Hepatitis: Ueno Y

Ueno Y, Sollano JD, Farrell GC. · Tohoku University Graduate School of Medicine, Division of Gastroenterology, 1-1 Seiryo, Aobaku, Sendai 980-8574, Japan. · J Gastroenterol Hepatol. · Pubmed #19368633 No free full text.

Abstract: Chronic hepatitis C virus (HCV) infection accounts for most cases of hepatocellular carcinoma (HCC) in Japan and is the second major cause in many other countries. Development of HCC takes a considerable time after onset of HCV infection, between 20-40 years in most cases, and usually develops after cirrhosis is established. Although only a minority of HCV infections reach this stage, the high prevalence of chronic HCV infection in many countries (1-3%) is such that HCC related to HCV infection poses a significant public health issue 20-50 years after the onset of HCV epidemics. Due to advances in testing, and accessibility of clean, disposable medical apparatus including syringes and needles, and particularly screening of donor blood for anti-HCV and by nucleic acid testing, new cases of HCV infection have decreased in most countries, except for continued transmission by injection drug users (IDU). A key difference between HBV and HCV infection is that HCV can be eradicated by effective antiviral treatment. Sustained eradication of HCV reverses hepatic fibrosis, thereby preventing progression to cirrhosis and risk of HCC. Further, it has been well demonstrated that interferon-based antiviral therapy suppresses development of HCC in high-risk patients, particularly when sustained viral response (SVR) is obtained. In summary, the two key approaches to prevent development of HCV-related HCC are primary prevention of HCV infection (adequate programs to screen donor blood, universal precautions to stop medical transmission of blood-borne viruses, curbing transmission by IDU) and potent antiviral therapy of chronic HCV infection.

Moritoki Y, Lian ZX, Ohsugi Y, Ueno Y, Gershwin ME. · Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 E. Health Sciences Drive, Suite 6510, Davis, CA 95616, USA. · Autoimmun Rev. · Pubmed #16920571 No free full text.

Abstract: Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the three major autoimmune diseases affecting the liver. They are all characterized by the presence of a variety of autoantibodies, some of which are found in all three diseases, whereas others are restricted to one or two of them or are even specific for the particular disease. In this review we will first provide details of the serological features of these three autoimmune diseases that target the liver. In addition, we will highlight the possible pathogenic roles of autoreactive B cells, focusing on their immunological functions as autoantibody producing cells and as antigen-presenting cells for T cell priming. As well, we will describe the contribution of toll-like receptor (TLR) signaling to the activation of autoimmune B cells and the putative role of defects in regulatory T cell function in the development of autoimmune liver diseases.

Shibata M, Yanaga K, Morizane T, Yanagawa T, Hirakawa M, Ueno Y, Esquivel CO, Mitamura K. · Department of Gastroenterology, Kanto Medical Center NTT EC, Tokyo, Japan. · J Gastroenterol. · Pubmed #12858850 No free full text.

Abstract: A patient with hepatitis C virus (HCV)-related liver cirrhosis and hepatocellular carcinoma (HCC) was treated successfully with an orthotopic liver transplantation (OLT) followed by interferon therapy. The 36-year-old Japanese man was diagnosed as having liver cirrhosis in 1983. HCC was detected in 1991, and by 1994, jaundice and ascites had developed. The patient underwent OLT in June 1995, after which hepatitis C recurred, with elevated aminotransferases. His liver biopsy specimen showed chronic active hepatitis. He was given interferon-alpha three times weekly for 24 weeks in 1999. Six months after the end of the interferon treatment, the patient's serum HCV RNA became negative, with normalization of aminotransferases, and his liver histology exhibited amelioration of fibrosis and inflammation. At the present time, he remains free of HCC (more than 6.5 years after the OLT) and free of HCV RNA (more than 2.5 years since interferon therapy was completed). This is the first Japanese patient whose HCC was cured by OLT and HCV was eradicated by interferon therapy.

Toyota T, Ueno Y. · Tohoku University School of Medicine, Department of Internal Medicine. · Nippon Rinsho. · Pubmed #10707561 No free full text.

Abstract: Troglitazone, a PPAR-gamma agonist, is a new drug for type 2 diabetes. The drug decreases blood glucose via enhancing insulin action. Recently Sankyo pharmaceutical company is warning severe hepatotoxicity by troglitazone. It recommends to examine liver function every month in diabetic patients treated with the drug in order early to find drug-induced hepatitis. In Japan 153 diabetic patients treated with the drug developed severe hepatitis and 8 of them died of drug-side effects. Quinone metabolite of troglitazone predominantly in the liver to a sulfate conjugate and activation of PPAR gamma and PXR(pregnane X receptor) by troglitazone are supposed to be factors of hepatotoxic mechanism.

Kogure T, Ueno Y, Fukushima K, Nagasaki F, Kondo Y, Inoue J, Matsuda Y, Kakazu E, Yamamoto T, Onodera H, Miyazaki Y, Okamoto H, Akahane T, Kobayashi T, Mano Y, Iwasaki T, Ishii M, Shimosegawa T. · Division of Gastroenterology, Tohoku University Hospital, 1-1, Seiryo, Aobaku, Sendai 980-8574, Japan. · World J Gastroenterol. · Pubmed #19084938 links to  free full text

Abstract: AIM: To evaluate the efficacy of pegylated interferon alpha-2b (peg-IFN alpha-2b) plus ribavirin (RBV) therapy in Japanese patients with chronic hepatitis C (CHC) genotype Ib and a high viral load. METHODS: One hundred and twenty CHC patients (58.3% male) who received peg-IFN alpha-2b plus RBV therapy for 48 wk were enrolled. Sustained virological response (SVR) and clinical parameters were evaluated. RESULTS: One hundred (83.3%) of 120 patients completed 48 wk of treatment. 53 patients (44.3%) achieved SVR. Early virological response (EVR) and end of treatment response (ETR) rates were 50% and 73.3%, respectively. The clinical parameters (SVR vs non-SVR) associated with SVR, ALT (108.4 IU/L vs 74.5 IU/L, P = 0.063), EVR (76.4% vs 16.4%, P < 0.0001), adherence to peg-IFN (>or= 80% of planned dose) at week 12 (48.1% vs 13.6%, P = 0.00036), adherence to peg-IFN at week 48 (54.7% vs 16.2%, P < 0.0001) and adherence to RBV at week 48 (56.1% vs 32.1%, P = 0.0102) were determined using univariate analysis, and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis. In the older patient group (> 56 years), SVR in females was significantly lower than that in males (17% vs 50%, P = 0.0262). EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR. CONCLUSION: Peg-IFN alpha-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%. Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFN alpha-2b is important in improving the SVR rate.

Nagasaki F, Niitsuma H, Ueno Y, Inoue J, Kogure T, Fukushima K, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Tohoku J Exp Med. · Pubmed #17917412 links to  free full text

Abstract: Hepatitis B virus (HBV) infection remains to be one of the most prevailing infection in the world, causing chronic liver diseases. Although lamivudine has been effective to suppress HBV replication, longer durations of administration can lead to the emergence of drug-resistant mutant viruses, followed by reactivation of hepatic inflammation (breakthrough hepatitis). Moreover, the optimal period of administration as well as the effects of anti-viral nucleot(s)ide such as lamivudine, adefovir, and entecavir, has not been established. To evaluate the efficacy of the anti-viral effects of entecavir for lamivudine-resistant HBV, we administered entecavir sequentially in four patients with chronic HBV infection, who demonstrated the emergence of lamivudine-resistant HBV and histological active hepatitis. The antiviral effects were evaluated by the serum viral loads and biochemical laboratory data. After follow-up periods of more than 36 months, we found high incidence in the emergence of entecavir resistant mutants (3/4, i.e., 75%). An additional mutation at the 184th amino acid, different from the previously reported lamivudine-resistant mutations (80th, 180th, and 204th), seemed to have a close relationship with the induction of entecavir-resistant mutants at least for Japanese HBV genotype C. Our observation draws attention to the possibility that the usage of entecavir for lamivudine-resistant HBV could promptly induce entecavir-resistant mutations in addition to lamivudine-resistance.

Inoue J, Ueno Y, Nagasaki F, Akahane T, Fukushima K, Kogure T, Kondo Y, Kakazu E, Tamai K, Kido O, Nakagome Y, Ninomiya M, Obara N, Wakui Y, Takahashi M, Okamoto H, Shimosegawa T. · Division of Gastroenterology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. · J Gastroenterol. · Pubmed #19271116 No free full text.

Abstract: BACKGROUND: Recent studies have shown that indigenous hepatitis E virus (HEV) strains cause hepatitis E in industrialized countries. We aimed to clarify the characteristics of HEV infection in sporadic hepatitis patients during the last decade in Miyagi, northeast Japan. METHODS: We analyzed 94 serum samples obtained from acute or fulminant hepatitis patients of non-A, non-B, and non-C etiology between 1999 and 2008. Antibody to HEV (anti-HEV) was assayed, and patients who were positive for IgM- and/or IgA-class anti-HEV were diagnosed with hepatitis E. HEV RNA was tested in these patients, and phylogenetic analysis was performed. The occurrence of hepatitis E was compared with that of hepatitis A. RESULTS: Eight acute hepatitis patients (8.5%) were diagnosed with hepatitis E, and HEV RNA was detectable in seven patients. Five isolates of HEV were segregated into genotype 3 and the remaining two isolates into genotype 4. The year of the occurrence of hepatitis E was distributed almost equally from 1999 to 2008, whereas the cases of acute hepatitis A (n = 16) have decreased markedly in the last several years. In 2004-2008, the occurrence of hepatitis E was greater than that of hepatitis A (five cases vs. one case). As for seasonality, hepatitis E occurred more frequently from September to December than hepatitis A (five cases vs. four cases), although less frequently from January to April (one case vs. seven cases). CONCLUSION: The occurrence of hepatitis E has not decreased during the last decade in northeast Japan, in contrast to hepatitis A.

Ueno Y, Watanabe Y, Shibata A, Yoshikawa K, Takano T, Kohara M, Kitade Y. · Department of Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan. · Bioorg Med Chem. · Pubmed #19200743 No free full text.

Abstract: RNA interference (RNAi) induced by small interfering RNA (siRNA) has emerged as a powerful technique for the silencing of gene expression at the post-transcriptional level. It has been shown that in the RNAi machinery, the 3'-overhang region of a guide strand (an antisense strand) of siRNA is recognized by the PAZ domain in the Argonaute protein, and the 2-nucleotide (nt) 3'-overhang is accommodated into a binding pocket composed of hydrophobic amino acids in the PAZ domain. Based on this background information, we designed and synthesized siRNAs possessing aromatic compounds at their 3'-overhang regions. It was found that the modified siRNAs possessing aromatic compounds are more potent than the siRNAs without the 3'-overhang regions. Further, the silencing activities of the modified siRNAs are almost equal to those of normal siRNAs with natural nucleosides at their 3'-overhang regions. We also found that the siRNAs possessing the aromatic compounds at their 3'-overhang region could be used to inhibit hepatitis C virus (HCV) replication. Moreover, the RNAs with aromatic groups at their 3'-ends were more resistant to nucleolytic degradation by snake venom phosphodiesterase (SVPD) (a 3'-exonuclease) than natural RNAs. The aromatic compounds described in this report do not have functional groups capable of forming hydrogen bonds with nucleobases. Therefore, we expect that they can serve as the universal overhang units that can improve the nuclease resistance of siRNAs.

Kondo Y, Machida K, Liu HM, Ueno Y, Kobayashi K, Wakita T, Shimosegawa T, Lai MM. · Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, USA; Division of Gastroenterology, Tohoku University, Sendai City. · J Infect Dis. · Pubmed #19199548 No free full text.

Abstract: BACKGROUND: A lymphotropic hepatitis C virus strain (HCV, SB strain, hereafter "SB-HCV") has been shown to infect established T cell lines (Molt-4 and Jurkat) and primary human naive CD4(+) T cells. During T cell development and activation, transient expression of CD44 splicing variant 6 (CD44v6) plays a significant role. METHODS: SB-HCV was used to infect Molt-4 cells, and their cellular proliferation and CD44 expression was examined. RESULTS: SB-HCV-infected Molt-4 cells expressed a significantly lower level of the CD44v6 isoform. The infected cells could be divided into 2 carboxyfluorescein succinimidyl ester (CFSE) groups, CFSE-high (indicating low proliferation activity; 34.2% of the cells) and CFSE-low (indicating high proliferation activity; 62.5% of the cells), whereas uninfected cells consisted of only a CFSE-low population. Of the CFSE-high cells, 82.4% were positive for the HCV protein NS5A, whereas only 1.2% of the CFSE-low cells were positive for this protein. Among the HCV proteins, NS5A alone caused the down-regulation of CD44v6 expression. After cells were stimulated with phorbol myristate acetate, the amount of phosphorylated mitogen-activated protein (MAP) kinase was significantly reduced in CFSE-high, SB-HCV-infected Molt-4 cells. After Fas ligand stimulation, SB-HCV-infected Molt-4 cells had increased cleavage of caspase 8 and 3 and enhanced apoptosis, compared with the rates of cleavage and apoptosis in control groups, indicating that SB-HCV infection increased Fas-mediated apoptosis. CONCLUSION: HCV replication in T cells suppresses cellular proliferation and enhances susceptibility to Fas signaling by inhibiting CD44v6 signaling and expression.

Yamamoto T, Kondo S, Sugawara A, Yonechi M, Nishioka K, Meguro T, Abe M, Murakami K, Inoue J, Ueno Y, Shimosegawa T. · Department of Gastroenterology, Tohoku Kosei-Nenkin Hospital. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #19057164 No free full text.

Abstract: A 82-year-old asymptomatic HBV carrier man was admitted with liver dysfunction in May 2007. With anti-HBe antibody and high viral load, he had fulminant hepatic failure without proximate cause. He was treated with entecavir and corticosteroids, but died about one month later. Autopsy specimen of liver revealed submassive hepatic necrosis with faint regeneration. HBV obtained was segregated into genotype Bj, and mutation was detected at nt1896 in a precore region.

Obara N, Ueno Y, Fukushima K, Nakagome Y, Kakazu E, Kimura O, Wakui Y, Kido O, Ninomiya M, Kogure T, Inoue J, Kondo Y, Shiina M, Iwasaki T, Yamamoto T, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai 980-8574, Japan. · J Gastroenterol. · Pubmed #18807134 No free full text.

Abstract: BACKGROUND: Many studies have reported the efficiency of transient elastography, a noninvasive, reproducible, and reliable method for predicting liver fibrosis, in patients with chronic hepatitis C (CHC) and B (CHB), but there are few reports about nonviral chronic liver disease (CLD) such as primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NAFLD), and autoimmune hepatitis (AIH). We therefore compared the efficiency of transient elastography between CHC and nonviral CLD. METHODS: We assessed the accuracy of liver stiffness measurement (LSM) using Fibroscan, and compared these values with those of hyaluronic acid, type 4 collagen, platelet count, prothrombin index, and AST/platelet ratio index (APRI) as indices for the diagnosis of liver fibrosis in 114 patients with a variety of chronic liver diseases: CHC (n = 51), CHB (n = 11), NAFLD (n = 17), PBC (n = 20), and AIH (n = 15). The histology was assessed according to the METAVIR score by two pathologists. RESULTS: The number of fibrosis stage (F0/1/2/3/4) with CHC was 9/15/12/6/10, and that with nonviral CLD was 10/21/11/4/6, respectively. The ability, assessed by area under receiver operating characteristic (AUROC) curve, to predict liver fibrosis F >or= 2 for LSM, HA, type 4 collagen, platelet count, prothrombin index, and APRI, was 0.92, 0.81, 0.87, 0.85, 0.85, and 0.92 in CHC patients, respectively; and 0.88, 0.72, 0.81, 0.67, 0.81, and 0.77 in nonviral CLD patients, respectively. CONCLUSIONS: In patients with nonviral CLD, LSM was most helpful in predicting significant fibrosis (F >or= 2). Transient elastography is a reliable method for predicting significant liver fibrosis, not only in CHC patients but also in nonviral CLD patients.

Fukushima K, Ueno Y, Inoue J, Wakui Y, Obara N, Kimura O, Kido O, Nakagome Y, Kakazu E, Matsuda Y, Kogure T, Kondo Y, Nagasaki F, Yamagiwa Y, Ashino Y, Shimosegawa T. · Department of Internal Medicine, Tohoku University Hospital, Sendai, Japan. · Hepatol Res. · Pubmed #18498361 No free full text.

Abstract: We report a case of a HIV and hepatitis B virus (HBV)-co-infected patient to whom entecavir (ETV) was administered initially before the notification regarding the potential mutagenesis effect on HIV against the nucleoside analog. Since initial evaluations indicated the advanced stage of chronic hepatitis B and preserved numbers of peripheral CD4+ lymphocytes without the manifestation of immunodeficiency, priority was given to the management of HBV. We started HBV therapy with ETV at a dose of 0.5 mg daily without using any HIV drugs. The viral loads of both HBV and HIV-1 decreased gradually during the 5 months following the initial administration of ETV. HBV was well controlled by the gradual replacement of ETV with highly-active antiretroviral therapy against HIV with a regimen including atazanavir, emtricitabine, and tenofovir. HBV was genotyped as A2 with the quasispecies pool consisting of the -1G precore/core deletion mutant strain.

Nagasaki F, Ueno Y, Niitsuma H, Inoue J, Kogure T, Fukushima K, Kobayashi K, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · J Med Virol. · Pubmed #18428142 No free full text.

Abstract: We encountered five consecutive patients with fulminant hepatitis induced by acute hepatitis B virus (HBV) infection in 2000--2001 in Japan. They had not had previous contact each other, and were referred to us from different hospitals. Although a 69-year-old woman could be rescued by intensive internal treatment, the four patients died. We analyzed the partial (nt 278-646) and entire nucleotide sequences of the HBV obtained from them, and their divergences were 0-0.3% and 0-0.2%, respectively. The results suggested that they had been infected with the same HBV isolates. The isolates belonged to genotype B and subgenotype B2 on the phylogenetic tree analysis (AB302942-AB302946). As for the nucleotides sequences of them, previously reported mutations of G1896A, A1762T, and G1764A were present. Amino acid analysis revealed that previously reported Ile97Leu and Pro130Non-Pro in the core region and Trp28Stop in the precore region were present. As for the entire nucleotide sequences among B2, AB302942 showed low divergences with AF121245 and AB073834 (1.7%), and X97850 from patients with fulminant hepatitis (3.2%). We compared the two consensus nucleotides derived from AB302942 and X97850 (fulminant hepatitis) versus AY121245 and AB073834 (non-fulminant hepatitis), which revealed a difference in nt 1,504 located in the P and X region. Nucleotide 1,504 was C for isolates from fulminant hepatitis and G for non-fulminant hepatitis, and it was recognized among most of the isolates belonging to B2 registered on GenBank. Further studies could disclose the mechanism of severe inflammation of liver that finally leads to fulminant hepatitis.

Inoue J, Ueno Y, Kogure T, Nagasaki F, Kimura O, Obara N, Kido O, Nakagome Y, Kakazu E, Matsuda Y, Fukushima K, Segawa H, Nakajima I, Itoyama Y, Takahashi M, Okamoto H, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. · J Clin Virol. · Pubmed #18291715 No free full text.

Abstract: Although many extrahepatic manifestations have been described in patients with acute or chronic hepatitis B, there are few reports about neurological disorders. We describe a 55-year-old man who contracted acute hepatitis B virus (HBV) infection and transverse myelitis. His neurological findings were gradually reduced along with the recovery from hepatitis. The cerebrospinal fluid (CSF) was revealed to be positive for HBsAg and HBV DNA. Full-length sequences of HBV in his serum and CSF were determined, and it was revealed that these two isolates had mutations at nucleotide (nt) 1762/1764 in the core promoter region and nt 1896 in the precore region. They were identical to each other except for two ambiguous codes at nt 2020 and 2631 in the CSF isolate. After cloning of the amplicons, substitutions at nt 2020 and 2631 were found in 6 (38%) of the 16 CSF clones. One clone of the 6 CSF clones had an additional substitution at nt 2119. These substitutions were not found in 16 serum clones. The presence of HBV clones unique to CSF suggests that HBV was a possible causative agent of the myelitis.

Fukushima K, Ueno Y, Kanegane H, Yamagiwa Y, Inoue J, Kido O, Nagasaki F, Kogure T, Kakazu E, Nakagome Y, Matsuda Y, Obara N, Kimura O, Shimosegawa T. · Department of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Hepatol Res. · Pubmed #18021227 No free full text.

Abstract: Severe hepatitis with an indistinct etiology manifested in a 16-year-old boy who had no particular history. The histological features of the liver and clinical course of the patient were similar to those of patients with autoimmune hepatitis characterized by interface hepatitis and severe lobular inflammation of the liver and recurrent exacerbations of hepatitis. We administered intravenous glycyrrhizin preparation daily or three times a week combined with the oral administration of ursodeoxycholic acid daily throughout the term after the initial onset of disease for the control of disease activity. The normalization of the concentration of alanine aminotransferase in serum was achieved in response to the therapy during the course. The serum concentration of immunoglobulins of the patient gradually decreased from the onset of the disease to an unacceptable level without globulin preparation during the following period of 17 months. Immunological tests revealed impairment of immunoglobulin production bythe B cell population of the patient, which led to the diagnosis of the patient as common variable immunodeficiency (CVID). The patient, with improved liver histology after 27 months from the onset of disease, benefited from the current combination therapy without severe infection through the avoidance of overimmunosuppression. CVID is defined as a heterogeneous syndrome characterized by various degrees of hypogammaglobulinemia without any specific predisposing causes, frequently associated with autoimmunity. Diagnostic criteria and therapeutic options of persistent hepatitis with CVID are to be established, as discussed in the current report.

Kakazu E, Kanno N, Ueno Y, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan. · J Immunol. · Pubmed #17982106 links to  free full text

Abstract: The functions of dendritic cells (DCs) are impaired in patients with liver cirrhosis. It is well-known that cirrhotic patients show decreased levels of plasma branched-chain amino acids (BCAA). Although amino acids are associated with maintaining the cell structure and function in many organs, limited data are available regarding the role of amino acids including BCAA in the immune system. We aimed to investigate the roles of BCAA in the function of human monocyte-derived DCs (MoDC). CD14-positive monocytes (CD14 (+)) were isolated from PBMC from healthy volunteers and hepatitis C virus (HCV) cirrhotic patients. In medium deprived of BCAA or valine, monocytes were able to differentiate into immature, but not into mature, DCs and showed weak expression of CD83. The deprivation of leucine or isoleucine did not affect this process. The MoDC allostimulatory capacity was significantly decreased in medium deprived of BCAA or valine (p = 0.017, p = 0.012, Bonferroni's analysis, respectively). Annexin V(FITC)/propidium iodide staining showed that the DC yield and viability were not significantly different under any medium. Immunoblotting demonstrated that depletion of valine or leucine decreased phospho-S6 kinase expression. Valine increased dose-dependently the allostimulatory capacity and IL-12 production of MoDC from both healthy volunteers and HCV cirrhotic patients. An elevated extracellular concentration of valine could improve the DC function in cirrhotic patients. These data provide a rationale for nutrition therapy that could be beneficial to patients with cirrhosis.

Kogure T, Ueno Y, Fukushima K, Nagasaki F, Inoue J, Kakazu E, Matsuda Y, Kido O, Nakagome Y, Kimura O, Obara N, Wakui Y, Iwasaki T, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai City 980-8574, Japan. · World J Gastroenterol. · Pubmed #17708618 links to  free full text

Abstract: A 27-year-old Caucasian female with hepatitis C virus (HCV) infection treated with interferon (IFN) who developed severe autoimmune hepatitis (AIH) is described. The infecting viral strain was of genotype Ib and the pre-treatment HCV viral load was at a high level. The patient was treated with pegylated IFN-alpha 2b and ribavirin, and her HCV-RNA became negative at wk 12, but after that she developed fulminant hepatic failure. The patient recovered after steroid pulse therapy consisting of methylprednisolone 1000 mg/d for three days which was administered twice. A needle liver biopsy revealed the typical pathological findings of AIH.

Shibazaki K, Iguchi Y, Kimura K, Wada K, Ueno Y, Sunada Y. · Stroke Center, Department of Neurology, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama, 701-0192, Japan. · J Clin Neurosci. · Pubmed #17493820 No free full text.

Abstract: Central nervous system involvement in hepatitis C virus (HCV)-related cryoglobulinemia is uncommon. We report a patient with HCV-related type II mixed cryoglobulinemia who suffered a transient ischemic attack (TIA) associated with deep venous thrombosis and pulmonary embolism. The mechanism of TIA was diagnosed as paradoxical embolism, and we suspect that the cause of the TIA was associated with HCV-related type II mixed cryoglobulinemia.

Shiina M, Kobayashi K, Kobayashi T, Kondo Y, Ueno Y, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · J Gastroenterol. · Pubmed #16988764 No free full text.

Abstract: BACKGROUND: The cellular immune response is important in chronic hepatitis C (CHC). To better understand its mechanism, we examined dendritic cells (DCs) and hepatitis C virus (HCV)-specific cytotoxic T cells (CTLs), which are thought to contribute to liver injury and viral clearance. METHODS: CHC patients received 24 weeks of interferon-alpha-based antiviral therapy. We analyzed time-sequential frequencies of peripheral DCs, classified as myeloid DCs (mDCs) or plasmacytoid DCs (pDCs), together with peptide major histocompatibility class I tetramers, epitope specific for HCV core 129-137 (t*24/c129) or HCV NS3 1296-1304 (t*24/ns1294), directly ex vivo. RESULTS: The mDC and pDC populations changed in parallel (P < 0.05), showing a significant transient decrease at weeks 12 and 16 during the therapy, and then recovering. However, neither of the tetramer results showed a direct correlation with the kinetics of peripheral DCs. CONCLUSIONS: There is an apparent effect of antiviral therapy or a subsequent reduction of HCV on host immunity, but the effect may not include the induction of CTLs in CHC.

Nagasaki F, Ueno Y, Yamamoto T, Nakagomi Y, Kido O, Kakazu E, Matsuda Y, Kogure T, Yamagiwa Y, Kikuchi K, Fukushima K, Kanno N, Niitsuma H, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan. · Tohoku J Exp Med. · Pubmed #16960342 links to  free full text

Abstract: Hepatitis B virus (HBV) infection, which causes liver cirrhosis and hepatocellular carcinoma, remains a major health problem in Asian countries. Recent development of vaccine for prevention is reported to be successful in reducing the size of chronically infected carriers, although the standard medical therapies have not been established up to now. In this report, we encountered a patient with decompensated HBV-related cirrhosis who exhibited the dramatic improvements after antiviral therapy. The patient was a 50-year-old woman. Previous conventional medical treatments were not effective for this patient, thus this patient had been referred to our hospital. However, the administration of lamivudine, a reverse transcriptase inhibitor, for 23 months dramatically improved her liver severity. During this period, no drug resistant mutant HBV emerged, and the serum HBV-DNA level was continuously suppressed. These virological responses were also maintained even after the antiviral therapy was discontinued. Moreover, both hepatitis B surface antigen and e antigen were observed to have disappeared in this patient. The administration of lamivudine to patients with HBV-related cirrhosis, like our present case, should be considered as an initial medical therapeutic option, especially in countries where liver transplantation is not reliably available.

Kogure T, Ueno Y, Kanno N, Fukushima K, Yamagiwa Y, Nagasaki F, Kakazu E, Matsuda Y, Kido O, Nakagome Y, Ninomiya M, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai 980-8574, Japan. · World J Gastroenterol. · Pubmed #16937453 links to  free full text

Abstract: A 29-year-old nurse with a hepatitis C virus (HCV) infection caused by needle-stick injury was treated with interferon-beta starting about one year after the onset of acute hepatitis. The patient developed acute hepatitis C with symptoms of general fatigues, jaundice, and ascites 4 wk after the needle-stick injury. When these symptoms were presented, the patient was pregnant by artificial insemination. She hoped to continue her pregnancy. After delivery, biochemical liver enzyme returned to normal levels. Nevertheless, HCV RNA was positive and the pathological finding indicated a progression to chronicity. The genotype was 1b with low viral load. Daily intravenous injection of interferon-beta at the dosage of six million units was started and continued for eight weeks. HCV was eradicated without severe adverse effects. In acute hepatitis C, delaying therapy is considered to reduce the efficacy but interferon-beta therapy is one of the useful treatments for hepatitis C infection in chronic phase.

Kondo Y, Kobayashi K, Ueno Y, Shiina M, Niitsuma H, Kanno N, Kobayashi T, Shimosegawa T. · Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. · World J Gastroenterol. · Pubmed #16865771 links to  free full text

Abstract: AIM: To study the mechanisms of hyporesponsiveness of HBV-specific CD4+ T cells by testing TH1 and TH2 commitment and regulatory T cells. METHODS: Nine patients with chronic hepatitis B were enrolled. Peripheral blood mononuclear cells were stimulated with HBcAg or HBsAg to evaluate their potential to commit to TH1 and TH2 differentiation. HBcAg-specific activity of regulatory T cells was evaluated by staining with antibodies to CD4, CD25, CTLA-4 and interleukin-10. The role of regulatory T cells was further assessed by treatment with anti-interleukin-10 antibody and depletion of CD4+CD25+ cells. RESULTS: Level of mRNAs for T-bet, IL-12R beta2 and IL-4 was significantly lower in the patients than in healthy subjects with HBcAg stimulation. Although populations of CD4+CD25highCTLA-4+ T cells were not different between the patients and healthy subjects, IL-10 secreting cells were found in CD4+ cells and CD4+CD25+ cells in the patients in response to HBcAg, and they were not found in cells which were stimulated with HBsAg. Addition of anti-IL-10 antibody recovered the amount of HBcAg-specific TH1 antibody compared with control antibody (P < 0.01, 0.34% +/- 0.12% vs 0.15% +/- 0.04%). Deletion of CD4+CD25+ T cells increased the amount of HBcAg-specific TH1 antibody when compared with lymphocytes reconstituted using regulatory T cells (P < 0.01, 0.03% +/- 0.02% vs 0.18% +/- 0.05%). CONCLUSION: The results indicate that the mechanism of T cell hyporesponsiveness to HBcAg includes activation of HBcAg-induced regulatory T cells in contrast to an increase in TH2-committed cells in response to HBsAg.

Nagasaki F, Niitsuma H, Cervantes JG, Chiba M, Hong S, Ojima T, Ueno Y, Bondoc E, Kobayashi K, Ishii M, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan. · J Gen Virol. · Pubmed #16603518 links to  free full text

Abstract: The entire nucleotide sequences were determined for hepatitis B virus (HBV) genotype B (HBV/B) genomes extracted from five patients in the Philippines and designated GenBank AB219426, AB219427, AB219428, AB219429 and AB219430. The serotype of the first four isolates was ayw and that of GenBank AB219430 was adw. Divergences of entire sequences were 1.0-2.0 % between the first four isolates and 3.8-4.2 % between these four and GenBank AB219430. Phylogenetic-tree analysis revealed that, worldwide, HBV/B comprises five subgenotypes: B1, B2, B3, B4 and the new Philippines group, designated B5. Divergences of the entire genome sequences between four isolates in subgenotype B5 and isolates from other countries (subgenotypes) were 4.4-4.8 % with Vietnam (B4), 2.9-3.5 % with Indonesia (B3), 4.7-5.1 % with China (B2) and 5.4-6.0 % with Japan (B1). Similarly, GenBank AB219430 showed the lowest divergences: 3.4 % with the isolate from Indonesia (B3), 5.0 % with Vietnam (B4), 5.4 % with China (B2) and 6.1 % with Japan (B1). This is the first report of entire nucleotide sequences of HBV/B from the Philippines and the results show that these sequences belong to a new subgenotype, B5. The present study identified that HBV/B isolates throughout the world are divided genetically into five subgenotypes, the relationships between geographical distances and the genetic distances of HBV/B being well-correlated.

Tamai K, Fukushima K, Ueno Y, Moritoki Y, Yamagiwa Y, Kanno N, Jefferson DM, Shimosegawa T. · Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574, Japan. · Hepatol Res. · Pubmed #16406793 No free full text.

Abstract: Aquaporins (AQPs) are the channel forming membranous proteins involved in the biliary physiological homeostasis. Recently, we have reported the heterogeneous expression of AQPs in intrahepatic biliary epithelial cells or cholangiocytes in mice. However, the involvements of AQPs in hepatobiliary disorder are still unclear. Thus, we hypothesized that the AQP protein expressions are altered in human cholestatic disorders. METHODS: The AQP expressions of the immortalized human cholangiocytes cell line (H69) were assessed by immunoblotting. The expression of AQPs in liver biopsy specimens from various human cholestatic diseases as well as viral hepatitis were evaluated immunohistochemically. The degrees of staining were classified into four grades by comparison with staining intensity from controls. RESULTS: AQP1 expression, predominantly membranous, was confirmed by immunoblotting analysis. However, the other subtypes of AQP expression were not detected. In human pathological tissues, AQP1 expression by interlobular bile ducts was similar to normal and viral hepatitis, although this expression was attenuated according to bile duct injuries in PBC. On the contrary, the AQP1 expression by proliferating bile ductile (equivalent for small cholangiocytes) was enhanced. In intrahepatic cholestasis, AQP1 expressions were diminished, which was further associated with the aberrant expressions by periportal hepatocytes. CONCLUSIONS: AQP1 was expressed intensely in smaller proliferating bile ducts in human cholestatic liver disease. Also, the AQP1 expression was decreased in injured duct cells undergoing degeneration in PBC. The AQP1 expression was decreased in intrahepatic cholestasis probably due to negative feed back of the decreased bile flow. The role of AQP expression profiles may help the understanding of the pathogenesis of human cholestatic liver diseases.

Kobayashi K, Ueno Y, Kobayashi Y, Akahane T, Satoh S, Kikuchi K, Okamoto H, Ishii M, Shimosegawa T, Anonymous00008. · Tohoku University, School of Health Sciences and Comprehensive Research and Education, Center for Planning of Drug Development and Clinical Evaluation, Japan. · Hepatol Res. · Pubmed #16377237 No free full text.

Abstract: Ribavirin and interferon-alpha induce Th1 polarization of human CD4+ T cells. The study was conducted to investigate the whether cellular immune response during ribavirin/interferon-alpha therapy is associated with viral eradication by examining mRNA expression of molecules relevant to Th1 and Th2 polarization in CD4+ cells of 13 patients with chronic hepatitis C (seven patients with sustained viral response and six with transient response). Peripheral CD4+ T lymphocytes at 0, 4 and 24 weeks of treatment were tested. There were no significant differences in the mRNA levels at each point of time of the treatment between patients with sustained viral response and those with transient response. The percent increase in mRNA level of the IL-12R beta2 chain from the baseline to the end of the treatment was significantly higher in patients with sustained viral response (15.3+/-6.1%) than in those with transient response (-1.6+/-4.7%, p<0.05). There was no significant difference in percent changes in level of IL-12R beta1 chain mRNA between the two groups. In conclusion, the results of this study indicate that the increase of Th1 response is related to the inflammatory activity in the liver and possibly to ribavirin and interferon-alpha therapy. It is also suggested that the measurement of Th1 response has the potential to distinguish patients with relapse from those with sustained virus response.