Date de mise en ligne : Jeudi 21 février 2008
Yoichi Hiasa, Hiroyuki Kuzuhara, Yoshio Tokumoto, Ichiro Konishi, Nobuyuki Yamashita, Bunzo Matsuura, Kojiro Michitaka, Raymond T. Chung, Morikazu Onji
Hepatitis C virus replication is inhibited by 22[beta]-methoxyolean-12-ene-3[beta], 24(4[beta])-diol (ME3738) through enhancing interferon-[beta]
A derivative of soyasapogenol, 22[beta]-methoxyolean-12-ene-3[beta], 24(4[beta])-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-[alpha] (IFN-[alpha]) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-[beta] (IFN-[beta]) and of IFN-stimulated genes (2[prime]-5[prime] oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-[beta] knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-[alpha]. Conclusion: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-[beta] suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-[alpha]. ME3738 might be a useful anti-HCV drug either with or without IFN-[alpha]. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 05 mai 2008
Felix Flohr, Jan Harder, Jochen Seufert, Hubert E. Blum, Hans C. Spangenberg
Hypothyroidism in patients with hepatocellular carcinoma treated by transarterial chemoembolization
No abstract.

Date de mise en ligne : Jeudi 21 février 2008
Masaru Harada, Shinichiro Hanada, Diana M. Toivola, Nafisa Ghori, M. Bishr Omary
Autophagy activation by rapamycin eliminates mouse Mallory-Denk bodies and blocks their proteasome inhibitor-mediated formation
The proteasomal and lysosomal/autophagy pathways in the liver and other tissues are involved in several biological processes including the degradation of misfolded proteins. Exposure of hepatocyte cell lines to proteasome inhibitors (PIs) results in the formation of inclusions that resemble Mallory-Denk bodies (MDBs). Keratins are essential for MDB formation and keratin 8 (K8)-overexpressing transgenic mice are predisposed to MDB formation. We tested the hypothesis that PIs induce MDBs in vivo and that autophagy participates in MDB turnover. The effect of the PI bortezomib (which is used to treat some malignancies) on MDB formation was tested in K8-overexpressing mice and in cultured cells. Inclusion formation was examined using immune and conventional electron microscopy (EM). Bortezomib induced MDB-like inclusions composed of keratins, ubiquitin, and p62 in cultured cells. Short-term exposure to bortezomib induced similar inclusions in K8-overexpressing but not in nontransgenic mice, without causing liver injury. In bortezomib-treated mice, autophagy was activated in hepatocytes as determined by EM and biochemical analysis. Further activation of autophagy by rapamycin (Rap) decreased the number of inclusions in bortezomib-treated K8 transgenic mice significantly. Rap also led to resorption of spontaneously formed MDBs in aging K8-overexpressing mice. Immune EM demonstrated K8-positive and ubiquitin-positive structures in autophagic vacuoles in the mouse liver. Conclusion: PIs alone are sufficient to induce MDBs in susceptible animals, while Rap-mediated activation of autophagy prevents MDB formation and causes MDB resorption. These findings suggest that some patients treated with PIs may become predisposed to MDB formation. Autophagy provides a potential cellular mechanism for the resorption of cytoplasmic inclusions. (HEPATOLOGY 2008.)

Date de mise en ligne : Vendredi 01 février 2008
Martin Lagging, Nina Langeland, Court Pedersen, Martti Färkkilä, Mads Rauning Buhl, Kristine Mørch, Amar P. Dhillon, Åsa Alsiö, Kristoffer Hellstrand, Johan Westin, Gunnar Norkrans, NORDynamIC Study Group
Randomized comparison of 12 or 24 weeks of peginterferon [alpha]-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection
Previous trials investigating the efficacy of treatment durations shorter than the standard of 24 weeks for chronic hepatitis C virus (HCV) genotype 2/3 infections have yielded discordant results. The aims of this investigator-initiated phase III study were to compare the efficacy of 12 or 24 weeks of treatment and to identify patients suitable for short-term therapy. Three hundred eighty-two genotype 2/3-infected patients [intention-to-treat (ITT) population] at 31 centers in Denmark, Finland, Norway, and Sweden were randomized to 12 or 24 weeks of peginterferon [alpha]-2a (180 [mu]g/week) plus ribavirin (800 mg/day). Twelve weeks of therapy was inferior to 24 weeks in the ITT population (sustained viral response [SVR] rates: 59% versus 78%, P < 0.0001) and in the subgroups of patients infected with genotype 2 (56% versus 82%, P = 0.006) or 3 (58% versus 78%, P = 0.0015). These differences were observed regardless of the fibrosis stage. Age and HCV-RNA levels on days 7 and 29 were independent predictors of SVR. Short-term treatment was useful in patients < 40 years old, especially if HCV-RNA was undetectable on day 29, and also in patients [ge] 40 years old, provided that HCV-RNA was below 1000 IU/mL on day 7 in addition to being undetectable on day 29. If neither of these two criteria were met for patients [ge] 40 years old, 24 weeks of therapy was superior (P < 0.0001). Conclusion: Peginterferon/ribavirin treatment for 12 weeks in HCV genotype 2/3 infection is overall inferior to 24 weeks of treatment but may be useful in some patients with a rapid initial clearance of virus. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 31 janvier 2008
Christoph Neumann-Haefelin, Jörg Timm, Hans Christian Spangenberg, Natalie Wischniowski, Natalja Nazarova, Nadine Kersting, Michael Roggendorf, Todd M. Allen, Hubert E. Blum, Robert Thimme
Virological and immunological determinants of intrahepatic virus-specific CD8+ T-cell failure in chronic hepatitis C virus infection
Virus-specific CD8+ T-cells play an important role in the outcome of acute hepatitis C virus (HCV) infection. In the chronic phase, however, HCV can persist despite the presence of virus-specific T-cell responses. Therefore, we set out to perform a full-breadth analysis of the intrahepatic virus-specific CD8+ T-cell response, its relation to the peripheral T-cell response, and the overall influence of viral escape and the genetic restriction on intrahepatic CD8+ T-cell failure. Intrahepatic and peripheral CD8+ T-cells from 20 chronically HCV infected patients (genotype 1) were comprehensively analyzed using overlapping peptides spanning the entire HCV polyprotein in concert with autologous viral sequences that were obtained for all targeted regions. HCV-specific CD8+ T-cell responses were detectable in most (90%) chronically HCV-infected patients, and two thirds of these responses targeted novel previously undescribed epitopes. Most of the responses were detectable only in the liver but not in the peripheral blood, indicating accumulation and enrichment at the site of disease. Of note, only approximately half of the responses were associated with viral sequence variations supported by functional analysis as viral escape mutations. Escape mutations were more often associated with HLA-B alleles. Conclusion: Our results show an unexpected high frequency of intrahepatic virus-specific CD8+ T-cells, a large part of which continue to target the present viral antigens. Thus, our results suggest that factors other than mutational escape contribute to the failure of intrahepatic virus-specific CD8+ T-cells. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 21 janvier 2008
Reiichiro Kuwahara, Alexander V. Kofman, Charles S. Landis, E. Scott Swenson, Els Barendswaard, Neil D. Theise
The hepatic stem cell niche: Identification by label-retaining cell assay
Label retention assays remain the state-of-the-art approach to identify the location of intraorgan epithelial stem cell niches, in situ and in vivo. They are commonly used in organs with rapid cell turnover but have not been applied to the liver, where cell turnover is very slow. We used a sublethal dose of acetaminophen administered coincident with bromodeoxyuridine to load possible hepatic stem cells in mice with label and then administered a second, sublethal chase of acetaminophen to accomplish "washout" of label from transit amplifying cell populations. Conclusion: Four possible hepatic stem cell niches are identified by this approach: the canal of Hering (proximal biliary tree), intralobular bile ducts, periductal "null" mononuclear cells, and peribiliary hepatocytes. These results confirm several different and often contradictory lines of investigation regarding the intrahepatic location of stem/progenitor cells and suggest that the liver has a multi-tiered, flexible system of regeneration rather than a single stem/progenitor cell location. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 05 mai 2008
Eirini I. Rigopoulou, George N. Dalekos
Autoimmune hepatitis: Of host and pathogen
No abstract.

Date de mise en ligne : Jeudi 21 février 2008
Winston Dunn, Ronghui Xu, Jeffrey B. Schwimmer
Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease
People at risk for coronary heart disease are often at risk for nonalcoholic fatty liver disease (NAFLD). The association of modest wine consumption with NAFLD has not been studied and the recommendation of wine for patients at risk for both diseases is controversial. The aim is to test the hypothesis that modest wine consumption is associated with decreased prevalence of NAFLD. We included Third National Health and Nutrition Examination Survey participants who either reported no alcohol consumption or preferentially drinking wine with total alcohol consumption up to 10 g per day. Suspected NAFLD was based on unexplained serum alanine aminotransferase (ALT) elevation over the cut point of the reference laboratory (ALT > 43) and the cut point based on the 95th percentile of healthy subjects (ALT > 30 for men; ALT > 19 for women). Multivariate analysis was adjusted for age, gender, race, neighborhood, income, education, caffeine intake, and physical activity. A total of 7,211 nondrinkers and 945 modest wine drinkers comprised the study sample. Based on the reference laboratory cut point, suspected NAFLD was observed in 3.2% of nondrinkers and 0.4% of modest wine drinkers. The adjusted odds ratio was 0.15 (95% confidence interval, 0.05-0.49). Using the healthy subject cut point, suspected NAFLD was observed in 14.3% of nondrinkers and 8.6% of wine drinkers. The adjusted odds ratio was 0.51 (95% confidence interval, 0.33-0.79). Conclusion: Modest wine consumption is associated with reduced prevalence of suspected NAFLD. The current study supports the safety of one glass of wine per day for cardioprotection in patients at risk for both coronary heart disease and NAFLD. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 05 mai 2008
Daniel A. Langer, Amitava Das, David Semela, Ningling Kang-Decker, Helen Hendrickson, Steven F. Bronk, Zvonimir S. Katusic, Gregory J. Gores, Vijay H. Shah
Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species
Hepatic stellate cells (HSCs) contribute to portal hypertension through multiple mechanisms that include collagen deposition, vasoconstriction, and regulation of sinusoidal structure. Under normal physiologic conditions, endothelial nitric oxide (NO) synthase-derived NO exerts paracrine effects on HSCs; however, in cirrhosis, NO generation is impaired in association with concomitant HSC activation and changes in sinusoidal structure, events that contribute significantly to the development of portal hypertension. These concepts, in combination with recent evidence that induction of HSC-selective apoptosis may represent a useful target for treatment of chronic liver disease, led us to examine if NO may further limit HSC function through apoptosis. Indeed, both NO donors and endothelial NO synthase overexpression promoted HSC apoptotic pathways. HSC death conferred by NO occurred through mitochondrial membrane depolarization and through a caspase-independent pathway. Furthermore, NO-induced apoptosis of HSC did not occur through the canonical pathways of soluble guanylate cyclase or protein nitration, but rather through the generation of superoxide and hydroxyl radical intermediates. Lastly, HSC isolated from rats after bile duct ligation were more susceptible to NO-induced apoptosis. These data indicate that NO promotes HSC apoptosis through a signaling mechanism that involves mitochondria, is mediated by reactive oxygen species, and occurs independent of caspase activation. Conclusion: We postulate that NO-dependent apoptosis of HSCs may maintain sinusoidal homeostasis, and may represent an additional beneficial effect of NO donors for therapy of portal hypertension. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 05 mai 2008
Hilde Herrema, Terry G. J. Derks, Theo H. van Dijk, Vincent W. Bloks, Albert Gerding, Rick Havinga, Uwe J. F. Tietge, Michael Müller, G. Peter A. Smit, Folkert Kuipers, Dirk-Jan Reijngoud
Disturbed hepatic carbohydrate management during high metabolic demand in medium-chain acyl-CoA dehydrogenase (MCAD)-deficient mice
Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD-/- mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD-/- mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1[alpha] (Pgc-1[alpha]) and decreased peroxisome proliferator-activated receptor alpha (Ppar [alpha]) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD-/- mice in both conditions, suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD-/- mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD-/- mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD-/- mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD-/- mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD-/- mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 07 février 2008
Craig Lammert, Stefan Einarsson, Chandan Saha, Anna Niklasson, Einar Bjornsson, Naga Chalasani
Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: Search for signals
Idiosyncratic drug-induced liver injury (DILI) is traditionally thought not to be dose-related. However, it has been pointed out that most medicines that were withdrawn from marketing or received a black-box warning because of hepatotoxicity were prescribed at daily doses greater than 50 mg/day. To examine the relationship between daily dose of medications and idiosyncratic DILI, we conducted a study with two aims. First, using two pharmaceutical databases, we examined the relationship between daily dose of commonly prescribed medicines in the United States and reported frequency of their selected hepatic adverse events. Second, we examined serious DILI cases reported to the Swedish Adverse Drug Reactions Advisory Committee (1970-2004) for any signals supporting the relationship between daily dose and idiosyncratic DILI. Medications were categorized into [le]10 mg/day, 11-49 mg/day, and [ge]50 mg/day groups. Among US prescription medicines, a statistically significant relationship was observed between daily dose of oral medicines and reports of liver failure (P = 0.009), liver transplantation (P < 0.001), and death caused by DILI (P = 0.004) but not alanine aminotransferase (ALT) > 3 × upper limit of normal (P = 0.10) or jaundice (P = 0.16). Of 598 eligible Swedish DILI cases, 9% belonged to the [le]10 mg/day group, 14.2% to the 11-49 mg/day group, and 77% of cases were caused by medications given at dose [ge]50 mg/day. A statistically significant relationship was noted between daily dose and poor outcome (death or liver transplantation) of Swedish DILI cases (2%, 9.4%, and 13.2% in [le]10, 11-49, and [ge]50 mg/day groups, respectively, P = 0.03). Conclusion: These data suggest a relationship between daily doses of oral prescription medications and idiosyncratic DILI. More studies are needed to validate these observations and to explore their implications. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 04 février 2008
Peter Ferenci, Harald Brunner, Hermann Laferl, Thomas-Matthias Scherzer, Andreas Maieron, Michael Strasser, Gabriele Fischer, Harald Hofer, Martin Bischof, Rudolf Stauber, Michael Gschwantler, Petra Steindl-Munda, Katharina Staufer, Karin Löschenberger, Austrian Hepatitis Study Group
A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a in hepatitis C virus genotypes 2 and 3
We compared the efficacy and tolerability of 24 weeks of treatment with ribavirin 800 mg/day (group A) or 400 mg/day (group B) plus peginterferon alfa-2a 180 [mu]g/week in treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3. A total of 97 of 141 patients randomized to group A (68.8%, 95% confidence interval [CI] 60.5%-76.3%) and 90 of 141 patients randomized to group B (63.8; 95% CI 55.3%-71.7%) achieved a sustained virological response, defined as undetectable serum HCV RNA at the end of untreated follow-up (week 48). Among patients infected with genotype 3, the rate of sustained virological response was 67.5% (95% CI 58.4%-75.6%) in group A and 63.9% (95% CI 54.7%-72.4%) in group B, and among patients infected with genotype 2, the rate of sustained virological response was 77.8% (95% CI 54.2%-93.6%) in group A and 55.6% (95% CI 38.4%-83.7%) in group B. Relapse rates in the 2 treatment groups were similar (17% in group A and 20% in group B). The incidence of adverse events, laboratory abnormalities, and dose reductions was similar in the 2 treatment groups. Conclusion: The results suggest that when administered for 24 weeks with peginterferon alfa-2a, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 04 février 2008
Samuel Martín-Vílchez, Paloma Sanz-Cameno, Yolanda Rodríguez-Muñoz, Pedro L. Majano, Francisca Molina-Jiménez, Manuel López-Cabrera, Ricardo Moreno-Otero, Enrique Lara-Pezzi
The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells
Chronic hepatitis B virus (HBV) infection is a major cause of liver fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma. Although the involvement of the X protein of HBV (HBx) in viral replication and tumor development has been extensively studied, little is known about its possible role in the development of fibrosis. In this work we show that expression of HBx in hepatocytes results in paracrine activation and proliferation of hepatic stellate cells (HSCs), the main producers of extracellular matrix proteins in the fibrotic liver. Both human primary HSCs and rat HSCs exposed to conditioned medium from HBx-expressing hepatocytes showed increased expression of collagen I, connective tissue growth factor, [alpha] smooth muscle actin, matrix metalloproteinase-2, and transforming growth factor-[beta] (TGF-[beta]), together with an enhanced proliferation rate. We found that HBx induced TGF-[beta] secretion in hepatocytes and that the activation of HSCs by conditioned medium from HBx-expressing hepatocytes was prevented by a neutralizing anti-TGF-[beta] antibody, indicating the involvement of this profibrotic factor in the process. Conclusion: Our results propose a direct role for HBx in the development of liver fibrosis by the paracrine activation of stellate cells and reinforce the indication of antiviral treatment in patients with advanced HBV-related chronic liver disease and persistent liver replication. (HEPATOLOGY 2008.)

Date de mise en ligne : Vendredi 01 février 2008
Hung-Yun Lin, I-Chen Yu, Ruey-Shen Wang, Yei-Tsung Chen, Ning-Chun Liu, Saleh Altuwaijri, Cheng-Lung Hsu, Wen-Lung Ma, Jenny Jokinen, Janet D. Sparks, Shuyuan Yeh, Chawnshang Chang
Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor
Early studies demonstrated that whole-body androgen receptor (AR)-knockout mice with hypogonadism exhibit insulin resistance. However, details about the mechanisms underlying how androgen/AR signaling regulates insulin sensitivity in individual organs remain unclear. We therefore generated hepatic AR-knockout (H-AR-/y) mice and found that male H-AR-/y mice, but not female H-AR-/- mice, fed a high-fat diet developed hepatic steatosis and insulin resistance, and aging male H-AR-/y mice fed chow exhibited moderate hepatic steatosis. We hypothesized that increased hepatic steatosis in obese male H-AR-/y mice resulted from decreased fatty acid [beta]-oxidation, increased de novo lipid synthesis arising from decreased PPAR[alpha], increased sterol regulatory element binding protein 1c, and associated changes in target gene expression. Reduced insulin sensitivity in fat-fed H-AR-/y mice was associated with decreased phosphoinositide-3 kinase activity and increased phosphenolpyruvate carboxykinase expression and correlated with increased protein-tyrosine phosphatase 1B expression. Conclusion: Together, our results suggest that hepatic AR may play a vital role in preventing the development of insulin resistance and hepatic steatosis. AR agonists that specifically target hepatic AR might be developed to provide a better strategy for treatment of metabolic syndrome in men. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 31 janvier 2008
Thomas Vanwolleghem, Jens Bukh, Philip Meuleman, Isabelle Desombere, Jean-Christophe Meunier, Harvey Alter, Robert H. Purcell, Geert Leroux-Roels
Polyclonal immunoglobulins from a chronic hepatitis C virus patient protect human liver-chimeric mice from infection with a homologous hepatitis C virus strain
The role of the humoral immune response in the natural course of hepatitis C virus (HCV) infection is widely debated. Most chronically infected patients have immunoglobulin G (IgG) antibodies capable of neutralizing HCV pseudoparticles (HCVpp) in vitro. It is, however, not clear whether these IgG can prevent a de novo HCV infection in vivo and contribute to the control of viremia in infected individuals. We addressed this question with homologous in vivo protection studies in human liver-urokinase-type plasminogen activator (uPA)+/+ severe combined immune deficient (SCID) mice. Chimeric mice were loaded with chronic phase polyclonal IgG and challenged 3 days later with a 100% infectious dose of the acute phase H77C virus, both originating from patient H. Passive immunization induced sterilizing immunity in five of eight challenged animals. In the three nonprotected animals, the HCV infection was attenuated, as evidenced by altered viral kinetics in comparison with five control IgG-treated animals. Plasma samples obtained from the mice at viral challenge neutralized H77C-HCVpp at dilutions as high as 1/400. Infection was completely prevented when, before administration to naïve chimeric mice, the inoculum was pre-incubated in vitro at an IgG concentration normally observed in humans. Conclusion: Polyclonal IgG from a patient with a long-standing HCV infection not only displays neutralizing activity in vitro using the HCVpp system, but also conveys sterilizing immunity toward the ancestral HCV strain in vivo, using the human liver-chimeric mouse model. Both experimental systems will be useful tools to identify neutralizing antibodies for future clinical use. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 31 janvier 2008
Xudong Wu, Luyong Zhang, Emily Gurley, Elaine Studer, Jing Shang, Tao Wang, Cuifen Wang, Ming Yan, Zhenzhou Jiang, Phillip B. Hylemon, Arun J. Sanyal, William M. Pandak Jr, Huiping Zhou
Prevention of free fatty acid-induced hepatic lipotoxicity by 18[beta]-glycyrrhetinic acid through lysosomal and mitochondrial pathways
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and affects millions of people worldwide. Despite the increasing prevalence of NAFLD, the exact molecular/cellular mechanisms remain obscure and effective therapeutic strategies are still limited. It is well-accepted that free fatty acid (FFA)-induced lipotoxicity plays a pivotal role in the pathogenesis of NAFLD. Inhibition of FFA-associated hepatic toxicity represents a potential therapeutic strategy. Glycyrrhizin (GL), the major bioactive component of licorice root extract, has a variety of pharmacological properties including anti-inflammatory, antioxidant, and immune-modulating activities. GL has been used to treat hepatitis to reduce liver inflammation and hepatic injury; however, the mechanism underlying the antihepatic injury property of GL is still poorly understood. In this report, we provide evidence that 18 [beta]-glycyrrhetinic acid (GA), the biologically active metabolite of GL, prevented FFA-induced lipid accumulation and cell apoptosis in in vitro HepG2 (human liver cell line) NAFLD models. GA also prevented high fat diet (HFD)-induced hepatic lipotoxicity and liver injury in in vivo rat NAFLD models. GA was found to stabilize lysosomal membranes, inhibit cathepsin B expression and enzyme activity, inhibit mitochondrial cytochrome c release, and reduce FFA-induced oxidative stress. These characteristics may represent major cellular mechanisms, which account for its protective effects on FFA/HFD-induced hepatic lipotoxicity. Conclusion: GA significantly reduced FFA/HFD-induced hepatic lipotoxicity by stabilizing the integrity of lysosomes and mitochondria and inhibiting cathepsin B expression and enzyme activity. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 21 janvier 2008
Guo-Xiang Yang, Zhe-Xiong Lian, Ya-Hui Chuang, Yuki Moritoki, Ruth Y. Lan, Kanji Wakabayashi, Aftab A. Ansari, Richard A. Flavell, William M. Ridgway, Ross L. Coppel, Koichi Tsuneyama, Ian R. Mackay, M. Eric Gershwin
Adoptive transfer of CD8+ T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice
We recently reported that mice with a T cell-restricted expression of a dominant negative form of transforming growth factor [beta] receptor type II (dnTGF[beta]RII) spontaneously develop autoimmune cholangitis that resembles human primary biliary cirrhosis (PBC), including antimitochondrial antibodies (AMAs) and extensive portal CD4+ and CD8+ lymphocytic infiltrates. On the basis of these data, we performed a series of experiments to determine whether the pathology was secondary to direct dnTGF[beta]RII disruption of the liver and/or alternatively the appearance of autoreactive T cells. First, using dnTGF[beta]RIIRag1-/- mice, we noted a normal hepatic and biliary structure. Hence, we performed a rigorous series of adoptive transfer studies, transferring Ly5.1+ unfractionated spleen cell CD4+ or CD8+ T cells from dnTGF[beta]RII mice into B6/Rag-/- (Ly 5.2) recipients. In unmanipulated dnTGF[beta]RII mice, there was a marked increase in CD4+ and CD8+ T cell biliary infiltrates with AMA. Indeed, B6/Rag-/- recipients of dnTGF[beta]RII unfractionated cells develop features of liver disease similar to PBC, suggesting that splenic loss of self-tolerance alone is sufficient to cause disease in this model and therefore that there is no specific abnormality in the biliary targets required for appearance of disease. More importantly, adoptive transfer of CD8+ but not CD4+ T cells into B6/Rag-/- mice led to liver histopathology remarkably similar to PBC, emphasizing a prominent role for CD8 T cell-mediated pathogenesis. In contrast, B6/Rag-/- recipients of CD4+ T cells from dnTGF[beta]RII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon [gamma] and tumor necrosis factor [alpha]. Conclusion: These data suggest that in this model of PBC, autoreactive CD8+ cells destroy bile ducts. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 07 février 2008
Muhammad Y. Sheikh, Jinah Choi, Ishtiaq Qadri, Jacob E. Friedman, Arun J. Sanyal
Hepatitis C virus infection: Molecular pathways to metabolic syndrome
Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent fashion, thus contributing to steatosis, progression of fibrosis and resistance to interferon therapy. The molecular mechanisms in genotype 1 patients that lead to metabolic syndrome are still ambiguous. Based on our current understanding, HCV proteins associate with mitochondria and endoplasmic reticulum and promote oxidative stress. The latter mediates signals involving the p38 mitogen-activated protein kinase and activates nuclear factor kappa B. This transcription factor plays a key role in the expression of cytokines, tumor necrosis factor alpha (TNF-[alpha]), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF-[alpha] inhibits the function of insulin receptor substrates and decreases the expression of the glucose transporter and lipoprotein lipase in peripheral tissues, which is responsible for the promotion of insulin resistance. Furthermore, reduced adiponectin levels, loss of adiponectin receptors, and decreased anti-inflammatory peroxisome proliferator-activated receptor alpha in the liver of HCV patients may contribute to reduced fatty acid oxidation, inflammation, and eventually lipotoxicity. This chain of events may be initiated by HCV-associated IR and provides a direction for future research in the areas of therapeutic intervention. (HEPATOLOGY 2008.)

Date de mise en ligne : Vendredi 01 février 2008
Yannick Ladeiro, Gabrielle Couchy, Charles Balabaud, Paulette Bioulac-Sage, Laura Pelletier, Sandra Rebouissou, Jessica Zucman-Rossi
MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations
Molecular classifications defining new tumor subtypes have been recently refined with genetic and transcriptomic analyses of benign and malignant hepatocellular tumors. Here, we performed microRNA (miRNA) profiling in two series of fully annotated liver tumors to uncover associations between oncogene/tumor suppressor mutations and clinical and pathological features. Expression levels of 250 miRNAs in 46 benign and malignant hepatocellular tumors were compared to those of 4 normal liver samples with quantitative reverse-transcriptase polymerase chain reaction. miRNAs associated with genetic and clinical characteristics were validated in a second series of 43 liver tumor samples and 16 nontumor samples. miRNA profiling unsupervised analysis classified samples in unique clusters characterized by histological features (tumor/nontumor, P < 0.001; benign/malignant tumors, P < 0.01; inflammatory adenoma and focal nodular hyperplasia, P < 0.01), clinical characteristics [hepatitis B virus (HBV) infection, P < 0.001; alcohol consumption, P < 0.05], and oncogene/tumor suppressor gene mutations [[beta]-catenin, P < 0.01; hepatocyte nuclear factor 1[alpha] (HNF1[alpha]), P < 0.01]. Our study identified and validated miR-224 overexpression in all tumors and miR-200c, miR-200, miR-21, miR-224, miR-10b, and miR-222 specific deregulation in benign or malignant tumors. Moreover, miR-96 was overexpressed in HBV tumors, and miR-126* was down-regulated in alcohol-related hepatocellular carcinoma. Down-regulations of miR-107 and miR-375 were specifically associated with HNF1[alpha] and [beta]-catenin gene mutations, respectively. miR-375 expression was highly correlated to that of [beta]-catenin-targeted genes as miR-107 expression was correlated to that of HNF1[alpha] in a small interfering RNA cell line model. Thus, this strongly suggests that [beta]-catenin and HNF1[alpha] could regulate miR-375 and miR-107 expression levels, respectively. Conclusion: Hepatocellular tumors may have a distinct miRNA expression fingerprint according to malignancy, risk factors, and oncogene/tumor suppressor gene alterations. Dissecting these relationships provides a new hypothesis to understand the functional impact of miRNA deregulation in liver tumorigenesis and the promising use of miRNAs as diagnostic markers. (HEPATOLOGY 2008.)

Date de mise en ligne : Vendredi 01 février 2008
Maureen M. Jonas, Deirdre Kelly, Henry Pollack, Jacek Mizerski, Jeff Sorbel, David Frederick, Elsa Mondou, Franck Rousseau, Etienne Sokal
Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B
This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV-treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo-treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV-treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV-associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment-related adverse events were reported for 12% of ADV-treated and 10% of placebo-treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment-naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. Conclusion: ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 31 janvier 2008
Guilherme M. Campos, Kiran Bambha, Eric Vittinghoff, Charlotte Rabl, Andrew M. Posselt, Ruxandra Ciovica, Umesh Tiwari, Linda Ferrel, Mark Pabst, Nathan M. Bass, Raphael B. Merriman
A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients
Nonalcoholic steatohepatitis (NASH) is common in morbidly obese persons. Liver biopsy is diagnostic but technically challenging in such individuals. This study was undertaken to develop a clinically useful scoring system to predict the probability of NASH in morbidly obese persons, thus assisting in the decision to perform liver biopsy. Consecutive subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. The outcome was pathologic diagnosis of NASH. Predictors evaluated were demographic, clinical, and laboratory variables. A clinical scoring system was constructed by rounding the estimated regression coefficients for the independent predictors in a multivariate logistic model for the diagnosis of NASH. Of 200 subjects studied, 64 (32%) had NASH. Median body mass index was 48 kg/m2 (interquartile range, 43-55). Multivariate analysis identified six predictive factors for NASH: the diagnosis of hypertension (odds ratio [OR], 2.4; 95% confidence interval [CI], 1-5.6), type 2 diabetes (OR, 2.6; 95% CI, 1.1-6.3), sleep apnea (OR, 4.0; 95% CI, 1.3-12.2), AST > 27 IU/L (OR, 2.9; 95% CI, 1.2-7.0), alanine aminotransferase (ALT) > 27 IU/L (OR, 3.3; 95% CI, 1.4-8.0), and non-Black race (OR, 8.4; 95% CI, 1.9-37.1). A NASH Clinical Scoring System for Morbid Obesity was derived to predict the probability of NASH in four categories (low, intermediate, high, and very high). Conclusion: The proposed clinical scoring can predict NASH in morbidly obese persons with sufficient accuracy to be considered for clinical use, identifying a very high-risk group in whom liver biopsy would be very likely to detect NASH, as well as a low-risk group in whom biopsy can be safely delayed or avoided. (HEPATOLOGY 2008.)

Date de mise en ligne : Lundi 04 février 2008
Yann Malato, Leif E. Sander, Christian Liedtke, Malika Al-Masaoudi, Frank Tacke, Christian Trautwein, Naiara Beraza
Hepatocyte-specific inhibitor-of-kappaB-kinase deletion triggers the innate immune response and promotes earlier cell proliferation during liver regeneration
Nuclear factor [kappa]B (NF-[kappa]B) is one of the main transcription factors involved in liver regeneration after partial hepatectomy (PH). It is activated upon I[kappa]B phosphorylation by the I[kappa]B kinase (IKK) complex comprising inhibitor of kappaB kinase 1 (IKK1), inhibitor of kappaB kinase 2 (IKK2), and nuclear factor-B essential modifier (NEMO). We studied the impact of hepatocyte-specific IKK2 deletion during liver regeneration. A 70% PH was performed on IKK2f/f (wild-type) and IKK2[Delta]LPCmice (hepatocyte-specific IKK2 knockout mice). PH in IKK2[Delta]LPC compared with IKK2f/f mice resulted in weaker and delayed NF-[kappa]B activation in hepatocytes, while nonparenchymal liver cells showed earlier NF-[kappa]B activation and higher tumor necrosis factor expression. Additionally, these animals showed increased and earlier serum amyloid A and chemotactic cytokine L-1 levels followed by enhanced polymorphonuclear cell recruitment to the liver. These results correlated with earlier Jun kinase activity, c-myc expression, and matrix metalloproteinase-9 activity, suggesting earlier priming in IKK2[Delta]LPC mice after PH. These data preceded a more rapid cell cycle progression and earlier hepatocyte proliferation as evidenced through cyclin and 5-bromo-2-deoxyuridine analysis. Interestingly, despite faster G1/S progression, IKK2[Delta]LPC mice exhibited an enduring mitosis phase, because mitotic bodies were still observed at later stages after PH. Conclusion: We demonstrate that PH in IKK2[Delta]LPC mice triggers a more rapid and pronounced inflammatory response in nonparenchymal liver cells, which triggers earlier hepatocyte proliferation. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 07 février 2008
Beate Katharina Straub, Pamela Stoeffel, Hans Heid, Ralf Zimbelmann, Peter Schirmacher
Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis
Fatty change (steatosis) is the most frequent liver pathology in western countries and is caused by a broad range of disorders such as alcohol abuse and metabolic syndrome. The surface layer of lipid droplets (LDs) contains members of a protein family that share homologous sequences and domains, the so-called PAT proteins, named after their constituents, perilipin, adipophilin, and TIP47. We characterized the LD-associated proteins in normal and diseased liver connected with LD accumulation. Adipophilin and TIP47 are expressed in LDs of vitamin A-storing hepatic stellate cells and additionally in LDs of steatotic hepatocytes. Perilipin, which was thought to be characteristic for LDs of adipocytes and steroidogenic cells, becomes de novo expressed in hepatocytes of human steatotic liver. Perilipin splice variant A was found in human steatotic hepatocytes by biochemical, molecular biological, and immunohistochemical methods. Its association with LDs is different from TIP47 and adipophilin, and depends on size and localization of the LDs, suggesting that the different PAT proteins play specific roles during maturation of LDs. (HEPATOLOGY 2008.)

Date de mise en ligne : Jeudi 17 janvier 2008
Matthew W. Lawless, Arun K. Mankan, Anthony W. Ryan, Suzanne Norris
Tauroursodeoxycholic acid: Relieving the pathogenesis of HFE C282Y hereditary hemochromatosis
No abstract.

Date de mise en ligne : Jeudi 08 mai 2008
Godlee, F.
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