Okayama University Medical SchoolActa Medica Okayama0386-300X7012016Entecavir Reduces Hepatocarcinogenesis in Chronic Hepatitis B Patients112ENTetsuyaYasunakaFusaoIkedaNozomuWadaYukiMorimotoShin-ichiFujiokaJunichiToshimoriHaruhikoKobashiKazuyaKariyamaYoichiMorimotoHirokiTakayamaTomonoriSenoKoichiTakaguchiAkioMoriyaHirokazuMiyatakeRyoichiOkamotoKazuhisaYabushitaAkinobuTakakiKazuhideYamamotoOriginal Article10.18926/AMO/53996Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged ≥ 35 years, HBV DNA ≥ 4 log copies/mL and positive HBeAg at diagnosis (n=184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p=0.013). Among the patients aged ≥ 35 years with HBV DNA ≥ 4 log copies/mL and negative HBeAg (n=237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p>0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged≥35 years with HBV DNA ≥4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.No potential conflict of interest relevant to this article was reported.Nature Publishing GroupActa Medica Okayama2045-232262016Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis21721ENAtsukoNakatsukaMakotoMatsuyamaSatoshiYamaguchiAkihiroKatayamaJunEguchiKazutoshiMurakamiSanaeTeshigawaraDaisukeOgawaNozomuWadaTetsuyaYasunakaFusaoIkedaAkinobuTakakiEijiroWatanabeJunWada@Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt|/| mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt|/| mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4Ώ resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.No potential conflict of interest relevant to this article was reported.Nature Publishing GroupActa Medica Okayama2045-232252015Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis16920ENAkihiroKatayamaAtsukoNakatsukaJunEguchiKazutoshiMurakamiSanaeTeshigawaraMotokoKanzakiTomokazuNunoueKazuyukiHidaNozomuWadaTetsuyaYasunakaFusaoIkedaAkinobuTakakiKazuhideYamamotoHiroshiKiyonariHirofumiMakinoJunWadaNonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6942015Effectiveness of Extending Treatment Duration in Therapy with Pegylated Interferon and Ribavirin for Genotype 2 Hepatitis C Virus Infection237244ENShintarouNanbaFusaoIkedaShin-ichiFujiokaYasuyukiArakiKouichiTakaguchiNoriakiHashimotoHiroyukiSekiAkinobuTakakiYoshiakiIwasakiKazuhideYamamotoOriginal Article10.18926/AMO/53560The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51΅), and 89΅ of them obtained sustained virological response (SVR), while 69΅ of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence80΅ pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6942015Local Recurrence and Complications after Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma : A Retrospective Cohort Study Focused on Tumor Location219226ENJunichiToshimoriKazuhiroNousoShinichiroNakamuraNozomuWadaYukiMorimotoYasutoTakeuchiTetsuyaYasunakaKenjiKuwakiHidekiOhnishiFusaoIkedaHidenoriShirahaAkinobuTakakiKazuhideYamamotoOriginal Article10.18926/AMO/53558We conducted a retrospective cohort study to investigate the predisposing factors for local recurrence and complications after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). HCC patients (n397) consecutively treated with RFA (256 males, 141 females, median age 69 years) were enrolled. In these patients, 1,455 nodules (median size 17mm) were ablated. Predisposing factors for overall recurrence and local recurrence in the context of tumor location and complications were examined. Local recurrence was observed for 113 of the 1,455 nodules. The 1-, 3- and 5-year local recurrence rates were 2.2΅, 7.4΅ and 9.5΅, respectively. A multivariate Cox proportional hazard analysis revealed that large tumor size (2cm), tumor location (adjacent to the major portal branch or hepatic vein), and small ablated margin (3mm) were independent predisposing factors for local recurrence after RFA (HR1.70-2.81). Tumor location (adjacent to the major portal branch, hepatic vein, or diaphragm) was also revealed as a risk factor for liver damage due to RFA. HCC adjacent to the major portal vein or hepatic vein was associated with a higher risk for local recurrence and for complications;therefore, special precautions are necessary when applying RFA to HCC near vessels even when the tumors are located at an easy-to-puncture site.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6932015Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis137144ENHiroyukiSekiFusaoIkedaShintaroNanbaYukiMoritouYasutoTakeuchiTetsuyaYasunakaHidekiOnishiYasuhiroMiyakeAkinobuTakakiKazuhiroNousoYoshiakiIwasakiMinoruNakamuraKazuhideYamamotoOriginal Article10.18926/AMO/53520A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patientsʼ hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-117445112010Laparoscopic findings of reddish markings predict hepatocellular carcinoma in patients with hepatitis B virus-related liver disease11721182ENBonShojiFusaoIkedaShin-ichiFujiokaHaruhikoKobashiTetsuyaYasunakaYasuhiroMiyakeHidenoriShirahaAkinobuTakakiKazuhiroNousoYoshiakiIwasakiKazuhideYamamotoFor patients with chronic hepatitis due to hepatitis B virus (HBV), factors predicting hepatocellular carcinoma (HCC) other than high levels of HBV-DNA and alanine aminotransferase (ALT) are needed to prevent HCC development, as many patients with chronic HBV infection fulfill these conditions. The purpose of this study was to clarify factors predictive of HCC development for those patients.
The study was a systematic cohort analysis of 303 consecutive patients with hepatitis B e-antigen, receiving laparoscopic examination for assessment of liver disease. Laparoscopic, histological, and clinical characteristics were investigated as related to HCC development.
HCC occurred in 27 patients during a mean follow-up of 8.0 +/- A 5.0 years, at the age of 37-72 years. Significant associations with HCC development were shown for liver cirrhosis, histological activity grade, reddish markings, and older age. Multivariate analysis revealed that HCC development was strongly associated with older age and male gender (P = 0.002 and P = 0.043, respectively). HCC occurred more frequently in patients of age a parts per thousand yen30 years even with early stage than in patients of age < 30 years (P = 0.031). Severe reddish markings, a laparoscopic finding of widespread parenchymal destruction, were highly associated with HCC development in patients of age a parts per thousand yen30 years at diagnosis (odds ratio = 1.67, P = 0.034), while histological activity grade and ALT level were not (P = 0.075 and P = 0.69, respectively).
HCC development is associated with older age, male gender, and liver cirrhosis. Reddish markings, rather than histological activity or ALT level, can be useful to predict HCC for HBV patients of age a parts per thousand yen30 years.No potential conflict of interest relevant to this article was reported.Public Library ScienceActa Medica Okayama1932-6203972014L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial PathwayENHisashiIshikawaAkinobuTakakiRyuichiroTsuzakiTetsuyaYasunakaKazukoKoikeYasuyukiShimomuraHiroyukiSekiHiroshiMatsushitaYasuhiroMiyakeFusaoIkedaHidenoriShirahaKazuhiroNousoKazuhideYamamotoNon-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% alpha-tocopherol (alpha-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial beta-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although alpha-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial beta-oxidation and redox system.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744832013The impact of patatin-like phospholipase domain-containing protein 3 polymorphism on hepatocellular carcinoma prognosis405412ENYasutoTakeuchiFusaoIkedaYukiMoritouHiroakiHagiharaTetsuyaYasunakaKenjiKuwakiYasuhiroMiyakeHidekiOhnishiShinichiroNakamuraHidenoriShirahaAkinobuTakakiYoshiakiIwasakiKazuhiroNousoKazuhideYamamotoThe single nucleotide polymorphism (SNP) rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) is associated with hepatic fat accumulation and disease progression in patients with non-alcoholic fatty liver disease and alcoholic liver disease (ALD). This study was conducted to determine whether PNPLA3 rs738409 SNPs affect development and prognosis of hepatocellular carcinoma (HCC) in patients with various liver diseases.
We enrolled 638 consecutive Japanese patients newly diagnosed with HCC between 2001 and 2010: 72 patients with hepatitis B virus (HBV), 462 with hepatitis C virus (HCV), and 104 with non-B non-C (NBNC).
NBNC patients exhibited large tumors of advanced TNM stages at HCC diagnosis, and had significantly poorer prognosis than HBV or HCV patients (P < 0.001 and < 0.001, respectively; log-rank test). The G/G genotype of PNPLA3 rs738409 SNP had significantly higher distribution in NBNC patients (P < 0.001) and was significantly associated with higher body mass index (BMI) and an increased aspartate aminotransferase to platelet ratio index. No significant differences were observed in survival with differences in PNPLA3 SNP genotypes among the patients, although ALD patients with the G/G genotype of PNPLA3 SNP and low BMI had significantly poorer survival than those with high BMI (P = 0.028).
The G/G genotype of PNPLA3 rs738409 SNP was more frequently distributed, and associated with BMI and fibrosis among NBNC-HCC patients but not among HBV or HCV patients. These genotypes might affect HCC prognosis in ALD patients, but not in HBV, HCV, or NAFLD patients.No potential conflict of interest relevant to this article was reported.American Society for MicrobiologyActa Medica Okayama0095-11375222014Necessity for Reassessment of Patients with Serogroup 2 Hepatitis C Virus (HCV) and Undetectable Serum HCV RNA544548ENYukiMoritouFusaoIkedaYasutoTakeuchiHiroyukiSekiShintaroNanbaYoshiakiIwasakiKazuhideYamamotoWe encountered a patient positive for anti-hepatitis C virus (HCV) whose serum HCV RNA was undetectable with the Roche AmpliPrep/Cobas TaqMan HCV assay (CAP/CTM) version 1 but showed a high viral load with the Abbott RealTime HCV assay (ART). Discrepancies in the detectability of serum HCV RNA were investigated among 891 consecutive patients who were positive for anti-HCV. Specific nucleotide variations causing the undetectability of HCV RNA were determined and confirmed by synthesizing RNA coding those variations. Serum samples with the discrepancies were also reassessed by CAP/CTM version 2. Among the 891 anti-HCV-positive patients, 4 patients had serum HCV RNA levels that were undetectable by CAP/CTM version 1 despite having levels of > 5 log IU/ml that were detected by ART. All four patients had HCV genotype 2a and high titers of anti-HCV. Sequencing of the HCV 5' noncoding regions revealed 2 common variations, A at nucleotide (nt) 145 and T at nt 151. Synthesized RNAs of the HCV 5' noncoding region with standard (NCR145G151C) and variant nucleotides at nt 145 and nt 151 were quantified with CAP/CTM. RNAs of NCR145G151C and NCR145G151T were quantifiable with CAP/CTM version 1, while those of NCR145A151T and NCR145A151C went undetected. The substitution from G to A at nt 145 specifically conferred this undetectability, while this undetectability was reverted in synthesized HCV RNA with correction of this variation. Reassessment of these samples by CAP/CTM version 2 resulted in similar levels of HCV RNA being detected by ART. We conclude that HCV patients with undetectable HCV RNA by CAP/CTM version 1 should be reassessed for viral quantification.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6852014Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation291302ENRyuichiroTsuzakiAkinobuTakakiTakahitoYagiFusaoIkedaKazukoKoikeYoshiakiIwasakiHidenoriShirahaYasuhiroMiyakeHiroshiSadamoriSusumuShinouraYuzoUmedaRyuichiYoshidaDaisukeNobuokaMasashiUtsumiEiichiNakayamaToshiyoshiFujiwaraKazuhideYamamotoOriginal Article10.18926/AMO/52898It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-Α) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6852014Nursing Support Increases the Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C263268ENShihokoNambaKayokoMiyakeFusaoIkedaTomokoHazamaYuHitobeNorikoYamasakiHidenoriShirahaAkinobuTakakiKazuhiroNousoYoshiakiIwasakiKazuhideYamamotoOriginal Article10.18926/AMO/52894Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0815-93192922014Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C337343ENHiroshiMatsushitaFusaoIkedaYoshiakiIwasakiHiroyukiSekiShintaroNanbaYasutoTakeuchiYukiMoritouTetsuyaYasunakaHidekiOnishiYasuhiroMiyakeAkinobuTakakiKazuhiroNousoKazuhideYamamotoBackground and Aim: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms.
Methods: The present study enrolled 228 CHC patients and assessed their HRQOLs prospectively with the 36-item short-form health survey.
Results: The patients with CHC have lower physical HRQOL status than the general population (P = 0.037, the Z-test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and RBV than the non-SVR group (P = 0.031, the Mann-Whitney U-test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score <= 400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable single-nucleotide polymorphism type of IL28B, and HCV serotype 2. The patients with low HRQOL score will have significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045).
Conclusion: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and RBV independently from IL28B polymorphism.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0012-28238622012Serum Levels of Soluble Adhesion Molecules as Prognostic Factors for Acute Liver Failure122128ENAtsuyukiOhnishiYasuhiroMiyakeHiroshiMatsushitaKazuyukiMatsumotoAkinobuTakakiTetsuyaYasunakaKazukoKoikeFusaoIkedaHidenoriShirahaKazuhiroNousoKazuhideYamamotoBackground/Aims: In patients with septic shock, the degree of liver dysfunction is correlated with serum levels of soluble intercellular adhesion molecule (sICAM)-1. We aimed to assess the usefulness of serum levels of soluble adhesion molecules as prognostic factors for acute liver failure (ALF). Methods: Serum levels of soluble platelet endothelial cell adhesion molecule (sPECAM)-1, sICAM-3, soluble endothelial (sE) selectin, sICAM-1, soluble platelet selectin, and soluble vascular cell adhesion molecule-1 on admission were measured in 37 ALF patients and 34 healthy controls. Results: Twenty-two ALF patients (59%) reached to fatal outcomes. Serum levels of sPECAM-1, sICAM-3, sE-selectin and sICAM-1 were higher in ALF patients than healthy controls. In 37 ALF patients, by the multivariate logistic regression analysis, ratio of direct to total bilirubin (per 0.1 increase; OR 0.11, 95% CI 0.01-0.99), serum sPECAM-1 level (per 100 ng/ml increase; OR 4.37, 95% CI 1.23-15.5) and serum sICAM-1 level (per 100 ng/ml increase; OR 0.49, 95% CI 0.27-0.89) were associated with fatal outcomes. Using receiver operating characteristics curve, each area under the curve of serum sPECAM-1 and sICMA-1 levels as prognostic factors was 0.71 and 0.74, respectively. Conclusion: Serum sPECAM-1 and sICAM-1 levels may be useful for predicting the prognosis of ALF.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6842014Prevalence and Outcomes of Acute Hepatitis B in Okayama, Japan, 2006-2010243247ENNozomuWadaTetsuyaYasunakaFusaoIkedaSohjiNishinaMasaakiKorenagaKeisukeHinoShin-ichiFujiokaToshiyaOsawaTatsuyaItoshimaMiwaKawanakaGotaroYamadaKazuyaKariyamaHirokiTakayamaJunichiKubotaYoichiMorimotoTakaakiMizushimaHaruhikoYamashitaHiroakiTaniokaYujiNegoroJunichiToshimoriHaruhikoKobashiAtsushiHiranoYasuoItanoAkinobuTakakiKazuhideYamamotoOriginal Article10.18926/AMO/52790Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HBV were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%,
p0.01), among men who had sex with men (100%, p0.005), and among patients having sex with unspecified partners (44.8%, p0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0815-93192612011Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure116121ENHirokiTakayamaYasuhiroMiyakeKazuhiroNousoFusaoIkedaHidenoriShirahaAkinobuTakakiHaruhikoKobashiKazuhideYamamotoBackground and Aims:
In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF).
Methods:
Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls.
Results:
Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050 +/- 1572 pg/mL vs 4521 +/- 2419 pg/mL vs 8506 +/- 5500 pg/mL, VEGF; 39 +/- 38 pg/mL vs 144 +/- 122 pg/mL vs 205 +/- 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38).
Conclusions:
We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6812014Impact of Comorbid Hepatic Steatosis on Treatment of Chronic Hepatitis C in Japanese Patients and the Relationship with Genetic Polymorphism of IL28B, PNPLA3 and LDL Receptor1722ENYukiMoritouFusaoIkedaYoshiakiIwasakiNobuyukiBabaKouichiTakaguchiTomonoriSenohTakuyaNaganoYasutoTakeuchiTetsuyaYasunakaHidekiOhnishiYasuhiroMiyakeAkinobuTakakiKazuhiroNousoKazuhideYamamotoOriginal Article10.18926/AMO/52139The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association
(p0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p0.049, and 0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor
did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744742012Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma421426ENHideakiKinugasaKazuhiroNousoYasutoTakeuchiTetsuyaYasunakaHidekiOnishiShin-ichiroNakamuraHidenoriShirahaKenjiKuwakiHiroakiHagiharaFusaoIkedaYasuhiroMiyakeAkinobuTakakiKazuhideYamamotoRadiofrequency ablation (RFA) is a standard therapy for the treatment of hepatocellular carcinoma (HCC) with 3 or fewer tumors of up to 3 cm (early-stage HCC); when RFA is unsuccessful or unfeasible, transcatheter arterial chemoembolization (TACE) has often been performed. However, little information about the outcome of TACE for early-stage HCC has been reported and it is hard to decide whether to perform additional treatment following TACE in these difficult conditions. The aim of this study was to determine the risk factors for local or intrahepatic distant recurrence after TACE in early-stage HCC.
Among 1,560 newly diagnosed HCC patients who were admitted to Okayama University Hospital, 43 patients with early-stage HCC who received only TACE in at least one nodule were enrolled in this study. We analyzed the risk factors for local and distant recurrence by the Cox proportional hazard model.
The local recurrence rates and intrahepatic distant recurrence rates at 3 months, 6 months, and 1 year were 18.6, 33.4, and 61.8%, and 2.8, 2.8, and 10.2%, respectively. Among 12 parameters examined as possible risk factors for recurrence, heterogeneous Lipiodol uptake (risk ratio 3.38; 95% confidence interval 1.14-10.60) and high serum des-gamma-carboxy prothrombin (DCP) (2.58; 1.03-7.14) were significantly correlated with local recurrence, and the presence of multiple tumors (10.64; 1.76-93.75) was significantly correlated with intrahepatic distant recurrence.
Heterogeneous Lipiodol uptake, high serum DCP, and multiple tumors are risk factors for recurrence in patients with early-stage HCC who have undergone palliative TACE.No potential conflict of interest relevant to this article was reported.Acta Medica Okayama0944-11744492009Mortality rate of patients with asymptomatic primary biliary cirrhosis diagnosed at age 55 years or older is similar to that of the general population10001006ENJunichiKubotaFusaoIkedaRyoTeradaHaruhikoKobashiShin-ichiFujiokaRyoichiOkamotoShinsukeBabaYouichiMorimotoMasaharuAndoYasuhiroMakinoHideakiTaniguchiTetsuyaYasunakaYasuhiroMiyakeYoshiakiIwasakiKazuhideYamamotoRecent routine testing for liver function and anti-mitochondrial antibodies has increased the number of newly diagnosed patients with primary biliary cirrhosis (PBC). This study investigated the prognosis of asymptomatic PBC patients, focusing on age difference, to clarify its effect on the prognosis of PBC patients.
The study was a systematic cohort analysis of 308 consecutive patients diagnosed with asymptomatic PBC. We compared prognosis between the elderly (55 years or older at the time of diagnosis) and the young patients (< 55 years). The mortality rate of the patients was also compared with that of an age- and gender-matched general population.
The elderly patients showed a higher aspartate aminotransferase-to-platelet ratio, and lower alanine aminotransferase level than the young patients (P < 0.01 and P = 0.03, respectively). The two groups showed similar values for alkaline phosphatase and immunoglobulin M. Death in the young patients was more likely to be due to liver failure (71%), while the elderly were likely to die from other causes before the occurrence of liver failure (88%; P < 0.01), especially from malignancies (35%). The mortality rate of the elderly patients was not different from that of the age- and gender-matched general population (standardized mortality ratio, 1.1; 95% confidence interval, 0.6-1.7), although this rate was significantly higher than that of the young patients (P = 0.044).
PBC often presents as more advanced disease in elderly patients than in the young. However, the mortality rate of the elderly patients is not different from that of an age- and gender-matched general population.No potential conflict of interest relevant to this article was reported.Wiley-BlackwellActa Medica Okayama1386-634643102013Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma10781092ENMamoruNishimuraAkinobuTakakiNaofumiTamakiTakayukiMaruyamaHidekiOnishiSayoKobayashiKazuhiroNousoTetsuyaYasunakaKazukoKoikeHiroakiHagiharaKenjiKuwakiShinichiroNakamuraFusaoIkedaYoshiakiIwasakiTakaakiTomofujiManabuMoritaKazuhideYamamotoAim
Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients.
Methods
We recruited a study population of 208 patients, including healthy volunteers (HV; n = 15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated.
Results
Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR.
Conclusion
HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication.No potential conflict of interest relevant to this article was reported.Wiley-BlackwellActa Medica Okayama1386-634642122012Clinical utility of serum fucosylated hemopexin in Japanese patients with hepatocellular carcinoma11871195ENSayoKobayashiKazuhiroNousoHideakiKinugasaYasutoTakeuchiTakeshiTomodaKojiMiyaharaHiroakiHagiharaKenjiKuwakiHidekiOnishiShinichiroNakamuraFusaoIkedaYasuhiroMiyakeHidenoriShirahaAkinobuTakakiKazuhideYamamotoAim: Hepatocellular carcinoma (HCC) is a common clinical problem all over the world. Fucosylated hemopexin (Fuc-Hpx) is a newly reported glycoprotein for the diagnosis of HCC, however, its clinical implications are unclear. The aim of this study was to elucidate the clinical utility of Fuc-Hpx in Japanese patients with HCC.
Methods: The sera from 331 HCC patients, 45 with liver cirrhosis (LC), 85 with chronic hepatitis (CH) and 22 healthy people were examined for the expression of Fuc-Hpx; the level was compared with clinical parameters as well as hemopexin (Hpx) expression. The expressions of Fuc-Hpx in 12 HCC tissues and corresponding adjacent non-cancerous liver tissues were also examined.
Results: No correlation was observed between Hpx and Fuc-Hpx level. The median Fuc-Hpx levels in healthy people and CH, LC and HCC patients were 3.8, 3.7, 6.1 and 7.6 AU/mL, respectively (CH vs LC, P = 0.002; CH vs HCC, P < 0.001; LC vs HCC, P = 0.02). Multivariate analysis revealed that low albumin, low prothrombin time and the presence of HCC were significantly correlated with high Fuc-Hpx (P = 0.013, =0.001 and <0.001, respectively). Among the HCC patients, albumin was correlated with high Fuc-Hpx; however, none of the tumor factors, such as tumor size, tumor number and tumor stage, was correlated with Fuc-Hpx level. The expression of Fuc-Hpx in cancer tissue was not different from that in non-cancerous tissue.
Conclusion: Fuc-Hpx is a valuable biomarker for HCC but it might be a marker for hypercarcinogenic liver rather than a marker for tumor-bearing liver.No potential conflict of interest relevant to this article was reported.