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.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-) 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.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.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.Okayama University Medical SchoolActa Medica Okayama0386-300X6662012Eradication of Hepatitis C Virus Subgenomic Replicon by Interferon Results in Aberrant Retinol-Related Protein Expression461468ENKazukoKoikeAkinobuTakakiNobuyukiKatoMamoruOuchidaHirotakaKanzakiTetsuyaYasunakaHidenoriShirahaYasuhiroMiyakeKazuhideYamamotoOriginal Article10.18926/AMO/49042Hepatitis C virus (HCV) infection induces several changes in hepatocytes, such as oxidative stress, steatosis, and hepatocarcinogenesis. Although considerable progress has been made during recent years, the mechanisms underlying these functions remain unclear. We employed proteomic techniques in HCV replicon-harboring cells to determine the effects of HCV replication on host-cell protein expression. We examined two-dimensional electrophoresis (2-DE) and mass spectrometry to compare and identify differentially expressed proteins between HCV subgenomic replicon-harboring cells and their gcuredh cells. One of the identified proteins was confirmed using enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Full-length HCV genome RNA replicating and cured cells were also assessed using ELISA. Replicon-harboring cells showed higher expression of retinal dehydrogenase 1 (RALDH-1), which converts retinol to retinoic acid, and the cured cells showed higher expression of retinol-binding protein (RBP), which transports retinol from the liver to target tissues. The alteration in RBP expression was also confirmed by ELISA and Western blot analysis. We conclude that protein expression profiling demonstrated that HCV replicon eradication affected retinol-related protein expression.No potential conflict of interest relevant to this article was reported.