Mise à jour le : 15-11-2013
Les derniers abstracts de la revue Journal of Hepatology : |
Date de mise en ligne : Vendredi 01 novembre 2013
EASL iLiver app
EASL iLiver app
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00560-6/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
Editorial Board
Editorial Board
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00561-8/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
EASL Physician Scientist Fellowship
EASL Physician Scientist Fellowship
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00562-X/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
Journal of Hepatology iPad Application
Journal of Hepatology iPad Application
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00563-1/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
Translational Research in Chronic Viral Hepatitis: EASL Monothematic Conference, Lyon 2013
Translational Research in Chronic Viral Hepatitis: EASL Monothematic Conference, Lyon 2013
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00564-3/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
Call for applications for the Journal of Hepatology: Editor-in-Chief 2015–2020
Call for applications for the Journal of Hepatology: Editor-in-Chief 2015–2020
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00565-5/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
Contents
Contents
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00567-9/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
See you in London for the International Liver CongressTM 2014
See you in London for the International Liver CongressTM 2014
http://www.journal-of-hepatology.eu/article/S0168-8278(13)00662-4/abstract?rss=yes
Date de mise en ligne : Lundi 19 août 2013
Scott L. Friedman
Focus
A lovely study in this month’s issue of the Journal provides a nice example of using complementary approaches to dissect cell-specific function in an animal model of liver injury. The study by Morán-Salvador et al. examines the contributions of PPARγ activity in both parenchymal and non-parenchymal cells during CCl4-induced liver injury by combining a method to genetically deplete this gene in specific cell types in vivo with a model of tissue function using precision cut liver slices (PCLS) ex vivo.
Date de mise en ligne : Mercredi 14 août 2013
Rajiv Jalan, Mauro Bernardi
Effective albumin concentration and cirrhosis mortality: From concept to reality
Albumin is the most abundant protein in human plasma that is produced exclusively in the liver. Traditionally, albumin has been thought of being important in providing plasma with its oncotic property and therefore its use in clinical practice has been mainly aimed at promoting plasma volume expansion. The past 10years or so has seen an explosion in the knowledge of albumin biology such that it is now clear that it has multifunctional properties ranging from provision of oncotic pressure, immune regulation and endothelial stabilization to being a molecule that works in the intracellular compartment modifying several key pathophysiological mechanisms (reviewed in Garcie-Martinez et al.) . It has been hypothesized that the pleiotropic effects of albumin in cirrhosis and its proven effectiveness in spontaneous bacterial peritonitis, prevention of post paracentesis circulatory dysfunction, hepatorenal syndrome and hepatic encephalopathy relates to these functional characteristics rather than simple volume expansion . Indeed, albumin administration, but not hydroxyethyl starch, improves systemic hemodynamics in patients with spontaneous bacterial peritonitis by decreasing endothelial activation . Moreover, in experimental cirrhosis in rats, albumin exerts a positive cardiac inotropic effect counteracting oxidative stress- and TNF-α-induced impairment of cardiac contractility . Given the pathophysiological importance of cirrhotic cardiomyopathy in hepatorenal syndrome, it is likely that the beneficial effects of albumin in this setting are mediated, at least in part, by these mechanisms. The paper in the current issue of the Journal of Hepatology by Oettl et al. adds to that growing literature by suggesting that albumin may be irreversibly oxidized in advanced cirrhosis, and this reduction in albumin function predicts mortality .
Date de mise en ligne : Lundi 19 août 2013
Jörg Schrader
The role of MDSCs in hepatocellular carcinoma – in vivo veritas?
The inflammatory microenvironment has been increasingly coming into the focus of tumour biology both in basic research and in translational research and clinical application. Pro-inflammatory stimuli have been proven to be associated with the early process of carcinogenesis including malignant transformation and initiation of tumour growth. At later stages of cancer progression, inflammation is the Janus face of tumor biology: on the one hand, distinct pro-inflammatory stimuli and infiltrating immune cells like macrophages and granulocytes are needed for proper angiogenesis, tissue remodeling, and especially for the process of metastasis development. On the other hand, anti-inflammatory mechanisms ensue to suppress an anti-tumor immune response by T cells and NK cells. A central position between these two faces of inflammation is taken by myeloid derived suppressor cells [MDSCs], which are immature myeloid cells of the monocytic and granulocytic lineage released from the bone marrow. They can function as macrophage-like cells within the tumour microenvironment fostering tumour-supporting inflammation, but are also effective suppressors of T-cell and NK-cell mediated anti-tumour responses . In line with studies in most epithelial cancers, MDSCs accumulate in the blood and tumours of patients with hepatocellular carcinoma (HCC) . Up to now, the functional role of MDSCs in development and progression of hepatocellular carcinoma has still to be defined. One reason for the paucity of data might be related to the lack of a well characterized mouse model of HCC with regard to MDSC accumulation and distribution in vivo.
Date de mise en ligne : Mercredi 07 août 2013
Fabio Piscaglia, Alessandro Cucchetti, Christoph F. Dietrich, Veronica Salvatore
Towards new tools for refined management of patients with advanced hepatocellular carcinoma under systemic therapy: Some enthusiasm with a word of caution
In the present issue of the Journal of Hepatology, Dr. Zocco and coworkers from Rome, Italy, showed original data on a much debated and burning issue: is it possible to early predict response to antiangiogenic treatment in hepatocellular carcinoma (HCC) prior to the first standard assessment at approximately two months ?
Date de mise en ligne : Jeudi 27 juin 2013
José Antonio Carrión, Elena Gonzalez-Colominas, Montserrat GarcÃa-Retortillo, Nuria Cañete, Isabel Cirera, Susanna Coll, Maria Dolors Giménez, Carmen Márquez, Victoria Martin-Escudero, Pere CastellvÃ, Ricard Navinés, Juan Ramon Castaño, Josep Anton Galeras, Esther Salas, Felipe Bory, RocÃo MartÃn-Santos, Ricard SolÃ
A multidisciplinary support programme increases the efficiency of pegylated interferon alfa-2a and ribavirin in hepatitis C
Background & Aims: Adherence to antiviral treatment is important to achieve sustained virological response (SVR) in chronic hepatitis C (CHC). We evaluated the efficiency of a multidisciplinary support programme (MSP), based on published HIV treatment experience, to increase patient adherence and the efficacy of pegylated interferon alfa-2a and ribavirin in CHC.Methods: 447 patients receiving antiviral treatment were distributed into 3 groups: control group (2003–2004, n=147), MSP group (2005–2006, n=131), and MSP-validation group (2007–2009, n=169). The MSP group included two hepatologists, two nurses, one pharmacist, one psychologist, one administrative assistant, and one psychiatrist. Cost-effectiveness analysis was performed using a Markov model.Results: Adherence and SVR rates were higher in the MSP (94.6% and 77.1%) and MSP-validation (91.7% and 74.6%) groups compared to controls (78.9% and 61.9%) (p<0.05 in all cases). SVR was higher in genotypes 1 or 4 followed by the MSP group vs. controls (67.7% vs. 48.9%, p=0.02) compared with genotypes 2 or 3 (87.7% vs. 81.4%, p=n.s.). The MSP was the main predictive factor of SVR in patients with genotype 1. The rate of adherence in patients with psychiatric disorders was higher in the MSP groups (n=95, 90.5%) compared to controls (n=28, 75.7%) (p=0.02). The cost per patient was € 13,319 in the MSP group and € 16,184 in the control group. The MSP group achieved more quality-adjusted life years (QALYs) (16.317 QALYs) than controls (15.814 QALYs) and was dominant in all genotypes.Conclusions: MSP improves patient compliance and increases the efficiency of antiviral treatment in CHC, being cost-effective.
Date de mise en ligne : Lundi 01 juillet 2013
Jasmin Hoffmann, Caroline Boehm, Kiyoshi Himmelsbach, Christian Donnerhak, Hendrik Roettger, Thomas S. Weiss, Daniela Ploen, Eberhard Hildt
Identification of α-taxilin as an essential factor for the life cycle of hepatitis B virus
Background & Aims: α-taxilin was identified as binding partner of syntaxins and is supposed to regulate vesicular trafficking. However, the physiological functions of α-taxilin and its potential relevance for the life cycle of hepatitis B virus (HBV) are still poorly understood.Methods: Transfected hepatoma cells, infected primary human hepatocytes, and liver tissue of HBV-infected patients were used to study the expression of α-taxilin. Subcellular localization and colocalization were analyzed by confocal laser scanning microscopy (CLSM). Protein-protein interactions were further investigated by co-immunoprecipitations. Silencing of α-taxilin expression was performed by lentiviral gene transfer.Results: HBV producing cells show a significant higher level of α-taxilin. HBV induces α-taxilin expression, by its regulatory proteins HBx and LHBs via c-Raf. This indicates that α-taxilin is essential for the release of HBV particles. CLSM and co-immunoprecipitations demonstrated that the PreS1PreS2 domain of LHBs interacts with α-taxilin. α-taxilin harbors a YXXL motif that represents a classic late domain. In accordance with this, it was found by co-immunoprecipitations that α-taxilin interacts with the ESCRT I component tsg101. CLSM revealed that a fraction of α-taxilin colocalizes with LHBs and tsg101.Conclusions: α-taxilin plays an essential role for release of HBV-DNA containing particles. It might act as an adapter that binds, on the one hand, to LHBs and, on the other hand, to tsg101 and thereby helps recruit the ESCRT machinery to the viral envelope proteins.
Date de mise en ligne : Lundi 08 juillet 2013
Kaku Goto, Wenyu Lin, Leiliang Zhang, Nikolaus Jilg, Run-Xuan Shao, Esperance A.K. Schaefer, Hong Zhao, Dahlene N. Fusco, Lee F. Peng, Naoya Kato, Raymond T. Chung
The AMPK-related kinase SNARK regulates hepatitis C virus replication and pathogenesis through enhancement of TGF-β signaling
Background & Aims: Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. The biological and therapeutic importance of host cellular cofactors for viral replication has been recently appreciated. Here we examined the roles of SNF1/AMP kinase-related kinase (SNARK) in HCV replication and pathogenesis.Methods: The JFH1 infection system and the full-length HCV replicon OR6 cell line were used. Gene expression was knocked down by siRNAs. SNARK mutants were created by site-directed mutagenesis. Intracellular mRNA levels were measured by qRT-PCR. Endogenous and overexpressed proteins were detected by Western blot analysis and immunofluorescence. Transforming growth factor (TGF)-β signaling was monitored by a luciferase reporter construct. Liver biopsy samples from HCV-infected patients were analyzed for SNARK expression.Results: Knockdown of SNARK impaired viral replication, which was rescued by wild type SNARK but not by unphosphorylated or kinase-deficient mutants. Knockdown and overexpression studies demonstrated that SNARK promoted TGF-β signaling in a manner dependent on both its phosphorylation and kinase activity. In turn, chronic HCV replication upregulated the expression of SNARK in patients. Further, the SNARK kinase inhibitor metformin suppressed both HCV replication and SNARK-mediated enhancement of TGF-β signaling.Conclusions: Thus reciprocal regulation between HCV and SNARK promotes TGF-β signaling, a major driver of hepatic fibrogenesis. These findings suggest that SNARK will be an attractive target for the design of novel host-directed antiviral and antifibrotic drugs.
Date de mise en ligne : Jeudi 11 juillet 2013
Emanuel K. Manesis, Georgia Vourli, George Dalekos, Themistoclis Vasiliadis, Nina Manolaki, Athina Hounta, Sotirios Koutsounas, Irini Vafiadis, Georgia Nikolopoulou, Gregory Giannoulis, George Germanidis, George Papatheodoridis, Giota Touloumi
Prevalence and clinical course of hepatitis delta infection in Greece: A 13-year prospective study
Background & Aims: Hepatitis D virus (HDV) has decreased in Europe, but recent reports indicate a rising trend. We report the epidemiological changes, clinical progress, and effect of treatment on the natural course of HDV infection in Greece during the last 13years.Methods: Prospective data were extracted from the HepNet.Greece Cohort-Study.Results: Since 1997, 4673 chronic HBV (CHB) cases (4527 adults, 146 children) have been followed prospectively. Two thousand one hundred thirty-seven patients were tested for anti-HDV [101 (4.7%) positive]. Anti-HDV testing in Greece decreased significantly (57.0% before 2003, 35.3% thereafter; p<0.001). Anti-HDV prevalence among HBsAg-positives was 4.2%; lower in native Greeks (2.8%) than in immigrants (7.5%) or in children (15.3%; p<0.001). Within 2.3years of follow-up, HDV occurred in 11/2047 HBsAg-positive patients (2.2 new delta-infected adults and 8.7 children per 1000 HBsAg-positive annually). HDV-positive compared to CHB adults were younger (p=0.035) and had more active and advanced disease at baseline, as indicated by laboratory indices and the higher prevalence of cirrhosis at younger age. During a 4.2-year median observation, significantly more anti-HDV-positive than CHB adults developed a liver-related first event (20.0% vs. 8.5%, pLog-rank=0.014).Treatment was received by 46/90 (51.1%) patients, 40 of them interferon-based. In multivariable analysis, interferon significantly decreased disease progression in HDV-positive patients [HR=0.14 (95% CI: 0.02–0.86; p=0.033)].Conclusions: In Greece, HDV serology is currently tested in only one-third of HBsAg-positive patients. HDV prevalence is lower in native Greeks compared to immigrants, who may contribute >50% of the HDV infection burden in Greece. Data show that HDV infection is a rapidly progressive disease, but interferon-based treatment may alter its course.
Date de mise en ligne : Jeudi 11 juillet 2013
Hwalih Han, Mazen Noureddin, Michael Witthaus, Yoon J. Park, Jay H. Hoofnagle, T. Jake Liang, Yaron Rotman
Temperature rise after peginterferon alfa-2a injection in patients with chronic hepatitis C is associated with virological response and is modulated by IL28B genotype
Background & Aims: Interferon treatment for chronic hepatitis C is associated with non-specific symptoms including fever. We aimed to determine the association of temperature changes with interferon antiviral activity.Methods: 60 treatment-naïve patients with chronic hepatitis C (67% genotype 1/4/6, 33% genotype 2/3) were admitted to start peginterferon alfa-2a and ribavirin in a clinical trial. Temperature was measured at baseline and 3 times daily for the first 24h and the maximal increase from baseline during that time (ΔTmax) was determined. Serum HCV-RNA, interferon-gamma-inducible protein-10 (IP-10) and expression of interferon-stimulated genes (ISGs – CD274, ISG15, RSAD2, IRF7, CXCL10) in peripheral blood mononuclear cells (PBMCs) were measured at very early time points, and response kinetics calculated. The IL28B single nucleotide polymorphism, rs12979860, was genotyped.Results: Temperatures rose by 1.2±0.8°C, peaking after 12.5h. ΔTmax was strongly associated with 1st phase virological decline (r=0.59, p<0.0001) and was independent of gender, cirrhosis, viral genotype or baseline HCV-RNA. The association with 1st phase decline was seen in patients with rs12989760CC genotype (r=0.65, p<0.0001) but not in CC/CT (r=0.13, p=0.53) and patients with CC genotype had a higher ΔTmax (1.4±0.8°C vs. 0.8±0.6°C, p=0.001). ΔTmax was associated with 6- and 24-h induction of serum IP-10 and of PBMC ISG expression, but only in patients with rs12989760CC. ΔTmax weakly predicted early virological response (AUC=0.68, CI 0.49–0.88).Conclusions: Temperature rise following peginterferon injection is closely associated with virological response and is modulated by IL28B polymorphism, reflecting host interferon-responsiveness.
Date de mise en ligne : Jeudi 11 juillet 2013
Thomas-Matthias Scherzer, Albert Friedrich Stättermayer, Rudolf Stauber, Andreas Maieron, Michael Strasser, Hermann Laferl, Remy Schwarzer, Christian Datz, Karoline Rutter, Sandra Beinhardt, Petra Steindl-Munda, Harald Hofer, Peter Ferenci
Effect of gender and ITPA polymorphisms on ribavirin-induced anemia in chronic hepatitis C patients
Background & Aims: Single nucleotide polymorphisms (SNPs) in the inosine triphosphate pyrophosphatase (ITPA) gene protect patients from ribavirin induced anemia. To investigate other possible protective cofactors, gender differences were analyzed in patients with HCV genotype 1.Methods: Hemoglobin levels at baseline (Hb0) and the decline after 4weeks of treatment (HbΔ4) were analyzed in 308 chronic hepatitis C patients participating in 5 Austrian trials (n=308, age 43.9±11.1, male:185, female:123, BMI 25.3±3.9, no cirrhosis: n=259, liver cirrhosis: n=49). All patients were treated with 180μg peginterferon-alpha 2a and ribavirin [1000–1200mg/d; females: mean (95% CI) 15.8mg/kg (15.4–16.2); males 14.3 (14.1–14.5); p<0.001]. The SNPs rs6051702, rs1127354, rs7270101 and IL28B rs12979860 were analyzed by the StepOnePlus Real time PCR System.Results: 188 were major alleles homozygotes; 95 (30.8%) carried the minor allele (C) of rs6051702, 47 (15.3%) of rs1127354 (A), and 69 (22.4%) of rs7270101 (C). The overall Hb0 was 14.8g/dl (14.6–14.9) [mean (95%CI); females 13.7 (13.5–13.9); males 15.5; 15.3–15.6; p<0.001]. The overall HbΔ4 was greater in major allele homozygotes [2.8g/dl (2.6–3.0)] than in minor allele carriers [1.6 (1.4–1.9); p<0.001]. Irrespective of the ITPA genotypes HbΔ4 was smaller in female [2.0 (1.7–2.2)] than in male patients [2.6 (2.4–2.8); p<0.001] and among females in premenopausal [1.5 (1.3–1.8)] than in postmenopausal patients [2.7 (2.3–3.1); p<0.001].Conclusions: Irrespective of the protective effect of ITPA mutations, premenopausal females less likely develop ribavirin induced anemia.
Date de mise en ligne : Jeudi 11 juillet 2013
Sandra Beinhardt, Berit Anna Payer, Christian Datz, Michael Strasser, Andreas Maieron, Livia Dorn, Evelyn Grilnberger-Franz, Emina Dulic-Lakovic, Rudolf Stauber, Hermann Laferl, Judith H. Aberle, Heidemarie Holzmann, Christoph Krall, Wolfgang Vogel, Peter Ferenci, Harald Hofer
A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection
Background & Aims: IL28B polymorphisms, jaundice, decline in HCV-RNA, IP-10, and gender have been proposed to be indicative of spontaneous clearance of acute hepatitis C virus infection. The aim of this study was to define a score enabling the discrimination of patients with spontaneous clearance of HCV from those with development of viral persistence and need for early antiviral treatment.Methods: 136 patients (74 male; 35±15years) were analyzed. From variables predictive of spontaneous clearance, calculated by univariate analysis, three scores were built. Analogous cut-offs were evaluated by computing area under the receiver operating characteristic curves. Candidate variables and cut-offs were: (I) presence of IL28B C/C (p=0.027), (II) age (p=0.031; cut-off: 35years), (III) peak-bilirubin (p=0.018; cut-off: 6mg/dl), (IV) HCV-RNA decline within 4weeks (p<0.001;cut-off: >2.5log), (V) serum IP-10 (p=0.003; cut-off: 546pg/ml), (VI) presence of CD4(+) Th1 cells (p=0.024). Each variable was allocated to 0 or 1 point, an HCV-RNA decline of ⩾1log10 but <2.5log10 to 1 point, a decline of ⩾2.5log10 to 2 points. Three scores were evaluated (Score 1: I–IV; Score 2: I–V; Score 3: I–VI).Results: A cut-off of ⩾3 points out of 5 in Score 1 (AUROC: 0.82; DeLong 95% CI: 0.76–0.93) predicted spontaneous clearance with a sensitivity of 71% (95% CI: 0.53–0.86) and specificity of 87% (95% CI: 0.73–0.95). PPV and NPV were 79% and 82%. Corresponding findings for Score 2 including IP-10 (AUROC: 0.93; DeLong 95% CI: 0.86–0.93) at a cut-off of ⩾4 were: sensitivity 81%, specificity 95% (PPV: 100%; NPV: 77%). A cut-off of ⩾5 in Score 3 (AUROC: 0.98; DeLong 95% CI: 0.95–1.0) predicted spontaneous resolution with a sensitivity of 75% and specificity of 100% (PPV: 100%; NPV: 88%).Conclusions: The scores enable a reliable discrimination between AHC-patients with high potential for spontaneous clearance from candidates for early therapeutic intervention due to marginal chance of spontaneous resolution.
Date de mise en ligne : Mercredi 26 juin 2013
Karl Oettl, Ruth Birner-Gruenberger, Walter Spindelboeck, Hans Peter Stueger, Livia Dorn, Vanessa Stadlbauer, Csilla Putz-Bankuti, Peter Krisper, Ivo Graziadei, Wolfgang Vogel, Carolin Lackner, Rudolf E. Stauber
Oxidative albumin damage in chronic liver failure: Relation to albumin binding capacity, liver dysfunction and survival
Background & Aims: Impaired binding function of albumin has been demonstrated in end-stage liver disease. This and other functional disturbances of albumin may be related to oxidative stress which is believed to play an important role in the pathogenesis of liver failure as well as sepsis. The aim of the present study was to relate oxidative modification of albumin to loss of albumin binding function in advanced chronic liver failure and in sepsis.Methods: Patients with decompensated cirrhosis or sepsis and healthy controls were investigated. Three fractions of albumin were separated by chromatography according to the redox state of cysteine-34: non-oxidized human mercaptalbumin, reversibly oxidized human non-mercaptalbumin-1, and irreversibly oxidized human non-mercaptalbumin-2 (HNA2). Binding properties of albumin site II were measured using dansylsarcosine as a ligand.Results: Both in cirrhotic and septic patients, fractions of oxidized albumin were increased and binding capacity for dansylsarcosine was decreased. Mass spectroscopy confirmed specific oxidation of cysteine-34. In cirrhotic patients, dansylsarcosine binding correlated strongly with liver function parameters and moderately with HNA2. Baseline levels of HNA2 accurately predicted 30-day and 90-day survival in cirrhotic patients and this was confirmed in an external validation cohort.Conclusions: Our results suggest that oxidative damage impairs binding properties of albumin. In advanced liver disease, reduced binding capacity of albumin site II is mainly related to impaired liver function. The plasma level of HNA2 is closely related to survival and may represent a novel biomarker for liver failure.
Date de mise en ligne : Lundi 01 juillet 2013
Andrea Schlegel, Rolf Graf, Pierre-Alain Clavien, Philipp Dutkowski
Hypothermic oxygenated perfusion (HOPE) protects from biliary injury in a rodent model of DCD liver transplantation
Background & Aims: The use of livers from donors after cardiac arrest (DCD) is increasing in many countries to overcome organ shortage. Due to additional warm ischemia before preservation, those grafts are at higher risk of failure and bile duct injury. Several competing rescue strategies by machine perfusion techniques have been developed with, however, unclear effects on biliary injury. We analyze the impact of an end-ischemic Hypothermic Oxygenated PErfusion (HOPE) approach applied only through the portal vein for 1h before graft implantation.Methods: Rat livers were subjected to 30-min in situ warm ischemia, followed by subsequent 4-h cold storage, mimicking DCD-organ procurement and conventional organ transport. Livers in the HOPE group underwent also passive cold storage for 4h, but were subsequently machine perfused for 1h before implantation. Outcome was tested by liver transplantation (LT) at 12h after implantation (n=10 each group) and after 4weeks (n=10 each group), focusing on early reperfusion injury, immune response, and later intrahepatic biliary injury.Results: All animals survived after LT. However, reperfusion injury was significantly decreased by HOPE treatment as tested by hepatocyte injury, Kupffer cell activation, and endothelial cell activation. Recipients receiving non-perfused DCD livers disclosed less body weight gain, increased bilirubin, and severe intrahepatic biliary fibrosis. In contrast, HOPE treated DCD livers were protected from biliary injury, as detected by cholestasis parameter and histology.Conclusions: We demonstrate in a DCD liver transplant model that end-ischemic hypothermic oxygenated perfusion is a powerful strategy for protection against biliary injury.
Date de mise en ligne : Lundi 08 juillet 2013
Bryan C. Fuchs, Huifang Wang, Yan Yang, Lan Wei, Miloslav Polasek, Daniel T. Schühle, Gregory Y. Lauwers, Ashfaq Parkar, Anthony J. Sinskey, Kenneth K. Tanabe, Peter Caravan
Molecular MRI of collagen to diagnose and stage liver fibrosis
Background & Aims: The gold standard in assessing liver fibrosis is biopsy despite limitations like invasiveness and sampling error and complications including morbidity and mortality. Therefore, there is a major unmet medical need to quantify fibrosis non-invasively to facilitate early diagnosis of chronic liver disease and provide a means to monitor disease progression. The goal of this study was to evaluate the ability of several magnetic resonance imaging (MRI) techniques to stage liver fibrosis.Methods: A gadolinium (Gd)-based MRI probe targeted to type I collagen (termed EP-3533) was utilized to non-invasively stage liver fibrosis in a carbon tetrachloride (CCl4) mouse model and the results were compared to other MRI techniques including relaxation times, diffusion, and magnetization transfer measurements.Results: The most sensitive MR biomarker was the change in liver:muscle contrast to noise ratio (ΔCNR) after EP-3533 injection. We observed a strong positive linear correlation between ΔCNR and liver hydroxyproline (i.e. collagen) levels (r=0.89) as well as ΔCNR and conventional Ishak fibrosis scoring. In addition, the area under the receiver operating curve (AUR0C) for distinguishing early (Ishak ⩽3) from late (Ishak ⩾4) fibrosis was 0.942±0.052 (p<0.001). By comparison, other MRI techniques were not as sensitive to changes in fibrosis in this model.Conclusions: We have developed an MRI technique using a collagen-specific probe for diagnosing and staging liver fibrosis, and validated it in the CCl4 mouse model. This approach should provide a better means to monitor disease progression in patients.
Date de mise en ligne : Mercredi 17 juillet 2013
Hooi-Tin Ong, Mark J. Federspiel, Chang M. Guo, London Lucien Ooi, Stephen J. Russell, Kah-Whye Peng, Kam M. Hui
Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth
Background & Aims: Although attenuated measles virus (MV) has demonstrated potent oncolytic activities towards human cancers, it has not yet been widely adopted into clinical practice. One of the major hurdles is the presence of pre-existing anti-MV immunity in the recipients. In this study, we have evaluated the combination of the potent oncolytic activity of the attenuated MV with the unique immunoprivileged and tumor-tropic biological properties of human bone marrow-derived mesenchymal stem cells (BM-hMSCs) to combat human hepatocellular carcinoma (HCC), orthotopically implanted in SCID mice, passively immunized with human neutralizing antibodies against MV as a preclinical model.Methods: SCID mice were orthotopically implanted with patient-derived HCC tissues and established HCC cell lines. SCID mice were passively immunized with human neutralizing anti-measles antibodies. Bioluminescence and fluorescence imaging were employed to monitor the ability of systemically delivered MV-infected BM-hMSCs to infiltrate the implanted tumors and their effects on tumor growth.Results: Systemically delivered MV-infected BM-hMSCs homed to the HCC tumors implanted orthotopically in the liver and it was evidenced that BM-hMSCs could transfer MV infectivity to HCC via heterofusion. Furthermore, therapy with MV-infected BM-hMSCs resulted in significant inhibition of tumor growth in both measles antibody-naïve and passively-immunized SCID mice. By contrast, when cell-free MV viruses were delivered systemically, antitumor activity was evident only in measles antibody-naïve SCID mice.Conclusions: MV-infected BM-hMSCs cell delivery system provides a feasible strategy to elude the presence of immunity against MV in most of the potential cancer patients to be treated with the oncolytic MV viruses.
Date de mise en ligne : Lundi 24 juin 2013
Tamar Kapanadze, Jaba Gamrekelashvili, Chi Ma, Carmen Chan, Fei Zhao, Stephen Hewitt, Lars Zender, Veena Kapoor, Dean W. Felsher, Michael P. Manns, Firouzeh Korangy, Tim F. Greten
Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma
Background & Aims: Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease.Methods: The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages.Results: An accumulation of MDSC was found in mice with HCC irrespective of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN-induced HCC. Enhanced expression of genes associated with MDSC generation (GM-CSF, VEGF, IL6, IL1β) and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF overexpression or anti-KC and anti-GM-CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib.Conclusions: Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied.
Date de mise en ligne : Mercredi 26 juin 2013
Maria Assunta Zocco, Matteo Garcovich, Andrea Lupascu, Enrico Di Stasio, Davide Roccarina, Brigida Elenora Annicchiarico, Laura Riccardi, Maria Elena Ainora, Francesca Ponziani, Gianluigi Caracciolo, Gian Lodovico Rapaccini, Raffaele Landolfi, Massimo Siciliano, Maurizio Pompili, Antonio Gasbarrini
Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: The role of dynamic contrast enhanced ultrasound
Background & Aims: Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points.Methods: Twenty-eight HCC patients treated with sorafenib 400mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, TP; area under the curve, AUC; slope of wash in, Pw; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value <0.05 was considered statistically significant.Results: The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and Pw; p=0.002, <0.001, and 0.003, respectively). A decrease of AUC (p=0.045) and an increased/unchanged value of TP (p=0.029) and MTT (p=0.010) were associated with longer survival. Three D-CEUS parameters (AUC, TP, Pw) were significantly associated with PFS.Conclusions: D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment.
Date de mise en ligne : Mercredi 26 juin 2013
Julianne Bayliss, Lucy Lim, Alexander J.V. Thompson, Paul Desmond, Peter Angus, Stephen Locarnini, Peter A. Revill
Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma
Background & Aims: The hepatitis B virus (HBV) genome encodes specific sequence elements which promote splicing of viral DNA. It has been previously suggested that spliced HBV (spHBV) variants promote viral replication and protein production, leading to hepatocellular carcinoma (HCC). In this study, we have analysed changes in spHBV over time; providing the first longitudinal analysis of spHBV in relation to the development of HCC.Methods: Serial serum samples were collected from 165 patients with chronic HBV monoinfection, including 58 patients who later developed HCC. Real-time PCR was used to amplify and quantify wt and sp DNA loads.Results: spHBV was detected in over 80% of patients with chronic HBV infection. Median serum spHBV levels were significantly higher in HCC patients than HCC-free control patients (p<0.001). Univariate analysis revealed a strong correlation between time to HCC diagnosis and spHBV DNA levels (Ï„=0.203; p=0.016). Asian HBV genotype (p=0.025) and increased viral load (p<0.001) were also significantly associated with increased spHBV DNA levels. Multiple regression analysis revealed time to diagnosis of HCC, Asian HBV genotypes, and viral load to be associated with increased spHBV DNA (model p<0.001; R2=0.189).Conclusions: HBV splicing is a common event during chronic infection and increases prior to diagnosis of HCC. Measurement of HBV splicing may prove a valuable adjunct to be used in the identification of chronically infected patients who are at increased risk of developing HCC.
Date de mise en ligne : Mercredi 26 juin 2013
Michael Vouche, Robert J. Lewandowski, Rohi Atassi, Khairuddin Memon, Vanessa L. Gates, Robert K. Ryu, Ron C. Gaba, Mary F. Mulcahy, Talia Baker, Kent Sato, Ryan Hickey, Daniel Ganger, Ahsun Riaz, Jonathan Fryer, Juan Carlos Caicedo, Michael Abecassis, Laura Kulik, Riad Salem
Radiation lobectomy: Time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection
Background & Aims: Portal vein embolization (PVE) is a standard technique for patients not amenable to liver resection due to small future liver remnant ratio (FLR). Radiation lobectomy (RL) with 90Y-loaded microspheres (Y90) is hypothesized to induce comparable volumetric changes in liver lobes, while potentially controlling the liver tumor and limiting tumor progression in the untreated lobe. We aimed at testing this concept by performing a comprehensive time-dependent analysis of liver volumes following radioembolization.Methods: 83 patients with right unilobar disease with hepatocellular carcinoma (HCC; N=67), cholangiocarcinoma (CC; N=8) or colorectal cancer (CRC; N=8) were treated by Y90 RL. The total liver volume, lobar (parenchymal) and tumor volumes, FLR and percentage of FLR hypertrophy from baseline (%FLR hypertrophy) were assessed on pre- and post-Y90 CT/MRI scans in a dynamic fashion.Results: Right lobe atrophy (p=0.003), left lobe hypertrophy (p<0.001), and FLR hypertrophy (p<0.001) were observed 1month after Y90 and this was consistent at all follow-up time points. Median %FLR hypertrophy reached 45% (5–186) after 9months (p<0.001). The median maximal %FLR hypertrophy was 26% (−14→86). Portal vein thrombosis was correlated to %FLR hypertrophy (p=0.02). Median Child-Pugh score worsening (6→7) was seen at 1 to 3months (p=0.03) and 3 to 6months (p=0.05) after treatment. Five patients underwent successful right lobectomy (HCC N=3, CRC N=1, CC N=1) and 6 HCCs were transplanted.Conclusions: Radiation lobectomy by Y90 is a safe and effective technique to hypertrophy the FLR. Volumetric changes are comparable (albeit slightly slower) to PVE while the right lobe tumor is treated synchronously. This novel technique is of particular interest in the bridge-to-resection setting.
Date de mise en ligne : Lundi 08 juillet 2013
Keita Kanki, Yuji Akechi, Chisa Ueda, Hiroyuki Tsuchiya, Hiroki Shimizu, Naoki Ishijima, Kan Toriguchi, Etsuro Hatano, Kanenori Endo, Yasuaki Hirooka, Goshi Shiota
Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells
Background & Aims: Accumulating data from epidemiological and experimental studies have suggested that retinoids, which are vitamin A derivatives, exert antitumor activity in various organs. We performed a gene screening based on in silico analysis of retinoic acid response elements (RAREs) to identify the genes facilitating the antitumor activity of retinoic acid (RA) and investigated their clinical significance in hepatocellular carcinoma (HCC).Methods: In silico analysis of RAREs was performed in the 5-kb upstream region of EST clusters. Chromatin immunoprecipitation analysis of the retinoic acid receptors and gene expression analysis were performed in HuH7, HepG2, and MCF7 cells treated with all-trans RA (ATRA). mRNA expression of RA-responsive genes was investigated using tumor and non-tumor tissues of clinical HCC samples from 171 patients. The association between gene expression and survival of patients was examined by Cox regression analysis.Results: We identified 201 candidate genes with promoter regions containing consensus RARE and finally selected 26 RA-responsive genes. Of these, downregulation of OTU domain-containing 7B (OTUD7B) gene, which was upregulated by ATRA, in tumor tissue was associated with a low cancer-specific survival of HCC patients. Functional analyses revealed that OTUD7B negatively regulates nuclear factor κB (NF-κB) signaling and decreases the survival of HCC cells.Conclusions: We identified RA-responsive genes which are regulated by retinoid signal and found that low-OTUD7B mRNA expression is associated with a poor prognosis for HCC patients. OTUD7B-mediated inhibition of NF-κB signaling may be an effective target for antitumor therapy for HCC.
Date de mise en ligne : Lundi 08 juillet 2013
Eva Morán-Salvador, Esther Titos, Bibiana Rius, Ana González-Périz, Verónica GarcÃa-Alonso, Cristina López-Vicario, Rosa Miquel, Yaacov Barak, Vicente Arroyo, Joan Clà ria
Cell-specific PPARγ deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells
Background & Aims: PPARγ plays an essential role in the transcriptional regulation of genes involved in lipid and glucose metabolism, insulin sensitivity, and inflammation. We recently demonstrated that PPARγ plays a causative role in hepatocyte lipid deposition, contributing to the pathogenesis of hepatic steatosis. In this study, we investigated the role of PPARγ in the inflammatory and fibrogenic response of the liver.Methods: Heterozygous floxed/null Cre/LoxP mice with targeted deletion of PPARγ in either hepatocytes (Alb-Cre), macrophages (LysM-Cre) or hepatic stellate cells (HSCs) (aP2-Cre) were submitted to carbon tetrachloride (CCl4) liver injury. Further analyses were performed in precision-cut liver slices (PCLS) and primary cultures of hepatocytes, macrophages, and HSCs.Results: LysM-Cre mice displayed an exacerbated response to chronic CCl4 injury and showed higher necroinflammatory injury, lipid peroxidation, inflammatory infiltrate, cleaved-caspase-3 and caspase 3/7 activity, and COX-2, TNF-α, CXCL2, and IL-1β expression than Alb-Cre and control mice. The deleterious effects of PPARγ disruption in liver macrophages were confirmed in an acute model of CCl4 injury as well as in PCLS incubated with LPS. Moreover, LysM-Cre mice showed an aggravated fibrogenic response to CCl4, as revealed by more prominent Sirius Red and Masson’s trichrome staining, elevated hydroxyproline content and induced α-SMA and TIMP-1 expression. Importantly, aP2-Cre mice with specific disruption of PPARγ in HSCs, as confirmed by immunocytochemical analysis of individual liver cells, also showed exacerbated liver damage and fibrogenic response to CCl4.Conclusions: These data unveil anti-inflammatory and anti-fibrogenic roles for PPARγ in non-parenchymal liver cells.
Date de mise en ligne : Mercredi 26 juin 2013
Mark Davenport, Chris Parsons, Sarah Tizzard, Nedim Hadzic
Steroids in biliary atresia: Single surgeon, single centre, prospective study
Background & Aims: The effect of adjuvant steroids in infants with biliary atresia (BA) is not clear and evidence of benefit is lacking.Methods: During the period Jan. 2000–Dec. 2011, 153 infants with isolated (CMV IgM−ve) BA underwent Kasai portoenterostomy (KPE) at<70days. They were divided into three groups: LOW-dose steroid (from a previous randomized trial; starting prednisolone 2mg/kg/day, n=18), HIGH-dose steroid (starting prednisolone 5mg/kg/day, n=44), and NO steroid [n=72+19 placebo (from randomized trial)=91]. Outcome was assessed by early liver biochemistry, clearance of jaundice (<20μmol/L), and actuarial native liver survival. Data are quoted as median (IQ range) and compared with non-parametric ANOVA, Chi or Log-rank tests as appropriate. p⩽0.05 was regarded as significant.Results: All three groups were comparable for age (ANOVA, p=0.31) and a surrogate marker of liver fibrosis [aspartate-aminotransferase index (APRi), ANOVA, p=0.67]. At 1month post KPE, there was a significant reduction in bilirubin [58 (25–91) vs. 91 (52–145)μmol/L, p=0.0015], AST [118 (91–159) vs. 155 (108–193)IU/L, p=0.0015], and APRi [0.49 (0.28–0.89) vs. 0.82 (0.45–1.2), p=0.005] for HIGH vs. NO steroid. There was a significant increase in % clearance of jaundice with the use of steroids [47/91 (52%) vs. 12/18 (67%) vs. 29/44 (66%); steroids vs. no steroids, p=0.037]. There was no statistical difference in 4-year patient survival (96% vs. 94% vs. 95%) or native liver survival (4year=46% vs. 50 vs. 57%).Conclusions: The adjuvant use of prednisolone significantly improved early post-operative liver biochemistry (especially at the higher dose), and increased the proportion of infants who cleared their jaundice at 6months post-KPE.
Date de mise en ligne : Mercredi 26 juin 2013
Yoh Zen, Rodrigo Liberal, Yasuni Nakanuma, Nigel Heaton, Bernard Portmann
Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis
Background & Aims: IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition.Methods: Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4low PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4high PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs.Results: In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4low PSC (p=0.002) and IgG4high PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4high PSC than in IgG4low PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4high PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8+ lymphocytes. On immunohistochemistry, GATA3+ Th2 lymphocytes and FOXP3+ Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3+/T-bet+ cell ratio to be shifted in favour of Th2 in periductal and perivascular areas.Conclusions: CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.
Date de mise en ligne : Mercredi 19 juin 2013
Hung-Tsung Wu, Feng-Hwa Lu, Horng-Yih Ou, Yu-Chu Su, Hao-Chang Hung, Jin-Shang Wu, Yi-Ching Yang, Chao-Liang Wu, Chih-Jen Chang
The role of Hepassocin in the development of non-alcoholic fatty liver disease
Background & Aims: While non-alcoholic fatty liver disease (NAFLD) is the most common risk factor of chronic liver disease, the mechanisms that initiate its development are obscure. Hepassocin (HPS) is a hepatokine that has been reported to be involved in liver regeneration. In addition to the mitogenic activity of HPS, HPS expression is decreased in patients with hepatoma. However, the role of HPS in NAFLD is still unknown.Methods: A total of 393 subjects with (n=194) or without (n=199) NAFLD were enrolled to evaluate the serum HPS concentration. In order to clarify the causal inference between HPS and NAFLD, we used experimental animal and cell models. Hepatic overexpression or silencing of HPS was achieved by lentiviral vector delivery in mice and lipofectamine transfection in HepG2 cells. Lipogenesis related proteins were detected by Western blots. The expression of inflammatory factors was determined by real-time polymerase chain reaction.Results: Subjects with NAFLD had a higher serum HPS concentration than those without it. Overexpression of HPS increased hepatic lipid accumulation and NAFLD activity scores (NAS), whereas deletion of HPS improved high fat diet-induced hepatic steatosis and decreased NAS in mice. Additionally, oleic acid, a steatogenic reagent, increased HPS expression in hepatocytes. Furthermore, overexpression of HPS in HepG2 cells induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway, whereas deletion of HPS decreased oleic acid-induced lipid accumulation.Conclusions: The present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway.
Date de mise en ligne : Lundi 15 juillet 2013
Ding-Shinn Chen, Stephen Locarnini, Suzanne Wait, Si-Hyun Bae, Pei-Jer Chen, James Y.Y. Fung, Hong Soo Kim, Sheng-Nan Lu, Joseph Sung, Junko Tanaka, Takaji Wakita, John Ward, Jack Wallace, CEVHAP North Asia Workshop on Viral Hepatitis
Report from a Viral Hepatitis Policy Forum on implementing the WHO framework for global action on viral hepatitis in North Asia
Background & Aims: The World Health Organisation (WHO) Prevention & Control of Viral Hepatitis Infection: Framework for Global Action offers a global vision for the prevention and control of viral hepatitis. In October 2012, the Coalition to Eradicate Viral Hepatitis in Asia Pacific (CEVHAP) organised the North Asia Workshop on Viral Hepatitis in Taipei to discuss how to implement the WHO Framework in the North Asia region. This paper presents outcomes from this workshop.Methods: Twenty-eight representatives from local liver associations, patient organisations, and centres of excellence in Hong Kong, Japan, Korea, and Taiwan participated in the workshop.Findings: Priority areas for action were described along the four axes of the WHO Framework: (1) awareness, advocacy and resources; (2) evidence and data; (3) prevention of transmission; and (4) screening and treatment. Priorities included: axis 1: greater public and professional awareness, particularly among primary care physicians and local advocacy networks. Axis 2: better economic data and identifying barriers to screening and treatment uptake. Axis 3: monitoring of vaccination outcomes and targeted harm reduction strategies. Axis 4: strengthening links between hospitals and primary care providers, and secure funding of screening and treatment, including for hepatocellular carcinoma.Conclusions: The WHO Framework provides an opportunity to develop comprehensive and cohesive policies in North Asia and the broader region. A partnership between clinical specialists, primary care physicians, policy makers, and people with or at risk of viral hepatitis is essential in shaping future policies.
Date de mise en ligne : Mercredi 26 juin 2013
Martin Rössle
TIPS: 25years later
Summary: In the 25years since the first TIPS intervention has been performed, technical standards, indications, and contraindications have been set up. The previous considerable problem of shunt failure by thrombosis or intimal proliferation in the stent or in the draining hepatic vein has been reduced considerably by the availability of polytetrafluoroethylene (PTFE)–covered stents resulting in reduced rebleeding and improved survival. Unfortunately, most clinical studies have been performed prior to the release of the covered stent and, therefore, do not represent the present state of the art. In spite of this, TIPS has gained increasing acceptance in the treatment of the various complications of portal hypertension and vascular diseases of the liver.
Date de mise en ligne : Mercredi 26 juin 2013
Carmen Peralta, Mónica B. Jiménez-Castro, Jordi Gracia-Sancho
Hepatic ischemia and reperfusion injury: Effects on the liver sinusoidal milieu
Summary: Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction post-transplantation. Cellular and biochemical processes occurring during hepatic ischemia-reperfusion are diverse and complex, and include the deregulation of the healthy phenotype of all liver cellular components. Nevertheless, a significant part of these processes are still unknown or unclear. The present review aims at summarizing the current knowledge in liver ischemia-reperfusion, but specifically focusing on liver cell phenotype and paracrine interaction deregulations. Moreover, the most updated therapeutic strategies including pharmacological, genetic and surgical interventions, as well as some of the scientific controversies in the field will be described. Finally, the importance of considering the subclinical situation of liver grafts when translating basic knowledge to the bedside is discussed.
Date de mise en ligne : Lundi 08 juillet 2013
Floriane Pez, Anaïs Lopez, Miran Kim, Jack R. Wands, Claude Caron de Fromentel, Philippe Merle
Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs
Summary: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. HCC can be cured by radical therapies if early diagnosis is done while the tumor has remained of small size. Unfortunately, diagnosis is commonly late when the tumor has grown and spread. Thus, palliative approaches are usually applied such as transarterial intrahepatic chemoembolization and sorafenib, an anti-angiogenic agent and MAP kinase inhibitor. This latter is the only targeted therapy that has shown significant, although moderate, efficiency in some individuals with advanced HCC. This highlights the need to develop other targeted therapies, and to this goal, to identify more and more pathways as potential targets. The Wnt pathway is a key component of a physiological process involved in embryonic development and tissue homeostasis. Activation of this pathway occurs when a Wnt ligand binds to a Frizzled (FZD) receptor at the cell membrane. Two different Wnt signaling cascades have been identified, called non-canonical and canonical pathways, the latter involving the β-catenin protein. Deregulation of the Wnt pathway is an early event in hepatocarcinogenesis and has been associated with an aggressive HCC phenotype, since it is implicated both in cell survival, proliferation, migration and invasion. Thus, component proteins identified in this pathway are potential candidates of pharmacological intervention. This review focuses on the characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects.
Date de mise en ligne : Jeudi 11 juillet 2013
Daniel J. Felmlee, Thomas F. Baumert
Hepatitis C virus co-opts innate immunity component for lipid droplet formation
COMMENTARY ON: Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly. Li Q, Pène V, Krishnamurthy S, Cha H, Liang TJ. Nat Med. 2013 Jun;19(6):722-9. Copyright (2012). Abstract reprinted by permission from Macmillan Publishers Ltd.
Date de mise en ligne : Mercredi 17 juillet 2013
Frank G. Schaap, Isabelle A. Leclercq, Peter L.M. Jansen, Steven W. Olde Damink
Prometheus’ little helper, a novel role for fibroblast growth factor 15 in compensatory liver growth
COMMENTARY ON: Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Uriarte I, Fernandez-Barrena MG, Monte MJ, Latasa MU, Chang HC, Carotti S, Vespasiani-Gentilucci U, Morini S, Vicente E, Concepcion AR, Medina JF, Marin JJ, Berasain C, Prieto J, Avila MA. Gut 2013, 62:899–910. Copyright © 2013. Abstract reprinted with permission from BMJ Publishing Group Ltd.
Date de mise en ligne : Jeudi 30 mai 2013
Veronika Lukacs-Kornek, Detlef Schuppan
Dendritic cells in liver injury and fibrosis: Shortcomings and promises
Summary: The phenotype and function of liver dendritic cells (LDCs) are poorly understood. This Snapshot summarizes our current knowledge on LDCs in the healthy and injured liver, and their role in fibrosis progression and reversal. It also draws attention to various pitfalls in the current experimental design and conclusions based on available data.
Date de mise en ligne : Jeudi 30 mai 2013
Ye Htun Oo, Shimon Sakaguchi
Regulatory T-cell directed therapies in liver diseases
Immunological self-tolerance is maintained in two stages; central and peripheral tolerance. The thymus orchestrates self-tolerance by negative selection (clonal deletion) of self-reactive T cells and by producing CD4+CD25highFoxp3+ regulatory T cells (Tregs). Tregs are essential for the maintenance of peripheral self-tolerance and immune homeostasis in various tissues including the liver . Depletion of Tregs in rodents result in spontaneous development of a variety of organ-specific and systemic autoimmune diseases and reconstitution of Tregs prevents disease development . Tregs constitutively express the transcription factor FOXP3. In humans, mutations in the FOXP3 gene result in impairment of Treg development and function. This leads to the occurrence of immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome accompanying autoimmune diseases (in particular, type 1 diabetes and thyroiditis), inflammatory bowel disease, and allergy . In addition to their thymic origin, FOXP3+ Tregs can also be generated in the periphery (Addendum). FOXP3 is essential for the development of Tregs, yet its expression is insufficient for establishing the Treg cell lineage. Treg cell development was achieved by the combination of two independent processes, i.e., the expression of FOXP3 and the establishment of a Treg cell-specific CpG hypomethylation pattern . They both are required for Treg cell-type gene expression, lineage stability, and full suppressive activity. Thymus-derived and/or peripherally generated FOXP3+ Tregs control a variety of lymphocyte populations, especially CD4+ helper T (Th) cells and CD8+ cytotoxic T cells.
Date de mise en ligne : Mercredi 05 juin 2013
Giovanni Sitia, Matteo Iannacone, Luca G. Guidotti
Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma
Summary: Previous studies in mouse models of self-limited viral hepatitis showed that platelets contribute to acute liver damage by promoting the intrahepatic accumulation of virus-specific CD8 T cells and, secondarily, virus-non-specific inflammatory cells. Built on these observations, a recent preclinical study took advantage of a previously established hepatitis B virus (HBV) transgenic mouse model of immune-mediated chronic hepatitis that progresses to hepatocellular carcinoma (HCC), to demonstrate that clinically achievable doses of the anti-platelet drugs aspirin and clopidogrel – administered continuously after the onset of liver disease – can prevent hepatocarcinogenesis and greatly improve overall survival. These outcomes were preceded by and associated with reduced hepatic accumulation of virus-specific CD8 T cells and virus-non-specific inflammatory cells, reduced hepatocellular injury and hepatocellular proliferation, and reduced severity of liver fibrosis. The observation that anti-platelet therapy inhibits HCC development identifies platelets as key players in the pathogenesis of HBV-associated liver cancer and supports the notion that a sustained immune-mediated necroinflammatory liver disease is sufficient to trigger HCC. The results abovementioned and their clinical implications are discussed in this report.
Date de mise en ligne : Lundi 17 juin 2013
Nicolas Goossens, Laurent Spahr, Laura Rubbia-Brandt
Severe immune-mediated drug-induced liver injury linked to ibandronate: A case report
Abstract: Ibandronate is a widely used bisphosphonate with no previously well documented hepatotoxicity. We report the first case of ibandronate-related hepatotoxicity and, to our knowledge, the first case of immune-mediated drug-induced liver injury (DILI) related to bisphosphonates.
Date de mise en ligne : Mardi 09 juillet 2013
Pierluigi Marzuillo, Anna Grandone, Laura Perrone, Emanuele Miraglia del Giudice
Weight loss allows the dissection of the interaction between abdominal fat and PNPLA3 (adiponutrin) in the liver damage of obese children
In the patatin-like phospholipase domain-containing 3 gene (PNPLA3), there is a polymorphism named rs738409, which encodes for the adiponutrin I148M variant and is a genetic determinant of liver fat and non-alcoholic fatty liver disease (NAFLD).
Date de mise en ligne : Mercredi 07 août 2013
Stelios F. Assimakopoulos, Aristidis S. Charonis
Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: The pivotal role of enterocyte tight junctions and future perspectives
We read with great interest the recently published research study by Dr. Du Plessis and colleagues on the role of intestinal macrophages in intestinal epithelial barrier dysfunction and hyperpermeability in patients with cirrhosis . The authors demonstrated that decompensated liver cirrhosis was associated with the presence of significantly higher numbers of activated intestinal macrophages (CD33+/CD14+/Trem-1+) expressing iNOS and secreting NO and IL-6, in conjunction with increased duodenal paracellular permeability and increased expression of the tight junction (TJ) protein Claudin-2. They speculated that activation of intestinal macrophages might represent an important molecular event implicated in the disruption of the intestinal epithelial barrier in cirrhosis through secretion of TJ-regulating factors such as NO and IL-6.
Date de mise en ligne : Mercredi 07 août 2013
Johannie du Plessis, Schalk W. van der Merwe
Reply to: “Uncovering the molecular events associated with increased intestinal permeability in liver cirrhosis: The pivotal role of enterocyte tight junctions and future perspectives�
We thank Assimakopoulos and colleagues for their interest in our recent article . As suggested, important efforts are being made to understand why the intestinal barrier fails in cirrhosis and the mechanism by which viable bacteria translocate from the gastrointestinal tract.
Date de mise en ligne : Jeudi 11 juillet 2013
Jay V. Patankar, Vinay Sachdev, Sascha Obrowsky, Sanja Levak-Frank, Dagmar Kratky
Intestinal GATA4 deficiency induces proximal fibroblast growth factor 15 expression and represses hepatic gluconeogenesis
We have recently reported that conditional deletion of intestinal GATA4 leads to an increased protection from obesity-associated hepatic steatosis . Using two independent murine models of diet-induced hepatic steatosis, we demonstrated that intestine specific GATA4 knockout (GATA4iKO) mice are protected from high fat diet-induced hepatic steatosis. Our findings showed that intestinal GATA4 deficiency was protective only in case where hepatic de novo lipogenesis was involved, secondary to insulin resistance. GATA4iKO mice were not protected upon induction of steatosis via dietary deficiency of methionine and choline. Methionine and choline-deficient diet leads to hepatic steatosis by suppressing VLDL release and beta-oxidation and does not significantly impact de novo lipogenesis. The underlying mechanism for the observed benefit is the ectopic upregulation of GLP-1 and higher number of GLP-1 producing L-cells in the proximal intestine of GATA4iKO mice.
Date de mise en ligne : Vendredi 01 novembre 2013
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http://www.journal-of-hepatology.eu/article/S0168-8278(13)00587-4/abstract?rss=yes
Date de mise en ligne : Vendredi 01 novembre 2013
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http://www.journal-of-hepatology.eu/article/S0168-8278(13)00588-6/abstract?rss=yes