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Les derniers abstracts de la revue Hepatology :


    Date de mise en ligne : Mardi 19 septembre 2017
    David Wyles, Fred Poordad, Stanley Wang, Laurent Alric, Franco Felizarta, Paul Y Kwo, Benedict Maliakkal, Kosh Agarwal, Tarek Hassanein, Frank Weilert, Samuel S Lee, Jens Kort, Sandra S Lovell, Ran Liu, Chih‐Wei Lin, Tami Pilot‐Matias, Preethi Krishnan, Federico J Mensa
    Glecaprevir/Pibrentasvir for HCV Genotype 3 Patients with Cirrhosis and/or Prior Treatment Experience: A Partially Randomized Phase III Clinical Trial
    Background: This study assessed the efficacy and safety of ribavirin (RBV)‐free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus (HCV) genotype (GT) 3 infection with either prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. Methods: SURVEYOR‐II, Part 3 was a partially‐randomized, open‐label, multicenter, phase 3 study. Treatment‐experienced (prior interferon (IFN) or pegIFN ± ribavirin or SOF plus ribavirin ± pegIFN therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment‐naĂŻve or treatment‐experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at post‐treatment week 12 (SVR12). Safety was evaluated throughout the study. Results: There were 131 patients enrolled and treated. Among treatment‐experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; CI 72‐97) and 95% (21/22; CI 78‐99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; CI 87‐99) of treatment‐naĂŻve patients treated for 12 weeks, and 96% (45/47; CI 86‐99) of patients with prior treatment experience treated for 16 weeks. No adverse events (AEs) led to discontinuation of study drug and no serious AEs were related to study drug. Conclusions: Patients with HCV GT3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 19 septembre 2017
    Runping Liu, Xiaojiaoyang Li, Zhiming Huang, Derrick Zhao, Bhagyalaxmi Sukka Ganesh, Guanhua Lai, William M. Pandak, Phillip B Hylemon, Jasmohan S Bajaj, Arun J Sanyal, Huiping Zhou
    CHOP‐induced loss of intestinal epithelial stemness contributes to bile duct ligation‐induced cholestatic liver injury
    Impaired intestinal barrier function promotes the progression of various liver diseases including cholestatic liver disease. The close association of primary sclerosing cholangitis (PSC) with inflammatory bowel disease highlights the importance of the gut‐liver axis. It has been reported that bile duct ligation (BDL)‐induced liver fibrosis is significantly reduced in C/EBP homologous protein knock out (CHOP‐/‐) mice. However, the underlying mechanisms remain unclear. In the current study, we demonstrate that BDL induces striking and acute hepatic ER stress responses after 1 day, which return to normal after 3 days. No significant hepatocyte apoptosis is detected 7 to 14 days following BDL. However, the inflammatory response is significantly increased after 7 days, which is similar to what we found in human PSC liver samples. BDL‐induced loss of stemness in intestinal stem cells (ISCs), disruption of intestinal barrier function, bacterial translocation, activation of hepatic inflammation and M2 macrophage polarization and liver fibrosis are significantly reduced in CHOP‐/‐ mice. In addition, intestinal organoids derived from CHOP‐/‐ mice contain more and longer crypt structures than those from WT mice, which is consistent with the upregulation of stem cell markers (Lgr5, Olfm4 and Sox9) and in vivo findings that CHOP‐/‐ mice have longer villi and crypts as compared to WT mice. Similarly, the mRNA levels of CD14, IL‐1ÎČ, TNF‐α and MCP‐1 are increased and stem cell proliferation is suppressed in the duodenum of cirrhotic patients. Conclusion: Activation of ER stress and subsequent loss of stemness of ISCs plays a critical role in BDL‐induced systemic inflammation and cholestatic liver injury. Modulation of the ER stress response represents a potential therapeutic strategy for cholestatic liver diseases as well as other inflammatory diseases This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 19 septembre 2017
    Sarah Bussler, Mandy Vogel, Diana Pietzner, Kristian Harms, Theresa Buzek, Melanie Penke, Norman HÀndel, Antje Körner, Ulrich Baumann, Wieland Kiess, Gunter Flemming
    New pediatric percentiles of liver enzyme serum levels (ALT, AST, GGT): Effects of age, sex, BMI and pubertal stage
    The present study aims to clarify the effects of sex, age, BMI and puberty on transaminase serum levels in children and adolescents and to provide new age‐ and sex‐related percentiles for alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ‐glutamyltransferase (GGT). Venous blood and anthropometric data were collected from 4,126 cases. Excluded were cases of participants with potential hepatotoxic medication, with evidence of potential illness at the time of blood sampling and non‐normal BMI (BMI < 10th or > 90th). The resulting data (N = 3,131 cases) were used for the calculations of ALT, AST, and GGT percentiles. Age‐ and sex‐related reference intervals were established by using an LMSP‐type method. Serum levels of transaminases follow age‐specific patterns and relate to the onset of puberty. This observation is more pronounced in girls than in boys. The ALT percentiles showed similar shaped patterns in both sexes. Multivariate regression confirmed significant effects of puberty and BMI‐SDS (ÎČ = 2.21) on ALT. Surprisingly, AST serum levels were negatively influenced by age (ÎČ = ‐1.42) and BMI‐SDS (ÎČ = ‐0.15). The GGT percentiles revealed significant sex‐specific differences, correlated positively with age (ÎČ = 0.37) and showed significant association with BMI‐SDS (ÎČ = 1.16). Conclusion: Current reference values of ALT, AST and GGT serum levels were calculated for children between 11 months and 16.0 years, using modern analytical and statistical methods. This study extends the current knowledge about transaminases by revealing influences of age, sex, BMI, and puberty on the serum concentrations of all three parameters and has for these parameters one of the largest sample sizes published so far. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 19 septembre 2017
    Daniel Jahn, Andreas Geier
    Bile acids in NASH: pathophysiological driving force or innocent bystanders?
    n/a


    Date de mise en ligne : Lundi 18 septembre 2017
    Oihane Erice, Patricia Munoz‐Garrido, Javier Vaquero, Maria J. Perugorria, Maite G. Fernandez‐Barrena, Elena Saez, Alvaro Santos‐Laso, Ander Arbelaiz, Raul Jimenez‐AgĂŒero, Joaquin Fernandez‐Irigoyen, Enrique Santamaria, VerĂłnica Torrano, Arkaitz Carracedo, Meenakshisundaram Ananthanarayanan, Marco Marzioni, Jesus Prieto, Ulrich Beuers, Ronald P. Oude Elferink, Nicholas F. LaRusso, Luis Bujanda, Jose J.G. Marin, Jesus M. Banales
    MiRNA‐506 promotes primary biliary cholangitis‐like features in cholangiocytes and immune activation
    Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease associated with autoimmune phenomena targeting intrahepatic bile duct cells (cholangiocytes). Although PBC etiopathogenesis still remains obscure, development of anti‐mitochondrial auto‐antibodies against pyruvate dehydrogenase complex‐E2 (PDC‐E2) is a common feature. MicroRNA (miR) dysregulation occurs in liver and immune cells of PBC patients, but their functional relevance is largely unknown. We previously reported that miR‐506 is overexpressed in PBC cholangiocytes and directly targets both Cl–/HCO3– anion exchanger 2 (AE2) and type III inositol 1,4,5‐trisphosphate receptor (InsP3R3), leading to cholestasis. Here, the regulation of miR‐506 gene expression and its role in cholangiocyte pathophysiology and immune activation was studied. Several pro‐inflammatory cytokines overexpressed in PBC livers [such as IL8, IL12, IL17, IL18 and TNFα] stimulated miR‐506 promoter activity in human cholangiocytes, as revealed by luciferase reporter assays. Experimental overexpression of miR‐506 in cholangiocytes dysregulated the cell proteomic profile (by mass spectrometry), affecting proteins involved in different biological processes including mitochondrial metabolism. In cholangiocytes, miR‐506: i) induced dedifferentiation with downregulation of biliary and epithelial markers together with upregulation of mesenchymal, pro‐inflammatory and pro‐fibrotic markers; ii) impaired cell proliferation and adhesion; iii) increased oxidative and endoplasmic reticulum (ER) stress; iv) caused DNA damage; and v) sensitized to caspase‐3‐dependent apoptosis induced by cytotoxic bile acids. These events were also associated with impaired energy metabolism in mitochondria (proton leak and less ATP production) and PDC‐E2 overexpression. Co‐culture of miR‐506 overexpressing cholangiocytes with PBC immunocytes induced activation and proliferation of PBC immunocytes. Conclusion: different pro‐inflammatory cytokines enhance the expression of miR‐506 in biliary epithelial cells. MiR‐506 induces PBC‐like features in cholangiocytes and promotes immune activation, representing a potential therapeutic target for PBC patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 18 septembre 2017
    Barret Rush, Keith R. Walley, Leo Anthony Celi, Neil Rajoriya, Mayur Brahmania
    Reply to: HEP‐17‐1544
    n/a


    Date de mise en ligne : Lundi 18 septembre 2017
    Vasveebye Sonoo, Jay V. Kumar, Xibei Liu, Johnson Ukken, Mary Froehlich, Ji Won Yoo
    Necessity of more sensitivity analyses and interpretations from public health perspectives
    n/a


    Date de mise en ligne : Samedi 16 septembre 2017
    Mei‐Hsuan Lee, Yu‐Han Huang, Hsuan‐Yu Chen, Charles Seik‐Soon Khor, Ya‐Hsuan Chang, Yu‐Ju Lin, Chin‐Lan Jen, Sheng‐Nan Lu, Hwai‐I Yang, Nao Nishida, Masaya Sugiyama, Masashi Mizokami, Yong Yuan, Gibert L'Italien, Katsushi Tokunaga, Chien‐Jen Chen,
    Human Leukocyte Antigen Variants and Risk of Hepatocellular Carcinoma Modified by HCV Genotypes: A Genome‐wide Association Study
    Background & aims: We conducted a genome‐wide association study (GWAS) to discover genetic variants associated with hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC). Methods: We genotyped 502 HCC cases and 749 non‐HCC controls by using the AxiomTM‐CHB genome‐wide array. After identifying single nucleotide polymorphism (SNP) cluster located in the human leukocyte antigen region which were potentially associated with HCC, HLA‐DQB1 genotyping was performed to analyze 994 anti‐HCV seropositives collected in the period of 1991‐2013 in a community‐based cohort for evaluating long‐term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of HLA genotypes for determining the aforementioned HCC risk. Results: Eight SNPs in the proximity of HLA‐DQB1 were associated with HCC (p < 8.7 × 10−8) in GWAS. Long‐term follow‐up showed a significant association with HLA‐DQB1*03:01 and DQB1*06:02 (p < 0.05). The adjusted HRs associated with HCC were 0.45 (0.30‐0.68) and 2.11 (1.34‐3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non‐1 genotypes. HLA imputation analyses revealed that HLA‐DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio = 1.96, 95% CI = 1.31‐2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primary protective and susceptible variants, respectively. Conclusions: HLA‐DQB1 was independently associated with HCC. HCV genotypes modified the effects of HLA‐DQB1 on the risk of HCC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 16 septembre 2017
    Lisa B. VanWagner, Hongyan Ning, Maureen Whitsett, Josh Levitsky, Sarah Uttal, John T. Wilkins, Michael M. Abecassis, Daniela P. Ladner, Anton I. Skaro, Donald M. Lloyd‐Jones
    In Reply To: Xue et al. “Developing a Prediction Model for Cardiovascular Risk after Orthotopic Liver Transplantation”
    n/a


    Date de mise en ligne : Samedi 16 septembre 2017
    Heekyong R. Bae, Deborah L. Hodge, Guo‐Xiang Yang, Patrick S.C. Leung, Sathi Babu Chodisetti, Julio C. Valencia, Michael Sanford, John M. Fenimore, Ziaur S.M. Rahman, Koichi Tsuneyama, Gary L. Norman, M. Eric Gershwin, Howard A. Young
    The interplay of type I and type II interferons in murine autoimmune cholangitis as a basis for sex‐biased autoimmunity
    We have reported a murine model of autoimmune cholangitis, generated by altering the AU rich element by deletion of the IFN‐γ 3'UTR region (coined ARE‐Del‐/‐), that has striking similarities to human primary biliary cholangitis (PBC) with female predominance. Previously, we suggested that the gender bias of autoimmune cholangitis was secondary to intense and sustained type I and II IFN signaling. Based on this thesis, and to define the mechanisms that lead to portal inflammation, we specifically addressed the hypothesis that type I IFNs are the driver of this disease. To accomplish these goals, we crossed ARE‐Del‐/‐ mice with IFN type I receptor alpha chain (Ifnar1) knockout mice. We report herein that loss of type I IFN receptor signaling in the double construct of ARE‐Del‐/‐ Ifnar1‐/‐ mice dramatically reduces liver pathology and abrogated gender bias. More importantly, female ARE‐Del‐/‐ mice have an increased number of germinal center (GC) B cells as well as abnormal follicular formation, sites which have been implicated in loss of tolerance. Deletion of type I IFN signaling in ARE‐Del‐/‐ Ifnar1‐/‐ mice corrects these GC abnormalities, including abnormal follicular structure. In conclusion, our data implicate type I IFN signaling as a necessary component of the gender bias of this murine model of autoimmune cholangitis. Importantly these data suggest that drugs that target the type I IFN signaling pathway would have potential benefit in the earlier stages of PBC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 16 septembre 2017
    Bhanu P. Venkatesulu, Sunil Krishnan
    Radiosensitization by inhibiting DNA repair – turning the spotlight on homologous recombination
    n/a


    Date de mise en ligne : Samedi 16 septembre 2017
    Fu‐Shan Xue, Ya‐Yang Liu, Gui‐Zhen Yang
    Developing a Prediction Model for Cardiovascular Risk after Orthotopic Liver Transplantation
    n/a


    Date de mise en ligne : Samedi 16 septembre 2017
    Piero Amodio, Javier Ampuero
    Solving doubts about L‐Ornithine L‐Aspartate for overt HE: whom and how to treat
    Randomized controlled trials about the treatment of bouts of overt hepatic encephalopathy (OHE) are difficult to design and interpret, since bouts of OHE i) are relatively short episodes in which the dynamic of the response to treatment is relevant, ii) their occurrence and treatment is frequently linked to precipitating events. The study by Sidhu et al. in this issue of Hepatology is a model of proper design and provides evidence that L‐ornithine‐L‐aspartate infusion for 5 days is an effective add on treatment to speed up recovery from bouts of OHE in comparison with a placebo treatment that does not contain amino acid nutrients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 16 septembre 2017
    Julien Vionnet, Manuel Pascual, Barbara Testoni, Christophe Combet, SĂ©bastien Godat, Sandrine Vijgen, Vincent Aubert, Laura Rubbia‐Brandt, Fabien Zoulim, Darius Moradpour
    Late hepatitis B reactivation following DAA‐based treatment of recurrent hepatitis C in an anti‐HBc‐positive liver transplant recipient
    n/a


    Date de mise en ligne : Samedi 16 septembre 2017
    Yoshihiro Ono, Angelica Perez‐Gutierrez, Toshimasa Nakao, Helong Dai, Geoffrey Camirand, Osamu Yoshida, Shinichiro Yokota, Donna Beer Stolz, Mark A. Ross, Adrian E. Morelli, David A. Geller, Angus W. Thomson
    Graft‐infiltrating PD‐L1hi cross‐dressed dendritic cells regulate anti‐donor T cell responses in mouse liver transplant tolerance
    While a key role of cross‐dressing has been established in immunity to viral infection and more recently in the instigation of transplant rejection, its role in tolerance is unclear. Here, we investigated the role of intra‐graft dendritic cells (DC) and cross‐dressing in mouse major histocompatibility complex (MHC)‐mismatched liver transplant tolerance that occurs without therapeutic immunosuppression. While donor interstitial DC diminished rapidly following transplantation, they were replaced in the liver by host DC that peaked on postoperative day (POD) 7 and persisted indefinitely. About 60% of these recipient DC displayed donor MHC class I, indicating cross‐dressing. By contrast, only a very minor fraction (0‐2%) of cross‐dressed DC (CD‐DC) was evident in the spleen. CD‐DC sorted from liver grafts expressed much higher levels of T cell inhibitory programed death ligand 1 (PD‐L1) and high levels of IL‐10 compared with non CD‐DC (nCD‐DC) isolated from the graft. Concomitantly, high incidences of programed death protein 1 (PD‐1)hi T cell immunoglobulin and mucin domain containing‐3 (TIM‐3)+ exhausted graft‐infiltrating CD8+ T cells were observed. Importantly, unlike nCD‐DC, the CD‐DC failed to stimulate proliferation of allogeneic T cells but markedly suppressed anti‐donor host T cell proliferation. CD‐DC were much less evident in allografts from DNAX‐activating protein of 12kDa (DAP12)‐/‐ donors that were rejected acutely. Conclusion: These findings suggest that graft‐infiltrating PD‐L1hi CD‐DC may play a key role in the regulation of alloimmunity and in the induction of liver transplant tolerance. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 15 septembre 2017
    Oriana Lo Re, Caterina Fusilli, Francesca Rappa, Matthias Van Haele, Julien Douet, Jana Pindjakova, Sura Wanessa Rocha, Illar Pata, Barbora Valčíková, Stjepan Uldrijan, Raymond S. Yeung, Christina Alves Peixoto, Tania Roskams, Marcus Buschbeck, Tommaso Mazza, Manlio Vinciguerra
    Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma
    Hepatocellular carcinomas (HCC) contain a sub‐population of cancer stem cells (CSCs), which exhibit stem‐cell like features and are responsible for tumor relapse, metastasis, and chemoresistance. The development of effective treatments for HCC will depend on a molecular‐level understanding of the specific pathways driving CSC emergence and stemness. MacroH2A1 is a variant of the histone H2A and an epigenetic regulator of stem cell function, where it promotes differentiation and, conversely, acts as a barrier to somatic cell reprogramming. Here we focused on the role played by the histone variant macroH2A1 as a potential epigenetic factor promoting CSC differentiation. In human HCC sections we uncovered a significant correlation between low frequencies of macroH2A1 staining and advanced, aggressive HCC subtypes with poorly‐differentiated tumor phenotypes. Using HCC cell lines we found that shRNA‐mediated macroH2A1 knock‐down induces acquisition of CSC‐like features, including the growth of significantly larger and less‐differentiated tumors when injected into nude mice. MacroH2A1‐depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem‐like metabolic changes consistent with enhanced hypoxia responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness‐associated genes, and drove hyper‐activation of the NF‐ÎșBp65 pathway. Blocking phosphorylation of NF‐ÎșBp65 on Ser536 inhibited the emergence of CSC‐like features in HCC cells knocked‐down for macroH2A1. Conclusion: the absence of histone variant macroH2A1 confers a CSC‐like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of NF‐ÎșBp65. This pathway may hold valuable targets for the development of CSC‐focused treatments for HCC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 13 septembre 2017
    Alexander Wree, Matthew D. McGeough, Maria Eugenia Inzaugarat, Akiko Eguchi, Susanne Schuster, Casey D. Johnson, Carla A. Peña, Lukas J. Geisler, Bettina G Papouchado, Hal M. Hoffman, Ariel E. Feldstein
    NLRP3 inflammasome driven liver injury and fibrosis: Roles of IL‐ 17 and TNF
    The NLRP3 inflammasome, a caspase‐1 activation platform plays a key role in the modulation of liver inflammation and fibrosis. Here, we tested the hypothesis that interleukin 17 (IL‐17) and tumor necrosis factor (TNF) are key cytokines involved in amplifying and perpetuating the liver damage and fibrosis resulting from NLRP3 activation. To address this hypothesis gain of function Nlrp3A350V knock‐in mice were bred onto il17a and Tnf knockout backgrounds allowing for constitutive Nlrp3 activation in myeloid derived cells in mice deficient in IL‐17 or TNF. Livers of Nlrp3A350V knock‐in mice exhibited severe liver inflammatory changes characterized by infiltration with neutrophils, increased expression of CXCL1 and CXCL2 chemokines, activated inflammatory macrophages and elevated levels of IL‐17 and TNF. Mutants with ablation of il17a signal showed fewer neutrophils when compared to intact Nlrp3A350V mutants, but still significant inflammatory changes when compared to the non‐mutant il17a knockout littermates. The severe inflammatory changes associated with mutant Nlrp3 were almost completely rescued by Tnf knockout in association with a marked decrease in circulating IL‐1ÎČ levels. Intact Nlrp3A350Vmutants showed changes of liver fibrosis, as evidenced by morphometric quantitation of Sirius red staining and increased mRNA levels of profibrotic genes including CTGF and TIMP‐1. Il17a lacking mutants exhibited amelioration of the aforementioned fibrosis, while Tnf deficient mutants showed no signs of fibrosis when compared to littermate controls. Conclusion: Our study uncovers key roles for TNF, and to a lesser extent IL‐17, as mediators of liver inflammation and fibrosis induced by constitutive NLRP3 inflammasome activation in myeloid derived cells. These findings may lead to novel therapeutic strategies aimed at halting the progression of liver injury and fibrogenesis in various liver pathogenesis driven by NLRP3 activation. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 13 septembre 2017
    Graham F. Brady, Raymond Kwan, Peter J. Ulintz, Phirum Nguyen, Shirin Bassirian, Venkatesha Basrur, Alexey I. Nesvizhskii, Rohit Loomba, M. Bishr Omary
    Nuclear lamina genetic variants, including a truncated LAP2, in twins and siblings with nonalcoholic fatty liver disease
    Nonalcoholic fatty liver disease (NAFLD) is becoming the major chronic liver disease in many countries. Its pathogenesis is multifactorial but twin and familial studies indicate significant heritability, which is not fully explained by currently‐known genetic susceptibility loci. Notably, mutations in genes encoding nuclear lamina proteins, including lamins, cause lipodystrophy syndromes that include NAFLD. We hypothesized that variants in lamina‐associated proteins predispose to NAFLD and used a candidate gene‐sequencing approach to test for variants in 10 nuclear lamina‐related genes in a cohort of 37 twin and sibling pairs: 21 individuals with, and 53 without, NAFLD. Twelve heterozygous sequence variants were identified in four lamina‐related genes (ZMPSTE24/TMPO/SREBF1/SREBF2). The majority of NAFLD patients (>90%) had at least one variant, compared to <40% of controls (P<0.0001). When only insertions/deletions and changes in conserved residues were considered, the difference between the groups was similarly striking (>80% versus <25%; P<0.0001). Presence of a lamina variant segregated with NAFLD independent of the PNPLA3 I148M polymorphism. Several variants were found in TMPO, which encodes the lamina‐associated polypeptide‐2 (LAP2) that has not previously been associated with liver disease. One of these, a frameshift insertion that generates truncated LAP2, abrogated lamin‐LAP2 binding, caused LAP2 mislocalization, altered endogenous lamin distribution, increased lipid droplet accumulation after oleic acid treatment in transfected cells, and led to cytoplasmic association with the ubiquitin‐binding protein p62/SQSTM1. Conclusion: Novel variants in nuclear lamina‐related genes were identified in a cohort of twins and siblings with NAFLD. One novel variant, which results in a truncated LAP2 protein and a dramatic phenotype in cell culture, represents the first association of TMPO/LAP2 variants with NAFLD and underscores the potential importance of the nuclear lamina in NAFLD. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 13 septembre 2017
    Maurizio Cesari, Anna Chiara Frigo, Marta Tonon, Paolo Angeli
    Cardiovascular predictors of death in patients with cirrhosis
    Cirrhotic cardiomyopathy is associated with poor outcomes in patients with cirrhosis. We investigated if subclinical cardiac morphologic and functional modifications can influence survival in cirrhotic patients during follow‐up. A series of cirrhotic patients without cardiovascular or pulmonary disease underwent standard and tissue Doppler echocardiography to assess left ventricular (LV) geometry, systo/diastolic function and the main haemodynamic parameters. After baseline evaluation 115 cirrhotic patients were followed up for at least 6 years. During follow up 54 patients died (47%). On univariate analysis age, BSA, MELD, mean arterial pressure, heart rate, cardiac index, systemic vascular resistance index, the ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e') were associated with increased risk of death. In a Cox hazard regression analysis including these factors and other hypothesized important factors (but not MELD) increased age (p=0.04) and left atrial dimension (p=0.005), and lower BSA (p=0.03) were the strongest predictors of death. When MELD was included in the analysis the main predictors were MELD, age and BSA. When multivariate analysis was performed incorporating only cardiovascular parametres, increased E/e' (p=0.003) and heart rate (p= 0.03) and reduced mean blood pressure (p= 0.01) resulted significantly associated with poor prognosis. Conclusion: in a large cohort of cirrhotic patients and after a long follow‐up MELD, age and BSA were the main predictors of death. Among cardiovascular parameters, left atrium enlargement, increased heart rate and E/e' and reduced mean blood pressure resulted independent predictors of death. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 13 septembre 2017
    Adam C. Winters, Douglas Tremblay, Suzanne Arinsburg, John Mascarenhas, Thomas D. Schiano
    Reassessing the Safety Concerns of Utilizing Blood Donations from Patients with Hemochromatosis
    Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism which may lead to iron overload. Clinical penetrance is low, however those afflicted may develop cirrhosis, hepatocellular carcinoma, diabetes mellitus and cardiomyopathy. Treatment involves regular phlebotomy to reduce the systemic iron burden. In many countries—including the United States—numerous blood centers do not accept donated blood obtained from HH patients during therapeutic phlebotomy and there are inconsistent positions regarding this globally. This refusal is borne out of a few concerns. First, there is a theoretical increase in the infectious risk of these blood products, particularly by siderophilic organisms such as Yersinia enterocolitica. Second, given the increased incidence of hepatitis C infection from non‐voluntary donors in the 1970s, there is a concern that blood from HH donors may harbor additional risk given the non‐voluntary nature of their presentation. In this review, we examine the existing biologic and clinical data concerning infectious risk and summarize clinical experience from centers allowing HH donors, and demonstrate that blood from HH patients is safe and should be allowed into the donor pool. We conclude that there is no convincing evidence to exclude this population from serving as blood donors. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 13 septembre 2017
    F. Piscaglia, F. Tovoli, P. Pini, V. Salvatore
    A new horizon in the prevention of the postembolization syndrome after Transcatheter Arterial Chemioembolization for hepatocellular carcinoma
    n/a


    Date de mise en ligne : Mardi 12 septembre 2017
    Jordi Rimola, Álvaro Díaz‐González, Anna Darnell, María Varela, Fernando Pons, Manuel Hernandez‐Guerra, Manuel Delgado, Javier Castroagudin, Ana Matilla, Bruno Sangro, Carlos Rodriguez de Lope, Margarita Sala, Carmen Gonzalez, Carlos Huertas, Beatriz Minguez, Carmen Ayuso, Jordi Bruix, Maria Reig
    Complete response under sorafenib in patients with hepatocellular carcinoma. Relationship with dermatologic adverse events
    Background‐aims: The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses even though patients who develop early dermatologic reactions have shown very positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the aim is to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Methods: Ten Spanish centres submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions and cause of treatment discontinuation were annotated. Radiological images pre‐sorafenib, at first control, after starting sorafenib, at the time of complete response and at least 1 month after, were centrally reviewed. Results: 20/1119 patients had been classified as complete responders by the centres, but 8 were excluded after central review. Ten patients had complete disappearance of all tumor sites and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders [58% HCV, median age 59.7 years, 83.4% Child‐Pugh A, ECOG‐PS 0 91.7% and BCLC‐C 83.3%]. Median overall survival and treatment duration were 85.8 and 40.1 months respectively. All but one patient, developed early dermatologic reactions and 7 patients discontinued sorafenib after achieving complete response due to adverse events, patient decision or liver decompensation. Conclusion: Complete response affects 1% of the patients. Its association with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 12 septembre 2017
    Mutaz Sultan, Anuradha Rao, Orly Elpeleg, Frédéric M. Vaz, Bassam Y Abu Libdeh, Saul J. Karpen, Paul A. Dawson
    Organic Solute Transporter‐beta (SLC51B) Deficiency in Two Brothers with Congenital Diarrhea and Features of Cholestasis
    Primary bile acid malabsorption (PBAM) is associated with congenital diarrhea, steatorrhea, and a block in the intestinal return of bile acids in the enterohepatic circulation. Mutations in the ileal Na+‐dependent bile acid transporter (ASBT; SLC10A2) can cause PBAM, but do not appear to account for most familial cases. Another major transporter involved in the intestinal reclamation of bile acids is the heteromeric Organic Solute Transporter alpha‐beta (OSTα‐OSTÎČ; SLC51A‐SLC51B), which exports bile acid across the basolateral membrane. Here we report the first patients with OSTÎČ deficiency, clinically characterized by chronic diarrhea, severe fat soluble vitamin deficiency, and features of cholestatic liver disease including elevated serum gamma‐glutamyltransferase activity. Whole exome sequencing revealed a homozygous single nucleotide deletion in codon 27 of SLC51B, resulting in a frameshift and premature termination at codon 50. Functional studies in transfected cells showed that the SLC51B mutation resulted in markedly reduced taurocholic acid uptake activity and reduced expression of the OSTα partner protein. Conclusion: The findings identify OSTÎČ deficiency as a new cause of congenital chronic diarrhea with features of cholestatic liver disease. These studies underscore OSTα‐OSTÎČ's key role in the enterohepatic circulation of bile acids in humans. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 12 septembre 2017
    Bibo Wang, Jing Fu, Ting Yu, An Xu, Wenhao Qin, Zhishi Yang, Yao Chen, Hongyang Wang
    Contradictory Effects of Mitochondria‐ and Non‐mitochondria‐targeted Antioxidants on Hepatocarcinogenesis by Altering DNA Repair
    Conflicting effects of antioxidant supplementation on cancer prevention or promotion is of great concern to healthy people and cancer patients. Despite recent studies about antioxidants accelerating the progression of lung cancer and melanoma, it does not fully deny antioxidants for cancer prevention. Both tumor and antioxidants types influence the actual efficacy. However, little is known about the impact of different types of antioxidants on primary hepatocellular carcinoma (HCC), including non‐mitochondrial‐ and mitochondrial‐targeted antioxidants. Based on the mouse models of chemical hepatocarcinogenesis, we showed that administration of non‐mitochondria‐targeted antioxidants N‐acetylcysteine (NAC) and the soluble vitamin E analog Trolox prevented tumorigenesis, whereas administration of mitochondria‐targeted antioxidants SS‐31 (the mitochondria targeted peptide) and Mito‐Q (a derivative of ubiquinone) encouraged tumorigenesis. RNA sequencing revealed that NAC and SS‐31 cause highly different changes in oxidation‐reduction state and DNA damage response. Remarkably, in diethylnitrosamine (DEN)‐treated primary hepatocytes, NAC and Trolox alleviated DNA damage by activating ATM/ATR for DNA repair while SS‐31 and MitoQ aggravated damage by inactivating them. Interestingly, partial recovery of SS‐31‐scavengened mitochondrial ROS (mtROS) could alleviate SS‐31‐aggravated DNA damage. Localization of ATM between mitochondria and nuclei was changed after NAC and SS‐31 treatment. Furthermore, blockage of p‐ATR led to the recurrence of NAC‐ameliorated DEN HCC. In contrast, reactivation of p‐ATR blocked SS‐31‐promoted DEN HCC. These results demonstrate that the type of antioxidants plays a previously unappreciated role in hepatocarcinogenesis, and provide a mechanistic rationale for exploring the therapeutic use of antioxidants for liver cancer. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 11 septembre 2017
    Rohit Loomba, Eric Lawitz, Parvez S. Mantry, Saumya Jayakumar, Stephen H. Caldwell, Hays Arnold, Anna Mae Diehl, C. Stephen Djedjos, Ling Han, Robert P. Myers, G. Mani Subramanian, John G. McHutchison, Zachary D. Goodman, Nezam H. Afdhal, Michael R. Charlton,
    The ASK1 Inhibitor Selonsertib in Patients with Nonalcoholic Steatohepatitis: A Randomized, Phase 2 Trial
    Inhibition of apoptosis signal‐regulating kinase 1 (ASK1), a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis (NASH). We evaluated the safety and efficacy of selonsertib, a selective inhibitor of ASK1, alone or in combination with simtuzumab, in patients with NASH and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open‐label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once‐weekly injections of 125 mg of simtuzumab, or simtuzumab alone. The effect of treatment was assessed by paired pre‐ and post‐treatment liver biopsies, magnetic resonance elastography (MRE), and magnetic resonance imaging‐estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a ≄1‐stage reduction in fibrosis in the 18‐mg selonsertib group was 13 of 30 (43%; 95% CI, 26‐63), in 6‐mg selonsertib group, 8 of 27 (30%; 95% CI, 14‐50), and in the simtuzumab‐alone group, 2 of 10 (20%; 95% CI, 3‐56). Improvement in fibrosis was associated with reductions in liver stiffness on MRE, and collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups. Conclusions: These findings suggest that selonsertib may reduce liver fibrosis in patients with NASH and stage 2‐3 fibrosis. (Funded by Gilead Sciences; ClinicalTrials.gov number NCT02466516) This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 08 septembre 2017
    Chun‐Hung Liu, Guann‐Gen Chern, Fu‐Fei Hsu, Kuan‐Wei Huang, Yun‐Chieh Sung, Hsi‐Chien Huang, Jiantai Timothy Qiu, Sheng‐Kai Wang, Chu‐Chi Lin, Chien‐Hsun Wu, Han‐Chung Wu, Jia‐Yu Liu, Yunching Chen
    A multifunctional nanocarrier for efficient TRAIL‐based gene therapy against hepatocellular carcinoma with desmoplasia
    The anti‐cancer efficacy of TNF‐related apoptosis‐inducing ligand (TRAIL)‐based therapy is limited due to systemic toxicity, poor bioavailability, and the development of TRAIL‐resistance. We developed a tumor‐targeted LCPP (Lipid/Calcium/Phosphate/Protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells. TRAIL pDNA was encapsulated in a pH stimuli‐responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, the intracellular release of Ca2+ from the CaP core overcame TRAIL resistance via calcium influx‐dependent DR5 upregulation. TRAIL expression also attenuated fibrosis in the liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. Conclusion: TRAIL pDNA delivered by HCC‐targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL‐based cancer therapy that could be developed for clinical applications. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 07 septembre 2017
    Richard S. Finn, Andrew X. Zhu, Wigdan Farah, Jehad Almasri, Feras Zaiem, Larry J Prokop, Mohammad Hassan Murad, Khaled Mohammed
    Therapies for Advanced Stage Hepatocellular Carcinoma with Macrovascular invasion or Metastatic Disease: a Systematic Review and Meta‐analysis
    Hepatocellular carcinoma (HCC) is a complex disease most commonly arising in the background of chronic liver disease. In the past two decades there has been a significant increase in our understanding of both the clinical and molecular heterogeneity of HCC. There has been a robust increase in clinical trial activity in patients with poor prognostic factors such as macrovascular invasion and extrahepatic spread. We aimed to synthesize the evidence for the treatment of patients with advanced HCC based on these baseline characteristics including patients with both Child‐Pugh scores of A and B. A comprehensive search of several databases from each database inception to February 15th 2016, any language was conducted.We included 14 studies (3 randomized controlled studies (RCTs) and 11 observational studies).We included studies that compared sorafenib, transarterial bland embolisation/transarterial chemoembolization, yttrium‐90/radiation therapy, ablation (or combination) and no therapy. Two RCTs comparing sorafenib to best supportive care demonstrated a consistent improvement in OS for patients with advanced HCC and MVI and/or EHS and Child Pugh‐A liver disease (HR 0.66 (95% CI 0.51‐0.87), I2= 0%). Several observational studies evaluated loco‐regional therapies alone or in combination with other treatments and were limited by very low quality of evidence. This was true for both patients with EHS and MVI. Conclusion: In patients with advanced HCC and Child‐Pugh A liver function, sorafenib is the only treatment that has been shown to improve overall survival in randomized studies. High quality data supporting the use of other treatment modalities in this setting, or in the setting of patients with less compensated (CP B) liver disease is lacking. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 07 septembre 2017
    Keely Marshall, Junfei Jin, Carl Atkinson, Ali Alawieh, Fei Qiao, Biao Lei, Kenneth D. Chavin, Songqing He, Stephen Tomlinson
    Natural IgM initiates an inflammatory response important for both hepatic ischemia reperfusion injury and regeneration
    Rationale: Complement plays a role in both hepatic ischemia reperfusion (IR) injury (IRI) and liver regeneration, but it is not clear how complement is activated in either process. We investigated the role of self‐reactive IgM antibodies in activating complement after hepatic IR and liver resection. Main Results: Natural IgM antibodies that recognize danger associated molecular patterns (neoepitopes) activate complement following both hepatic IR and liver resection. Antibody‐deficient Rag1‐/‐ mice were protected from hepatic IRI, but had increased hepatic injury and an impaired regenerative response after 70% partial hepatectomy (PHx). We identified two IgM mAbs that specifically reversed the effect of Rag1 deficiency in both models; B4 (recognizes annexin IV) and C2 (recognizes subset of phospholipids). Focusing on the B4‐specific response, we demonstrated sinusoidal colocalization of IgM and C3d in Rag1‐/‐ mice that were reconstituted with B4 mAb, and further that the annexin IV neoepitope is specifically and similarly expressed after both hepatic IR and PHx in wild‐type mice. A single‐chain Ab construct (scFv) derived from B4 mAb blocked IgM binding and reduced injury after IR in wild‐type mice, although interestingly B4scFv did not alter regeneration following PHx, indicating that anti‐annexin IV antibodies are sufficient, but not necessary for the regenerative response in the context of an entire natural antibody repertoire. We also demonstrated expression of the B4 neoepitope in post‐ischemic human liver samples obtained after transplantation, and a corollary depletion in IgM recognizing the B4 and C2 neoepitopes in patient sera following liver transplantation. Conclusion: These data indicate an important role for IgM in hepatic IRI and regeneration, with a similar cross‐species injury‐specific recognition system that has implications for the design of neoepitope targeted therapeutics. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 06 septembre 2017
    Harvey Alter, Timothy M. Block, Nathaniel Brown, Alan Brownstein, Carol Brosgart, Kyong‐Mi Chang, Pei‐Jer Chen, Francis V. Chisari, Chari Cohen, Hashem El‐Serag, Jordan Feld, Robert Gish, Jeffrey Glenn, Tim Greten, Haitao Guo, Juo‐Tao Guo, Yujin Hoshida, Jianming Hu, Kris V. Kowdley, Wenhui Li, Jake Liang, Stephen Locarnini, Anna S. Lok, William Mason, Brian McMahon, Anand Mehta, Robert Perrillo, Peter Revill, Charles M. Rice, JoAnn Rinaudo, Raymond Schinazi, Christoph Seeger, Kirty Shetty, John Tavis, Fabien Zoulim
    A Research Agenda for Curing Chronic Hepatitis B Virus Infection
    n/a


    Date de mise en ligne : Mardi 05 septembre 2017
    Hans Reinke, Gad Asher
    Liver Size: Waning by Day, Waxing by Night
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    Date de mise en ligne : Mardi 05 septembre 2017
    Patrick Borentain, Philippe Colson, E. Bolon, Philippe Gauchez, Diane Coso, René Gérolami
    Hepatocellular carcinoma complicating hepatitis E virus‐related cirrhosis
    n/a


    Date de mise en ligne : Mardi 05 septembre 2017
    Virginia Hernández‐Gea, Christophe Bureau
    Practice makes better: TIPS procedures in referral centers!
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    Date de mise en ligne : Mardi 05 septembre 2017
    Haesuk Park, Chao Chen, Wei Wang, Linda Henry, Robert L. Cook, David R. Nelson
    Chronic Hepatitis C Increases the Risk of Chronic Kidney Disease (CKD) while Effective HCV Treatment Decreases the Incidence of CKD
    We aimed to assess the risk of chronic kidney disease (CKD) in chronic hepatitis C virus (HCV) infected patients and the incidence reduction of CKD after receipt of HCV treatment. We also evaluated the risk of membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia in chronic HCV patients. A retrospective cohort analysis of the Truven Health MarketScan Database (2008‐2015) in the United States was conducted. In a cohort of 56,448 HCV‐infected patients and propensity score (1:3) matched 169,344 non‐HCV patients, we examined the association of HCV infection with the incidence of CKD. Of 55,818 HCV patients, 6.6% (n=3666), 6.3% (n=3534), and 8.3% (n=4628) patients received either interferon‐based dual, triple, or all‐oral direct acting antiviral agents (DAA) therapy, respectively, whereas 79% of patients did not receive any HCV treatment. Cox proportional hazards models were used to compare the risk of developing CKD in HCV patients compared to non‐HCV patients and treated patients compared to non‐treated HCV patients. In a multivariate time‐varying Cox regression model, HCV‐infected patients had a 27% increased risk of CKD compared to non‐HCV patients (hazard ratio (HR),1.27; 95% confidence interval (CI),1.18‐1.37). Among HCV patients, individuals who received the minimally effective HCV treatment for dual, triple, or all‐oral therapy had a 30% decreased risk of developing CKD (HR,0.70; 95% CI,0.55‐0.88). In addition, HCV‐infected patients experienced a twofold and a nearly 17‐fold higher risk of MPGN (HR,2.23; 95% CI,1.84‐2.71) and cryoglobulinemia (HR,16.91; 95% CI,12.00‐23.81), compared to non‐HCV patients. CONCLUSION: Individuals infected with HCV infection in U.S. are at greater risk of developing CKD, MPGN, and cryoglobulinemia. Minimally effective treatment of HCV infection can prevent the development of CKD, although the association was not significant for all‐oral therapy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 02 septembre 2017
    Zhenhua Luo, Anil G Jegga, Jorge A Bezerra
    Gene‐disease associations identify a connectome with shared molecular pathways in human cholangiopathies
    Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC] and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression and functional studies, and applied network‐based analytics in search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential‐ and hub‐genes. In addition to disease‐specific modules, we found a substantial overlap of disease neighborhoods, and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing STAT3, IL6, TNF and FOXP3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the AGE‐RAGE pathway, and showed that RAGE activation induced cholangiocyte proliferation. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC and PSC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 02 septembre 2017
    Hidenori Toyoda, Kazuaki Chayama, Fumitaka Suzuki, Ken Sato, Tomofumi Atarashi, Tsunamasa Watanabe, Masanori Atsukawa, Atsushi Naganuma, Kazuo Notsumata, Yukio Osaki, Makoto Nakamuta, Koichi Takaguchi, Satoru Saito, Koji Kato, David Pugatch, Margaret Burroughs, Rebecca Redman, Katia Alves, Tami J. Pilot‐Matias, Rajneet K. Oberoi, Bo Fu, Hiromitsu Kumada
    Efficacy and Safety of Glecaprevir/Pibrentasvir in Japanese Patients with Chronic Genotype 2 Hepatitis C Virus Infection
    Glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P), a coformulated once‐daily, all oral, ribavirin (RBV)‐free, direct‐acting anti‐viral (DAA) regimen was evaluated for safety and efficacy in Hepatitis C Virus GT2‐infected Japanese patients, including those with compensated cirrhosis. CERTAIN‐2 is a phase 3, open‐label, multicenter study assessing the safety and efficacy of G/P (300/120mg) once daily (QD) in treatment‐naĂŻve and interferon (IFN) ± RBV treatment‐experienced non‐cirrhotic Japanese patients with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (Arm A) or 12 weeks of sofosbuvir (400 mg QD) + RBV (600 ‐1000 mg weight‐based, BID) (Arm B). The primary endpoint was non‐inferiority of G/P compared to SOF+RBV by assessing sustained virologic response at post‐treatment week 12 (SVR12) among patients in the intent‐to‐treat (ITT) population. SVR12 was also assessed in treatment‐naĂŻve and IFN ± RBV treatment‐experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the phase 3, open‐label, multicenter CERTAIN‐1 study. A total of 136 patients were enrolled in CERTAIN‐2. SVR12 was achieved by 88/90 (97.8%) patients in Arm A and 43/46 (93.5%) patients in Arm B. No patient in Arm A experienced virologic failure, while two did in Arm B. The primary endpoint was achieved. In CERTAIN‐1, 100% (18/18) of GT2‐infected patients with compensated cirrhosis achieved SVR12. Treatment‐emergent serious adverse events were experienced by two non‐cirrhotic patients in each arm and no cirrhotic patient. Results demonstrate high efficacy and favorable tolerability of G/P in GT2‐infected Japanese patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 02 septembre 2017
    Frank G. Schaap, Peter L.M. Jansen, Steven W.M. Olde Damink
    Chronic elevation of plasma FGF19 in long‐term FXR agonist therapy, a happy marriage or cause for oncologic concern?
    n/a


    Date de mise en ligne : Vendredi 01 septembre 2017
    Mark Czaja, Muhammad Amir
    Inflammasome‐mediated inflammation and fibrosis – it is more than just the IL‐1ÎČ
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    Date de mise en ligne : Vendredi 01 septembre 2017
    Mohamed Bouattour, Eric Raymond, Shukui Qin, Ann‐Lii Cheng, Uz Stammberger, Giuseppe Locatelli, Sandrine Faivre
    Recent Developments of c‐Met as a Therapeutic Target in Hepatocellular Carcinoma
    Aberrant c‐Met activity is implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may mean that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve a complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Bing‐liang Lin, Jun‐feng Chen, Zhi‐liang Gao
    Reply to readers (Manuscript ID: HEP‐17‐1454)
    n/a


    Date de mise en ligne : Jeudi 31 août 2017
    George V Papatheodoridis, Spilios Manolakopoulos, Tung‐Hung Su, Spyros Siakavellas, Chun‐Jen Liu, Anastasia Kourikou, Hung‐Chih Yang, Jia‐Horng Kao
    Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg‐negative chronic hepatitis B
    Relapses are observed in most HBeAg‐negative chronic hepatitis B patients who discontinue nucleos(t)ide analogues (NAs), but the rates of relapse vary widely among studies and whether all patients with relapse need retreatment is unclear. The aim of this study was to assess the impact of different definitions on the rates of post‐treatment relapse and therefore on the probability of retreatment in such patients who discontinued effective long‐term NAs therapy. In total, 130 non‐cirrhotic HBeAg‐negative chronic hepatitis B patients before NAs were included. All had on‐therapy virological remission for ≄24 months and close follow‐up for ≄12 months after stopping NAs or until retreatment, which started on stringent predefined criteria. Relapses rates based on several predetermined definitions of virological and perhaps biochemical criteria were assessed. The median duration of therapy was 60 and of on‐therapy virological remission 43 months. During a median off‐NAs follow‐up of 15 months, no patient experienced liver decompensation or died. Cumulative relapse rates ranged between 2%‐49% at 3, 4%‐73% at 6, 11%‐82% at 12 and 16%‐90% at 24 months, whereas cumulative retreatment rates were 15%, 22% and 40% at 6, 12 and 24 months after NAs discontinuation. No patient characteristic was independently associated with the probability of relapse based on at least two definitions or of retreatment. In conclusion, in HBeAg‐negative chronic hepatitis B patients who discontinue NAs, the definition of relapse has great impact on the off‐NAs relapse rates and potentially on the probability of retreatment. Regardless of definition, off‐NAs relapses cannot be easily predicted by the patients' characteristics. A substantial proportion of such patients may not require retreatment if stringent criteria are adopted. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Raj Vuppalanchi, Mohammad S. Siddiqui, Mark L. Van Natta, Erin Hallinan, Danielle Brandman, Kris Kowdley, Brent A Neuschwander‐Tetri, Rohit Loomba, Srinivas Dasarathy, Manal Abdelmalek, Edward Doo, James A. Tonascia, David E. Kleiner, Arun J. Sanyal, Naga Chalasani,
    Performance Characteristics of Vibration‐Controlled Transient Elastography for Evaluation of Non‐Alcoholic Fatty Liver Disease
    Background: Vibration‐controlled transient elastography (VCTE) estimates liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) which are noninvasive assessments of hepatic fibrosis and steatosis respectively. However, prior VCTE studies reported high failure rate in patients with non‐alcoholic fatty liver disease (NAFLD). Aim: To examine the performance characteristics of Fibroscan 502 Touch with two probes, medium (M+) and extra‐large (XL+), in patients with NAFLD in a multicenter setting. Methods: A total of 1696 exams were attempted in 992 patients (BMI: 33.6 ± 6.5 kg/m2) with histologically confirmed NAFLD. Simultaneous assessment of LSM and CAP was performed using Fibroscan 502 Touch with an automatic probe selection tool. Testing was conducted twice in patients by either a single operator (88%) or two operators (12%). Failure was defined as the inability to obtain a valid examination. An examination was considered unreliable if LSM IQR/median was >30%. Significant disagreement between two readings was defined as greater than >95% limits of agreement between two readings. Results: A total of 1641 examinations yielded valid results with a failure rate of 3.2% (55/1696). The proportion of unreliable scans for LSM was 2.4%. The proportion of unreliable scans with operator experience in the top quartile (≄ 59 procedures) was significantly lower than lower three quarters combined (1.6% vs.4.7%, p=0.01 by Fisher's Exact test). The significant disagreement between first and second readings for LSM and CAP when obtained back to back was 18% and 11% respectively. Conclusion: VCTE for estimation of LSM and CAP can be successfully deployed in a multicenter setting with low failure (3.2%) and high reliability (>95%) rates and high reproducibility. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Alexander Wree, Maria Eugenia Inzaugarat, Ariel E. Feldstein
    Tmbim 1, a novel anti‐inflammatory approach for NASH treatment
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    Date de mise en ligne : Jeudi 31 août 2017
    Sheetal Trivedi, Satyapramod Murthy, Himanshu Sharma, Alex S. Hartlage, Arvind Kumar, Sashi Gadi, Peter Simmonds, Lokendra V. Chauhan, Troels K. H. Scheel, Eva Billerbeck, Peter D. Burbelo, Charles M. Rice, W. Ian Lipkin, Kurt Vandergrift, John M. Cullen, Amit Kapoor
    Viral persistence, liver disease and host response in Hepatitis C‐like virus rat model
    The lack of a relevant, tractable, and immunocompetent animal model for hepatitis C virus (HCV) has severely impeded investigations of viral persistence, immunity and pathogenesis. In the absence of immunocompetent models with robust HCV infection, homolog hepaciviruses in their natural host could potentially provide useful surrogate models. We isolated a rodent hepacivirus (RHV) from wild rats (Rattus norvegicus), RHV‐rn1, acquired the complete viral genome sequence and developed an infectious reverse genetics system. RHV‐rn1 resembles HCV in genomic features including the pattern of polyprotein cleavage sites and secondary structures in the viral 5' and 3' UTRs. We used site‐directed and random mutagenesis to determine that only the first of the two miR‐122 seed sites in viral 5'UTR is required for viral replication and persistence in rats. Next, we used the clone derived virus progeny to infect several inbred and outbred rat strains. Our results determined that RHV‐rn1 possesses several HCV‐defining hallmarks: hepatotropism, propensity to persist, and the ability of induce gradual liver damage. Histological examination of liver samples revealed the presence of lymphoid aggregates, parenchymal inflammation and macro/micro vesicular steatosis in chronically infected rats. Gene expression analysis demonstrated that the intrahepatic response during RHV‐rn1 infection in rats mirrors that of HCV infection, including persistent activation of interferon signaling pathways. Finally, we determined that the backbone drug of HCV direct acting antiviral (DAA) therapy, Sofosbuvir, effectively suppresses chronic RHV‐rn1 infection in rats. Taken together, we developed RHV‐rn1 infected rats as a fully immunocompetent and informative surrogate model to delineate the mechanisms of HCV‐related viral persistence, immunity and pathogenesis. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Filipe S. Cardoso, Michelle Gottfried, Shannan Tujios, Jody C. Olson, Constantine J. Karvellas,
    Continuous renal replacement therapy is associated with reduced serum ammonia levels and mortality in acute liver failure
    Background: Hyperammonemia has been associated with intracranial hypertension and mortality in patients with acute liver failure (ALF). We evaluated the effect of renal replacement therapy (RRT) on serum ammonia level and outcomes in ALF. Methods: Multicenter cohort study of consecutive ALF patients from the United States ALF Study Group registry between 01/1998‐12/2016. Firstly, we studied the association of ammonia with hepatic encephalopathy (HE) and 21‐day transplant‐free survival (TFS) (n=1186). Secondly, we studied the effect of RRT on ammonia for the first 3 days post study admission (n=340) and on 21‐day TFS (n=1186). Results: Higher admission (n=1186) median ammonia level was associated with grade 3‐4 HE (116 vs. 83ÎŒmol/l) and mortality at day 21 due to neurological (181 vs. 90ÎŒmol/l) and all causes (114 vs. 83ÎŒmol/l; P<0.001 for all). Amongst 340 patients with serial ammonia levels, 61 (18%) were on continuous RRT (CRRT), 59 (17%) were on intermittent RRT (IRRT), and 220 (65%) received no RRT for the first 2 days. From days 1 to 3, median ammonia decreased by 38%, 23%, and 19% with CRRT, IRRT, and no RRT, respectively. Comparing to no RRT use, while ammonia reduction with CRRT was significant (P=0.007), with IRRT it was not (P=0.75). After adjusting for year of enrollment, age, etiology, and disease severity, while CRRT (odds ratio [OR], 0.47 [95% confidence interval (CI), 0.26‐0.82]) was associated with reduction in 21‐day transplant‐free all‐cause mortality, IRRT (OR, 1.68 [95%CI, 1.04‐2.72]) was associated with an increase. Conclusions: In a large cohort of ALF patients, hyperammonemia was associated with high grade HE and worse 21‐day TFS. CRRT was associated with a reduction in serum ammonia level and improvement of 21‐day TFS. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Wuttiporn Manatsathit, Hrishikesh Samant, Warapan Nakayuenyongsuk
    Mesenchymal stem cells for hepatitis B patients with acute on chronic liver failure‐Are we there?
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    Date de mise en ligne : Jeudi 31 août 2017
    Laura Kulik, Julie K. Heimbach, Feras Zaiem, Jehad Almasri, Larry J Prokop, Zhen Wang, M. Hassan Murad, Khaled Mohammed
    Therapies for Patients with Hepatocellular Carcinoma Awaiting for Liver Transplantation: a Systematic Review and Meta‐analysis
    Patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation are often treated while on the waiting list with loco‐regional therapy (LRT) which is aimed at either preventing progression of HCC or reducing themeasurable disease burden of HCC in order to receive increased allocation priority. We aimed to synthesize evidence regarding the effectiveness of LRT in the management of patients with HCC who were on the liver transplant waitlist. We conducted a comprehensive search of multiple databases from 1996 to April 25, 2016, for studies that enrolled adults with cirrhosis awaiting liver transplantation and treated with bridging or down‐staging therapies before liver transplantation. Therapies included trans‐catheter arterial chemoembolization (TACE), trans‐arterial radio‐embolization (TARE), ablation or radiotherapy. We included both comparative and non‐comparative studies. There were no randomized controlled trials identified. Results: For adults with T1 HCC and waitingfor liver transplantation there were only 2 non‐randomized comparative studies, both with a high risk of bias, which reported the outcome of interest. In one series, the rate of dropout from all causes at 6 month in T1 HCC patients underwent loco‐regional therapy was 5.3%, while in the other series of T1 HCC patients who did not receive loco‐regional therapy, dropout rate at median follow up of 2.4 years and progression rate to T2 HCC was 30% and 88% respectively. For adults with T2 HCC awaiting liver transplantation, transplant with any bridging therapy showed a non‐significant reduction in the risk of waitlist dropout due to progression (RR 0.32 (95% CI 0.06 ‐ 1.85, I2 = 0%) and waitlist dropout from all causes (RR 0.38 (95% CI 0.060 ‐ 2.370, I2=85.7%), compared to no therapy based on 3 comparative studies. The quality of evidence is very low due to high risk of bias, imprecision and inconsistency. There were 5 comparative studies which reported on post‐transplant survival rates and 10 comparative studies which reported on post‐transplant recurrence and there was no significant difference seen in either of these endpoints. For adults initially with stage T3 HCC who got LRT, there were 3 studies available reporting on transplant with any down‐staging therapy versus no down‐staging and this showed significant increase in 1year (2 studies (51, 52)(RR 1.11 (95% CI 1.01‐1.23) and 5 year (1 study (52) (RR 1.17 (95% CI 1.03‐1.32)post‐LT survival rates for the patients who received LRT. The quality of evidence is very low due to serious risk of bias and imprecision.Conclusion: in patients with HCC listed for liver transplantation, the use of LRT is associated with a non‐significant trend toward improved waitlist and post‐transplant outcomes, though there is a high risk of selection bias in the available evidence. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Patricia C. Valery, Mathieu Laversanne, Paul J. Clark, Jessica L. Petrick, Katherine A McGlynn, Freddie Bray
    Projections of primary liver cancer to 2030 in 30 countries worldwide
    Primary liver cancer (PLC) is the sixth most common cancer worldwide and the second most common cause of cancer death. Future predictions can inform health planners and raise awareness of the need for cancer control action. We predicted the future burden of PLC in 30 countries around 2030. Incident cases of PLC (ICD‐10 C22) were obtained from 30 countries for 1993‐2007. We projected new PLC cases through to 2030 using age‐period‐cohort models (NORDPRED). Age‐standardized incidence rates per 100,000 person‐years were calculated by country and sex. Increases in new cases and rates of PLC are projected in both sexes. Among men, the largest increases in rates are in Norway (2.9% per annum), US whites (2.6%), and Canada (2.4%), and among women in the US (blacks 4.0%), Switzerland (3.4%), and Germany (3.0%). The projected declines are in China, Japan, Singapore, and parts of Europe (e.g. in Estonia, Czech Republic, Slovakia). A 35% increase in the number of new cases annually is expected compared to 2005. This increasing burden reflects both increasing rates (and the underlying prevalence of risk factors) and demographic changes. Japan is the only country with a predicted decline in the net number of cases and annual rates by 2030. Conclusion: Our reporting of a projected increase in PLC incidence to 2030 in 30 countries serves as a baseline for anticipated declines in the longer‐term via the control of HBV and HCV infections through vaccination and treatment. However, the prospects that rising levels of obesity and its metabolic complications may lead to an increased increasing risk of PLC that potentially offset these gains, is a concern. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Lewis R. Roberts, Claude B. Sirlin, Feras Zaiem, Jehad Almasri, Larry J. Prokop, Julie Heimbach, M. Hassan Murad, Khaled Mohammed
    Imaging for the Diagnosis of Hepatocellular Carcinoma: a Systematic Review and Meta‐analysis
    Multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) are both used for non‐invasive diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis. To determine if there is a relative diagnostic benefit of one over the other, we synthesized evidence regarding the relative performances of CT, extracellular‐contrast‐enhanced‐MRI, and gadoxetate‐enhanced‐MRI for diagnosis of HCC in patients with cirrhosis. We also assessed whether liver biopsy versus follow‐up with the same versus alternative imaging is best for CT‐ or MRI‐indeterminate liver nodules in patients with cirrhosis. We searched multiple databases from inception to April 27, 2016 for studies comparing CT with extracellular‐contrast‐enhanced‐MRI or gadoxetate‐enhanced‐MRI in adults with cirrhosis and suspected HCC. Two reviewers independently selected studies and extracted data. Of 33 included studies, 19 were comprehensive, while 14 reported sensitivity only. For all tumor sizes, the 19 comprehensive comparisons showed significantly higher sensitivity (0.82 vs. 0.66) and lower negative likelihood ratio (0.20 vs. 0.37) for MRI over CT. The specificities of MRI vs. CT (0.91 vs. 0.92) and the positive likelihood ratios (8.8 vs. 8.1) were not different. All three modalities performed better for HCCs ≄2 cm. Performance was poor for HCCs <1 cm. No studies examined whether adults with cirrhosis and an indeterminate nodule are best evaluated using biopsy, repeated imaging or alternative imaging. Concerns about publication bias, inconsistent study results, low study quality, and clinical factors precluded support for exclusive use of either gadoxetate‐enhanced or extracellular‐contrast‐enhanced MRI over CT. Conclusion: CT, extracellular‐contrast‐enhanced‐MRI or gadoxetate‐enhanced‐MRI could not be definitively preferred for HCC diagnosis in patients with cirrhosis. In patients with cirrhosis and an indeterminate mass, there was insufficient data comparing biopsy to repeat cross‐sectional imaging or,alternative imaging. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Yu‐Fu Zhou, Xiao‐Mei Wu, Gan Zhou, Ming‐dao Mu, Fa‐Li Zhang, Fe‐Mi Li, Christopher Qian, Fang Du, Wing‐Ho Yung, Zhong‐Ming Qian, Ya Ke
    Cystathionine ÎČ‐synthase is required for body iron homeostasis
    Cystathionine ÎČ‐synthase (CBS) catalyzes the transsulfuration pathway and contributes, among other functions, to the generation of hydrogen sulfide (H2S). In view of the exceptionally high expression of CBS in the liver and the common interleukin‐6 (IL‐6) pathway utilized in the regulatory systems of H2S and hepcidin, we speculate that CBS is involved in body iron homeostasis. We found that CBS knock‐out (CBS‐/‐) mice exhibited anemia and a significant increase in iron content in the serum, liver, spleen and heart, along with severe damage to the liver, displaying a hemochromatosis‐like phenotype. A high level of hepatic and serum hepcidin was also found. A major cause of the systemic iron‐overload is the reduced iron utilization due to suppressed erythropoiesis, which is consistent with an increase in IL‐6 and the reduced expression of erythropoietin. Importantly, in the liver, an absence of CBS caused both a reduction in the transcriptional factor NRF2 and an upregulation of hepcidin that lead to a decrease in the iron export protein ferroportin 1. The resulting suppression of iron export exacerbates iron retention, causing damage to hepatocytes. Finally, administration of CBS‐overexpressing adenovirus into CBS mutant mice could partially reverse the iron‐related phenotype. Our findings thus point to a previously unknown, yet critical role of CBS in iron homeostasis of the body, and the liver in particular. It is likely that a hemochromatosis‐like phenotype in patients can be induced by aberration not only in the expression of key molecules in the hepcidin pathway, but also in those related to CBS. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Jan Pfeiffenberger, Sandra Beinhardt, Daniel N Gotthardt, Nicola Haag, Clarissa Freissmuth, Ulrike Reuner, Annika Gauss, Wolfgang Stremmel, Michael L Schilsky, Peter Ferenci, Karl Heinz Weiss
    Pregnancy in Wilson disease – management and outcome
    Introduction Wilson disease (WD) is a rare inherited disorder of copper metabolism causing toxic hepatic and neural copper accumulation. Clinical symptoms vary widely, from asymptomatic disease to acute liver failure or chronic liver disease without or with neuropsychiatric symptoms. Continuation of specific medical treatment for WD is recommended during pregnancy, but reports of pregnancy outcomes in WD patients are sparse. Patients and methods In a retrospective, multicenter study, 282 pregnancies in 136 WD patients were reviewed. Age at disease onset, age at conception and WD‐specific treatments were recorded. Maternal complications during pregnancy, rate of spontaneous abortions and birth defects were analyzed with respect to medical treatment during pregnancy. Results Worsening of liver function tests was evident during 16/282 (6%) pregnancies and occurred in undiagnosed patients as well as in those under medical treatment. Liver test abnormalities resolved in all cases after delivery. Aggravation of neurological symptoms during pregnancy was rare (1%) but tended to persist after delivery. The overall spontaneous abortion rate in the study cohort was 73/282 (26%). Patients with an established diagnosis of WD receiving medical treatment experienced significantly fewer spontaneous abortions than patients with undiagnosed WD (Odds ratio: 2.853 [95% CI: 1.634‐4.982]). Birth defects occurred in 7/209 (3%) live births. Conclusion Pregnancy in WD patients on anti‐copper therapy is safe. The spontaneous abortion rate in treated patients was lower than that in therapy‐naive patients. Although the teratogenic potential of copper chelators is a concern, the rate of birth defects in our cohort was low. Treatment for WD should be maintained during pregnancy, and patients should be monitored closely for hepatic and neurologic symptoms. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 31 août 2017
    Elena Piccinin, Claudia Peres, Elena Bellafante, Simon Ducheix, Claudio Pinto, Gaetano Villani, Antonio Moschetta
    Hepatic PPARÎł coactivator 1ÎČ drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression
    The peroxisome proliferator‐activated receptor Îł (PPARÎł) coactivator‐1ÎČ (PGC‐1 ÎČ) coactivator is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically in the liver PGC‐1ÎČ also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC‐1ÎČ as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic‐specific PGC‐1ÎČ overexpressing (LivPGC‐1ÎČ) and PGC‐1ÎČ knockout (LivPGC‐1ÎČKO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC‐1ÎČ in driving liver tumor development. Indeed, whereas mice overexpressing PGC‐1ÎČ show greater tumor susceptibility, PGC‐1ÎČ knockout mice are protected from carcinogenesis. High levels of PGC‐1ÎČ are able to boost ROS scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC‐1ÎČ promotes the accumulation of ROS‐driven macromolecule damage, finally limiting tumor growth . The present data elect hepatic PGC‐1ÎČ as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 23 août 2017
    T. Joseph Mattingly, Eleanor M. Perfetto, Sophia Johnson
    Engaging hepatitis C infected patients in cost‐effectiveness analyses: A literature review
    Objectives: Cost‐effectiveness analyses (CEA) of hepatitis C virus (HCV) treatment strategies have become common but few appear to include patient engagement or the patient perspective. The objectives of the current study were to (i) identify published HCV CEA studies that include patient input; and (ii) derive insights on patient‐informed variable and outcome selection to build a framework for future economic analyses of HCV. Methods: A literature search was conducted using SCOPUS, EMBASE, and PubMed from January 1 2012 to May 28, 2017. Terms sought included a combination of “incremental cost‐effectiveness ratio” OR “economic evaluation” OR “cost effectiveness analysis” OR “cost utility analysis” OR “budget impact analysis” OR “cost benefit analysis” AND “hepatitis C”. Results: A total of 1040 articles were identified in the search and 7 articles were selected for further evaluation after abstracts and the full‐text of eligible articles were screened. One economic evaluation used direct patient engagement to account for patient preferences in the final model. The study endpoints identified included a variety of clinical, social, psychological, and economic outcomes. Costs primarily focused on productivity loss, missed work, out‐of‐pocket treatment costs, and indirect costs to family or friends supporting the patient. Conclusion: To date, the inclusion of the patient voice through patient engagement as part of methods in cost‐effectiveness research in existing published studies has been limited. Future CEA studies should consider how patient engagement may impact economic models and their implementation into practice. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 23 août 2017
    Dipen Vyas, Pedro M. Baptista, Matthew Brovold, Emma Moran, Matthew Brovold, Brandon Gaston, Chris Booth, Michael Samuel, Anthony Atala, Shay Soker
    Self‐assembled liver organoids recapitulate hepato‐biliary organogenesis in vitro
    Several 3D cell culture systems are currently available to create liver organoids. In general, these systems display better physiologic and metabolic aspects of intact liver tissue, compared with 2D culture systems. However, none of these reliably mimic human liver development, including parallel formation of hepatocyte and cholangiocyte anatomical structures. Here, we show that human fetal liver progenitor cells self‐assemble inside acellular liver extracellular matrix (ECM) scaffolds to form 3D liver organoids that recapitulated several aspects of hepato‐biliary organogenesis and resulted in concomitant formation of progressively more differentiated hepatocytes and bile duct structures. The duct morphogenesis process was interrupted by inhibiting Notch signaling, attempting to create a liver developmental disease model with a similar phenotype of Alagille syndrome. In the current study, we created an in vitro model of human liver development and disease, physiology and metabolism, supported by liver ECM substrata. We envision that it will be used in the future to study mechanisms of hepatic and biliary development, and for disease modeling and drug screening. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 21 août 2017
    Ju Dong Yang, Harmeet Malhi
    Green Tea Consumption ‐ A Potential Chemopreventive Measure for Hepatocellular Carcinoma?
    n/a


    Date de mise en ligne : Vendredi 18 août 2017
    Xupeng Hong, Elena S. Kim, Haitao Guo
    Epigenetic Regulation of Hepatitis B Virus Covalently Closed Circular DNA: Implications for Epigenetic Therapy against Chronic Hepatitis B
    Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma (HCC) is decreased but not eliminated. One major reason for the treatment failure is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA) which is a stable episomal form of viral genome decorated with host histones and non‐histone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize the progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure the chronic hepatitis B. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 18 août 2017
    TD Kabir, C Ganda, RM Brown, DJ Beveridge, KL Richardson, V Chaturvedi, P Candy, M Epis, L Wintle, F Kalinowski, C Kopp, LM Stuart, GC Yeoh, J George, PJ Leedman
    A miR‐7/GAS6/TYRO3 axis regulates the growth and invasiveness of sorafenib‐resistant cells in human hepatocellular carcinoma
    Sorafenib remains the only approved drug for treating patients with advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is transient and patients invariably develop sorafenib resistance (SR). Recently, TYRO3, a member of the TAM family of receptor tyrosine kinases, was identified as being aberrantly expressed in a significant proportion of HCC, however its role in SR is unknown. In this study, we generated two functionally distinct sorafenib resistant human Huh‐7 HCC cell lines, in order to identify new mechanisms to abrogate acquired SR, as well as new potential therapeutic targets in HCC. Initially, we investigated the effects of a microRNA, miR‐7, in both in vitro and in vivo preclinical models of human HCC and identified miR‐7 as a potent tumour suppressor of human HCC. We identified TYRO3 as a new functional target of miR‐7, which regulates proliferation, migration and invasion of Huh‐7 cells via the PI3‐Kinase/AKT pathway and is markedly elevated upon acquisition of SR. Furthermore, miR‐7 effectively silenced TYRO3 expression in both sorafenib‐sensitive and sorafenib‐resistant Huh‐7 cells inhibiting TYRO3/GAS6 mediated cancer cell migration and invasion. In conclusion, we identified a novel mechanism for acquiring SR in HCC which is via the aberrant expression of the TYRO3/PI3‐Kinase/AKT signal transduction pathway, a mechanism that can be overcome by miR‐7 over‐expression. Taken together, these data suggest a potential role for miR‐7 as an RNA‐based therapeutic to treat refractory and drug resistant HCC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 18 août 2017
    Ahsun Riaz, Ahmed Gabr, Nadine Abouchaleh, Rehan Ali, Ali Alasadi, Ronald Mora, Laura Kulik, Kush Desai, Bartley Thornburg, Samdeep Mouli, Ryan Hickey, Frank H Miller, Vahid Yaghmai, Daniel Ganger, Robert J Lewandowski, Riad Salem
    Radioembolization for Hepatocellular Carcinoma: Statistical Confirmation of Improved Survival in Responders by Landmark Analyses
    Does imaging response predict survival in hepatocellular carcinoma (HCC)? We studied the ability of post‐therapeutic imaging response to predict overall survival. Over 14 years, 948 HCC patients were treated with radioembolization. Patients with baseline metastases, vascular invasion, multifocal disease, Child‐Pugh>B7 and transplanted/resected were excluded. This created our homogenous study cohort of 134 Child‐Pugh≀B7 patients with solitary HCC. Response (using European Association for Study of the Liver [EASL] and Response Evaluation Criteria in Solid Tumors 1.1 [RECIST 1.1] criteria) was associated with survival using Landmark and risk‐of‐death methodologies after reviewing 960 scans. In a sub‐analysis, survival times of responders were compared to those of patients with stable disease (SD) and progressive disease (PD). Uni/multivariate survival analyses were performed at each Landmark. At the 3‐month Landmark, responders survived longer than nonresponders by EASL (HR:0.46; CI:0.26‐0.82; P=0.002) but not RECIST 1.1 criteria (HR:0.70; CI:0.37‐1.32; P=0.32). At the 6‐month Landmark, responders survived longer than nonresponders by EASL (HR:0.32; CI:0.15‐0.77; P<0.001) and RECIST 1.1 criteria (HR:0.50; CI:0.29‐0.87; P=0.021). At the 12‐month Landmark, responders survived longer than nonresponders by EASL (HR:0.34; CI:0.15‐0.77; P<0.001) and RECIST 1.1 criteria (HR:0.52;CI 0.27‐0.98; P=0.049). At 6 months, risk of death was lower for responders by EASL (P<0.001) and RECIST 1.1 (P=0.0445). In sub‐analyses, responders lived longer than patients with SD or PD. EASL response was a significant predictor of survival at 3, 6, and 12 month Landmarks on uni/multivariate analyses. Conclusion: Response to radioembolization in patients with solitary HCC can prognosticate improved survival. EASL necrosis criteria outperformed RECIST 1.1 size criteria in predicting survival. The therapeutic objective of radioembolization should be radiologic response and not solely to prevent progression. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 17 août 2017
    Neehar D Parikh, Wesley J Marrero, Jingyuan Wang, Justin Steuer, Elliot B. Tapper, Monica Konerman, Amit G Singal, David W Hutton, Eunshin Byon, Mariel S Lavieri
    Projected increase in obesity and non‐alcoholic steatohepatitis‐related liver transplantation waitlist additions in the United States
    Non‐alcoholic steatohepatitis (NASH) cirrhosis is the fastest growing indication for liver transplantation (LT) in the US. We aimed to determine the temporal trend behind the rise in obesity and NASH‐related additions to the LT waitlist in the US and make projections for future NASH burden on the LT waitlist. We used data from the Organ Procurement and Transplantation Network database from 2000‐2014 to obtain the number of NASH‐related LT waitlist additions. The obese population in the US from 2000‐2014 was estimated using data from the US Census Bureau and the National Health and Nutrition Examination Survey. Based on obesity trends, we established a time lag between obesity prevalence and NASH‐related waitlist additions. We used data from the US Census Bureau on population projections from 2016‐2030 to forecast obesity estimates and NASH‐related LT waitlist additions. From 2000‐2014, the proportion of obese individuals significantly increased 44.9% and the number of NASH‐related annual waitlist additions increased from 391 to 1605. Increase in obesity prevalence was strongly associated with LT waitlist additions 9 years later in derivation and validation cohorts (R2=0.9). Based on these data, annual NASH‐related waitlist additions are anticipated to increase by 55.4% (1,354 to 2,104) between 2016 and 2030. There is significant regional variation in obesity rates and in the anticipated increase in NASH‐related waitlist additions (p<0.01). Conclusion: We project a marked increase in demand for LT for NASH given population obesity trends. Continued public health efforts to curb obesity prevalence are needed to reduce the projected future burden of NASH. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 17 août 2017
    Elodie Thierion, Duncan T Odom
    Charting the transcriptional regulatory changes in mouse liver during fasting
    In a recent paper: Goldstein I, Baek S, Presman DM, Paakinaho V, Swinstead EE, Hager GL. Transcription factor assisted loading and enhancer dynamics dictate the hepatic fasting response. Genome Res. 2017 Mar;27(3):427‐39., the authors used a number of functional genomics approaches to explore the transcriptional regulatory dynamics that occur during hepatic fasting. They used chromatin landscape data to identify key fasting‐related transcription factors, four of which were further investigated because they are known players of the fasting response: CEBPB (CCAAT enhancer binding‐beta), CREB1 (cAMP responsive element binding protein I), GR (glucocorticoid receptor), and PPARA (peroxisome proliferator activated receptor alpha). The authors described two operating modules (GR‐CREB1 and PPARA‐GR) with synergistic effects driving gluconeogenesis through an assisted loading model and fatty acid oxidation/ketogenesis through a transcription factor cascade, respectively. Finally, using single‐cell tracking, they confirmed that GR facilitates CREB1 binding to DNA. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 17 août 2017
    Scott L. Friedman, Vlad Ratziu, Stephen A. Harrison, Manal F. Abdelmalek, Guruprasad P. Aithal, Juan Caballeria, Sven Francque, Geoffrey Farrell, Kris V. Kowdley, Antonio Craxi, Krzysztof Simon, Laurent Fischer, Liza Melchor‐Khan, Jeffrey Vest, Brian L. Wiens, Pamela Vig, Star Seyedkazemi, Zachary Goodman, Vincent Wai‐Sun Wong, Rohit Loomba, Frank Tacke, Arun Sanyal, Eric Lefebvre
    A Randomized, Placebo‐Controlled Trial of Cenicriviroc for Treatment of Nonalcoholic Steatohepatitis with Fibrosis
    The aim of this study was to evaluate cenicriviroc (CVC), a dual antagonist of C‐C chemokine receptor types 2 and 5, for treatment of nonalcoholic steatohepatitis (NASH) with liver fibrosis. A randomized, double‐blind, multinational phase 2b study enrolled subjects with NASH, a nonalcoholic fatty liver disease activity score [NAS] ≄4, and liver fibrosis (stages 1‐3, NASH Clinical Research Network) at 81 clinical sites. Subjects (N = 289) were randomly assigned CVC 150 mg or placebo. Primary outcome was ≄2‐point improvement in NAS and no worsening of fibrosis at year 1. Key secondary outcomes were: resolution of steatohepatitis and no worsening of fibrosis; improvement in fibrosis by ≄1 stage and no worsening of steatohepatitis. Biomarkers of inflammation and adverse events were assessed. Full study recruitment was achieved. The primary end point of NAS improvement in the intent‐to‐treat population and resolution of steatohepatitis was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144) (16% vs 19%, P = 0.52 and 8% vs 6%, P = 0.49, respectively). However, the fibrosis end point was met in significantly more subjects on CVC than placebo (20% vs 10%; P = 0.02). Treatment benefits were greater in those with higher disease activity and fibrosis stage at baseline. Biomarkers of systemic inflammation were reduced with CVC. Safety and tolerability of CVC were comparable to placebo. Conclusions: After 1 year of CVC treatment, twice as many subjects achieved improvement in fibrosis and no worsening of steatohepatitis compared with placebo. Given the urgent need to develop antifibrotic therapies in NASH, these findings warrant phase 3 evaluation. ClinicalTrials.gov no: NCT02217475 (CENTAUR). This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 14 septembre 2017
    Monica A. Konerman, Mary Thomson, Kristen Gray, Meghan Moore, Hetal Choxi, Elizabeth Seif, Anna S.F. Lok
    Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers
    Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record–based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record–based “best practice advisory” (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti‐HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre‐BPA and post‐BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post‐BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far. Conclusion: Implementation of an electronic health record–based prompt increased HCV screening rates among baby boomers in primary care by 5‐fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017).


    Date de mise en ligne : Samedi 27 mai 2017
    Kyle S. McCommis, Jerry R. Colca, Brian N. Finck
    Reply
    n/a


    Date de mise en ligne : Mardi 19 septembre 2017
    Masthead
    Masthead
    n/a


    Date de mise en ligne : Mardi 19 septembre 2017
    Table of contents
    Table of contents
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    Date de mise en ligne : Mardi 19 septembre 2017
    Nicholas Russo, Robert S. Brown, Robert E. Schwartz, Russell Rosenblatt, Shirley Cohen‐Mekelburg, Monica Saumoy, Clara Tow, Yecheskel Schneider, Vikas Gupta
    Hepatology Highlights
    1015


    Date de mise en ligne : Samedi 26 août 2017
    Anna S. Lok, Raymond T. Chung, Hugo E. Vargas, Arthur Y. Kim, Susanna Naggie, William G. Powderly
    Comments on cochrane review on direct‐acting antivirals for hepatitis C
    1019


    Date de mise en ligne : Mercredi 30 août 2017
    Hugo R. Rosen, Marc G. Ghany, Raymond T. Chung, Anna S.F. Lok
    NAM 2017 report: A national plan to eliminate hepatitis B and C in the United States by 2030 and the AASLD's response
    1022


    Date de mise en ligne : Samedi 26 août 2017
    Edward J. Gane
    Is hepatitis B immune globulin still needed after liver transplantation for chronic hepatitis B?
    1025


    Date de mise en ligne : Samedi 26 août 2017
    Luca Valenti, Paola Dongiovanni
    Mutant PNPLA3 I148M protein as pharmacological target for liver disease
    1028


    Date de mise en ligne : Samedi 26 août 2017
    Domenico Alvaro
    The challenge of cholangiocarcinoma diagnosis: The turning point is in extracellular vesicles?
    1031


    Date de mise en ligne : Samedi 26 août 2017
    John Y.L. Chiang
    Linking long noncoding RNA to control bile acid signaling and cholestatic liver fibrosis
    1035


    Date de mise en ligne : Samedi 26 août 2017
    James Fung, Tiffany Wong, Kenneth Chok, Albert Chan, Tan‐To Cheung, Jeff Wing‐Chiu Dai, Sui‐ling Sin, Ka‐Wing Ma, Kelvin Ng, Kevin Tak‐Pan Ng, Wai‐Kay Seto, Ching‐Lung Lai, Man‐Fung Yuen, Chung‐Mau Lo
    Long‐term outcomes of entecavir monotherapy for chronic hepatitis B after liver transplantation: Results up to 8 years
    Long‐term antiviral prophylaxis is required to prevent hepatitis B recurrence for patients with chronic hepatitis B after liver transplantation. We determined the long‐term outcome of 265 consecutive chronic hepatitis B liver transplant recipients treated with entecavir monotherapy without hepatitis B immune globulin. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow‐up. The median duration of follow‐up was 59 months. The cumulative rates of hepatitis B surface antigen (HBsAg) seroclearance were 90% and 95% at 1 and 5 years, respectively. At 1, 3, 5, and 8 years, 85%, 88%, 87.0%, and 92% were negative for HBsAg, respectively, and 95%, 99%, 100%, and 100% had undetectable hepatitis B virus (HBV) DNA, respectively. Fourteen patients remained persistently positive for HBsAg, all of whom had undetectable HBV DNA. There was no significant difference in liver stiffness for those who remained HBsAg‐positive compared to those who achieved HBsAg seroclearance (5.5 versus 5.2 kPa, respectively; P = 0.52). The overall 9‐year survival was 85%. There were 37 deaths during the follow‐up period, of which none were due to hepatitis B recurrence. Conclusion: Long‐term entecavir monotherapy is highly effective at preventing HBV reactivation after liver transplantation for chronic hepatitis B, with a durable HBsAg seroclearance rate of 92%, an undetectable HBV DNA rate of 100% at 8 years, and excellent long‐term survival of 85% at 9 years. (Hepatology 2017;66:1036‐1044).


    Date de mise en ligne : Samedi 26 août 2017
    Xuan Guo, Shu Wang, Zhi‐Gang Qiu, Ya‐Ling Dou, Wei‐Li Liu, Dong Yang, Zhi‐Qiang Shen, Zhao‐Li Chen, Jing‐Feng Wang, Bin Zhang, Xin‐Wei Wang, Xiang‐Fei Guo, Xue‐Lian Zhang, Min Jin, Jun‐Wen Li
    Efficient replication of blood‐borne hepatitis C virus in human fetal liver stem cells
    The development of pathogenic mechanisms, specific antiviral treatments and preventive vaccines for hepatitis C virus (HCV) infection has been limited due to lack of cell culture models that can naturally imitate the entire HCV life cycle. Here, we established an HCV cell culture model based on human fetal liver stem cells (hFLSCs) that supports the entire blood‐borne hepatitis C virus (bbHCV) life cycle. More than 90% of cells remained infected by various genotypes. bbHCV was efficiently propagated, and progeny virus were infectious to hFLSCs. The virus could be passed efficiently between cells. The viral infectivity was partially blocked by specific antibodies or small interfering RNA against HCV entry factors, whereas HCV replication was inhibited by antiviral drugs. We observed viral particles of approximately 55 nm in diameter in both cell culture media and infected cells after bbHCV infection. Conclusion: Our data show that the entire bbHCV life cycle could be naturally imitated in hFLSCs. This model is expected to provide a powerful tool for exploring the process and the mechanism of bbHCV infection at the cellular level and for evaluating the treatment and preventive strategies of bbHCV infection. (Hepatology 2017;66:1045‐1057).


    Date de mise en ligne : Samedi 26 août 2017
    Zhenhuan Cao, Yali Liu, Lina Ma, Junfeng Lu, Yi Jin, Shan Ren, Zhimin He, Chengli Shen, Xinyue Chen
    A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated‐interferon alpha
    Hepatitis B surface antigen (HBsAg) clearance represents a clinical cure, although the clearance rate is extremely low. The aim of this study was to evaluate the feasibility and safety profiles of pegylated‐interferon α‐2a (PEG‐IFNα‐2a) as a therapeutic option for inactive HBsAg carriers. There were 144 inactive HBsAg carriers enrolled and divided into a therapeutic group (102 subjects) and a control group (42 subjects). PEG‐IFNα‐2a and PEG‐IFNα‐2a combined with adefovir dipivoxil were used for treatment group subjects with hepatitis B virus DNA <20 IU/mL and 20 IU/mL ≀ hepatitis B virus DNA < 2,000 IU/mL, respectively. Total therapy duration was no more than 96 weeks. HBsAg clearance and seroconversion rates at therapeutic weeks 48 and 96 were used to evaluate the therapeutic efficacy. Per protocol analysis showed that the HBsAg clearance rate and seroconversion rate in the treatment group were 29.8% and 20.2% at week 48 and increased to 44.7% and 38.3% at week 96, respectively. However, the HBsAg clearance rate in the control group was 2.4% at weeks 48 and 96, and no subject achieved seroconversion. The quantitative HBsAg levels and changes during the early period of treatment (at week 12 and week 24) as well as the alanine aminotransferase elevation at week 12 were strong predictors of HBsAg clearance. The adverse events were similar to those with treatment for chronic hepatitis B patients. Conclusion: High rates of HBsAg clearance and seroconversion could be achieved by PEG‐IFNα‐2a‐based treatments and the treatments were relatively safe for inactive HBsAg carriers. (Hepatology 2017;66:1058‐1066).


    Date de mise en ligne : Samedi 26 août 2017
    Yingjie Bian, Zheng Zhang, Zhichen Sun, Juanjuan Zhao, Danming Zhu, Yang Wang, Sherry Fu, Jingya Guo, Longchao Liu, Lishan Su, Fu‐Sheng Wang, Yang‐Xin Fu, Hua Peng
    Vaccines targeting preS1 domain overcome immune tolerance in hepatitis B virus carrier mice
    Strong tolerance to hepatitis B virus (HBV) surface antigens limits the therapeutic effect of the conventional hepatitis B surface antigen (HBsAg) vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of the preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1‐polypeptide rather than HBsAg vaccination induced robust immune responses in HBV carrier mice. The anti‐preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1‐polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1‐polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg/hepatitis B surface antibody serological conversion and clear chronic HBV infection in carrier mice. Conclusion: These results suggest that preS1 can function as a therapeutic vaccine for the control of CHB. (Hepatology 2017;66:1067‐1082)


    Date de mise en ligne : Samedi 26 août 2017
    Edward J. Gane, Mitchell L. Shiffman, Kyle Etzkorn, Giuseppe Morelli, Catherine A.M. Stedman, Mitchell N. Davis, Federico Hinestrosa, Hadas Dvory‐Sobol, K.C. Huang, Anu Osinusi, John McNally, Diana M. Brainard, John G. McHutchison, Alex J. Thompson, Mark S. Sulkowski,
    Sofosbuvir‐velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct‐acting antiviral regimen
    The optimal retreatment strategy for patients chronically infected with hepatitis C virus who experience virologic failure after treatment with direct‐acting antiviral–based therapies remains unclear. In this multicenter, open‐label, phase 2 study, we evaluated the efficacy and safety of a fixed‐dose combination of sofosbuvir‐velpatasvir (400 mg/100 mg) plus weight‐adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response after prior treatment with direct‐acting antiviral regimens that included the nucleotide analogue nonstructural protein 5B inhibitor sofosbuvir plus the nonstructural protein 5A inhibitor velpatasvir with or without the nonstructural protein 3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval, 82%‐97%) patients achieved sustained virologic response at 12 weeks, including 36 of 37 (97%; 95% confidence interval, 86%‐100%) patients with hepatitis C virus genotype 1 infection, 13 of 14 (93%; 95% confidence interval, 66%‐100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% confidence interval, 52%‐94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all study drugs due to an adverse event (irritability). Conclusion: Retreatment of patients who previously failed direct‐acting antiviral–based therapies with sofosbuvir‐velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with hepatitis C virus genotype 1 or 2 infection. (Hepatology 2017;66:1083‐1089).


    Date de mise en ligne : Lundi 04 septembre 2017
    Varun Saxena, Vandana Khungar, Elizabeth C. Verna, Josh Levitsky, Robert S. Brown, Mohamed A. Hassan, Mark S. Sulkowski, Jacqueline G. O'Leary, Farrukh Koraishy, Joseph S. Galati, Alexander A. Kuo, Monika Vainorius, Lucy Akushevich, David R. Nelson, Michael W. Fried, Norah Terrault, K. Rajender Reddy
    Safety and efficacy of current direct‐acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV‐TARGET study
    Data outside of clinical trials with direct‐acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct‐acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≄3.5 g/dL, baseline total bilirubin ≀1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. Conclusion: In a large prospective observational cohort study, direct‐acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090‐1101).


    Date de mise en ligne : Samedi 26 août 2017
    Stefan Wirth, Philip Rosenthal, Regino P. Gonzalez‐Peralta, Maureen M. Jonas, William F. Balistreri, Chuan‐Hao Lin, Winita Hardikar, Kathryn Kersey, Benedetta Massetto, Bittoo Kanwar, Diana M. Brainard, Jiang Shao, Evguenia Svarovskaia, Brian Kirby, Ronen Arnon, Karen F. Murray, Kathleen B. Schwarz
    Sofosbuvir and ribavirin in adolescents 12‐17 years old with hepatitis C virus genotype 2 or 3 infection
    Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all‐oral combination of sofosbuvir and ribavirin in adolescents aged 12‐17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty‐two patients received sofosbuvir 400 mg once daily and weight‐based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS‐331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty‐three percent of patients were treatment‐naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%‐100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow‐up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS‐331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%‐200%. Conclusion: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102‐1110).


    Date de mise en ligne : Samedi 26 août 2017
    Soumik BasuRay, Eriks Smagris, Jonathan C. Cohen, Helen H. Hobbs
    The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation
    A sequence variation (I148M) in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) is strongly associated with fatty liver disease, but the underlying mechanism remains obscure. In this study, we used knock‐in (KI) mice (Pnpla3148M/M) to examine the mechanism responsible for accumulation of triglyceride (TG) and PNPLA3 in hepatic lipid droplets (LDs). No differences were found between Pnpla3148M/M and Pnpla3+/+ mice in hepatic TG synthesis, utilization, or secretion. These results are consistent with TG accumulation in the Pnpla3148M/M mice being caused by impaired TG mobilization from LDs. Sucrose feeding, which is required to elicit fatty liver in KI mice, led to a much larger and more persistent increase in PNPLA3 protein in the KI mice than in wild‐type (WT) mice. Inhibition of the proteasome (bortezomib), but not macroautophagy (3‐methyladenine), markedly increased PNPLA3 levels in WT mice, coincident with the appearance of ubiquitylated forms of the protein. Bortezomib did not increase PNPLA3 levels in Pnpla3148M/M mice, and only trace amounts of ubiquitylated PNPLA3 were seen in these animals. Conclusion: These results are consistent with the notion that the 148M variant disrupts ubiquitylation and proteasomal degradation of PNPLA3, resulting in accumulation of PNPLA3‐148M and impaired mobilization of TG from LDs. (Hepatology 2017;66:1111‐1124).


    Date de mise en ligne : Samedi 26 août 2017
    Ander Arbelaiz, Mikel Azkargorta, Marcin Krawczyk, Alvaro Santos‐Laso, Ainhoa Lapitz, Maria J. Perugorria, Oihane Erice, Esperanza Gonzalez, Raul Jimenez‐AgĂŒero, Adelaida Lacasta, Cesar Ibarra, Alberto Sanchez‐Campos, Juan P. Jimeno, Frank Lammert, Piotr Milkiewicz, Marco Marzioni, Rocio I.R. Macias, Jose J.G. Marin, Tushar Patel, Gregory J. Gores, Ibon Martinez, FĂ©lix Elortza, Juan M. Falcon‐Perez, Luis Bujanda, Jesus M. Banales
    Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma
    Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions, such as primary sclerosing cholangitis (PSC), are risk factors. Noninvasive differential diagnosis between intrahepatic CCA and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate noninvasive biomarkers for PSC, CCA, and HCC are not available. In the search for novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n = 43), PSC (n = 30), or HCC (n = 29) patients and healthy individuals (control, n = 32); and their protein content was characterized. By using nanoparticle tracking analysis, serum EV concentration was found to be higher in HCC than in all the other groups. Round morphology (by transmission electron microscopy), size (∌180 nm diameter by nanoparticle tracking analysis), and markers (clusters of differentiation 9, 63, and 81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the receiver operating characteristic curve of 0.878 for CCA versus control, 0.905 for CCA stage I‐II versus control, 0.789 for PSC versus control, 0.806 for noncirhottic PSC versus control, 0.796 for CCA versus PSC, 0.956 for CCA stage I‐II versus PSC, 0.904 for HCC versus control, and 0.894 for intrahepatic CCA versus HCC. Proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. Conclusion: Proteomic signatures found in serum EV of CCA, PSC, and HCC patients show potential usefulness as diagnostic tools. (Hepatology 2017;66:1125‐1143).


    Date de mise en ligne : Samedi 26 août 2017
    Mariya L. Samoylova, Mark J. Nigrini, Jennifer L. Dodge, John P. Roberts
    Biases in the reporting of hepatocellular carcinoma tumor sizes on the liver transplant waiting list
    We investigated the possibility that patients with hepatocellular carcinoma (HCC) listed for liver transplant with tumors just outside stage T2 size criteria may be inaccurately reported as just meeting the tumor size criteria for transplant. The United Network for Organ Sharing/Standard Transplant Analysis and Research database identified 12,958 patients listed for liver transplants with HCC exception points from 2006 to 2013, 9,168 of whom were listed with one tumor. A logistic power peak function was fitted to the single‐tumor size histogram, with the fitted values representing unbiased expected values. The difference between the observed and expected tumor counts for 2.0 cm and 5.0 cm was 238 (22%) and 66 (57%), respectively. This suggests that up to 304 (3.0%) patients with tumors outside of transplant criteria had their measurements recorded at the margins of eligibility. A risk‐adjusted Poisson model evaluated the ratio of observed to expected HCC recurrence by tumor size. There were 435 HCC recurrences among 6,049 transplants. Only 2.0‐cm tumors had observed to expected recurrence differing from 1 (ratio 0.73, 95% confidence interval 0.57‐0.94), indicating a 27% lower than expected rate of recurrence. Conclusion: Higher than expected observed tumor counts at the lower transplant criteria margin were corroborated by lower than expected HCC recurrence, suggesting that tumor sizes at the margins of HCC transplant criteria may be subject to inaccurate reporting. (Hepatology 2017;66:1144‐1150)


    Date de mise en ligne : Samedi 26 août 2017
    Dan Han, Jiangxue Li, Huamin Wang, Xiaoping Su, Jin Hou, Yan Gu, Cheng Qian, Yun Lin, Xiang Liu, Mingyan Huang, Nan Li, Weiping Zhou, Yizhi Yu, Xuetao Cao
    Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression
    Noncoding RNAs play important roles in cancer biology, providing potential targets for cancer intervention. As a new class of endogenous noncoding RNAs, circular RNAs (circRNAs) have been recently identified in cell development and function, and certain types of pathological responses, generally acting as a microRNA (miRNA) sponge to regulate gene expression. Identifying the deregulated circRNAs and their roles in cancer has attracted much attention. However, the expression profile and function of circRNAs in human hepatocellular carcinoma (HCC) remain to be investigated. Here, we analyzed the expression profile of human circRNAs in HCC tissues and identified circMTO1 (mitochondrial translation optimization 1 homologue; hsa_circRNA_0007874/hsa_circRNA_104135) as one circRNA significantly down‐regulated in HCC tissues. HCC patients with low circMTO1 expression had shortened survival. By using a biotin‐labeled circMTO1 probe to perform RNA in vivo precipitation in HCC cells, we identified miR‐9 as the circMTO1‐associated miRNA. Furthermore, silencing of circMTO1 in HCC could down‐regulate p21, the target of oncogenic miR‐9, resulting in the promotion of HCC cell proliferation and invasion. In addition, the tumor‐promoting effect of circMTO1 silencing was blocked by miR9 inhibitor. Intratumoral administration of cholesterol‐conjugated circMTO1 small interfering RNA promoted tumor growth in HCC‐bearing mice in vivo. Conclusion: circMTO1 suppresses HCC progression by acting as the sponge of oncogenic miR‐9 to promote p21 expression, suggesting that circMTO1 is a potential target in HCC treatment. The decrease of circMTO1 in HCC tissues may serve as a prognosis predictor for poor survival of patients. (Hepatology 2017;66:1151‐1164).


    Date de mise en ligne : Mercredi 30 août 2017
    Yawei Qian, Wei Yao, Tao Yang, Yan Yang, Yan Liu, Qi Shen, Jian Zhang, Weipeng Qi, Jianming Wang
    aPKC‐Îč/P‐Sp1/Snail signaling induces epithelial–mesenchymal transition and immunosuppression in cholangiocarcinoma
    Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial–mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C‐iota (aPKC‐Îč) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC‐Îč, Snail, and infiltrated immunosuppressive cells were significantly up‐regulated in CCA tumor tissues and linked to poor prognosis. aPKC‐Îč induced EMT and immunosuppression by regulating Snail in vitro and in vivo, although aPKC‐Îč did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC‐Îč and Snail in relation to EMT, quantitative iTRAQ‐based phosphoproteomic analysis and liquid chromatography–tandem mass spectrometry were conducted to identify the substrates of aPKC‐Îč‐dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC‐Îč on Ser59 (P‐Sp1). Both Sp1 and P‐Sp1 were up‐regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P‐Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P‐Sp1 also regulated aPKC‐Îč/Snail‐induced EMT‐like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT‐like features appear to generate immunosuppressive natural T regulatory–like cluster of differentiation 4–positive (CD4+)CD25– cells rather than to increase CD4+CD25+ natural T regulatory cells, in part by mediating T regulatory–inducible cytokines such as transforming growth factor ÎČ1 and interleukin 2. Conclusion: These results demonstrate that aPKC‐Îč promotes EMT and induces immunosuppression through the aPKC‐Îč/P‐Sp1/Snail signaling pathway and may be a potential therapeutic target for CCA. (Hepatology 2017;66:1165‐1182).


    Date de mise en ligne : Samedi 26 août 2017
    Yongfeng Song, Chune Liu, Xia Liu, Jocelyn Trottier, Michele Beaudoin, Li Zhang, Chad Pope, Guangyong Peng, Olivier Barbier, Xiaobo Zhong, Linheng Li, Li Wang
    H19 promotes cholestatic liver fibrosis by preventing ZEB1‐mediated inhibition of epithelial cell adhesion molecule
    Based on our recent finding that disruption of bile acid (BA) homeostasis in mice results in the induction of hepatic long noncoding RNA H19 expression, we sought to elucidate the role of H19 in cholestatic liver fibrosis. Hepatic overexpression of H19RNA augmented bile duct ligation (BDL)‐induced liver fibrosis, which was accompanied by the elevation of serum alanine aminotransferase, aspartate aminotransferase, bilirubin, and BA levels. Multiple genes related to liver fibrosis, inflammation, and biliary hyperplasia were increased in H19‐BDL versus null‐BDL mice, whereas genes in BA synthesis were decreased. Livers and spleens of H19‐BDL mice showed significant enrichment of CD3+γή+, interleukin‐4, and interleukin‐17 producing CD4+ and CD8+ immune cell populations. H19 down‐regulated hepatic zinc finger E‐box‐binding homeobox 1 (ZEB1) but up‐regulated epithelial cell adhesion molecule (EpCAM) and SRY (sex determining region Y)‐box 9 expression. Mechanistically, ZEB1 repressed EpCAM promoter activity and gene transcription. H19RNA impeded ZEB1's inhibitory action by interacting with ZEB1 protein to prevent its binding to the EpCAM promoter. Hepatic overexpression of ZEB1 or knockdown of EpCAM diminished H19‐induced fibrosis; the latter was also prevented in H19−/− mice. H19RNA was markedly induced by bile acids in mouse small cholangiocytes and to a lesser extent in mouse large cholangiocytes. The up‐regulation of H19RNA and EpCAM correlated positively with the down‐regulation of ZEB1 in primary sclerosing cholangitis and primary biliary cirrhosis liver specimens. Conclusion: The activation of hepatic H19RNA promoted cholestatic liver fibrosis in mice through the ZEB1/EpCAM signaling pathway. (Hepatology 2017;66:1183‐1196).


    Date de mise en ligne : Samedi 26 août 2017
    Tatyana V. Masyuk, Anatoliy I. Masyuk, Maria Lorenzo Pisarello, Brynn N. Howard, Bing Q. Huang, Pui‐Yuen Lee, Xavier Fung, Eduard Sergienko, Robert J. Ardecky, Thomas D.Y. Chung, Anthony B. Pinkerton, Nicholas F. LaRusso
    TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling
    Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein–coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m‐tolyl 5‐chloro‐2‐[ethylsulfonyl] pyrimidine‐4‐carboxylate [SBI‐115]), and (3) a combination of SBI‐115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA‐treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5−/−;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2‐fold to 3‐fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∌40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5‐deficient TGR5−/−;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∌2‐fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∌30% in cystic cholangiocytes after treatment with SBI‐115 alone and by ∌50% when SBI‐115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197‐1218).


    Date de mise en ligne : Samedi 26 août 2017
    AgustĂ­n Albillos, Javier Zamora, Javier MartĂ­nez, David Arroyo, Irfan Ahmad, Joaquin De‐la‐Peña, Juan‐Carlos Garcia‐PagĂĄn, Gin‐Ho Lo, Shiv Sarin, Barjesh Sharma, Juan G. Abraldes, Jaime Bosch, Guadalupe Garcia‐Tsao,
    Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta‐analysis
    Endoscopic variceal ligation plus beta‐blockers (EVL+BB) is currently recommended for variceal rebleeding prophylaxis, a recommendation that extends to all patients with cirrhosis with previous variceal bleeding irrespective of prognostic stage. Individualizing patient care is relevant, and in published studies on variceal rebleeding prophylaxis, there is a lack of information regarding response to therapy by prognostic stage. This study aimed at comparing EVL plus BB with monotherapy (EVL or BB) on all‐source rebleeding and mortality in patients with cirrhosis and previous variceal bleeding stratified by cirrhosis severity (Child A versus B/C) by means of individual time‐to‐event patient data meta‐analysis from randomized controlled trials. The study used individual data on 389 patients from three trials comparing EVL plus BB versus BB and 416 patients from four trials comparing EVL plus BB versus EVL. Compared with BB alone, EVL plus BB reduced overall rebleeding in Child A (incidence rate ratio 0.40; 95% confidence interval, 0.18‐0.89; P = 0.025) but not in Child B/C, without differences in mortality. The effect of EVL on rebleeding was different according to Child (P for interaction <0.001). Conversely, compared with EVL, EVL plus BB reduced rebleeding in both Child A and B/C, with a significant reduction in mortality in Child B/C (incidence rate ratio 0.46; 95% confidence interval, 0.25‐0.85; P = 0.013). Conclusion: Outcomes of therapies to prevent variceal rebleeding differ depending on cirrhosis severity: in patients with preserved liver function (Child A), combination therapy is recommended because it is more effective in preventing rebleeding, without modifying survival, while in patients with advanced liver failure (Child B/C), EVL alone carries an increased risk of rebleeding and death compared with combination therapy, underlining that BB is the key element of combination therapy. (Hepatology 2017;66:1219‐1231).


    Date de mise en ligne : Samedi 26 août 2017
    Daniel Markwardt, Lesca Holdt, Christian Steib, Andreas Benesic, Flemming Bendtsen, Mauro Bernardi, Richard Moreau, Daniel Teupser, Julia Wendon, Frederik Nevens, Jonel Trebicka, Elisabet Garcia, Marco Pavesi, Vicente Arroyo, Alexander L. Gerbes
    Plasma cystatin C is a predictor of renal dysfunction, acute‐on‐chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis
    The development of acute‐on‐chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. We investigated whether cystatin C (CysC) and neutrophil gelatinase‐associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF, and mortality. We determined the plasma levels of CysC and NGAL in 429 patients hospitalized for acute decompensation of cirrhosis in the EASL‐CLIF Acute‐on‐Chronic Liver Failure in Cirrhosis (CANONIC) study. The patients were followed for 90 days. Patients without RD or ACLF at inclusion but with development of either had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL, was found to be predictive of RD (odds ratio, 9.4; 95% confidence interval [CI], 1.8‐49.7), HRS (odds ratio, 4.2; 95% CI, 1.2‐14.8), and ACLF (odds ratio, 5.9; 95% CI, 1.3‐25.9). CysC at day 3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90‐day mortality, with hazard ratios for CysC of 3.1 (95% CI, 2.1‐4.7) and for NGAL of 1.9 (95% CI, 1.5‐2.4). Conclusion: Baseline CysC is a biomarker of RD, HRS, and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis, though determining CysC at day 3 did not provide any benefit; while NGAL is also associated with short‐term mortality, it fails to predict development of RD, HRS, and ACLF. Baseline CysC may help to identify patients at risk earlier and improve clinical management. (Hepatology 2017;66:1232‐1241)


    Date de mise en ligne : Samedi 26 août 2017
    Jörg‐Martin Bangen, Linda Hammerich, Roland Sonntag, Maike Baues, Ute Haas, Daniela Lambertz, Thomas Longerich, Twan Lammers, Frank Tacke, Christian Trautwein, Christian Liedtke
    Targeting CCl4‐induced liver fibrosis by RNA interference–mediated inhibition of cyclin E1 in mice
    Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSCs). Cyclin E1 (CcnE1) is the regulatory subunit of the cyclin‐dependent kinase 2 (Cdk2) and controls cell cycle re‐entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation, and survival of HSCs and protects from liver fibrogenesis. The aim of the present study was to translate these findings into preclinical applications using an RNA interference (RNAi)‐based approach. CcnE1‐siRNA (small interfering RNA) efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs, resulting in diminished proliferation and increased cell death. In C57BL/6 wild‐type (WT) mice, delivery of stabilized siRNA using a liposome‐based carrier targeted approximately 95% of HSCs, 70% of hepatocytes, and 40% of CD45+ cells after single injection. Acute CCl4‐mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and nonparenchymal cells, including CD45+ leukocytes. Pretreatment with CcnE1‐siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury, diminished proliferation of hepatocytes and leukocytes, and attenuated overall inflammatory response. For induction of liver fibrosis, WT mice were challenged with CCl4 for 4‐6 weeks. Co‐treatment with CcnE1‐siRNA once a week was sufficient to continuously block CcnE1 expression and cell‐cycle activity of hepatocytes and nonparenchymal cells, resulting in significantly ameliorated liver fibrosis and inflammation. Importantly, CcnE1‐siRNA also prevented progression of liver fibrosis if applied after onset of chronic liver injury. Conclusion: Therapeutic targeting of CcnE1 in vivo using RNAi is feasible and has high antifibrotic activity. (Hepatology 2017;66:1242‐1257).


    Date de mise en ligne : Lundi 04 septembre 2017
    Vasantha L. Kolachala, Sirish Palle, Ming Shen, Alayna Feng, Dmitry Shayakhmetov, Nitika A. Gupta
    Loss of L‐selectin‐guided CD8+, but not CD4+, cells protects against ischemia reperfusion injury in a steatotic liver
    Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic‐reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically nonexistent. The objective of the current study was to delineate the contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. RNA sequencing was performed on isolated steatotic primary hepatocytes, and T‐cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high‐fat diet (HFD)–fed mice. Cluster of differentiation 8 knockout (CD8−/−) and CD4−/− mice along with CD8 and L‐selectin antibody–treated mice were fed an HFD, and hepatocellular injury was assessed by histology, propidium iodide injection, and alanine aminotransferase after IRI. RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes versus lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8+ cells, alanine aminotransferase, and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8+/CD62L+(L‐selectin) cells in HFD‐fed mice after IRI. CD8−/− mice and CD8‐depleted C57BL/6 mice demonstrated significant protection from injury, which was not seen in CD4−/− mice. L‐selectin blockade also demonstrated significant hepatoprotection from IRI. L‐selectin ligand MECA‐79 was increased in HFD‐fed mice undergoing IRI. Conclusion: Blockade of CD8 and L‐selectin, but not CD4, ameliorated hepatocellular injury, confirming that CD8+ cells are critical drivers of injury in a steatotic liver; this represents a therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. (Hepatology 2017;66:1258‐1274).


    Date de mise en ligne : Samedi 26 août 2017
    Paul H. Hayashi, Don C. Rockey, Robert J. Fontana, Hans L. Tillmann, Neil Kaplowitz, Huiman X. Barnhart, Jiezhan Gu, Naga P. Chalasani, K. Rajender Reddy, Averell H. Sherker, Jay H. Hoofnagle,
    Death and liver transplantation within 2 years of onset of drug‐induced liver injury
    Drug‐induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities is poorly characterized, particularly when fatalities occur >26 weeks after DILI onset. We analyzed patients in the US Drug‐Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by eight network investigators and categorized as DILI having a primary, a contributory, or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute‐on‐chronic, or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1,089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%), and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute on chronic, and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy, and severe cutaneous reactions with multiorgan failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis, and thrombocytopenia were independently associated with DILI fatalities. New R ratio Hy's law had a higher positive predictive value for overall fatality (14% versus 10%) and a stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's law (hazard ratio, 6.2, 95% confidence interval 3.4‐11.1, versus 2.2, 95% confidence interval 1.3‐3.7). Conclusions: DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these had nonacute liver failure courses. New R ratio Hy's law better identifies risk for death compared to the original Hy's law. (Hepatology 2017;66:1275‐1285).


    Date de mise en ligne : Mercredi 30 août 2017
    Kaku A. So‐Armah, Joseph K. Lim, Vincent Lo Re, Janet P. Tate, Chung‐Chou H. Chang, Adeel A. Butt, Cynthia L. Gibert, David Rimland, Vincent C. Marconi, Matthew B. Goetz, Maria C. Rodriguez‐Barradas, Matthew J. Budoff, Hilary A. Tindle, Jeffrey H. Samet, Amy C. Justice, Matthew S. Freiberg,
    FIB‐4 stage of liver fibrosis predicts incident heart failure among HIV‐infected and uninfected patients
    Liver fibrosis is common, particularly in individuals who are infected with human immunodeficiency virus (HIV). HIV‐infected individuals have excess congestive heart failure (CHF) risk compared with uninfected people. It remains unknown whether liver fibrosis stage influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether 1) stage of liver fibrosis is independently associated with incident CHF and 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after April 1, 2003, in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease were followed until their first CHF event, death, last follow‐up date, or December 31, 2011. Liver fibrosis was measured using the fibrosis 4 index (FIB‐4), which is calculated using age, aminotransferases, and platelets. Cox proportional hazards regression models were adjusted for cardiovascular disease risk factors. Among 96,373 participants over 6.9 years, 3844 incident CHF events occurred. FIB‐4 between 1.45 and 3.25 (moderate fibrosis) and FIB‐4 > 3.25 (advanced fibrosis/cirrhosis) were associated with CHF (hazard ratio [95% confidence interval], 1.17 [1.07‐1.27] and 1.65 [1.43‐1.92], respectively). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status. Conclusion: Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom cardiovascular disease risk is elevated and liver disease is common. (Hepatology 2017;66:1286‐1295)


    Date de mise en ligne : Mardi 01 août 2017
    Anna S. Lok, Fabien Zoulim, Geoffrey Dusheiko, Marc G. Ghany
    Hepatitis B cure: From discovery to regulatory approval
    The majority of persons currently treated for chronic hepatitis B require long‐term or lifelong therapy. New inhibitors of hepatitis B virus entry, replication, assembly, or secretion and immune modulatory therapies are in development. The introduction of these novel compounds for chronic hepatitis B necessitates a standardized appraisal of the efficacy and safety of these treatments and definitions of new or additional endpoints to inform clinical trials. To move the field forward and to expedite the pathway from discovery to regulatory approval, a workshop with key stakeholders was held in September 2016 to develop a consensus on treatment endpoints to guide the design of clinical trials aimed at hepatitis B cure. The consensus reached was that a complete sterilizing cure, i.e., viral eradication from the host, is unlikely to be feasible. Instead, a functional cure characterized by sustained loss of hepatitis B surface antigen with or without hepatitis B surface antibody seroconversion, which is associated with improved clinical outcomes, in a higher proportion of patients than is currently achieved with existing treatments is a feasible goal. Development of standardized assays for novel biomarkers toward better defining hepatitis B virus cure should occur in parallel with development of novel antiviral and immune modulatory therapies such that approval of new treatments can be linked to the approval of new diagnostic assays used to measure efficacy or to predict response. Combination of antiviral and immune modulatory therapies will likely be needed to achieve functional hepatitis B virus cure. Limited proof‐of‐concept monotherapy studies to evaluate safety and antiviral activity should be conducted prior to proceeding to combination therapies. The safety of any new curative therapies will be paramount given the excellent safety of currently approved nucleos(t)ide analogues. (Hepatology 2017).


    Date de mise en ligne : Lundi 04 septembre 2017
    Manisha Balwani, Bruce Wang, Karl E. Anderson, Joseph R. Bloomer, D. Montgomery Bissell, Herbert L. Bonkovsky, John D. Phillips, Robert J. Desnick,
    Acute hepatic porphyrias: Recommendations for evaluation and long‐term management
    The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic pathway. These disorders present clinically with acute neurovisceral symptoms which may be sporadic or recurrent and, when severe, can be life‐threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions. There are four major subgroups: symptomatic patients with sporadic attacks (<4 attacks/year) or recurrent acute attacks (≄4 attacks/year), asymptomatic high porphyrin precursor excretors, and asymptomatic latent patients without symptoms or porphyrin precursor elevations. Given their clinical heterogeneity and potential for significant morbidity with suboptimal management, comprehensive clinical guidelines for initial evaluation, follow‐up, and long‐term management are needed, particularly because no guidelines exist for monitoring disease progression or response to treatment. The Porphyrias Consortium of the National Institutes of Health's Rare Diseases Clinical Research Network, which consists of expert centers in the clinical management of these disorders, has formulated these recommendations. These recommendations are based on the literature, ongoing natural history studies, and extensive clinical experience. Initial assessments should include diagnostic confirmation by biochemical testing, subsequent genetic testing to determine the specific acute hepatic porphyria, and a complete medical history and physical examination. Newly diagnosed patients should be counseled about avoiding known precipitating factors. The frequency of follow‐up depends on the clinical subgroup, with close monitoring of patients with recurrent attacks who may require treatment modifications as well as those with clinical complications. Comprehensive care should include subspecialist referrals when needed. Annual assessments include biochemical testing and monitoring for long‐term complications. These guidelines provide a framework for monitoring patients with acute hepatic porphyrias to ensure optimal outcomes. (Hepatology 2017;66:1314‐1322)


    Date de mise en ligne : Mercredi 30 août 2017
    Tanja Cvitanović, Matthias C. Reichert, Miha Moơkon, Miha Mraz, Frank Lammert, Damjana Rozman
    Large‐scale computational models of liver metabolism: How far from the clinics?
    Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases. This knowledge can be obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modeling can reveal hidden principles of the system by classification of individual components, analyzing their interactions and simulating the effects that are difficult to investigate experimentally. Herein, we review the state‐of‐the‐art computational models that describe liver dynamics from metabolic, gene regulatory, and signal transduction perspectives. We focus especially on large‐scale liver models described either by genome scale metabolic networks or an object‐oriented approach. We also discuss the benefits and limitations of each modeling approach and their value for clinical applications in diagnosis, therapy, and prevention of liver diseases as well as precision medicine in hepatology. (Hepatology 2017;66:1323‐1334).


    Date de mise en ligne : Mercredi 30 août 2017
    Meghan E. Sise
    Kidney transplant recipients with hepatitis C virus experienced 100% sustained virologic response at 12 weeks when treated with sofosbuvir–ledipasvir
    1337


    Date de mise en ligne : Mercredi 30 août 2017
    David Q.‐H. Wang, Piero Portincasa, Patrick Tso
    Transintestinal cholesterol excretion: A secondary, nonbiliary pathway contributing to reverse cholesterol transport
    1340


    Date de mise en ligne : Samedi 26 août 2017
    Michele Merli, Marco Frigeni, Manuel Gotti, Paolo Grossi, Raffaele Bruno, Francesco Passamonti, Luca Arcaini
    Direct‐acting antivirals during or after immunochemotherapy in hepatitis C virus–positive diffuse large B‐cell lymphomas
    1343


    Date de mise en ligne : Samedi 26 août 2017
    Atsushi Ono, Nicolas Goossens, Richard S. Finn, Warren N. Schmidt, Swan N. Thung, Gene Y. Im, Yujin Hoshida,
    Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature
    1346


    Date de mise en ligne : Samedi 26 août 2017
    Frank Kuo, Jonathan Park, Alice Chen
    Coil‐assisted retrograde transvenous obliteration and partial splenic artery embolization for hepatic encephalopathy
    1350


    Date de mise en ligne : Samedi 26 août 2017
    Marie‐Annick Buendia, Carolina Armengol, Stefano Cairo
    Molecular classification of hepatoblastoma and prognostic value of the HB 16‐gene signature
    1352


    Date de mise en ligne : Samedi 26 août 2017
    Yi‐Hsiang Huang, Shou‐Dong Lee
    Is antibody to surface antigen associated with hepatitis B reactivation in patients with resolved hepatitis B?
    1353


    Date de mise en ligne : Samedi 26 août 2017
    Sonali Paul
    Reply
    1354


    Date de mise en ligne : Samedi 26 août 2017
    Benjamin H. Mullish, Julie A. K. McDonald, Mark R. Thursz, Julian R. Marchesi
    Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial
    1355


    Date de mise en ligne : Samedi 26 août 2017
    Jasmohan S. Bajaj, Zain Kassam, I. Jane Cox, Thomas Gurry, Roger Williams, Eric Alm, Binu John, Mark Smith, Simon D. Taylor‐Robinson, Patrick M. Gillevet
    Reply
    1356


    Date de mise en ligne : Lundi 04 septembre 2017
    Zhengtao Liu, Shuping Que, Adil Mardinoglu
    Rediscussion on linearity between fibrosis stages and mortality risk in nonalcoholic fatty liver disease patients
    1358


    Date de mise en ligne : Lundi 04 septembre 2017
    Saeid Safiri, Salman Khazaei, Kamyar Mansori, Erfan Ayubi
    Comments on “Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis”
    1359


    Date de mise en ligne : Mardi 19 septembre 2017
    Siddharth Singh, Rohit Loomba
    Reply
    1360


    Date de mise en ligne : Samedi 26 août 2017
    Julie Steen Pedersen, Nina Kimer, Jens H. Henriksen, Flemming Bendtsen, SĂžren MĂžller
    The royal free hospital cirrhosis glomerular filtration rate: Validation in a danish cohort
    1361


    Date de mise en ligne : Samedi 26 août 2017
    Maria Kalafateli, Emmanuel A. Tsochatzis
    Reply
    1362


    Date de mise en ligne : Samedi 26 août 2017
    Tilman Sauerbruch
    Continuation of nonselective beta‐blockers for patients with liver cirrhosis and hemodynamic nonresponse?
    1363


    Date de mise en ligne : Samedi 26 août 2017
    CĂ ndid Villanueva, Isabel Graupera, Edilmar Alvarado
    Reply
    1364


    Date de mise en ligne : Lundi 04 septembre 2017
    Correction
    Correction
    1365


    Date de mise en ligne : Mercredi 23 août 2017
    Retraction statement: Equilibrative nucleoside transporter (ENT)‐1‐dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion
    Retraction statement: Equilibrative nucleoside transporter (ENT)‐1‐dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion
    1366


    Date de mise en ligne : Mardi 19 septembre 2017
    Notices
    Notices
    n/a


    Date de mise en ligne : Mardi 19 septembre 2017
    Instructions to authors and Information for readers
    Instructions to authors and Information for readers
    n/a