Hepatitis: Tokyo

Sato N. · Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan. · J Gastroenterol Hepatol. · Pubmed #17567455 No free full text.

Abstract: Mitochondria play a central role in cellular energy metabolism. Oxidative phosphorylation occurs in the electron transport system of the inner mitochondrial membrane. Cytochrome aa3, b and c1 are encoded by mitochondrial DNA whereas cytochrome c is encoded by the nuclear gene, and these mitochondrial-DNA dependent cytochromes are decreased and electron transport at complex II, III and IV is disturbed in liver carcinomas and during carcinogenesis. The more the decreased cytochrome and oxidase activity are seen, the more significant is the increase in reactive oxygen species (ROS) production. ROS produced in mitochondria may be the main cause of nuclear-gene mutation in carcinogenesis. The mitochondrial dysfunction and overproduction of ROS plays a key role in progression of chronic hepatitis C and ethanol-induced liver injury. Ethanol also causes bacterial translocation in the intestine and the resulting lipopolysaccharides (LPS) activates Kupffer cells to produce pro-inflammatory cytokines. We suspect that non-alcoholic steatohepatitis (NASH) also is the result of increased ROS production in Kupffer cells and hepatocytes.

Yotsuyanagi H, Koike K. · Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan. · J Gastroenterol. · Pubmed #17530355 No free full text.

Abstract: Treatments for infections with hepatitis B and C viruses have recently developed markedly, and range from nonspecific interferon-based treatments to specific antiviral treatments, such as those that inhibit hepatitis virus-coded protein production or activity. These developments have contributed to the achievement of excellent enhancement of the antiviral effect. On the other hand, the development of specific antiviral therapies has created unprecedented problems. Antiviral drug-resistant strains of viruses have emerged, leading to a poor prognosis for infected patients. Clarification of the mechanisms underlying the emergence of such resistance to drugs will be useful for the treatment of such patients. In this review, we outline pathological conditions associated with hepatitis B and C viruses and their treatments, and discuss the current situation and mechanisms underlying the emergence of antiviral drug-resistant strains.

Mishiro S. · Department of Medical Sciences, Toshiba General Hospital, 6-3-22 Higashi Oh-i, Shinagawa-ku, Tokyo 140-8522, Japan. · Shokuhin Eiseigaku Zasshi. · Pubmed #17515107 No free full text.

This publication has no abstract.

Midorikawa Y, Makuuchi M, Tang W, Aburatani H. · Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo 113-8655, Japan. · World J Gastroenterol. · Pubmed #17461438 links to  free full text

Abstract: Accumulation of mutations and alterations in the expression of various genes result in carcinogenesis, and the development of microarray technology has enabled us to identify the comprehensive gene expression alterations in oncogenesis. Many studies have applied this technology for hepatocellular carcinoma (HCC), and identified a number of candidate genes useful as biomarkers in cancer staging, prediction of recurrence and prognosis, and treatment selection. Some of these target molecules have been used to develop new serum diagnostic markers and therapeutic targets against HCC to benefit patients. Previously, we compared gene expression profiling data with classification based on clinicopathological features, such as hepatitis viral infection or liver cancer progression. The next era of gene expression analysis will require systematic integration of expression profiles with other types of biological information, such as genomic locus, gene function, and sequence information. We have reported integration between expression profiles and locus information, which is effective in detecting structural genomic abnormalities, such as chromosomal gains and losses, in which we showed that gene expression profiles are subject to chromosomal bias. Furthermore, array-based comparative genomic hybridization analysis and allelic dosage analysis using genotyping arrays for HCC were also reviewed, with comparison of conventional methods.

Yotsuyanagi H, Koike K. · Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo. · Nippon Rinsho. · Pubmed #17455669 No free full text.

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Okuda H. · Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo 162-8666, Japan. · Best Pract Res Clin Gastroenterol. · Pubmed #17223503 No free full text.

Abstract: The development of hepatocellular carcinoma (HCC), the mechanisms of hepatocarcinogenesis, the prevention of HCC, and screening for HCC will be discussed. Cirrhosis has been considered as a pre-neoplastic condition for the development of HCC. The worldwide incidence of HCC differs according to different hepatitis viruses, and information is lacking. Hepatocarcinogenesis is a multistep process involving a number of different genetic alterations and is poorly understood. Interferon should help prevent the development of HCC in patients with chronic hepatitis C. Screening is the only practical approach for improving the management of HCC patients, as early detection increases the application of curative treatments. However, the cost-effectiveness of various screening strategies needs to be analysed.

Koike K. · Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · J Infect Chemother. · Pubmed #17109084 No free full text.

Abstract: Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis. A substantial proportion of patients with chronic hepatitis C eventually develop hepatocellular carcinoma (HCC), which is one of the leading causes of death worldwide. Therefore, efficient antiviral treatments for HCV have long been needed. A recently developed combination therapy of pegylated interferon and ribavirin has dramatically improved the outcome of antiviral therapy for HCV infection. In genotype 1b HCV infection, 48 weeks of the combination therapy achieved eradication of the virus in 50% of patients, and in genotype 2 HCV infection, 24 weeks of the therapy resulted in viral eradication in 80%-90% of patients. By this eradication, an improvement in the hepatic fibrosis, an inhibition of HCC development, and an improvement in life expectancy were attained. Patients who did not respond to the combination therapy may be treated with long-term interferon monotherapy, which is not intended to eradicate HCV, but will lower the serum alanine aminotransferase (ALT) level. Thus, the treatment for HCV infection has progressed significantly, but therapies with new modalities, such as inhibitors of viral protease or RNA polymerase, are still being awaited.

Sugawara Y, Makuuchi M. · Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. · J Hepatobiliary Pancreat Surg. · Pubmed #17013710 No free full text.

Abstract: In the absence of preventative therapy, deceased-donor liver transplantation indicated for hepatitis B virus (HBV) cirrhosis results in dismal graft and patient survival due to HBV infection of the liver graft. Major advances in the management of HBV-infected recipients during the past 15 years have reduced the rate of graft infection, resulting in improved outcomes, comparable to those for patients transplanted for non-HBV indications. Long-term use of hepatitis B immunoglobulin for passive immunotherapy is effective in preventing re-infection. Combination therapy with hepatitis B immunoglobulin and lamivudine after liver transplantation reduces HBV recurrence. Adefovir dipoxil is a safe and effective alternative oral antiviral treatment for lamivudine-resistant mutant HBV. The high cost of hepatitis B immunoglobulin remains a problem that must be overcome by the development of HBV vaccines and potent adjuvants.

Ueda J, Yoshida H, Mamada Y, Taniai N, Mizuguchi Y, Shimizu T, Matsumoto S, Kakinuma D, Ishikawa Y, Kanda T, Akimaru K, Teranishi N, Naito Z, Tajiri T. · Surgery for Organ Function and Biological Regulation, Nippon Medical School Graduate School of Medicine, Tokyo, Japan. · J Nippon Med Sch. · Pubmed #16936448 links to  free full text

Abstract: We report a rare case of bleeding ileal varices successfully treated with emergency enterectomy. A 72-year old woman with hepatic cirrhosis due to hepatitis C was admitted to our hospital because of anemia and hematochezia. An endoscopic examination showed no evidence of bleeding in the upper and lower gastrointestinal tracts. Angiographic studies of portal hemodynamics revealed extravasation from the ileal varices and total occlusion of the portal vein due to portal thrombus. This made it difficult to remove the ileal varices using interventional radiology. Therefore, the patient underwent emergency enterectomy for the ileal varices. No further gastrointestinal bleeding occurred during the 1-year follow-up.

Sugawara Y, Makuuchi M. · Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. · World J Gastroenterol. · Pubmed #16874855 links to  free full text

Abstract: Living donor liver transplantation (LDLT) is an alternative therapeutic option for patients with end-stage hepatitis C virus (HCV) cirrhosis because of the cadaveric organ shortage. HCV infection is now a leading indication for LDLT among adults worldwide, and there is a worse prognosis with HCV recurrence. The antivirus strategy after transplantation, however, is currently under debate. Recent updates on the clinical and therapeutic aspects of living donor liver transplantation for HCV are discussed in the present review.

Horie Y, HiBi T, Ishii H. · Department of Internal Medicine, School of Medicine, Keio University. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #16869379 No free full text.

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Yugi H, Mizui M, Tanaka J, Yoshizawa H. · Department of NAT, Central Blood Institute, Japanese Red Cross Society Tokyo, Japan. · J Clin Virol. · Pubmed #16831695 No free full text.

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Sato K. · Institute of Clinical Endocrinology, Tokyo Women's Medical University. · Nippon Rinsho. · Pubmed #16776206 No free full text.

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Ishii H. · Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Keio University. · Nippon Rinsho. · Pubmed #16768104 No free full text.

Abstract: Since the first report by Ludwig, considerable progress has been made in the understanding of NASH and it is not currently considered as a merely benign clinical entity, but is rather thought as a common disease with a variety of clinical sequelae including liver cirrhosis and even hepatocellular carcinoma. Thus, NASH is considered as a type of a larger spectrum of nonalcoholic fatty liver disease (NAFLD) that is a consequence of insulin resistance and other underlining factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. In this brief review article, particular emphasis has been paid to the clinical entity, namely cryptogenic cirrhosis in relation to the pathogenesis of NASH.

Moriyama M, Arakawa Y. · Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan. · Expert Opin Pharmacother. · Pubmed #16732703 No free full text.

Abstract: Combination therapy with polyethylene glycosylated IFN-alpha2a or IFN-alpha2b and ribavirin is currently the standard therapy for chronic hepatitis C. However, even with this therapy, hepatitis C virus cannot be eradicated in 50% of patients with refractory chronic hepatitis C. In addition, withdrawal or dose reduction occurs in approximately 40% of patients due to adverse effects. This treatment is also a contraindication in some patients, such as in patients with coexisting diseases or in elderly patients. For these patients, standard IFN-alpha monotherapy is even safer and more effective. In patients with chronic hepatitis C, IFN-alpha monotherapy results in a significant increase in the cumulative survival rate by suppressing the progression to hepatocellular carcinoma or liver failure. In addition, other efficacious therapeutic regimens have been employed, such as prolonged administration of standard IFN-alpha in elderly patients; prolonged low-dose continuous administration in patients with decompensated cirrhosis or hepatocellular carcinoma postoperative patients; and combination therapy with 5-fluorouracil and standard IFN-alpha for advanced hepatocellular carcinoma. Monotherapy with standard IFN-alpha should thus be recognised as one of the important therapeutic strategies for chronic hepatitis C.

Aizaki H, Suzuki T, Miyamura T, Lai MM. · Department of Virology II, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan. · Seikagaku. · Pubmed #16715972 No free full text.

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Kato T, Wakita T. · Department of Microbiology, Tokyo Metropolitan Institute for Neuroscience, Tokyo. · Uirusu. · Pubmed #16557015 links to  free full text

Abstract: Hepatitis C virus (HCV) is a major public health problem, infecting an estimated 170 million people worldwide. Current therapy for HCV-related chronic hepatitis is based on the use of interferon. However, virus clearance rates are insufficient. Investigations to develop the anti-viral therapy or to understand the life cycle of this virus have been hampered by the lack of viral culture systems. We isolated the JFH-1 strain from a patient with fulminant hepatitis, and the JFH-1 subgenomic replicon could replicate efficiently in culture cell without adaptive mutation. Recently, we developed the HCV infection system in culture cells with this JFH-1 strain. The full-length JFH-1 RNA was transfected into Huh7 cells. Subsequently, viral RNA efficiently replicated in transfected cells and viral particles were secreted. Furthermore, secreted virus displayed infectivity for naive Huh7 cells. This system provides a powerful tool for studying the viral life cycle and constructing anti-viral strategies.

Sugawara Y, Makuuchi M. · Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. · Br Med Bull. · Pubmed #16474043 No free full text.

Abstract: The first successful living donor liver transplantation (LDLT) was performed in a child in 1989 in Brisbane and in an adult in 1994 by the Shinshu group. Over the past few years, LDLT has increased worldwide and is now an established alternative to deceased donor liver transplantation. The surgical procedures for LDLT are more technically challenging than those for whole liver transplantation. LDLT requires a full understanding of the hepatobiliary anatomy and continuous technical refinement of the procedure. Some of the technical highlights include selective vascular occlusion techniques for donor hepatectomy, hepatic arterial reconstruction under the microscope and the introduction of intraoperative ultrasound, graft volume estimation and hepatic venous reconstruction, all of which have improved the success rate of LDLT over the past few years. This review focuses on recent trends and surgical techniques for LDLT.

Yamashina S, Ikejima K, Enomoto N, Takei Y, Sato N. · From the Department of Gastroenterology (SY, KI, NE, YT, NS), Juntendo University School of Medicine, Tokyo, Japan. · Alcohol Clin Exp Res. · Pubmed #16344603 No free full text.

Abstract: Activation of Kupffer cells by gut-derived endotoxin is an important factor in ethanol hepatotoxicity. Further, it was shown that ethanol modulates both the expression and activity of several intracellular signaling molecules and transcription factors in Kupffer cells and chronic ethanol treatment enhances Kupffer cell sensitivity to endotoxin. These findings suggest that inhibition of Kupffer cell activation is effective for clinical application in alcoholic hepatitis. Recently, accumulating lines of evidence suggest a possibility that glycine is useful as an immuno-modulating amino acid. It has been shown that a diet containing glycine improved survival in endotoxin shock by preventing Kupffer cell activation. Glycine most likely prevents the LPS-induced elevation of intracellular Ca concentration in Kupffer cells, thereby minimizing LPS receptor signaling and cytokine production. Indeed, glycine prevents alcohol-induced liver injury in a long-term enteral ethanol feeding rats (Tsukamoto-French) by decreasing production of TNF-alpha in the liver. Moreover, glycine is protective against apoptosis of sinusoidal endothelial cells (SECs) that is one of the initial events in the development of liver injury. On the other hand, epidemiologic data have identified chronic alcohol consumption as a significant risk factor for carcinogenesis. Interestingly, glycine inhibits growth of tumor in vivo most likely because of the inhibition of angiogenesis. It was shown that the inhibitory effect of glycine on growth and migration of endothelial cells is due to activation of a glycine-gated Cl channel. It is hypothesized that the opening of this anion channel hyperpolarizes the cell membrane, blocks influx of Ca through voltage-dependent Ca channel, thereby blunting growth factor-mediated signaling. Therefore, glycine can be used not only for treatment of alcoholic hepatitis, but also for chemoprevention and treatment of hepatocellular carcinoma in alcoholic cirrhosis. Taken together, it is concluded that glycine is a potent therapeutic immuno-nutrient for various kinds of chronic liver diseases including alcoholic liver disease (ALD).

Omata M, Yoshida H, Shiratori Y. · Department of Gastroenterology, University of Tokyo Graduate School of Medicine, Tokyo, Japan. · Clin Gastroenterol Hepatol. · Pubmed #16234063 No free full text.

Abstract: Chronic hepatitis C is a leading cause of hepatocellular carcinoma (HCC) worldwide. Prevention of chronic hepatitis C-related HCC is one of the most important issues in current hepatology. We conducted 2 cohort studies, one among patients with chronic hepatitis C mostly without cirrhosis and another among those with compensated cirrhosis, to confirm the prevention of HCC by interferon. We also conducted a randomized controlled study among patients with HCV-related HCC treated completely by ablation to examine the effect of interferon therapy on prognosis. With the chronic hepatitis C cohort, we showed that the risk of HCC development, which was strongly associated with the stage of liver fibrosis, age, and gender, was reduced by interferon therapy to one fifth among sustained virologic responders compared with untreated patients. Life expectancy was also significantly prolonged. The benefit of interferon therapy was greater among those with the higher risk of HCC. We confirmed efficacy in HCC-prevention in the second study among patients with compensated cirrhosis who received interferon therapy. The third study among HCC patients who had received complete tumor ablation showed that interferon therapy was associated with better survival, primarily as a result of the preservation of liver function and also probably prevention of recurrence. We have shown beneficial effects of interferon therapy on HCC prevention and liver function preservation. They were the strongest in sustained virologic responders. Further improvement in prognosis may be expected in the future because the current combination therapy of pegylated interferon and ribavirin shows higher efficiency than interferon alone.

Koike K. · Department of Infectious Diseases, Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. · Clin Gastroenterol Hepatol. · Pubmed #16234061 No free full text.

Abstract: Despite numerous lines of epidemiologic evidence connecting HCV infection and the development of hepatocellular carcinoma (HCC), it remains controversial whether HCV itself plays a direct role or an indirect role in the pathogenesis of HCC. Through the use of transgenic mice, it has become evident that the core protein of HCV has oncogenic potential. HCV is directly involved in hepatocarcinogenesis, albeit other factors such as inflammation and environmental factors might also play a role. The direct involvement of HCV in hepatocarcinogenesis would be achieved via 2 pathways. In one pathway, the core protein acts on the function of mitochondria, leading to the overproduction of oxidative stress, which yields genetic aberrations in cell growth-related genes. The other pathway involves the modulation of cellular gene expressions and intracellular signal transductions, such as mitogen-activated protein kinase pathway, which results in the activation of transcription factors and cell cycle machineries. The combination of these alterations would be hypothesized to provoke the development of HCC in HCV infection. This would be a mechanism for HCC development in HCV infection that is distinct from those for other cancers. The presence of the HCV core protein, to which an oncogenic potential is ascribed, might allow some of the multiple steps to be bypassed in hepatocarcinogenesis. Therefore, unlike in other cancers, HCV infection can elicit HCC in the absence of a complete set of genetic aberrations. Such a scenario, "non-Vogelstein type" carcinogenesis, may explain the unusually high incidence and multicentric nature of HCC development in HCV infection.

Hashimoto N, Ikeda Y, Toda G. · Department of Gastroenterology, Tokyo Teishin Hospital. · Nippon Rinsho. · Pubmed #16111359 No free full text.

This publication has no abstract.

Hosoda H, Okawa-Takatsuji M, Hasimoto N, Ikeda Y. · Department of Clinical Laboratory Medicine, Tokyo Kosei Nenkin Hospital. · Nippon Rinsho. · Pubmed #16111353 No free full text.

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Ikeda Y, Hashimoto N. · Department of Internal Medicine, Tokyo Kosei Nenkin Hospital. · Nippon Rinsho. · Pubmed #16111352 No free full text.

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Yamauchi K. · Institute of Gastroenterology, Tokyo Women's Medical University. · Nippon Rinsho. · Pubmed #16111329 No free full text.

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