHIBASHI Hiromi 独立行政法人国立病院機構長崎医療センター, 臨床研究センター, センター長 (80127969)
• Project Period (FY): 2008 – 2010
• Keywords: 原発性胆汁性肝硬変 / 予後予測 / SNPs / 遺伝子多型 / HLA

Research Abstract

In order to establish a clinical classification and a criteria for predicting long-term outcome in primary biliary cirrhosis (PBC), we studied the autoantibodies (anti-gp210, anti-centromere), HLA-DRB1 and SNPs of various molecules concerning immune-regulation and bile acid metabolism. HLA-DRB1*0803 and CTLA4 SNPs confer susceptibility to PBC development. Positive anti-gp210 and anti-centromere antibodies as well as HLA-DRB1*1502 and *0901 are risk factors for the progression to liver cirrhosis or portal hypertension, while positive anti-gp210 antibodies as well as SNPs of MDR3 and integrin ・V are associated with progression to hepatic failure. Since positive anti-gp210 antibodies is a strong risk factor for jaundice-type progression (OR>30), the treatment for PBC became possible with monitoring anti-gp210 antibodies as a serological biomarker. Furthermore, our proposal of PBC progression, anti-gp210 type progression and anti-centromere type progression, was supported by the level of genetic polymorphisms.

Research Products

• [Journal Article] The genetic polymorphisms of CTLA4 and SLC4A2 are differentially associated with the pathogenesis of primary biliarycirrhosis in Japanese patients. (2011)
  • Author(s): Aiba Y, Nakamura M, Joshita S, Inamime T, Komori A, Yoshizawa K, Umemura T, Migita K, Yatsuhashi H, Nakamuta M, Fukushima N, Saito A, Kouno H, Ota H, Muro T, Hayashi S, Watanabe Y, Nakamura Y, Komeda T, Shimada M, Tsukamoto K, Tanaka E, Ishibashi H, the PBC Study Group in NHOSLJ.
  • Journal Title: J Gastroenterol Epub ahead of print
  • Peer Reviewed
• [Journal Article] Risk factors and prediction of long-term outcome in primary biliary cirrhosis. (2011)
  • Author(s): Ishibashi H, Komori A, 下田慎治, Ambrosini YM, Gershwin ME, Nakamura M
  • Journal Title: Intern Med 50 Pages: 1-10
  • Peer Reviewed
• [Journal Article] Evaluation of risk factors for the development of cirrhosis in autoimmune hepatitis : Japanese NHO-AIH prospective study. (2011)
  • Author(s): Migita K, Watanabe Y, Jiuchi Y, Nakamura Y, Saito A, Yagura M, Morimoto H, Shimada M, Mita E, Hijioka T, Yamashita H, Takezaki E, Muro T, Sakai H, Nakamuta M, Abiru S, Yano K, Komori A, Yatsuhashi H, Nakamura M, Ishibashi H
  • Journal Title: J Gastroenterol 46 Suppl 1 Pages: 56-62
  • Peer Reviewed
• [Journal Article] A polymorphism in the integrin・V subunit gene affects the progression of primary biliary cirrhosis in Japanese patients. (2011)
  • Author(s): Inamine T, Nakamura M, Kawauchi A, Shirakawa Y, Hashiguchi H, Aiba Y, Taketomi A, Shirabe K, Nakamuta M, Hayashi S, Saoshiro T, Komori A, Yatsuhashi H, Kondo S, Omagari K, Maehara Y, Ishibashi H, Tsukamoto K, the PBC Study Group in NHOSLJ.
  • Journal Title: J Gastroenterol 46 Pages: 676-686
  • Peer Reviewed
• [Journal Article] 自己免疫性胆管疾患の病態形成への自然免疫の関与 (2011)
  • Author(s): 小森敦正、中村稔、石橋大海
  • Journal Title: 肝胆膵 62 Pages: 639-643
• [Journal Article] PBCの予後予測:自己抗体を基盤に (2011)
  • Author(s): 中村稔、相葉佳洋、小森敦正、下田慎治、石橋大海
  • Journal Title: 肝胆膵 62 Pages: 707-714
• [Journal Article] PBCの病態の多様性と治療ガイドライン (2011)
  • Author(s): 石橋大海、下田慎治、小森敦正、中村稔
  • Journal Title: 肝胆膵 62 Pages: 715-722
• [Journal Article] PBCに関与するHLA個体差 (2011)
  • Author(s): 中村稔、石橋大海、安波道郎
  • Journal Title: 肝胆膵 62 Pages: 945-952
• [Journal Article] Association analysis of cytotoxic T-lymphocyte antigen 4 gene polynmorphism with primary biliary cirrhosis. (2011)
  • Author(s): Joshita S, Umemura T, Yoshizawa K, Katsuyama Y, Tanaka E, Nakamura M, Ishibashi H, Ota M, Shinshu PBC Study Group.
  • Journal Title: J.Hepatol 54 Pages: 537-541
  • Peer Reviewed
• [Journal Article] Serum Baff and APRIL levels in patients with PBC. (2011)
  • Author(s): Migita K, Ilyassova B, Kovzel EF, Nersesov A, Maeda Y, Komori A, Ito M, Yano K, Yatsuhashi H, Ishibashi H, Nakamura M
  • Journal Title: Clin Immunol 134 Pages: 217-225
  • Peer Reviewed
• [Journal Article] Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC) : the HLA-DRB1 polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC. (2011)
  • Author(s): Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Ito M, Shimoda S, Ishbiashi H, PBC Study Group in NHOSLJ.
  • Journal Title: Hepatol Res 40 Pages: 494-504
  • Peer Reviewed
• [Journal Article] Long term bacterial exposure can trigger nonsuppurative destructive cholangitis associated with multifocal epithelial inflammation. (2011)
  • Author(s): Haruta I, Kikuchi K, Hashimoto E, Nakamura M, Miyakawa H, et al.
  • Journal Title: Lab Invest 90 Pages: 577-588
  • Peer Reviewed
• [Journal Article] 原発性胆汁性肝硬変ガイドラインの作成 (2010)
  • Author(s): 石橋大海、小森敦正、中村稔、下田慎治
  • Journal Title: 肝胆膵 Vol.60, No9 Pages: 257-264
• [Journal Article] 胆汁酸の排泄に関与するABCトランスポーター多型と原発性胆汁性肝硬変の重症化との関連 (2010)
  • Author(s): 塚元和弘、大曲勝久、中村稔
  • Journal Title: 臨床薬理の進歩 Pages: 73-86
• [Journal Article] Liver architecture, cell function, and disease. (2009)
  • Author(s): Ishibashi H, Nakamura M, Komori A, Migita K,Shimoda S
  • Journal Title: Semin immunopathol 31 Pages: 399-409
• [Journal Article] Increased expression of toll-like- receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers. (2008)
  • Author(s): Nakamura M, Funami K, Komori A, Yokoyama T, Aiba Y, Araki A, Takii Y, Ito M, Matsuyama M, Koyabu M, Migita K, Taniguchi K, Fujioka H, Yatsuhashi H, Matsumoto M, Ishibashi H, Seya T
  • Journal Title: Hepatol Int 2 Pages: 222-230
  • Peer Reviewed
• [Journal Article] CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis. (2008)
  • Author(s): Shimoda S, Miyakawa H, Nakamura M, Ishibashi H, Kikuchi K, Kita H, Niiro H, Arinobu Y, Ono N, MacKay IR, Gershwin ME, Akashi K.
  • Journal Title: J Autoimmun 31 Pages: 110-115
  • Peer Reviewed
• [Journal Article] <クリニカル・トピックス>原発性胆汁性肝硬変における抗gp210抗体の臨床的意義 (2008)
  • Author(s): 中村稔, 下田愼治, 小森敦正, 石橋大海
  • Journal Title: BIO Clinica 23(12) Pages: 1136-1143
• [Journal Article] Single- nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis.
  • Author(s): Ohishi Y, Nakamura M, Iio N, Higa S, Inayoshi M, Aiba Y, Komori A, Omagari K, Ishibashi H, Tsukamoto K
  • Journal Title: Hepatology 2008 48 Pages: 853-62
  • Peer Reviewed
• [Journal Article] Biliary epithelial cells and primary biliary cirrhosis : the role of liver- infiltrating mononuclear cells.
  • Author(s): Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A, Maehara Y, Tsuneyama K, Nakamura M, Komori A, Migita K, Nakanuma Y, Ishibashi H, Selmi C, Gershwin ME.
  • Journal Title: Hepatology 2008 47 Pages: 958-65
  • Peer Reviewed
• [Presentation] 原発性胆汁性肝硬変(PBC)における免疫異常の基礎とそれに基づく予後予測について (2010)
  • Author(s): 下田慎治、中村稔、石橋大海
  • Organizer: 第14回日本肝臓学会大会(肝臓 51巻 2010, suppl.(2), A435.)
  • Place of Presentation: 横浜
  • Year and Date: 20101013-20101014
• [Presentation] 原発性胆汁性肝硬変における抗gp210抗体測定の意義の検証 (2010)
  • Author(s): 中村稔、伊東正博、山本和秀、銭谷幹男、大平弘正、橋本悦子、金子周一、上野義之、菊池健太郎、恩地森一、下田慎治、小森敦正、滝川一、大西三朗、坪内博仁、中沼安二、石橋大海
  • Organizer: 第46回日本肝臓学会総会(肝臓 51巻 2010, suppl.(1), A62.)
  • Place of Presentation: 山形
  • Year and Date: 20100527-20100528
• [Presentation] 原発性胆汁性肝硬変との関連が報告されている遺伝子多型の日本人でのreplication study. (2010)
  • Author(s): 相葉佳洋、小森敦正、長岡進矢、阿比留正剛、右田清志、八橋弘、石橋大海、齋藤晃、中牟田誠、矢倉道泰、高野弘嗣、林茂樹、小松達司、渡部幸夫、小林正和、杉和洋、太田肇、島田昌明、米田俊貴、古賀満明、山下晴弘、竹崎英一、佐藤丈顕、高橋正彦、酒井浩徳、山本哲夫、正木尚彦、中村稔
  • Organizer: 第46回日本肝臓学会総会(肝臓 51巻 2010, suppl.(1), A342)
  • Place of Presentation: 山形
  • Year and Date: 20100527-20100528
• [Presentation] ヒト肝内胆管細胞におけるSignal tranaducer and activator of transcription 3/5の役割 (2010)
  • Author(s): 小森敦正、相葉佳洋、中村稔、藤原紳祐、藤岡ひかる、右田清志、八橋弘、石橋大海
  • Organizer: 第46回日本肝臓学会総会(肝臓 51巻 2010, suppl.(1), A264)
  • Place of Presentation: 山形
  • Year and Date: 20100527-20100528
• [Presentation] Positive anti-gp210 antibodies is a strong risk factor for bile duct loss and hepatitis which induce jaundice-type progression of primary biliaruy cirrhosis in Japanese patients. (2010)
  • Author(s): Nakamura M, Ito M, Zeniya M, Ohira H, Hashimoto E, Kaneko S, Ueno Y, Kikuchi K, Onji M,Shimoda S, Komori A, Takikawa H, Onishi S, Tsubouchi H, Ishibashi H, Nakanuma Y
  • Organizer: EASL The International Liver Congress 2010 (A1109)
  • Place of Presentation: Vienna
  • Year and Date: 20100414-20100418
• [Presentation] Signal Transducer and activator of transcription and 5 : Distinct regulators in growth and differentiation of human cholangiocyte in vitro. (2010)
  • Author(s): Komori A, Aiba Y, Nakamura M, Fujiwara S, Migita K, Fujioka H, Yatsuhashi H, Ishibashi H
  • Organizer: EASL The International Liver Congress 2010 (A952)
  • Place of Presentation: Vienna
  • Year and Date: 20100414-20100418
• [Presentation] 原発性胆汁性肝硬変における慢性非化膿性破壊性胆管炎の場で特異的発現を示すケモカイン、特にCX3CL1の産生機序と自然免疫の関与 (2009)
  • Author(s): 下田慎治、中村稔、石橋大海
  • Organizer: 第17回浜名湖シンポジウム
  • Place of Presentation: 浜松
  • Year and Date: 20091222-20091223
• [Presentation] HLA-DRB1遺伝子多型が抗核抗体による原発性胆汁性肝硬変の予後予測に及ぼす影響の検討 (2009)
  • Author(s): 中村稔、安波道郎、近藤久義、相葉佳洋、小森敦正、長岡進矢、阿比留正剛、八橋弘、右田清志、石橋大海
  • Organizer: 第46回日本消化器免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 20090723-20090724
• [Presentation] 日本人原発性胆汁性肝硬変(PBC)患者のCTLA-4一塩基多型(SNP)の解析 (2009)
  • Author(s): 相葉佳洋、中村稔、小森敦正、右田清志、八橋弘、塚本和弘、石橋大海
  • Organizer: 第46回日本消化器免疫学会総会
  • Place of Presentation: 松山
  • Year and Date: 20090723-20090724
• [Presentation] 原発性胆汁性肝硬変の予後診断法の確立のための遺伝子解析 (2009)
  • Author(s): 中村稔、塚元和弘、安波道郎、近藤久義、相葉佳洋, 小森敦正、右田清志、八橋弘、竿代丈夫、林茂樹、中牟田誠、本田浩一、杉和洋、島田昌明、小林正和、渡部幸夫、森本日出雄、矢倉道泰、正木尚彦、高野弘嗣、竹崎英一、小松達司、山下晴弘、加藤道夫、古賀満明、長岡進矢、矢野公士、阿比留正剛、石橋大海
  • Organizer: 第45回日本肝臓学会総会(肝臓 50巻 2009, suppl.(1), A162, 0-78.)
  • Place of Presentation: 神戸
  • Year and Date: 20090604-20090605
• [Presentation] 当科におけるPBC-AIH overlap症候の特徴と予後 (2009)
  • Author(s): 小森敦正, 中村稔、本吉康英、橋元悟、裴成寛、立山雅邦、長岡進矢、柳謙二、田浦直太、阿比留正剛、矢野公士、右田清志、八橋弘、石橋大海
  • Organizer: 第45回日本肝臓学会総会(肝臓 50巻 2009, suppl.(1), A391,P-291.)
  • Place of Presentation: 神戸
  • Year and Date: 20090604-20090605
• [Presentation] PBC患者における血清BAFFの測定 (2009)
  • Author(s): 右田清志、中村稔、阿比留正剛、小森敦正、矢野公士、八橋弘、石橋大海
  • Organizer: 第45回日本肝臓学会総会(肝臓 50巻 2009, suppl.(1), A392, P-293.)
  • Place of Presentation: 神戸
  • Year and Date: 20090604-20090605
• [Presentation] Analysis of HLA-DRB1 polymorphism in Japanese patients with primary biliary cirrhosis (PBC) - HLA-DRB1 polymorphism determines the relative risk of anti-nuclear antibodies for the disease-progression in PBC. (2009)
  • Author(s): Nakamura M, Yasunami M, Kondo H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Nakamuta M, Hayashi S, Saito A, Honda K, Shimada M, Watanabe Y, Yagura M, Kohno H, Sugi K, Ota H, Komatsu T, Mannami T, Koga M, Satoh T, Takesaki E, Yamamoto T, Oohara Y, Masaki N, Ishibasi H
  • Organizer: Hepatology(Volume 50, Number 4 (Suppl), October 2009, 1004A, 1521.)
  • Place of Presentation: Boston
  • Year and Date: 2009-11-03
• [Presentation] Hepatic expression of peroxisome proliferators activated receptors A(PPARA) in primary biliary cirrhosis. (2009)
  • Author(s): Nakamura M, Ito M, Aiba Y, Komori A, Migita K, Yatsuhashi H, Ishibashi H
  • Organizer: Nuclear Receptors and Liver Disease.(Abstract page 87.)
  • Place of Presentation: Vienna
  • Year and Date: 2009-02-28
• [Presentation] Identification of serological and genetic biomarkers for predicting the prognosis of primary biliary cirrhosis (PBC). -A homozygous "Hap2/Hap2" diplotype in multidrug resistance protein 3 (MDR3) gene confers a strong susceptibility to jaundice-type progression of PBC- (2008)
  • Author(s): Nakamura M, Ohishi Y, Iio N, Aiba Y, Komori A, et al
  • Organizer: The 59th Annual Meeting of The American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: San Francisco
  • Year and Date: 20081031-20081104
• [Presentation] Redefining AMA negative primary biliary cirrhosis : CD4 T cell autoreactivity to the dominant mitochondrial autoantigen PDC-E2. (2008)
  • Author(s): Shimoda S, Miakawa H, Nakamura M, Ishibashi H, Kikuchi K, et al
  • Organizer: The 59th Annual meeting of The American Association for the Study of Liver Diseases (AASLD).
  • Place of Presentation: San Francisco
  • Year and Date: 20081031-20081104
• [Presentation] 原発性胆汁性肝硬変の予後予測診断法の確立 (2008)
  • Author(s): 中村稔, 大石裕樹, 相葉佳洋, 小森敦正, 右田清志, 八橋弘, 竿代丈夫, 中牟田誠, 本田浩一, 島田昌明, 小林正和, 渡部幸夫, 林茂樹, 古賀満明, 森本日出雄, 正木尚彦, 近藤久義, 大曲勝久, 安波道郎, 塚元和弘, 石橋大海
  • Organizer: 第44回日本肝臓学会総会(肝臓 49巻 2008, suppl.(1), A184, 0-115.)
  • Place of Presentation: 松山
  • Year and Date: 20080605-20080606
• [Presentation] 培養ヒト肝内胆管上皮細胞の急性相反応からみた遺伝子発現の可能性 (2008)
  • Author(s): 小森敦正, 植村隆, 藤原紳祐, 相葉佳洋, 中村稔, 矢野公士, 藤岡ひかる, 右田清志, 八橋弘, 石橋大海
  • Organizer: 第44回日本肝臓学会総会(一般演題,セッション60:胆管・胆汁うっ滞2)(肝臓 49 Suppl.(1):A235,2008.04.30)
  • Place of Presentation: 愛媛
  • Year and Date: 20080605-20080606
• [Presentation] OSTEOPONTIN, A PUTATIVE MARKER FOR DUCTULAR REACTION, IS INDUCED BY JAK/STAT3 ACTIVATION IN HUMAN BILIARY EPITHELIAL CELLS. (2008)
  • Author(s): Komori A, Uemura T, Fujiwara S, Aiba Y, Nakamura M, et al
  • Organizer: The 43rd Annual Meeting of the European Association For the Study of the Liver.
  • Place of Presentation: Milan, Italy
  • Year and Date: 20080000
• [Book] 原発性胆汁性肝硬変(PBC)の診療ガイド(厚生労働省"難治性の肝・胆道疾患に関する調査研究"班編) (2010)
  • Author(s): 坪内博仁、中沼安二、石橋大海、上野義之、上本伸二、江川裕人、向坂彰太郎、國土典宏、下田慎治、滝川一、中牟田誠、西原利治、廣原淳子、前原喜彦、松崎靖司、宮川浩、調憲、田中篤、中村稔
  • Publisher: 文光堂
• [Book] HLADRB1遺伝子多型が降格抗体による原発性胆汁性肝硬変の予後予測に及ぼす影響の検討,消化器と免疫N046, 2009 (2010)
  • Author(s): 中村稔、安波道郎、近藤久義、相葉佳洋、小森敦正、長岡進矢、阿比留正剛、八橋弘、右田清志、石橋大海
  • Total Pages: 108-112
  • Publisher: マイライフ社
• [Book] 日本人原発性胆汁性肝硬変患者(PBC)のCTLA4一塩基多型(SNP)の解析.消化器と免疫N046, 2009 (2010)
  • Author(s): 相葉佳洋、小森敦正、右田清志、八橋弘、塚元和弘、石橋大海、中村稔
  • Total Pages: 105-107
  • Publisher: マイライフ社
• [Book] 原発性胆汁性肝硬変の病因と予後,第4章:非ウイルス性肝障害,肝疾患Review 2008-2009 (2008)
  • Author(s): 石橋大海, 中村稔, 下田慎治
  • Total Pages: 75-81
  • Publisher: 日本メディカルセンター
• [Book] 免疫学的機序-原発性胆汁性肝硬変の病態と免疫機序, PBC, PSCと肝移植<第4回伊豆肝臓カンファレンス記録>(市田隆文編) (2008)
  • Author(s): 石橋大海, 下田慎治, 中村稔
  • Total Pages: 55-64
  • Publisher: アークメディア,東京
• [Remarks] ホームページ等