Faculty Profiles - TAKAKI Akinobu

水素水はマウスにおけるNASHの進行を抑制する

河合大介, 高木章乃夫, 山本和秀, 松本和幸, 津崎龍一郎, 安中哲也, 小池和子, 三宅康弘, 白羽秀則

日本消化器病学会雑誌 108 ( 臨増総会 ) A367 - A367 2011.3

+49A/G polymorphism of cytotoxic T-lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta-analysis Reviewed

Yasuhiro Miyake, Fusao Ikeda, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

HEPATOLOGY RESEARCH 41 ( 2 ) 151 - 159 2011.2

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Aim:
Recently, the associations of +49A/G polymorphisms of cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene with the susceptibility to type 1 autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have been reported; however these associations are yet to be fully elucidated. This study aimed to identify the associations of CTLA-4 gene +49A/G polymorphisms with the susceptibility to type 1 AIH and PBC by using a meta-analysis.
Methods:
PubMed was searched by using the following keywords: "autoimmune hepatitis AND (polymorphism OR polymorphisms)" or "primary biliary cirrhosis AND (polymorphism OR polymorphisms)". Meta-analyses of five studies including 526 patients with type 1 AIH and 631 controls and seven studies including 1500 patients with PBC and 2345 controls were performed.
Results:
For type 1 AIH, the odds ratio (OR) of G allele was 1.26 [95% confidence interval (CI) 1.06-1.51] although G/G homozygosity was not associated with the susceptibility to type 1 AIH. On the other hand, the OR of A/A homozygosity for type 1 AIH was 0.66 (95% CI 0.50-0.86). For PBC, the OR of G allele was 1.20 (95% CI 1.06-1.34). Furthermore, G/G homozygosity was significantly associated with the susceptibility to PBC (OR 1.29, 95% CI 1.01-1.66). The OR of A/A homozygosity for PBC was 0.81 (95% CI 0.70-0.94).
Conclusions:
This study suggests that CTLA-4 gene +49A/G polymorphisms may be associated with the susceptibility to type 1 AIH and PBC. Especially, while G/G genotype may be associated with the susceptibility to PBC, A/A genotype may be protective against type 1 AIH and PBC.

DOI： 10.1111/j.1872-034X.2010.00757.x

Prognostic model for hepatocellular carcinoma with time-dependent factors. Reviewed

Kuwaki K, Nouso K, Kobayashi Y, Nakamura S, Ito YM, Iwadou S, Hagihara H, Yasunaka T, Toshimori J, Miyatake H, Miyoshi K, Onishi H, Miyake Y, Shoji B, Takaki A, Shiraha H, Iwasaki Y, Kobashi H, Yamamoto K

Acta medica Okayama 65 ( 1 ) 11 - 19 2011.2

Language：English Publishing type：Research paper (scientific journal)

The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n=336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n=227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC.

DOI： 10.18926/AMO/43825

Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure Reviewed

Hiroki Takayama, Yasuhiro Miyake, Kazuhiro Nouso, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Haruhiko Kobashi, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 26 ( 1 ) 116 - 121 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Background and Aims:
In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF).
Methods:
Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls.
Results:
Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050 +/- 1572 pg/mL vs 4521 +/- 2419 pg/mL vs 8506 +/- 5500 pg/mL, VEGF; 39 +/- 38 pg/mL vs 144 +/- 122 pg/mL vs 205 +/- 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38).
Conclusions:
We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.

DOI： 10.1111/j.1440-1746.2010.06441.x

Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis Reviewed

Yutaka Nakanishi, Hidenori Shiraha, Shin-ichi Nishina, Shigetomi Tanaka, Minoru Matsubara, Shigeru Horiguchi, Masaya Iwamuro, Nobuyuki Takaoka, Masayuki Uemura, Kenji Kuwaki, Hiroaki Hagihara, Junichi Toshimori, Hideki Ohnishi, Akinobu Takaki, Shinichiro Nakamura, Yoshiyuki Kobayashi, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto

BMC CANCER 11 3 2011.1

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Runt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC).
Methods: RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis.
Results: RUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90 +/- 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 +/- 4% and 4 +/- 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation.
Conclusion: RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis.

DOI： 10.1186/1471-2407-11-3

Hepatic toxicity and prognosis in hepatitis C virus-infected patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy regimens: a Japanese multicenter analysis. Reviewed International journal

Ennishi D, Maeda Y, Niitsu N, Kojima M, Izutsu K, Takizawa J, Kusumoto S, Okamoto M, Yokoyama M, Takamatsu Y, Sunami K, Miyata A, Murayama K, Sakai A, Matsumoto M, Shinagawa K, Takaki A, Matsuo K, Kinoshita T, Tanimoto M

Blood 116 ( 24 ) 5119 - 5125 2010.12

Language：English Publishing type：Research paper (scientific journal) Publisher：24

The influence of hepatitis C virus (HCV) infection on prognosis and hepatic toxicity in patients with diffuse large B-cell lymphoma in the rituximab era is unclear. Thus, we analyzed 553 patients, 131 of whom were HCV-positive and 422 of whom were HCV-negative, with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP)-like chemotherapy. Survival outcomes and hepatic toxicity were compared according to HCV infection. The median follow-up was 31 and 32 months for patients who were HCV-positive and HCV-negative, respectively. HCV infection was not a significant risk factor for prognosis (3-year progression-free survival, 69% vs 77%, P = .22; overall survival, 75% vs 84%, P = .07). Of 131 patients who were HCV-positive, 36 (27%) had severe hepatic toxicity (grade 3-4), compared with 13 of 422 (3%) patients who were HCV-negative. Multivariate analysis revealed that HCV infection was a significant risk factor for severe hepatic toxicity (hazard ratio: 14.72; 95% confidence interval, 6.37-34.03; P < .001). An exploratory analysis revealed that pretreatment transaminase was predictive of severe hepatic toxicity. HCV-RNA levels significantly increased during immunochemotherapy (P = .006). These results suggest that careful monitoring of hepatic function and viral load is indicated during immunochemotherapy for HCV-positive patients.

DOI： 10.1182/blood-2010-06-289231

Scopus

Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease. Reviewed

Other Link： http://orcid.org/0000-0003-1761-6314

Shoji B, Ikeda F, Fujioka S, Kobashi H, Yasunaka T, Miyake Y, Shiraha H, Takaki A, Nouso K, Iwasaki Y, Yamamoto K

Journal of gastroenterology 45 ( 11 ) 1172 - 1182 2010.11

Amino acid substitutions of hepatitis C virus core protein are not associated with intracellular antiviral response to interferon-α in vitro. Reviewed

Ikeda F, Dansako H, Nishimura G, Mori K, Kawai Y, Ariumi Y, Miyake Y, Takaki A, Nouso K, Iwasaki Y, Ikeda M, Kato N, Yamamoto K

Liver international : official journal of the International Association for the Study of the Liver 30 ( 9 ) 1324 - 1331 2010.10

Hepatitis C virus NS4 protein impairs the Th1 polarization of immature dendritic cells Reviewed

A. Takaki, M. Tatsukawa, Y. Iwasaki, K. Koike, Y. Noguchi, H. Shiraha, K. Sakaguchi, E. Nakayama, K. Yamamoto

JOURNAL OF VIRAL HEPATITIS 17 ( 8 ) 555 - 562 2010.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Dendritic cells (DCs) in chronic hepatitis C patients display impaired function, although the details remain unclear. To investigate the hepatitis C virus (HCV) protein that has the most impact on DC function, we compared five recombinant proteins and seven HCV protein genes in modulating DC phenotype and function. Immature DCs (iDCs) were established from healthy donor peripheral blood monocytes with granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4. Lipopolysaccharide was used to establish mature DCs (mDCs). Cells were then pulsed with HCV recombinant proteins or transfected with HCV plasmids and subsequently assayed for cell surface marker expression by flow cytometry. For cytokine and proliferative T-cell response analysis, DCs were cultured with autologous CD4 T cells and tuberculin purified protein derivative (PPD). Mean fluorescent intensity of CD86 was reduced in HCV protein-pulsed iDCs. Proliferative T-cell responses and Th1 cytokine concentrations were reduced with HCV nonstructural proteins (NS), particularly with HCV NS4. HCV nonstructural proteins, particularly NS4, change the iDC phenotype and reduce antigen-specific T-cell stimulatory function with Th1 cytokine reductions.

DOI： 10.1111/j.1365-2893.2009.01213.x

Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma Reviewed

Y. Miyake, A. Takaki, Y. Iwasaki, K. Yamamoto

JOURNAL OF VIRAL HEPATITIS 17 ( 4 ) 287 - 292 2010.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Various clinical studies have indicated that interferon (IFN)-alpha treatment prevents the development of hepatocellular carcinoma (HCC) in people chronically infected with hepatitis C virus. However, it has been controversial whether IFN-alpha treatment prevents HCC recurrence. The aim of this study was to identify the preventive effect of IFN-alpha treatment after curative therapy of primary tumours within the Milan criteria (three or fewer nodules 3 cm or less in diameter or a single nodule of 5 cm or less) on HCC recurrence. We conducted a meta-analysis of five trials including 355 patients (167 patients received IFN-alpha treatment after curative therapy of primary tumours) and estimated relative risks (RRs) and 95% confidence intervals (CIs) for the effect of IFN-alpha on HCC recurrence according to the DerSimonian and Laird method. IFN-alpha treatment after curative therapy of primary tumours significantly prevented HCC recurrence (RR 0.33; 95%CI 0.19-0.58, P < 0.0001) without a significant heterogeneity (Q = 4.52, P = 0.34). An evaluation using the Begg method suggested no evidence of publication bias. Sub-group analyses revealed that IFN-alpha treatment reduced HCC recurrence in two studies achieving sustained virologic response (SVR) rates > 30% (RR 0.20; 95%CI 0.05-0.81, P = 0.02) and in three studies achieving SVR rates < 30% (RR 0.44; 95%CI 0.23-0.84, P = 0.01). In conclusion, IFN-alpha treatment after curative treatment of primary tumour within Milan criteria may be effective for the prevention of HCC recurrence, and higher SVR rate may be associated with better preventive effect of IFN-alpha treatment on HCC recurrence.

DOI： 10.1111/j.1365-2893.2009.01181.x

Clinical features of autoimmune hepatitis diagnosed based on simplified criteria of the International Autoimmune Hepatitis Group Reviewed

Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto

DIGESTIVE AND LIVER DISEASE 42 ( 3 ) 210 - 215 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background: Recently, simplified diagnostic criteria for autoimmune hepatitis have been proposed. Aim: We aimed to evaluate usefulness of the simplified criteria.
Methods: We applied the simplified criteria to 176 autoimmune hepatitis patients diagnosed according to the revised scoring system proposed in 1999 (original criteria). Furthermore, in order to compare predictabilities between these two diagnostic criteria, we included 168 patients with other liver disease than autoimmune hepatitis.
Results: Of 176 autoimmune hepatitis patients, 85% were diagnosed with autoimmune hepatitis according to the simplified criteria, and patients diagnosed according to the simplified criteria showed a higher frequency of antinuclear antibodies and/or smooth muscle antibodies of 1:80 or greater and slightly higher serum levels Of immunoglobulin G than those diagnosed according to the original criteria. However, 30% of male patients, 23% of patients with acute presentation, 50% of patients showing histological acute hepatitis and 46% of patients negative for antinuclear antibodies at presentation were not diagnosed with autoimmune hepatitis according to the simplified criteria. The simplified criteria showed lower sensitivity (85% vs. 100%) and higher specificity (99% vs. 93%) for autoimmune hepatitis than the original criteria.
Conclusions: The simplified criteria may be useless for the diagnosis of patients with atypical features, especially patients with histological acute hepatitis. (C) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dld.2009.06.013

Evolution of prognostic factors in hepatocellular carcinoma in Japan. Reviewed

Nouso K, Kobayashi Y, Nakamura S, Kobayashi S, Toshimori J, Kuwaki K, Hagihara H, Onishi H, Miyake Y, Ikeda F, Shiraha H, Takaki A, Iwasaki Y, Kobashi H, Yamamoto K

Alimentary pharmacology & therapeutics 31 ( 3 ) 407 - 414 2010.2

Autoimmune hepatitis with acute presentation in Japan Reviewed

Y. Miyake, Y. Iwasaki, H. Kobashi, T. Yasunaka, F. Ikeda, A. Takaki, K. Yamamoto

DIGESTIVE AND LIVER DISEASE 42 ( 1 ) 51 - 54 2010.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background: In Caucasians with autoimmune hepatitis, patients with acute presentation have autoimmune thyroiditis and histological zone 3 necrosis more frequently.
Aim: We aimed at investigating clinical features of Japanese autoimmune hepatitis patients with acute presentation.
Methods: Of 176 patients retrospectively reviewed, 53 were diagnosed with acute presentation.
Results: Patients with acute presentation had higher serum levels of bilirubin and transaminase, lower frequencies of autoimmune thyroiditis and antinuclear antibodies of 1:160 or greater, and a higher frequency of zone 3 necrosis. Of the 53 patients with acute presentation, 10 showed histological acute hepatitis; however, advanced staging of fibrosis was found in 13 patients. In patients with acute presentation, those with histological acute hepatitis were younger than those with chronic hepatitis. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels with prednisolone treatment was similar between patients with acute presentation and those with classical presentation.
Conclusions: In line with previous results, zone 3 necrosis is a histological characteristic of autoimmune hepatitis with acute presentation. Autoimmune hepatitis with acute presentation includes not only histological acute hepatitis but also acute exacerbation of pre-existing chronic disease. On the other hand, Japanese patients with acute presentation may also have different clinical features from Caucasian patients. (C) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dld.2009.04.009

Acute Hepatitis due to Hepatitis E Virus Genotype 1 As an Imported Infectious Disease in Japan Reviewed

Koji Miyahara, Yasuhiro Miyake, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Yoshiaki Iwasaki, Haruhiko Kobashi, Jong-Hon Kang, Kazuaki Takahashi, Masahiro Arai, Kazuhide Yamamoto

INTERNAL MEDICINE 49 ( 23 ) 2613 - 2616 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

An 18-year-old Nepalese man was admitted due to general malaise and anorexia a month after coming to Japan. Laboratory tests showed elevation of transaminase and positivity for IgM anti-HEV antibody. Serum HEV RNA was detected by RT-PCR amplifications. An HEV genome phylogenetic tree, constructed using an 821-nucleotide sequence in the open reading frame 1, indicated that the genotype was 1. HEV genotype 1 is epidemic in South Asia, Africa and South America, and the incidence of acute hepatitis due to HEV genotype 1 is low in Japan. Thereafter, attention should be paid to HEV genotype 1 infection as an imported infectious disease.

DOI： 10.2169/internalmedicine.49.4221

Efficacy of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis Reviewed

Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Ryoichi Okamoto, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Masaharu Ando, Kohsaku Sakaguchi, Kazuhide Yamamoto

HEPATOLOGY INTERNATIONAL 3 ( 4 ) 556 - 562 2009.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

This study aimed to investigate the efficacy of ursodeoxycholic acid (UDCA) for Japanese patients with autoimmune hepatitis (AIH).
One hundred forty-seven patients were investigated.
As initial treatment, 25 patients received UDCA (300-600 mg/day) monotherapy (UDCA group), 40 received a combination of prednisolone (PSL) (a parts per thousand yen20 mg/day) and UDCA (combination group), 68 received PSL monotherapy (PSL group), and 14 received other treatments. During the follow-up, in the UDCA group, PSL was added to 8 of 12 patients failing to achieve the normalization of serum transaminase levels with UDCA monotherapy. Cumulative incidence of the normalization of serum transaminase levels was 64% in the UDCA group, 95% in the combination group, and 94% in the PSL group (log-rank test, P = 0.0001). UDCA group required longest periods until the normalization of serum transaminase levels. Eleven patients, who achieved persistent normalization of serum transaminase levels with UDCA monotherapy, did not reach liver failure or develop hepatocellular carcinoma for 49.7 (range = 13.4-137.3) months. Meanwhile, during the taper of PSL, doses of PSL at the initial relapse were lower in patients treated with PSL and UDCA than in those treated with PSL monotherapy, and initial relapse occurred earlier in patients treated with PSL monotherapy.
UDCA monotherapy is effective for some Japanese AIH patients; however, UDCA monotherapy for patients with either high-grade inflammatory activity or poor residual capacity of liver function is not recommended because they may reach liver failure before achievement of remission. Meanwhile, additional use of UDCA during the taper of corticosteroids may be effective for the prevention of early relapse.

DOI： 10.1007/s12072-009-9155-9

HCVコア蛋白質のアミノ酸の違いとIFN応答性との関係についての培養細胞を用いた解析 Reviewed

池田房雄, 団迫浩方, 西村剛, 河合良成, 有海康雄, 池田正徳, 高木章乃夫, 岩崎良章, 加藤宣之, 山本和秀

肝臓 50 ( Suppl.2 ) A515 - A515 2009.9

Clinical features of type 1 autoimmune hepatitis in adolescence and early adulthood Reviewed

Yasuhiro Miyake, Yoshiaki Iwasaki, Haruhiko Kobashi, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Ryoichi Okamoto, Kouichi Takaguchi, Hiroshi Ikeda, Yasuhiro Makino, Kohsaku Sakaguchi, Masaharu Ando, Kazuhide Yamamoto

HEPATOLOGY RESEARCH 39 ( 8 ) 766 - 771 2009.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Aim:
The peak age of the presentation of autoimmune hepatitis (AIH) is between 40 years and 50 years. Elderly patients have been reported to have higher frequencies of concurrent thyroid or rheumatic diseases and histological cirrhosis and a lower occurrence of treatment failure. In this study, we assessed the clinical features of Japanese type 1 AIH in adolescence and early adulthood.
Methods:
Fifteen patients aged < 30 years (group 1) were compared with 79 patients aged between 40 years and 50 years (group 2).
Results:
At presentation, patients aged < 30 years accounted for 9% of the study population. Although frequencies of extrahepatic concurrent autoimmune diseases were similar between groups 1 and 2, a tendency toward a lower frequency of concurrent autoimmune thyroiditis was shown in group 1 (0 vs. 18%, P = 0.08). Group 1 had a lower frequency of human leukocyte antigen DR4 (27 vs. 78%, P = 0.002), and histological acute hepatitis was shown more frequently in group 1 (27 vs. 4%, P = 0.002). However, there were no differences in frequencies of the normalization of serum transaminase levels after the introduction of corticosteroid treatment or relapse after the normalization of serum transaminase levels between the two groups.
Conclusions:
Japanese type 1 AIH patients in adolescence and early adulthood respond well to corticosteroid treatment. However, they may frequently show atypical features, and the diagnosis of type 1 AIH in adolescence and early adulthood may be difficult and should be made carefully.

DOI： 10.1111/j.1872-034X.2009.00510.x

Twist expression promotes migration and invasion in hepatocellular carcinoma. Reviewed

Matsuo N, Shiraha H, Fujikawa T, Takaoka N, Ueda N, Tanaka S, Nishina S, Nakanishi Y, Uemura M, Takaki A, Nakamura S, Kobayashi Y, Nouso K, Yagi T, Yamamoto K

BMC cancer 9 240 2009.7

Clinical features of antinuclear antibodies-negative type 1 autoimmune hepatitis Reviewed

HEPATOLOGY RESEARCH 39 ( 3 ) 241 - 246 2009.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL PUBLISHING, INC

Antinuclear antibodies (ANA) are the main serologic markers of type 1 autoimmune hepatitis (AIH); however 20-30% of patients are negative for ANA. We assessed the clinical features of ANA-negative patients.
A retrospective analysis was performed of 176 patients with type 1 AIH (153 females, median age 55 years). A diagnosis of AIH was made based on the revised scoring system proposed by the International Autoimmune Hepatitis Group. ANA titers were measured using a standard indirect immunofluorescence technique.
Thirty-eight patients (22%) had low titers of ANA (1:40 or 1:80), and 114 (65%) had high titers (>= 1:160). Of 24 ANA-negative patients, 15 were positive for smooth muscle antibodies (SMA). Three of nine both ANA- and SMA-negative patients developed ANA during follow-up. The other six were diagnosed based on histological characteristics. Thirteen ANA-negative patients relapsed after the normalization of serum alanine aminotransferase (ALT) levels. ANA-negative patients more frequently showed acute presentation and, at presentation, had lower serum immunoglobulin G levels, higher serum levels of bilirubin and transaminase, and higher frequencies of histological acute hepatitis and zone 3 necrosis than those with high titers. However, the frequency of advanced stage of fibrosis was similar. The response to corticosteroids was not different among the three groups.
ANA-negative type 1 AIH shows acute-onset more frequently but may include not only acute autoimmune hepatitis, but also acute exacerbation of inactive chronic disease. Regarding the diagnosis of ANA-negative AIH, the determination of ANA during follow-up and the response to immunosuppressive treatment may be helpful.

DOI： 10.1111/j.1872-034X.2008.00454.x