Hepatitis: Kawata S

Saito T, Nishise Y, Ishii R, Watanabe H, Suzuki K, Kawata S. · Department of Gastroenterology, Yamagata University School of Medicine, Japan. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #19346718 No free full text.

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Saito T, Misawa K, Kawata S. · The Department of Gastroenterology, Yamagata University. · Intern Med. · Pubmed #17220609 links to  free full text

Abstract: Although steatohepatitis can be induced by an excessive intake of alcohol, it can also arise through various other causes, in which case it is known as non-alcoholic fatty liver disease (NAFLD). NAFLD is classified into two categories:simple fatty liver with a favorable clinical outcome, and non-alcoholic steatohepatitis (NASH), which is intractable and progressive. Recently in Japan, there has been an increase in the number of individuals at risk of lifestyle-related diseases, due to increased insulin resistance and visceral fat obesity. The metabolic syndrome (MS) is associated with several risk factors for atherosclerosis, including diabetes mellitus (DM), hypertension, and hyperlipidemia. Visceral fat obesity is the prime cause of NASH in the liver, and is therefore considered to be one of the phenotypic features of MS. Furthermore, most chronic liver diseases are associated with hepatitis C virus (HCV) infection. Fatty degeneration of hepatocytes is often observed in the liver of HCV-infected individuals, and results from viral suppression of mitochondrial beta-oxidation of fatty acid. The natural outcome of HCV infection is worse in patients with lifestyle-related high insulin resistance and visceral fat obesity. In this review, we describe the recent advances in research on progressive liver diseases that are the result of fat accumulation in the liver, with special reference to MS.

Saito T, Misawa K, Kawata S. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #16223146 No free full text.

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Saito T, Watanabe H, Togashi H, Kawata S. · Division of Gastroenterology, Department of Internal Medicine and Molecular Therapeutics, Yamagata University School of Medicine. · Nippon Rinsho. · Pubmed #15453339 No free full text.

This publication has no abstract.

Murakami T, Hori M, Kim T, Kawata S, Abe H, Nakamura H. · Department of Radiology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan. · Intervirology. · Pubmed #15383731 No free full text.

Abstract: It is important to diagnose hepatocellular carcinoma (HCC) correctly and in early stage, because viral hepatitis and liver cirrhosis are often complicated by HCC. Noncontrast and enhanced CT and MRI are very useful to visualize and diagnose HCC objectively. Especially, CT and MR imaging with dynamic study is essential to diagnose HCC, because it is usually hypervascular. Dynamic CT and MR study also improve differential diagnosis in the characterization of the tumor. However, to perform useful dynamic study, it is necessary to use a CT unit which can make a helical scan, or a MR system with fast imaging technique available that can obtain more than 15 slices within a single breath hold. Tissue specific contrast medium, such as superparamagnetic iron oxide that is available only on MRI, is also useful for diagnosis of HCC.

Saito T, Ji G, Shinzawa H, Okumoto K, Hattori E, Adachi T, Takeda T, Sugahara K, Ito JI, Watanabe H, Saito K, Togashi H, Ishii K, Matsuura T, Inageda K, Muramatsu M, Kawata S. · Division of Gastroenterology, Department of Internal Medicine and Molecular Therapeutics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. · Biochem Biophys Res Commun. · Pubmed #15063762 No free full text.

Abstract: The outcome of hepatitis C virus (HCV) infection varies among individuals, but the genetic factors involved remain unknown. We conducted a population-based association study in which 238 Japanese individuals positive for anti-HCV antibody were genotyped for 269 single nucleotide polymorphisms (SNPs) in 103 candidate genes that might influence the course of infection. Altogether, 50 SNPs in 32 genes were listed. Genetic polymorphisms in IL4, IL8RB, IL10RA, PRL, ADA, NFKB1, GRAP2, CABIN1, IFNAR2, IFI27, IFI41, TNFRSF1A, ALDOB, AP1B1, SULT2B1, EGF, EGFR, TGFB1, LTBP2, and CD4 were associated with persistent viremia (P < 0.05), whereas those in IL1B, IL1RL1, IL2RB, IL12RB1, IL18R1, STAT5A, GRAP2, CABIN1, IFNAR1, Mx1, BMP8, FGL1, LTBP2, CD34, and CD80 were associated with different serum alanine aminotransferase levels in HCV carriers (P < 0.05). The sorted genes allow us to draw novel hypotheses for future studies of HCV infection to ultimately identify bona fide genes and their variations.

Terui Y, Saito T, Watanabe H, Togashi H, Kawata S, Kamada Y, Sakuta S. · No affiliation provided · Hepatology. · Pubmed #12297856 No free full text.

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Saito T, Nishise Y, Makino N, Haga H, Ishii R, Okumoto K, Ito JI, Watanabe H, Saito K, Takeda H, Togashi H, Kubota I, Daimon M, Kato T, Kawata S. · Department of Gastroenterology, Yamagata University School of Medicine, Yamagata 990-9585, Japan. · Metabolism. · Pubmed #19411086 No free full text.

Abstract: Measurement of the serum alanine aminotransferase (ALT) level is used as an initial test for detection of liver diseases, and recent studies have also highlighted its potential value as a measure of overall health and survival as a marker of an increased risk of metabolic disorder. This study was designed to clarify the prevalence of elevated ALT levels in the Japanese population and to assess factors associated with ALT elevation. The subjects were 2165 individuals aged 40 to 85 years who participated in a Japanese community-based study referred to as the Takahata Study. Serum ALT levels and factors associated with ALT elevation were investigated. Among 2087 subjects who were negative for hepatitis B and C, the rates of elevated ALT greater than 30 U/L in men and greater than 25 U/L in women were 217 (22.7%) of 957 and 239 (21.2%) of 1130, respectively. These ALT cutoff levels had a specificity of more than 80% for exclusion of subjects with none or 1 of 3 metabolic risk factors: hypertension, lipid metabolism abnormality, and hyperglycemia. Multivariate analysis revealed 5 factors with a significant association with ALT elevation in men (n = 957): high gamma-glutamyltranspeptidase, low adiponectin, high low-density lipoprotein cholesterol, high body mass index, and high homeostasis model assessment insulin resistance index. Similarly, 4 factors were significantly associated with ALT elevation in women (n = 1130): high gamma-glutamyltranspeptidase, low adiponectin, high body mass index, and high homeostasis model assessment insulin resistance index. These results suggest that elevated ALT levels in the Japanese population older than 40 years have a strong association with metabolic syndrome-related features including obesity and insulin resistance.

Matsuura K, Tanaka Y, Hige S, Yamada G, Murawaki Y, Komatsu M, Kuramitsu T, Kawata S, Tanaka E, Izumi N, Okuse C, Kakumu S, Okanoue T, Hino K, Hiasa Y, Sata M, Maeshiro T, Sugauchi F, Nojiri S, Joh T, Miyakawa Y, Mizokami M. · Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Japan. · J Clin Microbiol. · Pubmed #19297602 No free full text.

Abstract: Acute hepatitis B virus (HBV) infection has been increasing through promiscuous sexual contacts, and HBV genotype A (HBV/A) is frequent in patients with acute hepatitis B (AHB) in Japan. To compare the geographic distribution of HBV genotypes in patients with chronic hepatitis B (CHB) in Japan between 2005 and 2006 and between 2000 and 2001, with special attention to changes in the proportion of HBV/A, a cohort study was performed to survey changes in genotypes of CHB patients at 16 hospitals throughout Japan. Furthermore, we investigated the clinical characteristics of each genotype and examined the genomic characteristics of HBV/A isolates by molecular evolutionary analyses. Of the 1,271 patients, 3.5%, 14.1%, and 82.3% were infected with HBV/A, -B, and -C, respectively. In comparison with our previous survey during 2000 and 2001, HBV/A was twice as frequent (3.5% versus 1.7%; P = 0.02). The mean age was lower in the patients with HBV/A than in those with HBV/B or -C. Based on phylogenetic analyses of 11 full-length genomes and 29 pre-S2/S region sequences from patients, HBV/A isolates were imported from Europe and the United States, as well as the Philippines and India. They clustered with HBV/A from AHB patients and have spread throughout Japan. HBV/A has been increasing in CHB patients in Japan as a consequence of AHB spreading in the younger generation through promiscuous sexual contacts, aided by a tendency of HBV/A to induce chronic hepatitis. The spread of HBV/A infection in Japan should be prevented by universal vaccination programs.

Karasawa T, Togashi H, Tajima K, Suzuki A, Onodera S, Haga H, Ishii R, Misawa K, Sanjo M, Okumoto K, Nishise Y, Ito J, Sugahara K, Saito K, Saito T, Kawata S. · Department of Gastroenterology, Yamagata University Faculty of Medicine, Japan. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #19262055 No free full text.

Abstract: We report a case of chronic hepatitis C complicated with idiopathic thrombocytopenic purpura (ITP), successfully treated with interferon (IFN) beta. A 65-year-old woman was admitted to our hospital for the treatment of chronic hepatitis C with IFN beta. ITP was also diagnosed because of the presence of platelet associated IgG and the findings of bone marrow examination. We started IFN therapy, which resulted in normalization of transaminases, complete HCV eradication, and increased number of platelet.

Togashi H, Hashimoto C, Yokozawa J, Suzuki A, Sugahara K, Saito T, Yamaguchi I, Badawi H, Kainuma N, Aoyama M, Ohya H, Akatsuka T, Tanaka Y, Mizokami M, Kawata S. · Department of Gastroenterology, Course of Internal Medicine and Therapeutics, Yamagata University Faculty of Medicine, Yamagata University Health Administration Center, 1-4-12 Kojirakawa-machi, Yamagata 990-8560, Japan. · J Hepatol. · Pubmed #18479773 No free full text.

Abstract: BACKGROUND/AIMS: We investigated what can be revealed by extending the sensitivity of HBsAg detection to below the present limit. METHODS: We examined the sensitivity of this immunoassay in comparison with real-time PCR detection of HBV DNA using serially diluted sera from HBV carriers. Low HBsAg was measured in 210 healthy volunteers and 368 patients with non-B chronic liver diseases who were negative for HBsAg by a standard EIA method. RESULTS: The radical immunoassay was able to detect HBsAg at a concentration of 0.025 ng/ml. Low HBsAg was positive in 6 of 210 normal volunteers (2.86%), 5 of 65 non-B, non-C cirrhosis patients (7.69%), 6 of 62 non-B, non-C hepatocellular carcinoma patients (9.68%: p=0.04 vs. volunteers), 12 of 134 chronic hepatitis C patients (8.96%: p<0.02 vs. volunteers), and 11 of 107 hepatocellular carcinoma patients complicated by chronic hepatitis C (10.28%: p<0.008 vs. volunteers). Although no HBV DNA was positive in healthy volunteers, 9 patients with non-B chronic liver diseases were positive for HBV DNA by real-time PCR analysis. CONCLUSIONS: Increasing the sensitivity of HBsAg detection to below the present limit has revealed that infection with HBV, including occult HBV, is far more endemic than suspected previously.

Sugahara K, Saito T, Watanabe H, Misawa K, Ishii R, Suzuki A, Haga H, Sanjo M, Okumoto K, Nishise Y, Ito J, Saito K, Togashi H, Kawata S. · Department of Gastroenterology, Yamagata University School of Medicine. · Nippon Shokakibyo Gakkai Zasshi. · Pubmed #17917401 No free full text.

Abstract: This report describes our experience with two cases of pyogenic spondylitis with chronic hepatitis C during combination therapy of interferon alfa and ribavirin. The first patient, a 59-year-old man, was treated conservatively and improved, but the second patient, a 69-year-old woman, was not improved by conservative therapy and reconstructive operation was performed. The combination therapy of interferon alfa and ribavirin has a high risk of severe infectious diseases as side effects. CT scan and MRI are recommended immediately to diagnose pyogenic spondylitis, when patients has pyrexia and lumbago with laboratory data suspected inflammation during interferon therapy.

Nishise Y, Saito T, Sugahara K, Ito JI, Saito K, Togashi H, Nagano-Fujii M, Hotta H, Kawata S. · Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan. · J Infect Dis. · Pubmed #17763321 No free full text.

Abstract: We conducted a retrospective study of 65 patients with chronic hepatitis C, to determine whether the secondary structure of the amino-terminal 120 residues of the hepatitis C virus (HCV) NS3 protein is associated with an increased risk of development of hepatocellular carcinoma (HCC). The cumulative incidence of HCC was highest among patients infected with group B HCV-1b, wherein the risk of HCC significantly increased compared with that among patients infected with group A (hazard ratio, 4.95 [95% CI, 1.43-17.11]) after adjustment for age and histological stage. This HCV-1b grouping may be a useful marker for detecting the risk of development of HCC.

Hiramatsu N, Kurashige N, Oze T, Takehara T, Tamura S, Kasahara A, Oshita M, Katayama K, Yoshihara H, Imai Y, Kato M, Kawata S, Tsubouchi H, Kumada H, Okanoue T, Kakumu S, Hayashi N. · Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan. · Hepatol Res. · Pubmed #17714473 No free full text.

Abstract: Aim: Ribavirin, used to treat chronic hepatitis C, can induce hemolytic anemia, forcing the discontinuance of treatment. To establish a predictive measure to help circumvent this, we evaluated the relationship of hemoglobin (Hb) decline with the discontinuance of treatment during the progression of ribavirin-induced anemia. Methods: One hundred and sixteen patients (71% male) with genotype 1 chronic hepatitis C were treated with pegylated interferon (PegIFN) alpha-2b and ribavirin. The mean age was 50.6 years and 55% were IFN naïve. A decline of Hb concentration by 2 g/dL at two weeks from the start of the treatment ("2 by 2" standard) was adopted as the predictive factor for the progression of anemia. Results: By applying the "2 by 2" standard, with DeltaHb >/= 2 g/dL (34%, n = 39), treatment was discontinued in 12 cases (31%), three of which (8%) because of severe anemia. ForDeltaHb < 2 g/dL (64%, n = 76), treatment was discontinued in 11 (14%) cases; none due to severe anemia. Ten percent (4/39) of patients showed the minimum Hb </= 8.5 g/dL in the DeltaHb >/= 2 g/dL group, with none in the DeltaHb < 2 g/dL group (P = 0.001). Furthermore, the patients with minimum Hb </= 8.5 g/dL were found only in the "2 by 2" standard-positive and low CL/F (<15) group (4/29, 14%). Conclusion: Monitoring the Hb decline using the "2 by 2" standard can identify patients who are prone to developing severe anemia. Further prospective studies are needed using ribavirin reduction based on the "2 by 2" standard.

Okumoto K, Saito T, Onodera M, Sakamoto A, Tanaka M, Hattori E, Haga H, Ito JI, Sugahara K, Saito K, Togashi H, Kawata S. · Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata City, Yamagata, Japan. · J Gastroenterol Hepatol. · Pubmed #17688667 No free full text.

Abstract: BACKGROUND AND AIM: Hematopoietic growth factors including stem cell factor (SCF), thrombopoietin (TPO) and granulocyte colony stimulating factor (G-CSF) have a potential role in inducing bone marrow hematopoietic stem cells to move into the circulation, and the association of these factors with liver regeneration has received a lot of attention recently. The aim of this study was to determine the serum levels of such factors in patients with acute liver injury. METHODS: The subjects were 25 patients with acute hepatitis (AH) who had a favorable prognosis and 26 patients with fulminant hepatitis (FH), of whom 11 were alive and 15 had died. Sixty-six healthy subjects matched for age and sex served as controls. Serum samples were collected before treatment, and the levels of SCF, TPO and G-CSF were measured using enzyme-linked immunosorbant assays. RESULTS: The levels of SCF and TPO were significantly lower in FH patients than in AH patients and the controls, and were also significantly lower in the FH patients who died, compared to the surviving patients. The G-CSF levels did not differ among them. CONCLUSIONS: These results suggest that low serum levels of SCF and TPO may be linked to poor prognosis in patients with severe liver injury.

Matsumoto A, Tanaka E, Minami M, Okanoue T, Yatsuhashi H, Nagaoka S, Suzuki F, Kobayashi M, Chayama K, Imamura M, Yotsuyanagi H, Nakaoka S, Maki N, Kawata S, Kumada H, Iino S, Kiyosawa K. · Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Hepatol Res. · Pubmed #17584261 No free full text.

Abstract: Aim: The clinical significance of hepatitis B virus (HBV) core-related antigen (HBcrAg) in predicting the reactivation of hepatitis after halting lamivudine administration was analyzed. Methods: A total of 34 patients with chronic hepatitis B were enrolled. Lamivudine was administered for at least 6 months before cessation, and reactivation of hepatitis was defined as elevation of alanine aminotransferase levels to more than 80 IU/L within 12 months of cessation. Results: In total, 20 (59%) patients experienced hepatitis reactivation. Although concentrations of HBV DNA and HBcrAg in serum did not differ between the two groups of patients at the onset of lamivudine administration, HBcrAg serum levels were significantly higher (P = 0.009) in the reactivation patients (median 4.9, 25-75% range 4.7- 5.9 log unit/mL) than the non-reactivation patients (median 3.2, 25-75% range <3.0-4.5 log unit/mL) post-lamivudine treatment. The concentration of HBV DNA did not differ between the two groups (median <3.7, 25-75% range <3.7-<3.7 log copy/mL in the reactivation group vs. median <3.7, 25-75% range <3.7-<3.7 log copy/mL in the non- reactivation group). Receiver operating characteristic analysis of HBcrAg concentration showed an area under the curve of 0.764 in predicting patients without reactivation of hepatitis. Conclusion: HBcrAg can be a useful marker to identify patients who are not at risk of reactivation of severe hepatitis after discontinuation of lamivudine administration.

Togashi H, Takahashi K, Onodera Y, Adachi T, Suzuki A, Karasawa T, Ishii R, Sugahara K, Okumoto K, Ito J, Saito T, Okada A, Sugai Y, Kawata S. · Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, 2-2-2 Iida-Nishi Yamagata 990-9585, Japan. · Hepatol Res. · Pubmed #16920400 No free full text.

Abstract: The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the sinusoidal surfaces of hepatocytes. However, regional expression and clinical significance of the ASGPR in acute hepatic damage is presently unknown. Our aim was to clarify the clinical significance of the regional expression of ASGPR in human livers with acute hepatitis (AH) and fulminant hepatic failure (FHF). Eighteen volunteers, 42 patients with AH and 10 with FHF were studied using a newly developed, conventional (99m)Tc-GSA SPECT analysis. Using Cantlie's line as a guide, ASGPR expression was analyzed separately in the right and left hepatic lobes, as well as in the whole liver, using novel indices (the liver uptake ratio [LUR] and liver uptake density [LUD], which reflect the amount and density of ASGPRs in the liver, respectively). Mean LUR and LUD values for the whole liver and the right and left lobes decreased in accordance with the severity of acute hepatic damage. In the FHF group, the reduction in LUR and LUD values in the right lobes was more significant than in the left lobes. The LUR and LUD values for the whole liver correlated well with hepatic functional reserve and total bilirubin levels. The right LUR and LUD values in particular correlated well with these parameters. A time-course observation of 13 patients with either AH or FHF revealed that the expression of ASGPRs in the right lobe recovered faster than in the left. We first evaluated the regional expression of AGSPRs by (99m)Tc-GSA SPECT analysis in both AH and FHF patients, which is a clinically useful and reliable indicator for assessing the severity of regional hepatic damage and evaluating regional liver regeneration.

Kimura T, Saito T, Yoshimura M, Yixuan S, Baba M, Ji G, Muramatsu M, Kawata S. · Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. · J Infect Dis. · Pubmed #16619184 No free full text.

Abstract: Transforming growth factor (TGF)-beta 1 suppresses the proliferation and cytotoxicity of natural killer (NK) cells, which play critical roles in resolving hepatitis C virus (HCV) infection, especially during the acute phase. We examined 230 anti-HCV antibody-positive subjects for HCV RNA and the -509T/C genotype in the TGF-beta 1 gene promoter. The -509CC genotype and the -509C allele were significantly associated with higher HCV clearance rates (P=.01) and with lower transcriptional activity. The genetic effect remained significant even after adjustment for a history of transfusion. Low TGF- beta 1 producers might have less suppression of NK cells and be more likely to resolve HCV infection.

Tanaka E, Matsumoto A, Suzuki F, Kobayashi M, Mizokami M, Tanaka Y, Okanoue T, Minami M, Chayama K, Imamura M, Yatsuhashi H, Nagaoka S, Yotsuyanagi H, Kawata S, Kimura T, Maki N, Iino S, Kiyosawa K, Anonymous00331. · Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan. · Liver Int. · Pubmed #16420514 No free full text.

Abstract: OBJECTIVE: The clinical usefulness of hepatitis B virus core-related antigen (HBVcrAg) assay was compared with that of HBV DNA assay in predicting the occurrence of lamivudine resistance in patients with chronic hepatitis B. PATIENTS: Of a total of 81 patients who were treated with lamivudine, 25 (31%) developed lamivudine resistance during a median follow-up period of 19.3 months. RESULTS: The pretreatment positive rate of HBe antigen, or pretreatment levels of HBVcrAg or HBV DNA did not differ between patients with and without lamivudine resistance. Levels of both HBVcrAg and HBV DNA decreased after the initiation of lamivudine administration; however, the level of HBVcrAg decreased significantly more slowly than that of HBV DNA. The occurrence of lamivudine resistance was significantly less frequent in the 56 patients whose HBV DNA level was less than 2.6 log copy/ml at 6 months of treatment than in the remaining 25 patients. The cumulative rate of lamivudine resistance was as high as 70% within 2 years in the latter group, while it was only 28% in the former group. Lamivudine resistance did not occur during the follow-up period in the 19 patients whose HBVcrAg level was less than 4.6 log U/ml at 6 months of treatment, while it did occur in 50% of the remaining patients within 2 years. CONCLUSION: These results suggest that measurement of HBV DNA is valuable for identifying patients who are at high risk of developing lamivudine resistance, and that, conversely, measurement of HBVcrAg is valuable for identifying those who are at low risk of lamivudine resistance.

Watanabe H, Saito T, Karasawa T, Kudo S, Nakano K, Ito JI, Sugahara K, Saito K, Togashi H, Kawata S. · Department of Gastroenterology, Faculty of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. · Hepatol Res. · Pubmed #16112898 No free full text.

Abstract: The efficacy of interferon (IFN) therapy for chronic hepatitis C is dependent on compliance. Anorexia is an important adverse effect in determining compliance. To clarify the mechanisms underlying anorexia, the level of ghrelin was determined during therapy. Fourteen patients with chronic hepatitis C received IFN-alpha2b with or without ribavirin (Rib+ or Rib- group; n=7 in each group) for 24 weeks. Serum ghrelin concentrations and body weight were determined before, 2 and 24 weeks after initiation of therapy. Serum ghrelin concentrations and body weight significantly decreased 2 weeks after initiation of therapy (P=0.0008 and 0.0062, respectively), and then returned to the level before therapy. The Deltaghrelin concentration correlated with Deltabody weight after 2 weeks (r=0.726, P=0.023). Percentage reduction of serum ghrelin was significantly higher in the Rib+ group than in the Rib- group (P=0.046). Percentage reduction in body weight tended to be higher in the Rib+ group (P=0.057). IFN-alpha2b therapy causes short-term reduction of serum ghrelin and body weight, and this may occur to a greater extent with combination therapy. Reduction of serum ghrelin might contribute partly to anorexia, leading to weight loss.

Imanaka K, Tamura S, Fukui K, Ito N, Kiso S, Imai Y, Naka T, Kishimoto T, Kawata S, Shinomura Y, Anonymous00262. · Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Japan. · J Viral Hepat. · Pubmed #15720527 No free full text.

Abstract: Interferon-alpha (IFN-alpha) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK-STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN-alpha is demonstrated here. The transcriptional levels of SOCS-1 and -3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription-polymerase chain reaction. We established stable transfectants of SOCS-1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS-1 on the phosphorylation of IFN-alpha-induced STAT-1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS-1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS-1, but not SOCS-3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN-alpha-induced STAT-1 phosphorylation and the expression of antiviral genes were inhibited in SOCS-1-transfected cells. Patients showing high SOCS-1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS-1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS-1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS-1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy.

Imai Y, Kasahara A, Tanaka H, Okanoue T, Hiramatsu N, Tsubouchi H, Yoshioka K, Kawata S, Tanaka E, Hino K, Hayashi K, Tamura S, Itoh Y, Sasaki Y, Kiyosawa K, Kakumu S, Okita K, Hayashi N. · Department of Internal Medicine, Ikeda Municipal Hospital, 3-1-18 Johnan, 563-8510, Ikeda, Japan. · J Gastroenterol. · Pubmed #15580400 No free full text.

Abstract: BACKGROUND: In Japan, generally, patients with chronic hepatitis C are aged. The aim of this study was to investigate the effect of interferon (IFN) therapy on the mortality of chronic hepatitis C patients over age 60. METHODS: Seven-hundred and seven patients with histologically proven chronic hepatitis C were enrolled in this study; 649 received IFN therapy (IFN group) and 58 did not (control group). The standardized mortality ratio (SMR) and Cox proportional hazard regression analysis were used to evaluate the effect of IFN on the survival of the patients. RESULTS: Mean follow-up periods in the IFN and control groups were 5.7 and 6.7 years, respectively. During follow-up, 13 patients in the control group died (7 of liver-related diseases) and 42 in the IFN group died (29 of liver-related diseases). The SMRs of the control and IFN groups were 1.40 (95% confidence interval [CI], 0.76-2.45) and 0.73 (95% CI, 0.52-0.98) for overall death, and 10.70 (95% CI, 4.29-22.05) and 5.05 (95% CI, 3.38-7.26) for liver-related death, respectively. Sustained and transient biochemical responders in the IFN group (SMR, 0.53; 95% CI, 0.01-2.97 and SMR, 3.25; 95% CI, 0.87-8.32, respectively) showed lower liver-related mortality compared with the control group. In patients with sustained virological response, liver-related mortality was also very low (SMR, 0.65; 95% CI, 0.01-3.61). The risk for liver-related death of sustained and transient biochemical responders was also low compared with that of the control group (adjusted risk ratios 0.10 [95% CI, 0.01-0.95] and 0.50 [95% CI, 0.11-2.21], respectively). CONCLUSIONS: These results suggest that IFN treatment could reduce liver-related mortality in chronic hepatitis C patients over age 60, notably in patients showing a biochemical response and in those showing a sustained virological response.

Makiyama A, Itoh Y, Kasahara A, Imai Y, Kawata S, Yoshioka K, Tsubouchi H, Kiyosawa K, Kakumu S, Okita K, Hayashi N, Okanoue T. · Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-Hirokouji, Kamigyou-ku, Japan. · Cancer. · Pubmed #15378504 links to  free full text

Abstract: BACKGROUND: The objective of the current study was to determine the characteristic features of sustained responders who develop hepatocellular carcinoma after treatment with interferon for chronic hepatitis C. METHODS: This study included 3626 patients with chronic hepatitis C who had received interferon monotherapy. Cox proportional hazards analysis was used to compare sustained responders who did and did not develop hepatocellular carcinoma, and nonsustained responders who developed hepatocellular carcinoma in a multicenter, retrospective cohort study. RESULTS: Among 1197 sustained responders, 27 patients developed hepatocellular carcinoma (2.3%). Compared with sustained responders who did not develop hepatocellular carcinoma, patients who developed disease more often were male (P = 0.0212), were older (P = 0.0068), and had advanced-stage histologic disease before interferon therapy (P = 0.0345). Conversely, compared with patients with hepatocellular carcinoma who were not sustained responders, patients who were sustained responders tended to be older at the time of the initiation of interferon therapy (P = 0.0552) and at the time hepatocellular carcinoma was detected (P = 0.0593), and they also were predominantly male (P = 0.0507). The histologic staging and serum aminotransferase levels at the initiation of interferon therapy, the interval to the detection of tumor, and the tumor size showed no significant differences between the two groups. CONCLUSIONS: Sustained responders in the group at high risk for developing hepatocellular carcinoma after interferon therapy were older, more often were male, and had more advanced histologic disease stage. Such patients should be followed carefully periodically for > 10 years after they complete interferon therapy.

Onodera S, Ukai K, Suzuki Y, Shinzawa H, Watanabe H, Saito T, Kawata S. · Department of Internal Medicine, Okitama Public General Hospital. · Nippon Rinsho. · Pubmed #15359804 No free full text.

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Kasahara A, Tanaka H, Okanoue T, Imai Y, Tsubouchi H, Yoshioka K, Kawata S, Tanaka E, Hino K, Hayashi K, Tamura S, Itoh Y, Kiyosawa K, Kakumu S, Okita K, Hayashi N. · Department of General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. · J Viral Hepat. · Pubmed #14996350 No free full text.

Abstract: Interferon therapy for chronic hepatitis C reduces the risk of hepatocellular carcinoma, especially among virological and biochemical responders. However, little is known about the effect of interferon therapy on mortality. We studied the long-term effect of interferon therapy on mortality in patients with chronic hepatitis C. For this retrospective cohort study, 2954 patients with chronic hepatitis C were recruited, of whom 2698 received interferon therapy and 256 did not. The effect of interferon therapy on survival was assessed by standardized mortality ratio (SMR) based on published mortality data for the general Japanese population and by risk ratio calculated by proportional hazard regression. Over 6.0 +/- 2.2 years follow-up, death from liver-related diseases was observed in 69 (68%) of 101 deaths among interferon-treated patients and in 42 (81%) of 52 deaths among untreated patients. Compared with the general population, overall mortality was high among untreated patients (SMR: 2.7; 95% CI: 2.0-3.6) but not among interferon-treated patients (SMR: 0.9; 95% CI: 0.7-1.1). Liver-related mortality was extremely high among untreated patients (SMR: 22.2; 95% CI: 16.0-30.0) and less among interferon-treated patients (SMR: 5.5; 95% CI: 4.3-6.9). The risk of death from all causes was lower for interferon-treated than untreated patients (risk ratio: 0.47; 95% CI: 0.261-0.836; P = 0.01). The risk of death from liver-related diseases was significantly lower for sustained virological responders (risk ratio: 0.04; 95% CI: 0.005-0.301; P = 0.002) compared with untreated patients, but not for nonsustained virological responders. Sustained biochemical responders (risk ratio: 0.03; 95% CI: 0.004-0.230; P < 0.001) and transient biochemical responders (risk ratio: 0.18; 95% CI: 0.063-0.532; P = 0.002) showed a significantly reduced risk of death from liver-related death, whereas biochemical nonresponders did not. Hence interferon treatment improved survival in chronic hepatitis C patients showing a biochemical as well as a virological response by preventing liver-related deaths.