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Les derniers abstracts de la revue Hepatology :


    Date de mise en ligne : Lundi 24 juillet 2017
    Michael Ronan Lucey
    Redefining successful treatment of severe alcoholic hepatitis
    n/a


    Date de mise en ligne : Lundi 24 juillet 2017
    Salvatore Petta, Luca Valenti, Antonino Tuttolomondo, Paola Dongiovanni, Rosaria Maria Pipitone, Calogero CammĂ , Daniela Cabibi, Vito Di Marco, Anna Ludovica Fracanzani, Sara Badiali, Valerio Nobili, Silvia Fargion, Stefania Grimaudo, Antonio CraxĂŹ
    IFNL4 rs368234815 TT>ήG Variant is Associated with Liver Damage in Patients with Non‐alcoholic Fatty Liver Disease
    Background and Aims: The IFNL3/4 locus influencing innate immunity regulation has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in NAFLD. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of NASH. To clarify the mechanism, we also evaluated the impact on interferon‐stimulated gene (ISG) hepatic expression in a subset of patients. Methods: We considered 946 consecutive Italian individuals at risk of NASH with liver histology evaluated according to Kleiner. The rs368234815 TT>ήG, rs12979860 C>T, and PNPLA3 rs738409 C>G polymorphisms were genotyped and ISG hepatic expression (n=16) tested by TaqMan assays. Results: We found that the rs368234815 TT allele was independently associated with severe F3‐F4 fibrosis (OR 1.53, 95% CI 1.15‐2.31; P=0.005), as well as with severe (grade 2‐3) lobular necroinflammation (OR 1.47, 95% CI 1.14‐1.88; P=0.002). The impact of rs368234815 on liver damage was generally more marked in non‐obese individuals, where association with severe fibrosis, necroinflammation and also NASH was observed (p<0.05). ISG were hypo‐expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (p<0.05). Similar results were observed when considering rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2=0.87). Conclusions: The IFNL4 genotype is associated with severity of fibrosis in NAFLD patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 24 juillet 2017
    Loreta A. Kondili, Federica Romano, Francesca Romana Rolli, Matteo Ruggeri, Stefano Rosato, Maurizia Rossana Brunetto, Anna Linda Zignego, Alessia Ciancio, Alfredo Di Leo, Giovanni Raimondo, Carlo Ferrari, Gloria Taliani, Guglielmo Borgia, Teresa Antonia Santantonio, Pierluigi Blanc, Giovanni Battista Gaeta, Antonio Gasbarrini, Luchino Chessa, Elke Maria Erne, Erica Villa, Donatella Ieluzzi, Francesco Paolo Russo, Pietro Andreone, Maria Vinci, Carmine Coppola, Liliana Chemello, Salvatore Madonia, Gabriella Verucchi, Marcello Persico, Massimo Zuin, Massimo Puoti, Alfredo Alberti, Gerardo Nardone, Marco Massari, Giuseppe Montalto, Giuseppe Foti, Maria Grazia Rumi, Maria Giovanna Quaranta, Americo Cicchetti, Antonio CraxĂŹ, Stefano Vella,
    Modelling cost‐effectiveness and health gains of a “universal” vs. “prioritized” HCV treatment policy in a real‐life cohort
    We evaluated the cost‐effectiveness of two alternative DAA treatment policies in a real‐life cohort of HCV‐infected patients: Policy 1 ‐ “universal”: treat all patients, regardless of the fibrosis stage; Policy 2 ‐ treat only “prioritized” patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and healthcare system perspective, was applied to the PITER cohort (representative of Italian HCV‐infected patients in care). Specifically, 8,125 patients naïve to DAA treatment, without clinical, sociodemographic or insurance restrictions was used to evaluate the policies' cost‐effectiveness. The patients' age, fibrosis stage, assumed DAA treatment cost of €15,000/patient and the Italian liver disease costs were used to evaluate Quality‐Adjusted Life‐Years (QALY) This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 24 juillet 2017
    CĂ ndid Villanueva, Isabel Graupera, Edilmar Alvarado
    Differentiating stages to stratify risk: This is the question
    n/a


    Date de mise en ligne : Lundi 24 juillet 2017
    Romina Fiorotto, Mariangela Amenduni, Valeria Mariotti, Luca Fabris, Carlo Spirli, Mario Strazzabosco
    Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves CFTR correctors efficacy
    CFTR, the channel mutated in cystic fibrosis (CF), is expressed by the biliary epithelium (i.e cholangiocytes) of the liver. Progressive clinical liver disease (CFLD) occurs in about 10% of CF patients and represents the third leading cause of death. Impaired secretion and inflammation contribute to CFLD, however the lack of human‐derived experimental models has hampered the understanding of CFLD pathophysiology and the search for a cure. We have investigated the cellular mechanisms altered in human CF cholangiocytes using induced pluripotent stem cells (iPSC) derived from healthy controls and a ΔF508 CFTR patient. We have devised a novel protocol for the differentiation of human iPSC into polarized monolayers of cholangiocytes. Our results show that iPSC‐cholangiocytes reproduced the polarity and the secretory function of the biliary epithelium. PKA/c‐AMP mediated fluid secretion was impaired in ΔF508 cholangiocytes and negligibly improved by VX‐770 and VX‐809, two small molecule drugs used to correct and potentiate ΔF508 CFTR. Moreover, ΔF508 cholangiocytes showed increased phosphorylation of Src kinase and TLR4 and pro‐inflammatory changes including increased NF‐kB activation, secretion of pro‐inflammatory chemokines (i.e MCP‐1 and IL8), as well as alterations of the F‐actin cytoskeleton. Treatment with Src inhibitor (PP2) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of Src along with administration of VX‐770 and VX‐809 successfully restored fluid secretion to normal levels. Conclusions: Our findings have strong translational potential and indicate that targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic ΔF508 defect in CF liver patients. These studies also demonstrate the promise of applying iPSC technology in modeling human cholangiopathies. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 24 juillet 2017
    Stavra A. Xanthakos, Andrew T. Trout, Jonathan R. Dillman
    Magnetic resonance elastography assessment of fibrosis in children with NAFLD: promising but not perfect
    n/a


    Date de mise en ligne : Samedi 22 juillet 2017
    Puneeta Tandon, Karen Madsen, Dina Kao
    Fecal microbiota transplantation for hepatic encephalopathy ‐ ready for prime time?
    n/a


    Date de mise en ligne : Samedi 22 juillet 2017
    Tilman Sauerbruch
    Continuation of non‐selective beta‐blockers for patients with liver cirrhosis and hemodynamic non‐response?
    n/a


    Date de mise en ligne : Vendredi 21 juillet 2017
    Hui Li, Xiaoqiang Li, Shuang Liu, Lei Guo, Bo Zhang, Jubo Zhang, Qinghai Ye
    PD‐1 Checkpoint Blockade in Combination with an mTOR Inhibitor Restrains Hepatocellular Carcinoma Growth Induced by Hepatoma Cell‐Intrinsic PD‐1
    Inhibitors of PD‐1 administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti PD‐1 immunotherapy. Here, we show that PD‐1 expression in hepatocellular carcinoma (HCC) promotes tumor growth independently of adaptive immunity. Knockdown of PD‐1 suppress tumor growth, whereas PD‐1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD‐1 binds the downstream mTOR effectors eukaryotic initiation factor 4E (eIF4E) and ribosomal protein S6 (S6), thus promoting their phosphorylation. Moreover, combining mTOR inhibition with anti‐PD‐1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. Therefore, targeting mTOR pathways in combination with PD‐1 may result in increased antitumor efficacy in cancer patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 21 juillet 2017
    Lixin Zhu, Robert D. Baker, Ruixin Zhu, Susan S. Baker
    Sequencing the gut metagenome as a non‐invasive diagnosis for advanced nonalcoholic steatohepatitis
    n/a


    Date de mise en ligne : Jeudi 20 juillet 2017
    Zhengtao Liu, Shuping Que, Adil Mardinoglu
    Re‐discussion on linearity between fibrosis stages and mortality risk in non‐alcoholic fatty liver disease patients
    n/a


    Date de mise en ligne : Jeudi 20 juillet 2017
    Maria Kalafateli, Emmanuel A. Tsochatzis
    Reply to “The Royal Free Hospital Cirrhosis Glomerular Filtration Rate: Validation in a Danish Cohort.”
    n/a


    Date de mise en ligne : Jeudi 20 juillet 2017
    Brenda S. Hijmans, Andreas Boss, Theo H. van Dijk, Maud Soty, Henk Wolters, Elodie Mutel, Albert K. Groen, Terry G.J. Derks, Gilles Mithieux, Arend Heerschap, Dirk‐Jan Reijngoud, Fabienne Rajas, Maaike H. Oosterveer
    Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia
    It is a longstanding enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production (EGP) despite the loss of glucose‐6‐phosphatase (G6Pase) activity. Insight into the source of residual EGP is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated G6Pase‐independent EGP in hepatocytes isolated from a liver‐specific GSD Ia mouse model (L‐G6pc‐/‐ mice), and performed real‐time analysis of hepatic glucose fluxes and glycogen metabolism in L‐G6pc‐/‐ mice using state‐of‐the‐art stable isotope methodologies. Here we show that G6pc‐deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase (GCK) flux was decreased by 95% in L‐G6pc‐/‐ mice. It also showed increased glycogen phosphorylase flux in L‐G6pc‐/‐ mice, which is coupled to the release of free glucose via glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α‐glucosidases, were unaltered in L‐G6pc‐/‐ mice, pharmacological inhibition of α‐glucosidase activity almost completely abolished residual glucose production by G6pc‐deficient hepatocytes. Conclusion. Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α‐glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L‐G6pc‐/‐ mice furthermore limits the phosphorylation of free glucose synthesized by G6pc‐deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc‐deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 20 juillet 2017
    Siddharth Singh, Rohit Loomba
    Response to Letters to the Editor
    n/a


    Date de mise en ligne : Jeudi 20 juillet 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
    n/a


    Date de mise en ligne : Jeudi 20 juillet 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
    n/a


    Date de mise en ligne : Mardi 18 juillet 2017
    Ying Fu, Shana Silverstein, Justine N. McCutcheon, Marcin Dyba, Raghu G. Nath, Monika Aggarwal, Heidi Coia, Angela Bai, Jishen Pan, Jiji Jiang, Bhaskar Kallakury, Hongkun Wang, Yu‐Wen Zhang, Giuseppe Giaccone, Aiwu Ruth He, Fung‐Lung Chung
    An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice
    Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related deaths worldwide, mainly because of its poor prognosis. A valid mechanism‐based prognostic biomarker is urgently needed. γ‐hydroxy‐1,N2‐propanodeoxyguanosine (γ‐OHPdG) is an endogenously formed mutagenic DNA adduct derived from lipid peroxidation (LPO). We examined the relationship of γ‐OHPdG with hepatocarcinogenesis in two animal models and its potential role as a prognostic biomarker for recurrence in HCC patients. Bioassays were conducted in the Xeroderma pigmentosum group A knockout mice (Xpa‐/‐), and the diethylnitrosamine (DEN)‐injected mice, both prone to HCC development. γ‐OHPdG levels in the livers of these animals were determined. The effects of antioxidant treatments on γ‐OHPdG and hepatocarcinogenesis were examined. Using two independent sets of HCC specimens from patients, we examined the relationship between γ‐OHPdG and survival or recurrence‐free survival. γ‐OHPdG levels in liver DNA showed an age‐dependent increase and consistently correlated with HCC development in all three animal models. Theaphenon E treatment significantly decreased γ‐OHPdG levels in the liver DNA of Xpa‐/‐ mice, and remarkably reduced HCC incidence in these mice to 14% from 100% in the controls. It also effectively inhibited HCC development in the DEN‐injected mice. Using clinical samples from two groups of patients, our study revealed that higher levels of γ‐OHPdG are strongly associated with low survival (p < 0.0001) and low recurrence‐free survival (p = 0.007), respectively. Conclusion: These results support γ‐OHPdG as a mechanism‐based biologically relevant biomarker for predicting the risk of HCC and its recurrence. Genetic and epigenetic alterations in oncogenes and tumor‐suppressor genes are crucial for carcinogenesis (1, 2). Somatic mutations may arise from DNA lesions that are not repaired. During lifetime, human genome will host a wide‐spectrum of mutagenic DNA lesions, induced by chemical carcinogens, viruses, and reactive oxygen and nitrogen species. This is believed to be the case for human liver as it is a major detoxifying organ that is exposed to a large number of risk factors (3‐5). This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 18 juillet 2017
    Cun Wang, René Bernards
    In vivo veritas: Finding novel genes involved in liver cancer through in vivo genetic screens
    n/a


    Date de mise en ligne : Mardi 18 juillet 2017
    Udayan Apte, Neil Kaplowitz
    Heparan sulfate promotes recovery from acute liver injury: Inhibition of progressive cell death or enhanced regeneration?
    n/a


    Date de mise en ligne : Lundi 17 juillet 2017
    Shimin An, Ling‐Ping Zhao, Li‐Jun Shen, Siyuan Wang, Kuo Zhang, Yu Qi, Jilin Zheng, Xiao‐Jing Zhang, Xue‐Yong Zhu, Rong Bao, Ling Yang, Yue‐Xin Lu, Zhi‐Gang She, Yi‐Da Tang
    USP18 protects against hepatic steatosis and insulin resistance via its DUB activity
    Non‐alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we first report that ubiquitin‐specific protease 18 (USP18), a member of the deubiquitinating (DUB) enzyme family, plays regulatory roles in NAFLD progression. The expression of USP18 was down‐regulated in the livers of non‐alcoholic steatohepatitis (NASH) patients and high‐fat diet (HFD) induced or genetically obese mice. When challenged with HFD, hepatocyte‐specific USP18 transgenic (HTG) mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression (HKO) showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18‐HTG mice and promoted in USP18‐HKO mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating TGFÎČ‐activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream JNK and NF‐ÎșB signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD‐fed USP18‐HKO mice administered with TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD‐fed mice injected with active‐site mutant USP18 failed to inhibit hepatic steatosis. Conclusion: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance and the inflammatory response. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Yue Hu, Dong‐Ju Shin, Hui Pan, Zhiqiang Lin, Jonathan M. Dreyfuss, Fernando D. Camargo, Ji Miao, Sudha B. Biddinger
    YAP suppresses gluconeogenic gene expression via PGC1α
    Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step towards understanding development, regeneration and cancer. The transcriptional regulator Yes‐associated protein 1 (YAP) is a key regulator of liver size, development and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator‐activated receptor gamma coactivator 1 (PGC1α). YAP inhibits the ability of PGC1α to bind to and activate transcription from the promoters of its gluconeogenic targets and the effects of YAP are blunted upon knockdown of PGC1α. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size. YAP therefore appears to reprogram cellular metabolism, diverting substrates away from the energy consuming process of gluconeogenesis, and towards the anabolic process of growth. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Heng Wu, Junyan Tao, Xiaolei Li, Tianpeng Zhang, Lei Zhao, Yao Wang, Lei Zhang, Jun Xiong, Zhi Zeng, Na Zhan, Clifford J. Steer, Li Che, Mingjie Dong, Xiaomei Wang, Junqi Niu, Zhuoyu Li, Guiqing Yan, Xin Chen, Guisheng Song
    MicroRNA‐206 Prevents the Pathogenesis of Hepatocellular Carcinoma Via Modulating Expression of cMet and Cdk6
    Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here we report that microRNA‐206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell cycle progression and cMet signaling pathway. MicroRNA‐206 was under‐expressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto‐oncogene), CCND1, and CDK6 as functional targets of microRNA‐206. By inhibiting expression of cMET, CCND1 and CDK6, microRNA‐206 delayed cell cycle progression, induced apoptosis and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA‐206 completely prevented HCC development in both cMyc and AKT/Ras HCC mice, while 100% of control mice died from lethal tumor burdens. Conversely, re‐introduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA‐206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA‐206 on the development of HCC. MicroRNA‐206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. In summary, this study defines a potentially critical role of microRNA‐206 in preventing the growth of HCC, and suggests its use as a potential therapeutic strategy for this malignancy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Benjamin H Mullish, Julie A K McDonald, Mark R Thursz, Julian R Marchesi
    Correspondence: Fecal Microbiota Transplant from a Rational Stool Donor Improves Hepatic Encephalopathy: A Randomized Clinical Trial
    n/a


    Date de mise en ligne : Lundi 17 juillet 2017
    Xiao‐Feng Li, Cheng Chen, Dai‐Min Xiang, Le Qu, Wen Sun, Xin‐Yuan Lu, Teng‐Fei Zhou, Shu‐Zhen Chen, Bei‐Fang Ning, Zhuo Cheng, Ming‐Yang Xia, Wei‐Feng Shen, Wen Yang, Wen Wen, Terence Kin Wah Lee, Wen‐Ming Cong, Hong‐Yang Wang, Jin Ding
    Chronic Inflammation‐elicited Liver Progenitor Cell Conversion to Liver Cancer Stem Cell with Clinical Significance
    The substantial heterogeneity and hierarchical organization in liver cancer supports the theory of liver cancer stem cell (LCSC). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in NOD/SCID mice, suggesting the malignant transformation of LPC toward LCSC. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed CK19+OV6+ tumor occurrence. Conversely, LPCs co‐cultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage‐secreted TNF‐α triggered chromosomal instability in LPCs via the deregulation of ubiquitin D and Checkpoint kinase 2, and enhanced the self‐renewal of LPCs through TNFR1/Src/STAT3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that CK19+OV6+ liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. In conclusion, our results not only clarified the cellular and molecular mechanism underlying the inflammation‐mediated LCSC generation, but also provided a novel molecular classification for the individualized treatment of liver cancer. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 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 to HEP‐17‐1121
    n/a


    Date de mise en ligne : Lundi 17 juillet 2017
    Naga Chalasani, Zobair Younossi, Joel E. Lavine, Michael Charlton, Kenneth Cusi, Mary Rinella, Stephen A. Harrison, Elizabeth M. Brunt, Arun J. Sanyal
    The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases
    This guidance provides a data‐supported approach to the diagnostic, therapeutic, and preventive aspects of NAFLD care. A “Guidance” document is different from a “Guideline.” Guidelines are developed by a multidisciplinary panel of experts and rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations, Assessment Development, and Evaluation (GRADE) system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Michael D. Thompson, Akshata Moghe, Pamela Cornuet, Rebecca Marino, Jianmin Tian, Pengcheng Wang, Xiaochao Ma, Marc Abrams, Joseph Locker, Satdarshan P. S. Monga, Kari Nejak‐Bowen
    ÎČ‐catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis
    Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation (ADP), and fibrosis. The Wnt/ÎČ‐catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver‐specific ÎČ‐catenin knockout (KO) mice and wild‐type (WT) littermates were subjected to cholestatic injury via bile duct ligation or short‐term exposure to 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) diet. Intriguingly, KO exhibit a dramatic protection from liver injury, fibrosis, and ADP, which coincided with significantly decreased total hepatic bile acids (BA). This led to the discovery of a novel role for ÎČ‐catenin in regulating BA synthesis and transport through regulation of farnesoid X receptor (FXR) activation. We show that ÎČ‐catenin functions as both an inhibitor of nuclear translocation and as a nuclear co‐repressor through formation of a physical complex with FXR. Loss of ÎČ‐catenin expedited FXR nuclear localization and FXR/RXRα association, culminating in small heterodimer protein (SHP) promoter occupancy and activation in response to BA or FXR agonist. Conversely, accumulation of ÎČ‐catenin sequesters FXR, thus inhibiting its activation. Finally, exogenous suppression of ÎČ‐catenin expression during cholestatic injury reduces ÎČ‐catenin/FXR complex, activates FXR to decrease total BA and alleviates hepatic injury. Conclusion: We have identified a novel FXR/ÎČ‐catenin interaction whose modulation via ÎČ‐catenin suppression promotes FXR activation and decreases hepatic BA, which may provide unique therapeutic opportunities in cholestatic liver diseases. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Alba Ardevol, Gemma Ibañez‐Sanz, Joaquim Profitos, Carles Aracil, Josep M Castellvi, Edilmar Alvarado, Alba Cachero, Diana Horta, Josep Miñana, BĂĄrbara Gomez‐Pastrana, Oana Pavel, Eva Dueñas, Meritxell Casas, Montserrat Planella, Jose Castellote J, Candid Villanueva
    Survival of patients with cirrhosis and acute peptic ulcer bleeding compared with variceal bleeding using current first‐line therapies
    The presence of cirrhosis increases the mortality of patients with peptic ulcer bleeding (PUB). Both acute variceal bleeding (AVB) and PUB are associated with substantial mortality in cirrhosis. This multicenter cohort study was performed to assess whether the mortality of cirrhotic patients with PUB is different from that of those with AVB. Patients with cirrhosis and acute gastrointestinal bleeding were consecutively included and treated with somatostatin and PPI infusion from admission and with antibiotic prophylaxis. Emergency endoscopy with endoscopic therapy was performed within the first 6‐hours. 646 patients with AVB and 144 with PUB were included. There were baseline differences between groups, such as use of gastro‐erosive drugs or ÎČ‐blockers. Child‐Pugh and MELD scores were similar. Further bleeding was more frequent in AVB‐group than in those PUB‐group (18% vs 10%; OR= 0.50, 95%CI= 0.29‐0.88). However, mortality risk at 45‐day was similar in both groups (19% in AVB‐group vs 17% in PUB‐group; OR= 0.85, 95% CI= 0.55‐1.33, P= 0.48). Different parameters, such as Child‐Pugh score, AKI, ACLF or presence of shock or bacterial infection, but not the cause of bleeding, were related to the risk of death. Only 2% of PUB‐group vs 3% of AVB‐group died with uncontrolled bleeding (P= 0.39), while the majority of patients in either group died from liver failure or due to other comorbidities. Conclusions: Using current first‐line‐therapy, patients with cirrhosis and acute peptic ulcer bleeding have a similar survival than those with variceal bleeding. The risk of further bleeding is higher in patients with variceal hemorrhage. However, few patients in both groups died from uncontrolled bleeding, while the cause of death was usually related to liver failure or co‐morbidities. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Marcello Persico, Andrea Aglitti, Rosa Caruso, Amalia De Renzo, Carmine Selleri, Catello Califano, Ludovico Abenavoli, Alessandro Federico, Mario Masarone
    Efficacy and safety of new direct antiviral agents in HCV infected patients with Diffuse Large B Cell Non‐Hodgkin Lymphoma
    Introduction: The association of HCV with Non‐Hodgkin Lymphoma (NHL) has been demonstrated all over the world. The new interferon‐free, direct antiviral agents (DAA), showed high efficacy and safety, and preliminary data seem to confirm their activity on low‐grade NHL. The question arises as whether or not ‐and how‐ to treat the HCV positive patients suffering from diffuse large B cell lymphomas(DLBCL). Aim of this observational study was to evaluate whether the DAAs antiviral treatment of DLBCL/HCV‐infected patients in concomitance with chemotherapy is a safe and effective option. Methods:20 (13 males and 7 females), HCV1b positive subjects, undergoing chemotherapy for DLBCL, were enrolled between June 2015 and December 2015. After informed consent, all the patients underwent to antiviral therapy with sofosbuvir/ledipasvir and chemotherapy (14 R‐CHOP and 6 CHOP) for DLBCL. Complete hematological (REAL,Ann‐Harbor and IPI scores) and hepatological (viral markers, liver stiffness and biochemical parameters) evaluations were made. A historical retrospective cohort of 101 DLBCL/HCV positive patients not undergone to antiviral treatment was enrolled for comparison. Results: DAA‐treated and untreated patients were similar for sex distribution, IPI score and NHL stage, and differed for age (older in treated), chemotherapy and use of antiviral therapy. Overall‐survival (OS) and disease‐free‐survival (DFS) were evaluated among a 52 weeks of follow‐up. No statistical difference was found in OS after 52 weeks (p:0.122), whereas a statistically significant higher DFS was achieved in treated patients(p:0.036). At the multivariate analysis, only IPI score and DAA were independently correlated with a better DFS. No differences in adverse events were reported. Conclusions: DAA‐treatment in concomitance with chemotherapy showed to be safe and effective in influencing the remission of aggressive lymphomas in HCV patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Monica A. Konerman, Mary Thomson, Kristen Gray, Meghan Moore, Hetal Choxi, Elizabeth Seif, Anna SF 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 (CHC), deficiencies in diagnosis and access preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record (EHR) based prompt on HCV screening rates in baby boomers in primary care, and access to specialty care and treatment among those newly diagnosed. We implemented an EHR based “Best Practice Advisory” (BPA) that prompted primary care providers (PCPs) to perform HCV screening for patients seen in primary care clinic: 1) born between 1945‐1965; 2) lacked a prior diagnosis of HCV infection; and 3) 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 and post BPA screening rates were compared and care of newly diagnosed patients 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 PCP 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 SVR thus far. Conclusions: Implementation of an EHR 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 work‐flow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into EHR systems to increase HCV diagnosis and linkage to care. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 17 juillet 2017
    Hugo R. Rosen, Marc Ghany, Raymond Chung, Anna Lok
    NAM 2017 Report: A National Plan To Eliminate Hepatitis B and C In the United States By 2030 And The AASLD's Response
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    Date de mise en ligne : Dimanche 16 juillet 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
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    Date de mise en ligne : Jeudi 13 juillet 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
    A Point‐based Prediction Model for Cardiovascular Risk in Orthotopic Liver Transplantation: The CAR‐OLT Score
    Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk assessment tool that allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point‐based prediction model (risk score) for CVD complications after OLT, the CAR‐OLT risk score, among a cohort of 1024 consecutive patients aged 18‐75 years who underwent first OLT in a tertiary‐care teaching hospital (2002‐2011). The main outcome measures were major 1‐year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias‐corrected 95% confidence intervals for the regression coefficients of the final model.Among 1024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included pre‐operative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the CAR‐OLT point‐based score (C statistic=0.78, bias‐corrected C statistic=0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer‐Lemeshow p=0.33). Conclusion: The point‐based CAR‐OLT risk score can identify patients at risk for CVD complications after OLT surgery (available at: www.carolt.us). This score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 11 juillet 2017
    Puneet Puri, Kalyani Daita, Andrew Joyce, Faridoddin Mirshahi, Prasanna K. Santhekadur, Sophie Cazanave, Velimir A Luketic, Mohammad S. Siddiqui, Sherry Boyett, Hae‐Ki Min, Divya P. Kumar, Rohit Kohli, Huiping Zhou, Phillip B. Hylemon, Melissa J Contos, Michael Idowu, Arun J. Sanyal
    The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids
    The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% NASH patients. Bile acids (BA) are linked to pathogenesis and therapy of NASH. We (a) characterized plasma BA profile in biopsy proven NAFL and NASH, and compared to controls, and (b) related plasma BA profile to liver histologic features, disease activity and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Eighty six patients (24 controls, 25 NAFL and 37 NASH, mean age 51.8 years and BMI 31.9 kg/m2), 66% were women. Increased total primary BAs and decreased secondary BAs (both p<0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH vs. NAFL (p=0.047) and vs. controls (p<0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (p=0.04), cholate (p=0.0004), and total primary BAs (p<0.0001). Total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (p=0.005) and with diabetes (p=0.02). Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD Activity Score. A higher ratio of total secondary to primary BA decreased (OR 0.57, p=0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≄2) (p=0.007). Conclusions: NAFLD is associated with significantly altered circulating bile acids composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH. These observations provide the foundation for future hypothesis‐driven studies of specific effects of bile acids on specific aspects of NASH. (Current count = 275) This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 11 juillet 2017
    Salvador Augustin, MĂČnica Pons, James B. Maurice, Christophe Bureau, Horia Stefanescu, Michel Ney, HĂ©lĂšne Blasco, Bogdan Procopet, Emmanuel Tsochatzis, Rachel H. Westbrook, Jaime Bosch, Annalisa Berzigotti, Juan G. Abraldes, Joan GenescĂ 
    Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease
    Patients with compensated advanced chronic liver disease (cACLD) can safely avoid screening endoscopy with a platelet count >150x109 cells/L and liver stiffness measurement (LSM) <20 kPa (Baveno VI criteria). However, the total number of avoided endoscopies using this rule is relatively low. We aimed at expanding the Baveno VI criteria and validating them in additional cohorts. Patients from the Anticipate cohort (499 patients with cACLD of different etiologies) were used to study the performance of different thresholds of platelets and LSM for the identification of patients at very low risk (<5%) of having varices needing treatment (VNT). The new criteria (Expanded‐Baveno VI) were validated in two additional cohorts from London (309 patients) and Barcelona (117 patients). The performance of the new criteria by etiology of cACLD was also assessed. The best new expanded classification rule was platelet count >110 x109 cells/L and LSM <25 kPa. This was validated in the two additional cohorts. Overall, the Expanded‐Baveno VI criteria would potentially spare 367 (40%) of endoscopies (21% with Baveno‐VI criteria) with a risk of missing VNT of 1.6% (95% CI: 0.7‐3.5%) in patients within the criteria and 0.6% (95% CI: 0.3‐1.4%) in the overall population of 925 patients evaluated. The Expanded‐Baveno VI criteria performed well in cACLD patients with hepatitis C virus, alcoholic and nonalcoholic steatohepatitis. Conclusion: The new Expanded‐Baveno VI criteria spare more endoscopies than the original criteria with a minimal risk of missing VNT in most of the main etiologies of cACLD. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 07 juillet 2017
    George G. Schweitzer, Samuel Klein
    Exercise and NAFLD: Is it worth the effort?
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    Date de mise en ligne : Vendredi 07 juillet 2017
    Yi‐Hsiang Huang, Shou‐Dong Lee
    Is antibody to surface antigen associated with hepatitis B reactivation in patients with resolved hepatitis B?
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    Date de mise en ligne : Vendredi 07 juillet 2017
    David Wyles, Heiner Wedemeyer, Ziv Ben‐Ari, Edward J. Gane, Jesper Bach Hansen, Ira M. Jacobson, Alex L. Laursen, Annie Luetkemeyer, Ronald Nahass, Stephen Pianko, Stefan Zeuzem, Patricia Jumes, Hsueh‐Cheng Huang, Joan Butterton, Michael Robertson, Janice Wahl, Eliav Barr, Hee‐Koung Joeng, Elizabeth Martin, Lawrence Serfaty,
    Grazoprevir, Ruzasvir, and Uprifosbuvir for HCV After NS5A Treatment Failure
    People with hepatitis C virus (HCV) infection who have failed treatment with an all‐oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor‐containing regimen. C‐SURGE (PN‐3682‐021) and C‐CREST Part C (PN‐3682‐011 and ‐012) were open‐label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all‐oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was undetectable HCV RNA (<15 IU/mL) 12 weeks after treatment completion (SVR12). In C‐SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24‐week no ribavirin arm and the 16‐week plus ribavirin arm (lost to follow‐up, n = 1), respectively. In C‐CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance‐associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor–containing therapy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 07 juillet 2017
    Sonali Paul
    Reply
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    Date de mise en ligne : Jeudi 06 juillet 2017
    Li Yang, Wei‐Hua Wang, Wei‐Lin Qiu, Zhen Guo, Erfei Bi, Cheng‐Ran Xu
    A single‐cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation
    How the bi‐potential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single‐cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from E10.5 to E17.5 mouse embryos, we found that hepatoblast‐to‐hepatocyte differentiation occurred gradually followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, the proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine the single‐cell and bulk‐cell analyses to define the precise timing of the hepatoblast‐to‐hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast‐to‐cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single‐cell analysis, we also discovered that the protein kinase C (PKC)/mitogen‐activated protein kinase (MAPK) signaling pathway promoted cholangiocyte maturation. Conclusions: Our studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate towards specific hepatic cell fates in vitro. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 06 juillet 2017
    Ammar Sarwar, Lujia Zhou, Victor Novack, Elliot B. Tapper, Michael Curry, Raza Malik, Muneeb Ahmed
    Hospital volume and mortality after trans‐jugular intrahepatic portosystemic shunt creation in the United States
    The link between higher procedure volume and better outcomes for surgical procedures is well established. We aimed to determine if procedure volume affected inpatient mortality in patients undergoing transjugular intra‐hepatic portosystemic shunt (TIPS). An epidemiological analysis of an all‐payer database recording hospitalizations during 2013 in the United States (Nationwide Readmissions Database) was performed. All patients' ≄18 years old undergoing TIPS during a hospital admission (n=5529) without concurrent or prior liver transplantation were selected. All‐cause inpatient mortality was assessed. Risk‐adjusted mortality was assessed for hospitals categorized into quintiles based on annual TIPS volume; very low (1‐4/year), low (5‐9/year), medium (10‐19/year), high (20‐29/year), and very high (≄30/year). TIPS were placed in 5529 patients (57±10.9 years; 37.5% female). Mortality decreased with rising annual TIPS volume (13% for very low to 6% for very high volume hospitals; p<0.01). Elective admissions were more common in hospitals with higher annual TIPS volume (20.3% for very low to 30.8% for very high; p<0.01). On multivariate analysis, compared to hospitals performing ≄30 TIPS per year, only hospitals performing 1‐4/year (aOR: 1.9, 95%CI:1.21‐3.01; p=0.01), 5‐9/year (aOR: 2.0, 95%CI:1.25‐3.17; p<0.01), and 10‐19/year (aOR: 1.9, 95%CI:1.17‐3.00; p=0.01) had higher inpatient mortality (20‐29/year [aOR: 1.4, 95%CI:0.84‐2.84; p=0.19]). The absolute difference between risk‐adjusted mortality rate for very low volume and very high volume hospitals was 6.1% (13.9% vs. 7.8%). TIPS volume of ≀20 TIPS/year, variceal bleeding, and nosocomial infections were independent risk factors for inpatient mortality in patients with both elective and emergent admissions. Conclusions: The risk of inpatient mortality is lower in hospitals performing ≄20 TIPS per year. Future research exploring preventable factors for higher mortality and benefits of patient transfer to higher volume centers is warranted. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 06 juillet 2017
    Changwei Dou, Xin Zheng, Qingguang Liu, Kangsheng Tu
    Whether the regulatory effect of PCAF and SIRT7 on PGK1 acetylation is a universal mechanism underlying HCC progression?
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    Date de mise en ligne : Jeudi 06 juillet 2017
    Angels Escorsell
    REPLY TO HEP‐17‐0545
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    Date de mise en ligne : Lundi 03 juillet 2017
    Douglas A Simonetto, Patrick S. Kamath, Vijay H. Shah
    Alcoholic Hepatitis: Continued drinking and the mourning after
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    Date de mise en ligne : Lundi 03 juillet 2017
    Anna Pellat, Javier Vaquero, Laura Fouassier
    Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology
    The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions including differentiation, proliferation, survival and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non‐malignant cholangiopathies is far from completed. Current acquaintance suggests a role for EGFR in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently evidenced in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti‐ErbB therapies were only efficient in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 30 juin 2017
    Xiaoming Cheng, Yuchen Xia, Elisavet Serti, Peter Daniel Block, Michelle Chung, Kazuaki Chayama, Barbara Rehermann, T. Jake Liang
    Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages
    Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with the hepatocytes or other cells in the liver remains controversial. To address this question, we utilized various cell culture models and humanized Alb‐uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV infected cells with known inducers of IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with the muted innate immune recognition of HBV. Upon exposure to high‐level HBV, macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by nor actively interferes with the intrinsic innate immunity of the infected hepatocytes. Macrophages are capable of sensing HBV but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 30 juin 2017
    Oyekoya T Ayonrinde, Leon A Adams, Trevor A Mori, Lawrence J Beilin, Nicholas de Klerk, Craig E Pennell, Scott White, John K Olynyk
    Gender differences between parental pregnancy characteristics and nonalcoholic fatty liver disease in adolescents
    Nonalcoholic fatty liver disease (NAFLD) is a complex chronic liver disorder. Examination of parental pregnancy‐related characteristics may provide insights into the origins of risk of NAFLD in offspring. We examined relationships between parental pregnancy‐related characteristics and NAFLD in 1170 adolescent offspring aged 17‐years participating in the Western Australian Pregnancy (Raine) Cohort Study. Fatty liver was diagnosed using liver ultrasound. NAFLD was diagnosed in 15.2% of the adolescents at age 17 years. In univariate analysis, maternal factors associated with NAFLD in female offspring were younger maternal age (p=0.02), higher maternal pre‐pregnancy BMI (p<0.001), higher maternal weight gain by 18 weeks gestation (p<0.001) and maternal smoking during pregnancy (p=0.04). Paternal age or BMI were not associated with NAFLD in female offspring. In contrast, higher paternal BMI (p<0.001), maternal pre‐pregnancy BMI (p<0.001) and lower family socio‐economic status at time of birth (p=0.001), but not parental age nor maternal gestational weight gain, were associated with NAFLD in male offspring. Using multivariate logistic regression, factors independently associated with NAFLD after adjusting for obesity in adolescent females included maternal obesity (OR 3.46, 95% CI 1.49‐8.05, p=0.004) and maternal weight gain ≄ 6.0kg by the 18th week of gestation (OR 1.10, 95% CI 1.04‐1.15, p <0.001). In adolescent males, family socio‐economic status at the time of birth (OR 9.07, 95% CI 1.54‐53.29, p=0.02) remained significantly associated with NAFLD after multivariate modeling adjusted for adolescent obesity. Conclusion: Early life contributors to NAFLD show considerable sexual dimorphism. Maternal obesity and higher early‐mid gestational weight gain were associated with NAFLD in female offspring, while lower family socio‐economic status at birth was associated with NAFLD in male offspring independent of adolescent obesity. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 30 juin 2017
    Reina Sasaki, Pradip Devhare, Ratna B. Ray, Ranjit Ray
    Hepatitis C virus induced tumor initiating cancer stem‐like cells activate stromal fibroblasts in xenograft tumor model
    Hepatitis C virus (HCV) often causes persistent infection, and is an increasingly important factor in the etiology of fibrosis/cirrhosis and hepatocellular carcinoma (HCC), although the mechanisms for the disease processes remain unclear. We have shown previously that HCV infection generates epithelial mesenchymal transition state (EMT) and tumor initiating cancer stem‐like cells (TISCs) in human hepatocytes. In this study, we investigated whether HCV induced TISC when implanted into mice activate stromal fibroblasts. A number of fibroblast activation markers, including metalloproteinase (MMP) 2 were significantly increased at the mRNA or protein level in the xenograft tumors, suggesting the presence of tumor‐associated fibroblasts (TAFs). Fibroblast activation markers of murine origin were specifically increased in tumor, suggesting that fibroblasts are migrated to form stroma. Next, we demonstrated that the conditioned medium (CM) from HCV infected human hepatocytes activates fibrosis related markers in hepatic stellate cells. We further observed that these HCV infected hepatocytes express TGF‐ÎČ which activates stromal fibroblast markers. Subsequent analysis suggest anti‐TGF‐ÎČ neutralizing antibody, when incubated with CM from HCV infected hepatocytes, inhibits fibrosis marker activation in primary human hepatic stellate cells (HSCs). Conclusion: HCV infected hepatocytes induce local fibroblast activation by secretion of TGF‐ÎČ, and preneoplastic or tumor state of the hepatocytes influences the network for TAF environment. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 29 juin 2017
    Barret Rush, Keith R. Walley, Leo Anthony Celi, Neil Rajoriya, Mayur Brahmania
    Palliative Care Access for Hospitalized Patients with End Stage Liver Disease Across the United States
    Objective: Patients with end‐stage liver disease (ESLD) often have a high symptom burden. Historically, palliative care (PC) services have been underutilized in this population. We investigated the use of PC services in patients with ESLD hospitalized across the United States. Methods: We utilized the Nationwide Inpatient Sample (NIS) to conduct a retrospective nationwide cohort analysis. All patients >18 years of age admitted with ESLD, defined as those with at least two liver decompensation events, were included in the analysis. A multivariate logistic regression model predicting referral to PC was created. Results: 55,208,382 hospitalizations from the 2006‐2012 NIS samples were analyzed with 39,349 (0.07%) patients meeting study inclusion. PC consultation was performed in 1,789 (4.5%) ESLD patients. The rate of PC referral in ESLD increased from 0.97% in 2006 to 7.1% in 2012 (p<0.01). In multivariate analysis, factors associated with lower referral to PC were Hispanic race (OR 0.77; 95% CI 0.66‐0.89; p<0.01) and insurance coverage (OR 0.74; 95% CI 0.65‐0.84; p<0.01). Factors associated with increased referral to PC were: age (per 5‐year increase, OR 1.05; 95% CI 1.03‐1.08; p<0.01), DNR status (OR 16.24; 95% CI 14.20‐18.56; p<0.01), treatment in a teaching hospital (OR 1.25; 95% CI 1.12‐1.39; p<0.01), presence of HCC (OR 2.00; 95% CI 1.71‐2.33; p<0.01), and presence of metastatic cancer (OR 2.39; 95% CI 1.80 ‐3.18; p<0.01). PC referral was most common in West coast hospitals (OR 1.81; 95% CI 1.53‐2.14; p<0.01) as well as large sized hospitals (OR 1.49; 95% CI 1.22‐1.82; p<0.01). Conclusions: From 2006‐2012 the use of PC in ESLD patients increased substantially. Socioeconomic, geographical and ethnic barriers to accessing PC were observed. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 juin 2017
    Jonas F Ludvigsson, Hanns‐Ulrich Marschall, Hannes Hagström, Jonas Höijer, Olof Stephansson
    Pregnancy Outcome in Women Undergoing Liver Biopsy During Pregnancy: A Nationwide Population‐Based Cohort Study
    Liver biopsy is an important procedure in the investigation of liver disease. We examined pregnancy outcomes in women who underwent liver biopsy during pregnancy. In a nationwide population‐based cohort study we linked data from the Swedish Medical Birth Registry (for births between 1992 and 2011) with those from the Swedish Patient Registry. We identified 23 pregnancies exposed to liver biopsy. We calculated relative risks (RRs) for adverse pregnancy outcomes according to liver biopsy status using 1,953,887 unexposed pregnancies with and without a record of liver disease as reference. Our main outcome measures were stillbirth and preterm birth. There were no stillbirths in pregnancies exposed to liver biopsies compared with 0.3% stillbirths in unexposed pregnancies. 3/23 (13%) exposed pregnancies were preterm (RR=2.6; 95%CI=0.9‐7.5). Compared with women with a record of liver disease, preterm birth was not increased in those exposed to liver biopsy (RR=0.9; 95%CI=0.1‐6.0). Except for an increased risk of small for gestational age birth in pregnancies exposed to liver biopsy (RR=5.2; 95%CI=1.8‐14.8), other adverse pregnancy outcomes were independent of liver biopsy status when the analysis was restricted to women with a diagnosis of liver disease. Compared with unexposed sibling pregnancies, pregnancies with a liver biopsy were 7 days shorter, but birth weights did not differ between the siblings (‐67g; p>0.05). Conclusion. Apart from a moderately increased risk of preterm birth and small for gestational age, there was no association between liver biopsy during pregnancy and adverse pregnancy outcome. Potential excess risks should be weighed against the advantages of having a liver biopsy that may influence clinical management of the patient indirectly influencing fetal health. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 juin 2017
    Junlai Liu, Xiao Hu, Jie Chen, Xinqi Li, Lu Wang, Binbin Wang, Wenbo Peng, Cuiwei Yang, Zhijie Li, Yan Chen, Yue J. Wang, Chuanjiang Li, Xiajun Li, Fang Yan, Yunfang Wang, Changzhen Shang, Xin Wang, Tao Chen, Pengyu Huang
    Pericentral hepatocytes produce IGF‐2 to promote liver regeneration during special injuries
    Liver regeneration happens after various types of injuries. Unlike the well‐studied liver regeneration caused by partial hepatectomy, there is accumulating evidence suggesting that liver regeneration during other injuries may result from some unknown mechanism. In this study, we found that insulin‐like growth factor 2 (IGF‐2) was drastically induced following the liver injuries caused by tyrosinemia or long‐term treatments of carbon tetrachloride (CCl4). However, it was not observed during the early phase of acute liver injuries after partial hepatectomy or single treatment of CCl4. Remarkably, most of IGF‐2 expressing hepatocytes were located at the histological area around the central vein of liver lobule after the liver injuries caused either in Fah‐deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by the induced IGF‐2 over‐expression, which could be inhibited by AAV‐delivered IGF‐2 shRNAs or linsitinib, an inhibitor of IGF‐2 signaling. Proliferating hepatocytes in vivo responded to IGF‐2 via both insulin receptor and IGF‐1 receptor. IGF‐2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF‐2 was also found to co‐localize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. Conclusion: IGF‐2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs after partial hepatectomy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 juin 2017
    Harrys A. Torres, Jeff Hosry, Parag Mahale, Minas P. Economides, Ying Jiang, Anna S. Lok
    Hepatitis C virus reactivation in patients receiving cancer treatment: A prospective observational study
    Hepatitis C virus (HCV) reactivation in patients receiving cancer treatment has been reported in retrospective studies. We sought to determine prospectively the incidence, predictors, and clinical significance of HCV reactivation during cancer treatment. HCV‐infected patients receiving cancer treatment at our institution (11/2012‐07/2016) were studied. Reactivation was defined as an increase in HCV‐RNA ≄1 log10 IU/mL over baseline and hepatitis flare as alanine aminotransferase (ALT) increase to ≄3 times the upper limit of normal. One hundred patients were studied, 50 with hematologic malignancies and 50 with solid tumors. Reactivation occurred in 23 patients (23%), including 18 patients (36%) with hematologic malignancies and 5 (10%) with solid tumors. In univariate analysis, patients with reactivation were more likely than those without, to have prolonged lymphopenia (median, 95 vs 22 days, P=0.01) and to have received rituximab (44% vs 9%, P<0.0001), bendamustine (22% vs 0%, P<0.001), high‐dose steroids (57% vs 21%, P=0.001), or purine analogs (22% vs 5%, P=0.02). Rituximab (odds ratio [OR]=9.52, P=0.001), and high‐dose steroids (OR=5.05, P=0.01) retained significance in multivariable analysis. Of the 23 patients with reactivation, 10 (43%) had hepatitis flare. No patient with reactivation experienced liver failure or liver‐related death within 36 weeks after initiation of cancer treatment. Fourteen patients with hepatitis flare of whom 6 had reactivation, required discontinuation or dose reduction of cancer treatment. Conclusions HCV reactivation occurred in 23% of HCV‐infected patients receiving cancer treatment, and most had an unremarkable clinical course. However, reactivation can affect the cancer treatment plan. Our findings suggest that HCV infection should not contraindicate cancer therapy and infected patients should have access to multiple cancer treatments with close monitoring while receiving regimens associated with HCV reactivation. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 juin 2017
    Q Lai, A Vitale, S Iesari, A Finkenstedt, G Mennini, G Spoletini, M Hoppe‐Lotichius, G Vennarecci, T.M. Manzia, D Nicolini, A.W. Avolio, A.C. Frigo, U Cillo, I Graziadei, M. Rossi, E. Tsochatzis, G Otto, G.M. Ettorre, G Tisone, M Vivarelli, S Agnes, J Lerut,
    Intention‐to‐treat survival benefit of liver transplantation in patients with hepatocellular cancer
    The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate “high‐” and “low‐benefit” patients. To do so, the innovative concept of intention‐to‐treat (ITT) survival benefit of LT has been created. Data of 2103 adult HCC patients consecutively enlisted during the period 1987‐2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non‐LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (MELD, alpha‐fetoprotein, Milan‐Criteria status and radiological response) displayed a high effect in terms of delta‐benefit. According to these risk factors, four benefit groups were identified. Patients with three‐four factors (“no‐benefit group”, n=405/2103; 19·2%) had no benefit of LT compared to alternative treatments. Inversely, patients without any risk factor (“large‐benefit group”, n=108; 5·1%) yielded the highest benefit from LT reaching 60 months. Conclusion: The here presented innovative ITT transplant survival benefit allows to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equal way for organ allocation. Patients with no benefit should be de‐listed, whilst patients with large benefit ratio should be prioritized for LT. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 juin 2017
    David Q.‐H. Wang, Piero Portincasa, Patrick Tso
    Transintestinal cholesterol excretion (TICE): A secondary, non‐biliary pathway contributing to reverse cholesterol transport
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    Date de mise en ligne : Mardi 27 juin 2017
    Hannelie Korf, Schalk van der Merwe
    Adipose‐derived exosomal miRNAs orchestrates gene regulation in the liver: Is this the missing link in NAFLD?
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    Date de mise en ligne : Lundi 26 juin 2017
    Meghan Sise
    Kidney transplant recipients with Hepatitis C virus experienced 100% SVR12 rate when treated with sofosbuvir‐ledipasvir
    n/a


    Date de mise en ligne : Vendredi 23 juin 2017
    Elodie Henriet, Aya Abou Hammoud, Jean‐William Dupuy, Benjamin Dartigues, Zakaria Ezzoukry, Nathalie Dugot‐Senant, Thierry Leste‐Lasserre, Nestor Pallares‐Lupon, Macha Nikolski, Brigitte Le Bail, Jean‐FrĂ©dĂ©ric Blanc, Charles Balabaud, Paulette Bioulac‐Sage, Anne‐AurĂ©lie Raymond, FrĂ©dĂ©ric Saltel
    Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk
    Hepatocellular adenomas (HCA) are rare benign tumors divided into three main subgroups defined by patho‐molecular features, HNF1A (H‐HCA), mutated ÎČ‐catenin (b‐HCA) and inflammatory (IHCA). In the case of unclassified HCA (UHCA), which are currently identified by default, a high risk of bleeding remains a clinical issue. The objective of this study was to explore UHCA proteome with the aim to identify specific biomarkers. Following dissection of the tumoral (T) and non‐tumoral (NT) tissue on formalin‐fixed paraffin‐embedded (FFPE) from HCA tissue sections using laser capture methodology, we performed mass spectrometry analysis to compare T and NT protein expression levels in HCA, H‐HCA, IHCA, b‐HCA, UHCA and focal nodular hyperplasia. Using this methodology, we searched for proteins, which are specifically deregulated in UHCA. We demonstrate that proteomic profiles allow discriminating known HCA subtypes through the identification of classical biomarkers in each HCA subgroup. We observed specific upregulation of the arginine synthesis pathway associated with overexpression of argininosuccinate synthase (ASS1) and arginosuccinate lyase (ASL) in UHCA. ASS1 immunohistochemistry identified all the UHCA, of which 64.7% presented clinical bleeding manifestations. Interestingly, we demonstrated that the significance of ASS1 was not restricted to UHCA but also encompassed certain hemorrhagic cases in other HCA subtypes, particularly inflammatory HCA. Conclusion: ASS1+ HCA combined with a typical hematoxylin and eosin stain aspect defined a new HCA subgroup at a high risk of bleeding. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 23 juin 2017
    JosĂ© Altamirano, Hugo LĂłpez‐Pelayo, Javier Michelena, Patricia D. Jones, Lluisa Ortega, Pere GinĂšs, Juan CaballerĂ­a, Antoni Gual, RamĂłn Bataller, Anna Lligoña
    Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long‐term survival
    Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short‐term prognosis, while factors associated with long‐term survival are largely unknown. The aims of our study were: 1) to determine the impact of complete abstinence from alcohol on long‐term survival and 2) to identify prognostic factors at admission capable of predicting abstinence during long‐term follow‐up in patients with AH. One hundred and forty‐two patients with biopsy‐proven AH that survived the first episode were included. Demographic, psychiatric and biochemical variables at admission and drinking status during follow‐up were obtained. Cox regression, logistic regression and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow‐up of 55 months. During follow‐up, complete abstinence was reported in 39% and was associated with better long‐term survival (HR 0.53; p=0.03). After adjustment for baseline prognostic scoring systems (MELD and ABIC scores), complete abstinence was independently associated with survival (p<0.05). Age and lack of prior alcoholism treatments were independently associated with complete abstinence (p<0.001 and p=0.02, respectively) during follow‐up. CART analysis generated a simple and practical algorithm based‐on the combination of prior alcoholism treatments and age. Using CART analysis we stratified 2 subgroups of patients with high (65%) and low (26‐29%) rates of complete abstinence after an episode of AH. Conclusions: Complete abstinence after an episode of AH positively impacts long‐term survival. The combination of 2 variables easily obtained at admission might be useful to predict long‐term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are mandatory. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 23 juin 2017
    Varun Takyar, Yaron Rotman
    Letter to the editor: Authors' Reply: Healthy Controls in Non‐Alcoholic Fatty Liver Disease Management: A Biomedical Research Perspective
    n/a


    Date de mise en ligne : Vendredi 23 juin 2017
    Yanfeng Liu, Yonglong Zhang, Shenghao Wang, Qiong‐Zhu Dong, Zhongliang Shen, Wei Wang, Shuai Tao, Chenjian Gu, Jing Liu, Youhua Xie, Lun‐Xiu Qin
    Prospero‐related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating IL‐8 expression
    Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero‐related homeobox 1 (PROX1) was identified as a novel pro‐angiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and NF‐ÎșB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 could enhance the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin specific protease 7 (USP7) to prevent p65 ubiquitination. Consequently, PROX1 activated the NF‐ÎșB signaling and selectively promoted the expression of the pro‐angiogenic IL‐8 by epigenetically stimulating the IL‐8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti‐IL‐8 mAb. Conclusions: We have identified PROX1 as a crucial promoter of HCC angiogenesis. Our study provides a novel insight into PROX1's function in HCC progression and the potential therapeutic application of anti‐IL‐8 antibody in high PROX1 expression HCC patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 20 juillet 2017
    Jae‐Kyung Won, Su Jong Yu, Chae Young Hwang, Sung‐Hwan Cho, Sang‐Min Park, Kwangsoo Kim, Won‐Mook Choi, Hyeki Cho, Eun Ju Cho, Jeong‐Hoon Lee, Kyung Bun Lee, Yoon Jun Kim, Kyung‐Suk Suh, Ja‐June Jang, Chung Yong Kim, Jung‐Hwan Yoon, Kwang‐Hyun Cho
    Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma
    Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low‐PDI‐expression group. Conclusion: These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017).


    Date de mise en ligne : Jeudi 20 juillet 2017
    Ekaterina Kachaylo, Christoph Tschuor, Nicolas Calo, Nathalie Borgeaud, Udo UngethĂŒm, Perparim Limani, Anne‐Christine Piguet, Jean‐Francois Dufour, Michelangelo Foti, Rolf Graf, Pierre A. Clavien, Bostjan Humar
    PTEN Down‐Regulation Promotes ÎČ‐Oxidation to Fuel Hypertrophic Liver Growth After Hepatectomy in Mice
    In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration‐associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor phosphatase and tensin homolog (PTEN) is a key inhibitor of the protein kinase B/mammalian target of rapamycin axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, whereas its role in regenerating liver remains unknown. Here, we show that PTEN down‐regulation promotes liver growth in a TRAS‐dependent way. In wild‐type mice, PTEN reduction occurred after TRAS formation, persisted during its disappearance, and correlated with up‐regulated ÎČ‐oxidation at the expense of lipogenesis. Pharmacological modulation revealed an association of PTEN with TRAS turnover and hypertrophic liver growth. In liver‐specific Pten–/– mice shortly after induction of knockout, hypertrophic regeneration was accelerated and led to hepatomegaly. The resulting surplus liver mass was functional, as demonstrated by raised survival in a lethal model of resection‐induced liver failure. Indirect calorimetry revealed lipid oxidation as the primary energy source early after hepatectomy. The shift from glucose to lipid usage was pronounced in Pten–/– mice and correlated with the disappearance of TRAS. Partial inhibition of ÎČ‐oxidation led to persisting TRAS in Pten–/– mice and abrogated hypertrophic liver growth. PTEN down‐regulation may promote ÎČ‐oxidation through ÎČ‐catenin, whereas hypertrophy was dependent on mammalian target of rapamycin complex 1. Conclusion: PTEN down‐regulation after hepatectomy promotes the burning of TRAS‐derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017).


    Date de mise en ligne : Jeudi 20 juillet 2017
    Enpeng Zhao, Ghulam Ilyas, Francesca Cingolani, Jae Ho Choi, François Ravenelle, Kathryn E. Tanaka, Mark J. Czaja
    Pentamidine blocks hepatotoxic injury in mice
    Toxin‐induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti‐inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the d‐galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase–mediated deoxyuridine triphosphate nick end‐labeling (TUNEL)‐positive cells and mortality compared with vehicle‐injected controls. VLX103 decreased GalN/LPS induction of tumor necrosis factor (TNF) but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS‐treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7, which resulted from reduced c‐Jun N‐terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 hours after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol‐induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL‐positive cells. Conclusion: VLX103 effectively decreases toxin‐induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. (Hepatology 2017).


    Date de mise en ligne : Jeudi 20 juillet 2017
    Songtao Li, Xiaobing Dou, Hua Ning, Qing Song, Wei Wei, Ximei Zhang, Chen Shen, Jiaxin Li, Changhao Sun, Zhenyuan Song
    Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity
    Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanisms remain to be fully elucidated. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide–dependent deacetylase located primarily inside mitochondria. In this study, we demonstrated that an SFA‐rich high‐fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated HFD rich in fatty acids. Unexpectedly, SIRT3 expression and activity were significantly elevated in the livers of mice exposed to the SFA‐rich HFD. Using cultured HepG2 and AML‐12 hepatocytes, we demonstrated that unlike monounsaturated fatty acids, SFAs up‐regulate SIRT3 expression and activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate‐induced cell death, which can be alleviated by SIRT3 small interfering RNA (siRNA) transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, thereby enhancing the susceptibility of hepatocytes to SFA‐induced cytotoxicity. Mechanistic investigations revealed that SIRT3 overexpression causes manganese superoxide dismutase deacetylation and activation, which depleted intracellular superoxide contents, leading to adenosine monophosphate–activated protein kinase (AMPK) inhibition and mammalian target of rapamycin C1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhanced autophagy flux. A similar result was observed in the liver tissue of SIRT3 knockout mice. Conclusion: Our data indicate that SIRT3 is a negative regulator of autophagy whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. (Hepatology 2017).


    Date de mise en ligne : Jeudi 20 juillet 2017
    Xiaobin Zheng, Fen Xu, Hua Liang, Huanyi Cao, Mengyin Cai, Wen Xu, Jianping Weng
    SIRT1/HSF1/HSP pathway is essential for exenatide‐alleviated, lipid‐induced hepatic endoplasmic reticulum stress
    Recent studies have indicated that lipid‐induced endoplasmic reticulum (ER) stress is a major contributor to the progression of hepatic steatosis. Exenatide (exendin‐4), a glucagon‐like peptide‐1 receptor agonist, is known to improve hepatic steatosis, with accumulating evidence. In this study, we investigated whether exenatide could alleviate lipid‐induced hepatic ER stress through mammal sirtuin 1 (SIRT1) and illustrated the detailed mechanisms. Male C57BL/6J mice challenged with a high‐fat diet (HFD) were treated with exenatide or normal saline by intraperitoneal injection for 4 weeks. We observed that HFD feeding induced hepatic ER stress as indicated by increased expression of glucose‐regulated protein 78, phosphorylated protein kinase‐like ER kinase, and phosphorylated eukaryotic initiation factor 2α, while these increases were significantly inhibited by exenatide. Exenatide notably decreased the liver weight and hepatic steatosis induced by HFD challenge. Consistently, in human HepG2 cells and primary murine hepatocytes, exendin‐4 also significantly alleviated the ER stress and lipid accumulation induced by palmitate. Importantly, further studies showed that exendin‐4 enhanced the binding of heat shock factor 1 to the promoter of heat shock protein (HSP) genes through SIRT1‐mediated deacetylation, which then increased the expression of molecular chaperones HSP70 and HSP40 to alleviate hepatic ER stress. Finally, inhibition of SIRT1 by genetic whole‐body heterozygous knockout or by lentiviral short hairpin RNA knockdown greatly diminished the effect of exenatide on deacetylating heat shock factor 1, increasing HSP expression and alleviating ER stress and hepatic steatosis in HFD‐fed mice. Conclusion: The SIRT1/heat shock factor 1/HSP pathway is essential for exenatide‐alleviated, lipid‐induced ER stress and hepatic steatosis, which provides evidence for a molecular mechanism to support exenatide and incretin mimetics as promising therapeutics for obesity‐induced hepatic steatosis. (Hepatology 2017)


    Date de mise en ligne : Jeudi 20 juillet 2017
    Toshihiro Tanaka, Weici Zhang, Ying Sun, Zongwen Shuai, Asiya Seema Chida, Thomas P. Kenny, Guo‐Xiang Yang, Ignacio Sanz, Aftab Ansari, Christopher L. Bowlus, Gregory C. Ippolito, Ross L. Coppel, Kazuichi Okazaki, Xiao‐Song He, Patrick S.C. Leung, M. Eric Gershwin
    Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics
    A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multilineage immune responses to mitochondrial self‐antigens in primary biliary cholangitis, the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC‐E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti‐PDC‐E2 autoantibodies cross‐react with the chemical xenobiotics 2‐octynoic acid and 6,8‐bis (acetylthio) octanoic acid and further that there is a high frequency of PDC‐E2‐specific peripheral plasmablasts. Herein we generated 104 recombinant monoclonal antibodies (mAbs) based on paired heavy‐chain and light‐chain variable regions of individual plasmablasts derived from primary biliary cholangitis patients. We identified 32 mAbs reactive with native PDC‐E2, including 20 specific for PDC‐E2 and 12 cross‐reactive with both PDC‐E2 and 2‐octynoic acid and 6,8‐bis (acetylthio) octanoic acid. A lower frequency of replacement somatic hypermutations, indicating a lower level of affinity maturation, was observed in the complementarity‐determining regions of the cross‐reactive mAbs in comparison to mAbs exclusively recognizing PDC‐E2 or those for irrelevant antigens. In particular, when the highly mutated heavy‐chain gene of a cross‐reactive mAb was reverted to the germline sequence, the PDC‐E2 reactivity was reduced dramatically, whereas the xenobiotic reactivity was retained. Importantly, cross‐reactive mAbs also recognized lipoic acid, a mitochondrial fatty acid that is covalently bound to PDC‐E2. Conclusion: Our data reflect that chemically modified lipoic acid or lipoic acid itself, through molecular mimicry, is the initial target that leads to the development of primary biliary cholangitis. (Hepatology 2017)


    Date de mise en ligne : Jeudi 20 juillet 2017
    Xiaojiaoyang Li, Runping Liu, Jing Yang, Lixin Sun, Luyong Zhang, Zhenzhou Jiang, Puneet Puri, Emily C. Gurley, Guanhua Lai, Yuping Tang, Zhiming Huang, William M. Pandak, Phillip B. Hylemon, Huiping Zhou
    The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice
    The multidrug resistance 2 knockout (Mdr2–/–) mouse is a well‐established model of cholestatic cholangiopathies. Female Mdr2–/– mice develop more severe hepatobiliary damage than male Mdr2–/– mice, which is correlated with a higher proportion of taurocholate in the bile. Although estrogen has been identified as an important player in intrahepatic cholestasis, the underlying molecular mechanisms of gender‐based disparity of cholestatic injury remain unclear. The long noncoding RNA H19 is an imprinted, maternally expressed, and estrogen‐targeted gene, which is significantly induced in human fibrotic/cirrhotic liver and bile duct–ligated mouse liver. However, whether aberrant expression of H19 accounts for gender‐based disparity of cholestatic injury in Mdr2–/– mice remains unknown. The current study demonstrated that H19 was markedly induced (∌200‐fold) in the livers of female Mdr2–/– mice at advanced stages of cholestasis (100 days old) but not in age‐matched male Mdr2–/– mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both taurocholate and estrogen significantly activated the extracellular signal–regulated kinase 1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced taurocholate/estrogen‐induced expression of fibrotic genes and sphingosine 1‐phosphate receptor 2 in cholangiocytes but also markedly reduced cholestatic injury in female Mdr2–/– mice. Furthermore, expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 short hairpin RNA in female Mdr2–/– mice. Similar findings were obtained in human primary sclerosing cholangitis liver samples. Conclusion: H19 plays a critical role in the disease progression of cholestasis and represents a key factor that causes the gender disparity of cholestatic liver injury in Mdr2–/– mice. (Hepatology 2017).


    Date de mise en ligne : Jeudi 20 juillet 2017
    Grace L. Guo
    Why is the female population more susceptible to cholestasis‐induced liver injury—Could it be long noncoding RNA H19?
    n/a


    Date de mise en ligne : Jeudi 20 juillet 2017
    Chun‐Seok Cho, David B. Lombard, Jun Hee Lee
    SIRT3 as a regulator of hepatic autophagy
    n/a


    Date de mise en ligne : Jeudi 20 juillet 2017
    Laurent Mailly, Mirjam B. Zeisel, Thomas F. Baumert
    Toward novel immunocompetent animal models for hepatitis B virus infection
    n/a


    Date de mise en ligne : Jeudi 20 juillet 2017
    Christophe HĂ©zode, Massimo Colombo, Marc BourliĂšre, Ulrich Spengler, Ziv Ben‐Ari, Simone I. Strasser, William M. Lee, Leslie Morgan, Jingjun Qiu, Peggy Hwang, Michael Robertson, Bach‐Yen Nguyen, Eliav Barr, Janice Wahl, Barbara Haber, Robert Chase, Rohit Talwani, Vito Di Marco,
    Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study
    Direct‐acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo‐controlled, phase III C‐EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty‐nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once‐daily, fixed‐dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate‐treatment group (ITG) or deferred‐treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow‐up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, ÎČ‐thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. Conclusion: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017)


    Date de mise en ligne : Mardi 18 juillet 2017
    Florian A. Lempp, Ellen Wiedtke, Bingqian Qu, Pierre Roques, Isabelle Chemin, Florian W. R. Vondran, Roger Le Grand, Dirk Grimm, Stephan Urban
    Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes
    Infections with the human hepatitis B virus (HBV) and hepatitis D virus (HDV) depend on species‐specific host factors like the receptor human sodium taurocholate cotransporting polypeptide (hNTCP). Complementation of mouse hepatocytes with hNTCP confers susceptibility to HDV but not HBV, indicating the requirement of additional HBV‐specific factors. As an essential premise toward the establishment of an HBV‐susceptible animal model, we investigated the role of hNTCP as a limiting factor of hepatocytes in commonly used laboratory animals. Primary hepatocytes from mice, rats, dogs, pigs, rhesus macaques, and cynomolgus macaques were transduced with adeno‐associated viral vectors encoding hNTCP and subsequently infected with HBV. Cells were analyzed for Myrcludex B binding, taurocholate uptake, HBV covalently closed circular DNA formation, and expression of all HBV markers. Sodium taurocholate cotransporting polypeptide (Ntcp) from the respective species was cloned and analyzed for HBV and HDV receptor activity in a permissive hepatoma cell line. Expression of hNTCP in mouse, rat, and dog hepatocytes permits HDV infection but does not allow establishment of HBV infection. Contrarily, hepatocytes from cynomolgus macaques, rhesus macaques, and pigs became fully susceptible to HBV upon hNTCP expression with efficiencies comparable to human hepatocytes. Analysis of cloned Ntcp from all species revealed a pronounced role of the human homologue to support HBV and HDV infection. Conclusion: Ntcp is the key host factor limiting HBV infection in cynomolgus and rhesus macaques and in pigs. In rodents (mouse, rat) and dogs, transfer of hNTCP supports viral entry but additional host factors are required for the establishment of HBV infection. This finding paves the way for the development of macaques and pigs as immunocompetent animal models to study HBV infection in vivo, immunological responses against the virus and viral pathogenesis. (Hepatology 2017).


    Date de mise en ligne : Mardi 18 juillet 2017
    Alessandro Soria, Massimiliano Fabbiani, Giuseppe Lapadula, Andrea Gori
    Unexpected viral relapses in hepatitis C virus–infected patients diagnosed with hepatocellular carcinoma during treatment with direct‐acting antivirals
    n/a


    Date de mise en ligne : Mardi 18 juillet 2017
    Biljana Atanasovska, Sander S. Rensen, Marijke R. Sijde, Glenn Marsman, Vinod Kumar, Iris Jonkers, Sebo Withoff, Ronit Shiri‐Sverdlov, Jan Willem M. Greve, Klaas Nico Faber, Han Moshage, Cisca Wijmenga, Bart van de Sluis, Marten H. Hofker, Jingyuan Fu
    A liver‐specific long noncoding RNA with a role in cell viability is elevated in human nonalcoholic steatohepatitis
    Hepatocyte apoptosis in nonalcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that long noncoding (lnc) RNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n = 48), simple steatosis but no NASH (n = 11), and healthy controls (n = 23), we discovered a liver‐specific lncRNA (RP11‐484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r = 0.51, P = 8.11 × 10–7), lobular inflammation (r = 0.49, P = 2.35 × 10–6), and nonalcoholic fatty liver disease activity score (r = 0.48, P = 4.69 × 10–6). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r = 0.47, P = 0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes coexpressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown. Conclusion: We identified an lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. (Hepatology 2017).


    Date de mise en ligne : Mardi 18 juillet 2017
    Luis Perea, Mar Coll, Lucia Sanjurjo, Delia Blaya, Adil El Taghdouini, Daniel Rodrigo‐Torres, JosĂ© Altamirano, Isabel Graupera, Beatriz Aguilar‐Bravo, Marta Llopis, Julia VallverdĂș, Joan Caballeria, Leo A. van Grunsven, Maria‐Rosa Sarrias, Pere GinĂšs, Pau Sancho‐Bru
    Pentraxin‐3 modulates lipopolysaccharide‐induced inflammatory response and attenuates liver injury
    Acute‐on‐chronic liver injury is characterized by an important inflammatory response frequently associated with endotoxemia. In this context, acute‐phase proteins such as Pentraxin‐3 (PTX3) are released; however, little is known about their role in chronic liver disease. The aim of this study was to elucidate the role of PTX3 in liver injury. The role of PTX3 was evaluated in cultured human cells, liver tissue slices, and mice with acute‐on‐chronic liver injury. PTX3 expression was assessed in tissue and serum samples from 54 patients with alcoholic hepatitis. PTX3 expression was up‐regulated in animal models of liver injury and strongly induced by lipopolysaccharide (LPS). Liver cell fractionation showed that macrophages and activated hepatic stellate cells were the main cell types expressing PTX3 in liver injury. Ex vivo and in vivo studies showed that PTX3 treatment attenuated LPS‐induced liver injury, inflammation, and cell recruitment. Mechanistically, PTX3 mediated the hepatic stellate cell wound‐healing response. Moreover, PTX3 modulated LPS‐induced inflammation in human primary liver macrophages and peripheral monocytes by enhancing a TIR domain–containing adapter‐inducing interferon–dependent response and favoring a macrophage interleukin‐10‐like phenotype. Additionally, hepatic and plasma PTX3 levels were increased in patients with alcoholic hepatitis, a prototypic acute‐on‐chronic condition; and its expression correlated with disease severity scores, endotoxemia, infections, and short‐term mortality, thus suggesting that expression of PTX3 found in patients could be a counterregulatory response to injury. Conclusion: Experimental and human evidence suggests that, in addition to being a potential biomarker for alcoholic hepatitis, PTX3 participates in the wound‐healing response and attenuates LPS‐induced liver injury and inflammation; therefore, administration of PTX3 could be a promising therapeutic strategy in acute‐on‐chronic conditions, particularly those associated with endotoxemia. (Hepatology 2017).


    Date de mise en ligne : Mardi 18 juillet 2017
    Reina Sasaki, Pradip B. Devhare, Robert Steele, Ranjit Ray, Ratna B. Ray
    Hepatitis C virus–induced CCL5 secretion from macrophages activates hepatic stellate cells
    Hepatitis C virus (HCV)–mediated chronic liver disease is a serious health problem around the world and often causes fibrosis/cirrhosis and hepatocellular carcinoma. The mechanism of liver disease progression during HCV infection is still unclear, although inflammation is believed to be an important player in disease pathogenesis. We previously reported that macrophages including Kupffer cells exposed to HCV induce proinflammatory cytokines. These secreted cytokines may activate hepatic stellate cells (HSCs) toward fibrosis. In this study, we examined crosstalk between macrophages and HSCs following HCV infection. Primary human HSCs and immortalized HSCs (LX2 cells) were incubated with conditioned medium derived from HCV‐exposed human macrophages. Expression of inflammasome and fibrosis‐related genes in these cells was examined, with increased expression of inflammatory (NLR family pyrin domain containing 3, interleukins 1ÎČ and 6, and cysteine‐cysteine chemokine ligand 5 [CCL5]) and profibrogenic (transforming growth factor ÎČ1, collagen type 4 alpha 1, matrix metalloproteinase 2, and alpha‐smooth muscle actin) markers. Further investigation suggested that CCL5, secreted from HCV‐exposed macrophages, activates inflammasome and fibrosis markers in HSCs and that neutralizing antibody to CCL5 inhibited activation. Conclusion: Together, our results demonstrate that human macrophages exposed to HCV induce CCL5 secretion, which plays a significant role in hepatic inflammation and fibrosis. (Hepatology 2017).


    Date de mise en ligne : Mardi 18 juillet 2017
    Young‐Suk Lim, Yung Sang Lee, Geum‐Youn Gwak, Kwan Soo Byun, Yoon Jun Kim, Jonggi Choi, Jihyun An, Han Chu Lee, Byung Chul Yoo, So Young Kwon
    Monotherapy with tenofovir disoproxil fumarate for multiple drug‐resistant chronic hepatitis B: 3‐year trial
    Combination therapy has been recommended for the treatment of patients harboring multiple drug‐resistant hepatitis B virus (HBV). However, we recently demonstrated that monotherapy with tenofovir disoproxil fumarate (TDF) for 48 weeks displayed noninferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with HBV resistant to multiple drugs, including ETV and adefovir. Nonetheless, whether prolonged TDF monotherapy would be safe and increase the virologic response rate in these patients was unclear. Among 192 patients with HBV‐resistance mutations to ETV and/or adefovir, who were randomized to receive TDF monotherapy (n = 95) or TDF/ETV combination therapy (n = 97) for 48 weeks, 189 agreed to continue TDF monotherapy (TDF‐TDF group) or to switch to TDF monotherapy (TDF/ETV‐TDF group) and 180 (93.8%) completed the 144‐week study. Serum HBV DNA <15 IU/mL at week 48, the primary efficacy endpoint, was achieved in 66.3% in the TDF‐TDF group and 68.0% in the TDF/ETV‐TDF group (P = 0.80). At week 144, the proportion with HBV DNA <15 IU/mL increased to 74.5%, which was significantly higher compared with that at week 48 (P = 0.03), without a significant difference between groups (P = 0.46). By on‐treatment analysis, a total of 79.4% had HBV DNA <15 IU/mL at week 144. Transient virologic breakthrough occurred in 6 patients, which was due to poor drug adherence. At week 144, 19 patients who had HBV DNA levels >60 IU/mL qualified for genotypic resistance analysis, and 6 retained some of their baseline resistance mutations of HBV. No patients developed additional resistance mutations throughout the study period. Conclusion: TDF monotherapy was efficacious and safe for up to 144 weeks, providing an increasing rate of virologic response in heavily pretreated patients with multidrug‐resistant HBV. (Hepatology 2017).


    Date de mise en ligne : Mardi 18 juillet 2017
    Tai‐Shuan Lai, Mei‐Hsuan Lee, Hwai‐I Yang, San‐Lin You, Sheng‐Nan Lu, Li‐Yu Wang, Yong Yuan, Gilbert L'Italien, Kuo‐Liong Chien, Chien‐Jen Chen,
    Hepatitis C viral load, genotype, and increased risk of developing end‐stage renal disease: REVEAL‐HCV study
    The association between hepatitis C virus (HCV) infection and end‐stage renal disease (ESRD) remains controversial without considering the role of HCV viral load and genotype. This study aimed to determine whether HCV RNA level and genotype affect the risk of developing ESRD. Between 1991 and 1992, 19,984 participants aged 30‐65 years were enrolled in a community‐based prospective cohort study in Taiwan. Chronic HCV infection was defined by detectable HCV viral load. ESRD was determined as the need for chronic dialysis or renal transplantation. Conventional Cox proportional hazard and competing risk models were used to determine the hazard ratio (HR) for ESRD. After a median follow‐up of 16.8 years, 204 cases were detected during 319,474 person‐years. The incidence rates of ESRD for nonchronically HCV‐infected and chronically HCV‐infected patients were 60.2 and 194.3 per 100,000 person‐years, respectively. The multivariable HR was 2.33 (95% confidence interval [CI] 1.40‐3.89) when comparing patients with and without chronic HCV infection. Patients with low and high HCV RNA levels were at higher risk of ESRD than those who were nonchronically HCV‐infected (HR, 2.11, 95% CI 1.16‐3.86, and HR, 3.06, 95% CI 1.23‐7.58; Ptrend < 0.001). This association remained robust after taking pre‐ESRD death as a competing event for ESRD. Patients with HCV genotype 1 tended to have a higher risk of developing ESRD (HR, 3.60 95% CI 1.83‐7.07) compared with nonchronically HCV‐infected subjects. Conclusions: This study reveals that chronic HCV infection is associated with an increased risk of developing ESRD and suggests that elevated serum levels of HCV RNA (>167,000 IU/mL) and HCV genotype 1 are strong predictors of ESRD, indicating clinical implications for the management of chronic HCV. (Hepatology 2017).


    Date de mise en ligne : Mardi 18 juillet 2017
    Luigia Florimonte, Massimo Iavarone, Massimo Castellani, Mariagiulia Longo, Francesco Pallotti, Lorenzo Maffioli, Eva Orunesu, Riccardo Benti
    Uncommon extrahepatic metastases from hepatocellular carcinoma
    n/a


    Date de mise en ligne : Mardi 18 juillet 2017
    Ming‐Ling Chang, Yun‐Fan Liaw
    Overt acute hepatitis B is more severe in female patients
    n/a


    Date de mise en ligne : Mardi 18 juillet 2017
    Marie Sinclair, Anthony Schelleman, Daljean Sandhu, Peter W. Angus
    Regression of hepatocellular adenomas and systemic inflammatory syndrome after cessation of estrogen therapy
    We report a case of dramatic systemic inflammatory symptoms and biochemical signs of inflammation related to multiple hepatic adenomas that completely resolved after cessation of the oral contraceptive pill (OCP) and associated adenoma regression. This represents a case of dramatic symptoms that resolved after estrogen withdrawal alone. (Hepatology 2017).


    Date de mise en ligne : Samedi 27 mai 2017
    Kyle S. McCommis, Jerry R. Colca, Brian N. Finck
    Reply
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    Date de mise en ligne : Lundi 08 mai 2017
    Fu‐Ming Chang, Yen‐Po Wang, Hui‐Chu Lang, Chia‐Fen Tsai, Ming‐Chih Hou, Fa‐Yauh Lee, Ching‐Liang Lu
    Statins decrease the risk of decompensation in hepatitis B virus– and hepatitis C virus–related cirrhosis: A population‐based study
    Statin use decreases the risk of decompensation and mortality in patients with cirrhosis due to hepatitis C virus (HCV). Whether this beneficial effect can be extended to cirrhosis in the general population or cirrhosis due to other causes, such as hepatitis B virus (HBV) infection or alcohol, remains unknown. Statin use also decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV and HCV infection. It is unclear whether the effect can be observed in patients with pre‐existing cirrhosis. The goal of this study was to determine the effect of statin use on rates of decompensation, mortality, and HCC in HBV‐, HCV‐, and alcohol‐related cirrhosis. Patients with cirrhosis were identified from a representative cohort of Taiwan National Health Insurance beneficiaries from 2000 to 2013. Statin users, defined as having a cumulative defined daily dose (cDDD) ≄28, were selected and served as the case cohort. Statin nonusers (<28 cDDD) were matched through propensity scores. The association between statin use and risk of decompensation, mortality, and HCC were estimated. A total of 1350 patients with cirrhosis were enrolled. Among patients with cirrhosis, statin use decreased the risk of decompensation, mortality, and HCC in a dose‐dependent manner (P for trend <0.0001, <0.0001, and 0.009, respectively). Regression analysis revealed a lower risk of decompensation among statin users with cirrhosis due to chronic HBV (adjusted hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.25‐0.62) or HCV infection (HR, 0.51; 95% CI, 0.29‐0.93). The lowered risk of decompensation was of borderline significance among statin users with alcohol‐related cirrhosis (HR, 0.69; 95% CI, 0.45‐1.07). Conclusion: Statin use decreases the decompensation rate in both HBV‐ and HCV‐related cirrhosis. Of borderline significance is a decreased decompensation rate in alcohol‐related cirrhosis. (Hepatology 2017).


    Date de mise en ligne : Mercredi 19 juillet 2017
    Masthead
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    Date de mise en ligne : Mercredi 19 juillet 2017
    Table of contents
    Table of contents
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    Date de mise en ligne : Mercredi 19 juillet 2017
    Yecheskel Schneider, Robert S. Brown, Monica Saumoy, Robert E. Schwartz, Vikas Gupta, Russell Rosenblatt
    Hepatology Highlights – August 2017
    311


    Date de mise en ligne : Lundi 26 juin 2017
    Albert D. Min
    Low‐level viremia in hepatitis b patients on antiviral treatment: Can we ignore it?
    314


    Date de mise en ligne : Lundi 26 juin 2017
    Giorgina Mieli‐Vergani, Diego Vergani
    The Riddle of Juvenile Sclerosing Cholangitis
    317


    Date de mise en ligne : Samedi 24 juin 2017
    Steven P. O'Hara, Nicholas F. La Russo
    Cellular senescence, neuropeptides and hepatic fibrosis: Additional insights into increasing complexity
    320


    Date de mise en ligne : Lundi 26 juin 2017
    Yong He, Bin Gao
    A small specific‐sized hyaluronic acid ameliorates alcoholic liver disease by targeting a small RNA: New hope for therapy?
    323


    Date de mise en ligne : Mercredi 05 juillet 2017
    Kathryn Stiede, Wenyan Miao, Heather S. Blanchette, Carine Beysen, Geraldine Harriman, H. James Harwood, Heather Kelley, Rosana Kapeller, Tess Schmalbach, William F. Westlin
    Acetyl‐coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double‐blind, crossover study
    NDI‐010976, an allosteric inhibitor of acetyl‐coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double‐blind, placebo‐controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI‐010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI‐010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1‐13C]acetate, and monitoring 13C incorporation into palmitate of circulating very low‐density lipoprotein triglyceride. Single‐dose administration of NDI‐010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10‐hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo‐treated subjects. Subjects administered single doses of NDI‐010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI‐010976 exposure was observed with >90% inhibition of fractional DNL associated with plasma concentrations of NDI‐010976 >4 ng/mL. Conclusion: ACC inhibition with a single dose of NDI‐010976 is well tolerated and results in a profound dose‐dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI‐010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (Hepatology 2017;66:324–334).


    Date de mise en ligne : Samedi 24 décembre 2016
    Jung Hee Kim, Dong Hyun Sinn, Wonseok Kang, Geum‐Youn Gwak, Yong‐Han Paik, Moon Seok Choi, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik
    Low‐level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment
    The long‐term clinical impact of low‐level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change in therapy. A retrospective cohort of 875 treatment‐naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 [65.5%], cirrhosis = 443 [50.6%]) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow‐up (range 1.0‐8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28‐3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34‐3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. Conclusion: LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335–343).


    Date de mise en ligne : Jeudi 22 juin 2017
    Juan Berenguer, Elena RodrĂ­guez‐Castellano, Ana Carrero, Miguel A. Von Wichmann, Marta Montero, MarĂ­a J. Galindo, Josep Mallolas, Manuel Crespo, MarĂ­a J. TĂ©llez, Carmen Quereda, JosĂ© Sanz, Carlos Barros, Cristina Tural, Ignacio Santos, Federico Pulido, Josep M. Guardiola, Rafael Rubio, Enrique Ortega, MarĂ­a L. Montes, Juan J. Jusdado, Gabriel Gaspar, Herminia Esteban, JosĂ© M. BellĂłn, Juan GonzĂĄlez‐GarcĂ­a,
    Eradication of hepatitis C virus and non‐liver‐related non–acquired immune deficiency syndrome–related events in human immunodeficiency virus/hepatitis C virus coinfection
    We assessed non‐liver‐related non–acquired immunodeficiency syndrome (AIDS)‐related (NLR‐NAR) events and mortality in a cohort of human immunodeficiency virus (HIV)/hepatitis C virus (HCV)–coinfected patients treated with interferon (IFN) and ribavirin (RBV), between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and nonresponders. Fine and Gray regression analysis was conducted to determine the adjusted subhazard rate (sHR) of NLR deaths and NLR‐NAR events considering death as the competing risk. The NLR‐NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR‐NAR cancer, bone events, and non‐AIDS‐related infections. The variables for adjustment were age, sex, past AIDS, HIV transmission category, nadir CD4+ T‐cell count, antiretroviral therapy, HIV RNA, liver fibrosis, HCV genotype, and exposure to specific anti‐HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median 5‐year follow‐up, SVR was found to be associated with a significant decrease in the hazard of diabetes mellitus (sHR, 0.57; 95% confidence interval [CI], 0.35‐0.93; P = 0.024) and decline in the hazard of chronic renal failure close to the threshold of significance (sHR, 0.43; 95% CI, 0.17‐1.09; P = 0.075). Conclusion: Our data suggest that eradication of HCV in coinfected patients is associated not only with a reduction in the frequency of death, HIV progression, and liver‐related events, but also with a reduced hazard of diabetes mellitus and possibly of chronic renal failure. These findings argue for the prescription of HCV therapy in coinfected patients regardless of fibrosis stage. (Hepatology 2017;66:344–356).


    Date de mise en ligne : Jeudi 10 novembre 2016
    Arielle Klepper, Francis J. Eng, Erin H. Doyle, Ahmed El‐Shamy, Adeeb H. Rahman, M. Isabel Fiel, Gonzalo Carrasco Avino, Moonju Lee, Fei Ye, Sasan Roayaie, Meena B. Bansal, Margaret R. MacDonald, Thomas D. Schiano, Andrea D. Branch
    Hepatitis C virus double‐stranded RNA is the predominant form in human liver and in interferon‐treated cells
    Hepatitis C virus (HCV) is unique among RNA viruses in its ability to establish chronic infection in the majority of exposed adults. HCV persists in the liver despite interferon (IFN)‐stimulated gene (ISG) induction; robust induction actually predicts treatment failure and viral persistence. It is unclear which forms of HCV RNA are associated with ISG induction and IFN resistance during natural infections. To thoroughly delineate HCV RNA populations, we developed conditions that fully separate the strands of long double‐stranded RNA (dsRNA) and allow the released RNAs to be quantified in reverse transcription/polymerase chain reaction assays. These methods revealed that dsRNA, a pathogen‐associated molecular pattern (PAMP), comprised 52% (standard deviation, 28%) of the HCV RNA in the livers of patients with chronic infection. HCV dsRNA was proportionally higher in patients with the unfavorable IL28B TT (rs12979860) genotype. Higher ratios of HCV double‐stranded to single‐stranded RNA (ssRNA) correlated positively with ISG induction. In Huh‐7.5 cells, IFN treatment increased the total amount of HCV dsRNA through a process that required de novo viral RNA synthesis and shifted the ratio of viral dsRNA/ssRNA in favor of dsRNA. This shift was blocked by ribavirin (RBV), an antiviral drug that reduces relapse in HCV patients. Northern blotting established that HCV dsRNA contained genome‐length minus strands. Conclusion: HCV dsRNA is the predominant form in the HCV‐infected liver and has features of both a PAMP and a genomic reservoir. Interferon treatment increased rather than decreased HCV dsRNA. This unexpected finding suggests that HCV produces dsRNA in response to IFN, potentially to antagonize antiviral defenses. (Hepatology 2017;66:357–370).


    Date de mise en ligne : Lundi 19 juin 2017
    William F. Balistreri, Karen F. Murray, Philip Rosenthal, Sanjay Bansal, Chuan‐Hao Lin, Kathryn Kersey, Benedetta Massetto, Yanni Zhu, Bittoo Kanwar, Polina German, Evguenia Svarovskaia, Diana M. Brainard, Jessica Wen, Regino P. Gonzalez‐Peralta, Maureen M. Jonas, Kathleen Schwarz
    The safety and effectiveness of ledipasvir−sofosbuvir in adolescents 12‐17 years old with hepatitis C virus genotype 1 infection
    No all‐oral, direct‐acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open‐label study to evaluate the efficacy and safety of ledipasvir–sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12‐17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS‐331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12‐17). A majority (80%) were HCV treatment‐naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%‐100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow‐up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration‐time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS‐331007 were within the predefined pharmacokinetic equivalence boundaries of 50%‐200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir. Conclusion: Ledipasvir−sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir−sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371–378).


    Date de mise en ligne : Jeudi 22 juin 2017
    Sonali Paul, Aaron Dickstein, Akriti Saxena, Norma Terrin, Kathleen Viveiros, Ethan M. Balk, John B. Wong
    Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: A meta‐analysis
    Patients with resolved hepatitis B virus (HBV) infection who are treated for hematological malignancies remain at risk for HBV reactivation. Because of conflicting studies about whether the antibody to hepatitis B surface antigen (anti‐HBs) protects against reactivation in patients with resolved infection (hepatitis B surface antigen negative) receiving chemotherapy for hematological malignancies, we conducted a meta‐analysis to determine if anti‐HBs reduces HBV reactivation risk. We sought English‐language studies through March 1, 2016, in Medline and other sources that examined reactivation in patients with resolved HBV infection receiving chemotherapy for hematologic malignancies. The absolute risks and odds ratio (OR) of reactivation with versus without anti‐HBs were estimated in random‐effects model meta‐analyses. In 20 studies involving 1,672 patients not receiving antiviral prophylaxis, the reactivation risk was 14% (95% confidence interval [CI] 9.4%‐19%) in 388 patients who had antibodies to hepatitis B core antigen only versus 5.0% (95% CI 3.0%‐7.0%) in 1,284 patients who also had anti‐HBs. Anti‐HBs reduced reactivation risk with a pooled OR of 0.21 (95% CI 0.14‐0.32) versus patients with antibody to hepatitis B core antigen only. Similar results were found when limiting the analysis to rituximab chemotherapy (OR = 0.19, 95% CI 0.11‐0.32) and lymphoma (OR = 0.18, 95% CI 0.11‐0.28). Conclusion: In patients with resolved HBV receiving chemotherapy for hematological malignancies without antiviral prophylaxis, anti‐HBs positivity is associated with a decreased risk of reactivation; HBV screening in this patient population should include the routine use of anti‐HBs, and those who are anti‐HBs‐negative should receive antiviral prophylaxis. Future studies should examine the effect of anti‐HBs serum titers, the potential role for booster vaccinations, and antiviral prophylaxis prior to chemotherapy in this patient population. (Hepatology 2017;66:379–388).


    Date de mise en ligne : Lundi 10 avril 2017
    Fred Poordad, Franco Felizarta, Armen Asatryan, Mark S. Sulkowski, Robert W. Reindollar, Charles S. Landis, Stuart C. Gordon, Steven L. Flamm, Michael W. Fried, David E. Bernstein, Chih‐Wei Lin, Ran Liu, Sandra S. Lovell, Teresa I. Ng, Jens Kort, Federico J. Mensa
    Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct‐acting antiviral treatment
    Although direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA‐containing regimens, particularly those with nonstructural protein 5A inhibitors, are limited and remain an area of unmet medical need. This phase 2, open‐label study (MAGELLAN‐1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1–infected patients with prior virologic failure to HCV DAA‐containing therapy. A total of 50 patients without cirrhosis were randomized to three arms: 200 mg GLE + 80 mg PIB (arm A), 300 mg GLE + 120 mg PIB with 800 mg once‐daily RBV (arm B), or 300 mg GLE + 120 mg PIB without RBV (arm C). By intent‐to‐treat analysis, sustained virologic response at posttreatment week 12 was achieved in 100% (6/6, 95% confidence interval 61‐100), 95% (21/22, 95% confidence interval 78‐99), and 86% (19/22, 95% confidence interval 67‐95) of patients in arms A, B, and C, respectively. Virologic failure occurred in no patients in arm A and in 1 patient each in arms B and C (two patients were lost to follow‐up in arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin were observed. Conclusion: The combination of GLE and PIB was highly efficacious and well tolerated in patients with HCV genotype 1 infection and prior failure of DAA‐containing therapy; RBV coadministration did not improve efficacy. (Hepatology 2017;66:389–397).


    Date de mise en ligne : Lundi 19 juin 2017
    Wen Zhang, Jieliang Chen, Min Wu, Xiaonan Zhang, Min Zhang, Lei Yue, Yaming Li, Jiangxia Liu, Baocun Li, Fang Shen, Yang Wang, Lu Bai, Ulrike Protzer, Massimo Levrero, Zhenghong Yuan
    PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation
    Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The covalently closed circular DNA (cccDNA) minichromosome, which serves as the template for the transcription of viral RNAs, plays a key role in viral persistence. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation of cccDNA‐bound histone 3 (H3) and H4, the potential contributions of histone methylation and related host factors remain obscure. Here, by screening a series of methyltransferases and demethylases, we identified protein arginine methyltransferase 5 (PRMT5) as an effective restrictor of HBV transcription and replication. In cell culture–based models for HBV infection and in liver tissues of patients with chronic HBV infection, we found that symmetric dimethylation of arginine 3 on H4 on cccDNA was a repressive marker of cccDNA transcription and was regulated by PRMT5 depending on its methyltransferase domain. Moreover, PRMT5‐triggered symmetric dimethylation of arginine 3 on H4 on the cccDNA minichromosome involved an interaction with the HBV core protein and the Brg1‐based human SWI/SNF chromatin remodeler, which resulted in down‐regulation of the binding of RNA polymerase II to cccDNA. In addition to the inhibitory effect on cccDNA transcription, PRMT5 inhibited HBV core particle DNA production independently of its methyltransferase activity. Further study revealed that PRMT5 interfered with pregenomic RNA encapsidation by preventing its interaction with viral polymerase protein through binding to the reverse transcriptase–ribonuclease H region of polymerase, which is crucial for the polymerase–pregenomic RNA interaction. Conclusion: PRMT5 restricts HBV replication through a two‐part mechanism including epigenetic suppression of cccDNA transcription and interference with pregenomic RNA encapsidation; these findings improve the understanding of epigenetic regulation of HBV transcription and host–HBV interaction, thus providing new insights into targeted therapeutic intervention. (Hepatology 2017;66:398–415).


    Date de mise en ligne : Jeudi 29 juin 2017
    Jung Eun Jang, Han‐Sol Park, Hyun Ju Yoo, In‐Jeoung Baek, Ji Eun Yoon, Myoung Seok Ko, Ah‐Ram Kim, Hyoun Sik Kim, Hye‐Sun Park, Seung Eun Lee, Seung‐Whan Kim, Su Jung Kim, Jaechan Leem, Yu Mi Kang, Min Kyo Jung, Chan‐Gi Pack, Chong Jai Kim, Chang Ohk Sung, In‐Kyu Lee, Joong‐Yeol Park, JosĂ© C. FernĂĄndez‐Checa, Eun Hee Koh, Ki‐Up Lee
    Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis in mice
    Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)‐containing plasmalogens, expression of glyceronephosphate O‐acyltransferase (Gnpat; the rate‐limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of FC in the liver. Cyclodextrin‐induced depletion of FC transactivated Δ‐6 desaturase by increasing sterol regulatory element‐binding protein 2 expression in cultured hepatocytes. DHA, the major product of Δ‐6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat small interfering RNA treatment significantly decreased peroxisome proliferator‐activated receptor α (Pparα) expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA‐containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor, alkyl glycerol (AG), prevented hepatic steatosis and NASH through a PPARα‐dependent increase in fatty acid oxidation. Gnpat+/– mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Conclusion: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis through GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. (Hepatology 2017;66:416–431).


    Date de mise en ligne : Vendredi 16 juin 2017
    Ling Lin, Ying Ding, Yi Wang, Zhenxin Wang, Xuefei Yin, Guoquan Yan, Lei Zhang, Pengyuan Yang, Huali Shen
    Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism
    Lipids are essential cellular components and energy sources of living organisms, and altered lipid composition is increasingly recognized as a signature of cancer. We performed lipidomic analysis in a series of hepatocellular carcinoma (HCC) cells and identified over 1,700 intact lipids originating from three major lipid categories. Comparative lipidomic screening revealed that 93 significantly changed lipids and decreased palmitic acyl (C16:0)–containing glycerophospholipids were positively associated with metastatic abilities of HCC cells. Furthermore, both in vitro and in vivo experiments demonstrated that C16:0 incubation specifically reduced malignant cell proliferation, impaired cell invasiveness, and suppressed tumor growth in mouse xenograft models. Biochemical experiments demonstrated that C16:0 treatment decreased cell membrane fluidity and limited glucose metabolism. A phosphoproteomics approach further revealed such C16:0 incubation attenuated phosphorylation levels of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) pathway proteins. Multiple reaction monitoring analysis of 443 lipid molecules showed 8 reduced C16:0‐containing lipids out of total 10 altered lipids when cancer tissues were compared with adjacent nontumor tissues in a cohort of clinical HCC specimens (P < 0.05). Conclusion: These data collectively demonstrate the biomedical potential of using altered lipid metabolism as a diagnostic marker for cancerous cells and open an opportunity for treating aggressive HCCs by targeting altered C16:0 metabolism. (Hepatology 2017;66:432–448).


    Date de mise en ligne : Mardi 16 mai 2017
    Hao Wang, Peng An, Enjun Xie, Qian Wu, Xuexian Fang, Hong Gao, Zhuzhen Zhang, Yuzhu Li, Xudong Wang, Jiaying Zhang, Guoli Li, Lei Yang, Wei Liu, Junxia Min, Fudi Wang
    Characterization of ferroptosis in murine models of hemochromatosis
    Ferroptosis is a recently identified iron‐dependent form of nonapoptotic cell death implicated in brain, kidney, and heart pathology. However, the biological roles of iron and iron metabolism in ferroptosis remain poorly understood. Here, we studied the functional role of iron and iron metabolism in the pathogenesis of ferroptosis. We found that ferric citrate potently induces ferroptosis in murine primary hepatocytes and bone marrow–derived macrophages. Next, we screened for ferroptosis in mice fed a high‐iron diet and in mouse models of hereditary hemochromatosis with iron overload. We found that ferroptosis occurred in mice fed a high‐iron diet and in two knockout mouse lines that develop severe iron overload (Hjv–/– and Smad4Alb/Alb mice) but not in a third line that develops only mild iron overload (Hfe–/– mice). Moreover, we found that iron overload–induced liver damage was rescued by the ferroptosis inhibitor ferrostatin‐1. To identify the genes involved in iron‐induced ferroptosis, we performed microarray analyses of iron‐treated bone marrow–derived macrophages. Interestingly, solute carrier family 7, member 11 (Slc7a11), a known ferroptosis‐related gene, was significantly up‐regulated in iron‐treated cells compared with untreated cells. However, genetically deleting Slc7a11 expression was not sufficient to induce ferroptosis in mice. Next, we studied iron‐treated hepatocytes and bone marrow–derived macrophages isolated from Slc7a11–/– mice fed a high‐iron diet. Conclusion: We found that iron treatment induced ferroptosis in Slc7a11–/– cells, indicating that deleting Slc7a11 facilitates the onset of ferroptosis specifically under high‐iron conditions; these results provide compelling evidence that iron plays a key role in triggering Slc7a11‐mediated ferroptosis and suggest that ferroptosis may be a promising target for treating hemochromatosis‐related tissue damage. (Hepatology 2017;66:449–465).


    Date de mise en ligne : Vendredi 30 juin 2017
    Jyoti Srivastava, Chadia L. Robertson, Kareem Ebeid, Mikhail Dozmorov, Devaraja Rajasekaran, Rachel Mendoza, Ayesha Siddiq, Maaged A. Akiel, Nidhi Jariwala, Xue‐Ning Shen, Jolene J. Windle, Mark A. Subler, Nitai D. Mukhopadhyay, Shah Giashuddin, Shobha Ghosh, Zhao Lai, Yidong Chen, Paul B. Fisher, Aliasger K. Salem, Arun J. Sanyal, Devanand Sarkar
    A novel role of astrocyte elevated gene‐1 (AEG‐1) in regulating nonalcoholic steatohepatitis (NASH)
    Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in‐depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene‐1(AEG‐1)/metadherin in NASH using a transgenic mouse with hepatocyte‐specific overexpression of AEG‐1 (Alb/AEG‐1) and a conditional hepatocyte‐specific AEG‐1 knockout mouse (AEG‐1ΔHEP). Alb/AEG‐1 mice developed spontaneous NASH whereas AEG‐1ΔHEP mice were protected from high‐fat diet (HFD)‐induced NASH. Intriguingly, AEG‐1 overexpression was observed in livers of NASH patients and wild‐type (WT) mice that developed steatosis upon feeding HFD. In‐depth molecular analysis unraveled that inhibition of peroxisome proliferator‐activated receptor alpha activity resulting in decreased fatty acid ÎČ‐oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B–mediated inflammation act in concert to mediate AEG‐1‐induced NASH. Therapeutically, hepatocyte‐specific nanoparticle‐delivered AEG‐1 small interfering RNA provided marked protection from HFD‐induced NASH in WT mice. Conclusion: AEG‐1 might be a key molecule regulating initiation and progression of NASH. AEG‐1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466–480).


    Date de mise en ligne : Mardi 27 juin 2017
    Yujie Li, Yongfeng Song, Meng Zhao, Yanjing Guo, Chunxiao Yu, Wenbin Chen, Shanshan Shao, Chao Xu, Xinli Zhou, Lifang Zhao, Zhenhai Zhang, Tao Bo, Yu Xia, Christopher G. Proud, Xuemin Wang, Li Wang, Jiajun Zhao, Ling Gao
    A novel role for CRTC2 in hepatic cholesterol synthesis through SREBP‐2
    Cholesterol synthesis is regulated by the transcription factor sterol regulatory element binding protein 2 (SREBP‐2) and its target gene 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR), which is the rate‐limiting enzyme in cholesterol synthesis. Cyclic adenosine monophosphate–responsive element (CRE) binding protein–regulated transcription coactivator (CRTC) 2 is the master regulator of glucose metabolism. However, the effect of CRTC2 on cholesterol and its potential molecular mechanism remain unclear. Here, we demonstrated that CRTC2 expression and liver cholesterol content were increased in patients with high serum cholesterol levels who underwent resection of liver hemangiomas, as well as in mice fed a 4% cholesterol diet. Mice with adenovirus‐mediated CRTC2 overexpression also showed elevated lipid levels in both serum and liver tissues. Intriguingly, hepatic de novo cholesterol synthesis was markedly increased under these conditions. In contrast, CRTC2 ablation in mice fed a 4% cholesterol diet (18 weeks) showed decreased lipid levels in serum and liver tissues compared with those in littermate wild‐type mice. The expression of lipogenic genes (SREBP‐2 and HMGCR) was consistent with hepatic CRTC2 levels. In vivo imaging showed enhanced adenovirus‐mediated HMGCR‐luciferase activity in adenovirus‐mediated CRTC2 mouse livers; however, the activity was attenuated after mutation of CRE or sterol regulatory element sequences in the HMGCR reporter construct. The effect of CRTC2 on HMGCR in mouse livers was alleviated upon SREBP‐2 knockdown. CRTC2 modulated SREBP‐2 transcription by CRE binding protein, which recognizes the half‐site CRE sequence in the SREBP‐2 promoter. CRTC2 reduced the nuclear protein expression of forkhead box O1 and subsequently increased SREBP‐2 transcription by binding insulin response element 1, rather than insulin response element 2, in the SREBP‐2 promoter. Conclusion: CRTC2 regulates the transcription of SREBP‐2 by interfering with the recognition of insulin response element 1 in the SREBP‐2 promoter by forkhead box O1, thus inducing SREBP‐2/HMGCR signaling and subsequently facilitating hepatic cholesterol synthesis. (Hepatology 2017;66:481–497).


    Date de mise en ligne : Lundi 26 juin 2017
    Kang Ho Kim, Sungwoo Choi, Ying Zhou, Eun Young Kim, Jae Man Lee, Pradip K. Saha, Sayeepriyadarshini Anakk, David D. Moore
    Hepatic FXR/SHP axis modulates systemic glucose and fatty acid homeostasis in aged mice
    The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global double knockout of FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver‐specific Fxr/Shp double knockout mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use. In both DKO and liver‐specific Fxr/Shp double knockout livers, these metabolic phenotypes were associated with altered expression of fatty acid metabolism and autophagy‐machinery genes. Loss of the hepatic FXR/SHP axis reprogrammed white and brown adipose tissue gene expression to boost fatty acid usage. Conclusion: Combined deletion of the hepatic FXR/SHP axis improves glucose/fatty acid homeostasis in aged mice, reversing the aging phenotype of body weight gain, increased adiposity, and glucose/insulin tolerance, suggesting a central role of this axis in whole‐body energy homeostasis. (Hepatology 2017;66:498–509).


    Date de mise en ligne : Lundi 26 juin 2017
    Takashi Kokudo, Kiyoshi Hasegawa, Yutaka Matsuyama, Tadatoshi Takayama, Namiki Izumi, Masumi Kadoya, Masatoshi Kudo, Shoji Kubo, Michiie Sakamoto, Osamu Nakashima, Takashi Kumada, Norihiro Kokudo,
    Liver resection for hepatocellular carcinoma associated with hepatic vein invasion: A Japanese nationwide survey
    Because of the rarity of hepatic vein tumor thrombus (HVTT) compared with portal vein tumor thrombus (PVTT) in patients with hepatocellular carcinoma, little is known about this disease entity. The aim of this study was to evaluate the prognosis of each treatment modality for HVTT through an analysis of data collected in a Japanese nationwide survey. We analyzed data for 1,021 Child‐Pugh A hepatocellular carcinoma patients with HVTT without inferior vena cava invasion registered between 2000 and 2007. Of these patients, 540 who underwent liver resection (LR) and 481 who received other treatments were compared. Propensity scores were calculated, and we successfully matched 223 patients (49.0% of the LR group). The median survival time in the LR group was 2.89 years longer than that in the non‐LR group (4.47 versus 1.58 years, P < 0.001) and 1.61 years longer than that in the non‐LR group (3.42 versus 1.81 years, P = 0.023) in a propensity score–matched cohort. After curative resection, median survival times were similar between patients with HVTT in the peripheral hepatic vein and those with HVTT in the major hepatic vein (4.85 versus 4.67 years, P = 0.974). In the LR group, the postoperative 90‐day mortality rate was 3.4% (16 patients). In patients without PVTT, the median survival time was significantly better than that in patients with PVTT (5.67 versus 1.88 years, P < 0.001). Conclusion: LR is associated with a good prognosis in hepatocellular carcinoma patients with HVTT, especially in patients without PVTT. (Hepatology 2017;66:510–517).


    Date de mise en ligne : Lundi 26 juin 2017
    Mark R. Deneau, Wael El‐Matary, Pamela L. Valentino, Reham Abdou, Khaled Alqoaer, Mansi Amin, Achiya Z. Amir, Marcus Auth, Fateh Bazerbachi, Annemarie Broderick, Albert Chan, Jillian Cotter, Sylvia Doan, Mounif El‐Youssef, Federica Ferrari, Katryn N. Furuya, Madeleine Gottrand, Frederic Gottrand, Nitika Gupta, Matjaz Homan, Binita M. Kamath, Kyung Mo Kim, Kaija‐Leena Kolho, Anastasia Konidari, Bart Koot, Raffaele Iorio, Oren Ledder, Cara Mack, Mercedes Martinez, Tamir Miloh, Parvathi Mohan, Niamh O'Cathain, Alexandra Papadopoulou, Amanda Ricciuto, Lawrence Saubermann, Pushpa Sathya, Eyal Shteyer, Vratislav Smolka, Atushi Tanaka, Raghu Varier, Veena Venkat, Bernadette Vitola, Miriam B. Vos, Marek Woynarowski, Jason Yap, M. Kyle Jensen
    The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration
    There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).


    Date de mise en ligne : Lundi 19 juin 2017
    Ying Wan, Fanyin Meng, Nan Wu, Tianhao Zhou, Julie Venter, Heather Francis, Lindsey Kennedy, Trenton Glaser, Francesca Bernuzzi, Pietro Invernizzi, Shannon Glaser, Qiaobing Huang, Gianfranco Alpini
    Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells
    Substance P (SP) is involved in the proliferation of cholangiocytes in bile duct–ligated (BDL) mice and human cholangiocarcinoma growth by interacting with the neurokinin‐1 receptor (NK‐1R). To identify whether SP regulates liver fibrosis during cholestasis, wild‐type or NK‐1R knockout (NK‐1R–/–) mice that received BDL or sham surgery and multidrug resistance protein 2 knockout (Mdr2–/–) mice treated with either an NK‐1R antagonist (L‐733,060) or saline were used. Additionally, wild‐type mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of tachykinin precursor 1 (coding SP) and NK‐1R in both BDL and Mdr2–/– mice compared to wild‐type mice. Expression of tachykinin precursor 1 and NK‐1R was significantly higher in liver samples from primary sclerosing cholangitis patients compared to healthy controls. Knockout of NK‐1R decreased BDL‐induced liver fibrosis, and treatment with L‐733,060 resulted in decreased liver fibrosis in Mdr2–/– mice, which was shown by decreased sirius red staining, fibrosis gene and protein expression, and reduced transforming growth factor‐ÎČ1 levels in serum and cholangiocyte supernatants. Furthermore, we observed that reduced liver fibrosis in NK‐1R–/– mice with BDL surgery or Mdr2–/– mice treated with L‐733,060 was associated with enhanced cellular senescence of hepatic stellate cells and decreased senescence of cholangiocytes. In vitro, L‐733,060 inhibited SP‐induced expression of fibrotic genes in hepatic stellate cells and cholangiocytes; treatment with L‐733,060 partially reversed the SP‐induced decrease of senescence gene expression in cultured hepatic stellate cells and the SP‐induced increase of senescence‐related gene expression in cultured cholangiocytes. Conclusion: Collectively, our results demonstrate the regulatory effects of the SP/NK‐1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. (Hepatology 2017;66:528–541).


    Date de mise en ligne : Lundi 19 juin 2017
    Luca Maroni, Simon D. Hohenester, Stan F.J. van de Graaf, Dagmar Tolenaars, Krijn van Lienden, Joanne Verheij, Marco Marzioni, Tom H. Karlsen, Ronald P.J. Oude Elferink, Ulrich Beuers
    Knockout of the primary sclerosing cholangitis‐risk gene Fut2 causes liver disease in mice
    The etiopathogenesis of primary sclerosing cholangitis is unknown. Genetic variants of fucosyltransferase 2 (FUT2) have been identified in genome‐wide association studies as risk factors for primary sclerosing cholangitis. We investigated the role of Fut2 in murine liver pathophysiology by studying Fut2–/– mice. Fut2–/– mice were viable and fertile, had lower body weight than wild‐type (wt) littermates and gray fur. Half of the Fut2–/– mice showed serum bile salt levels 40 times higher than wt (Fut2–/–high), whereas the remainder were normocholanemic (Fut2–/–low). Fut2–/– mice showed normal serum liver tests, bile flow, biliary bile salt secretion, fecal bile salt loss, and expression of major hepatocellular bile salt transporters and cytochrome P450 7a1, the key regulator of bile salt synthesis, indicating that elevated serum bile salts in Fut2–/–high mice were not explained by cholestasis. Fut2–/–high mice, but not Fut2–/–low mice, were sensitive to hydrophobic bile salt feeding (0.3% glycochenodeoxycholate); they rapidly lost weight and showed elevation of serum liver tests (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase) and areas of liver parenchymal necrosis. Histomorphological evaluation revealed the presence of paraportal shunting vessels, increased numbers of portal vascular structures, wall thickening of some portal arteries, and periductal fibrosis in Fut2–/–high mice more than Fut2–/–low mice and not wt mice. Unconjugated bilirubin and ammonia were or tended to be elevated in Fut2–/–high mice only. Portosystemic shunting was demonstrated by portal angiography, which disclosed virtually complete portosystemic shunting in Fut2–/–high mice, discrete portosystemic shunting in Fut2–/–low mice, and no shunting in wt littermates. Conclusion: Liver pathology in Fut2–/– mice is dominated by consequences of portosystemic shunting resulting in microcirculatory disturbances, mild (secondary) periductal fibrosis, and sensitivity toward human bile salt toxicity. (Hepatology 2017;66:542–554).


    Date de mise en ligne : Jeudi 22 juin 2017
    Julien Bissonnette, JosĂ© Altamirano, CĂ©cile Devue, Olivier Roux, Audrey PayancĂ©, Didier Lebrec, Pierre Bedossa, Dominique Valla, François Durand, Hafid Ait‐Oufella, Pau Sancho‐Bru, Joan Caballeria, Pere GinĂšs, Chantal M. Boulanger, Ramon Bataller, Pierre‐Emmanuel Rautou
    A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis
    The diagnosis of alcoholic hepatitis (AH) often requires a transjugular liver biopsy (TJLB), a procedure that is not always readily accessible. We analyzed plasma biomarkers to estimate the presence of histological features of AH among patients with clinical suspicion of AH. Using enzyme‐linked immunosorbent assay, we tested M65 and M30 (circulating fragments of cytokeratin‐18) and their respective fraction carried by microvesicles (MVs), CCL20 and TREM1. Leukocyte, platelet, and endothelial‐derived MVs were quantified by way of flow cytometry. Test and validation cohorts prospectively included patients with clinical features of AH undergoing TJLB. In the test cohort, 46 of 83 (55%) patients showed histological features of AH. Age, bilirubin, INR, and creatinine (ABIC) score was B or C in 83%. Patients with histologically proven AH had higher levels of total and MV‐bound M65 and total and MV‐bound M30 and CCL20 than those without (P < 0.001 for all tests). Levels of TREM‐1 and of subpopulations of MVs were not different between groups. M65 and M30 both had an area under the receiver operating characteristics curve of 0.84 to estimate the presence of AH. For M65, a cutoff of 2000 IU/L had a positive predictive value of 91%, whereas a cutoff of 641 IU/L had a negative predictive value of 88%. In the validation cohort, AH was histologically confirmed in 48 of 68 (71%) patients. ABIC score was B or C in 69% of patients. For M65, the above cutoffs had a diagnostic accuracy of 81%. Even better results were obtained in patients with suspicion of severe AH (ABIC B or C) in both cohorts. Conclusion: Plasma levels of cytokeratin‐18 fragments are reliable noninvasive markers of AH. Using the proposed cutoffs for M65, two thirds of TJLB can be avoided, which can be useful in centers where this technique is not readily available. (Hepatology 2017;66:555–563).


    Date de mise en ligne : Mercredi 28 juin 2017
    Jennifer C. Lai, Kenneth E. Covinsky, Jennifer L. Dodge, W. John Boscardin, Dorry L. Segev, John P. Roberts, Sandy Feng
    Development of a novel frailty index to predict mortality in patients with end‐stage liver disease
    Cirrhosis is characterized by muscle wasting, malnutrition, and functional decline that confer excess mortality not well quantified by the Model for End‐Stage Liver Disease (MELD) Sodium (MELDNa) score. We aimed to develop a frailty index to capture these extrahepatic complications of cirrhosis and enhance mortality prediction in patients with cirrhosis. Consecutive outpatients listed for liver transplantation at a single transplant center without MELD exceptions were assessed with candidate frailty measures. Best subset selection analyses with Cox regression identified subsets of frailty measures that predicted waitlist mortality (=death or delisting because of sickness). We selected the frailty index by balancing statistical accuracy with clinical utility. The net reclassification index (NRI) evaluated the %patients correctly reclassified by adding the frailty index to MELDNa. Included were 536 patients with cirrhosis with median MELDNa of 18. One hundred seven (20%) died/were delisted. The final frailty index consisted of: grip strength, chair stands, and balance. The ability of MELDNa and the frailty index to correctly rank patients according to their 3‐month waitlist mortality risk (i.e., concordance‐statistic) was 0.80 and 0.76, respectively, but 0.82 for MELDNa+frailty index together. Compared with MELDNa alone, MELDNa+frailty index correctly reclassified 16% of deaths/delistings (P = 0.005) and 3% of nondeaths/delistings (P = 0.17) with a total NRI of 19% (P < 0.001). Compared to those with robust frailty index scores (<20th percentile), cirrhotics with poor frailty index scores (>80th percentile) were more impaired by gait speed, difficulty with Instrumental Activities of Daily Living, exhaustion, and low physical activity (P < 0.001 for each). Conclusion: Our frailty index for patients with cirrhosis, comprised of three performance‐based metrics, has construct validity for the concept of frailty and improves risk prediction of waitlist mortality over MELDNa alone. (Hepatology 2017;66:564–574).


    Date de mise en ligne : Vendredi 30 juin 2017
    Wei Li, Tohti Amet, Yanyan Xing, Dennis Yang, Suthat Liangpunsakul, Puneet Puri, Patrick S. Kamath, Arun J. Sanyal, Vijay H. Shah, Barry P. Katz, Svetlana Radaeva, David W. Crabb, Naga Chalasani, Qigui Yu
    Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study
    Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty‐eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL‐6], IL‐8, interferon gamma–induced protein 10, IL‐4, IL‐9, IL‐10, fibroblast growth factor 2, IL‐7, IL‐15, and transforming growth factor alpha) but lower levels of the anti‐inflammatory macrophage‐derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon‐gamma in response to T‐cell stimulation. Up‐regulated IL‐6, IL‐8, CD38, and CD69 and down‐regulated macrophage‐derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL‐6, IL‐8, CD38, and CD69 were reduced, whereas levels of macrophage‐derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL‐8, IL‐10, fibroblast growth factor 2, and IL‐7 remained higher. Conclusion: AH patients were in a highly immune‐dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575–590).


    Date de mise en ligne : Lundi 26 juin 2017
    Christopher Koh, Sasan Sakiani, Pallavi Surana, Xiongce Zhao, Jason Eccleston, David E. Kleiner, David Herion, T. Jake Liang, Jay H. Hoofnagle, Milica Chernick, Theo Heller
    Adult‐onset cystic fibrosis liver disease: Diagnosis and characterization of an underappreciated entity
    Cystic fibrosis (CF) liver disease (CFLD), a leading cause of death in CF, is mostly described in pediatric populations. Adult‐onset CFLD lacks sufficient characterization and diagnostic tools. A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with newly proposed CFLD criteria. Thirty‐six CF patients were followed for a median of 24.5 years (interquartile range 15.6‐32.9). By the last follow‐up, 11 (31%) had died. With conventional criteria, 8 (22%) patients had CFLD; and by the new criteria, 17 (47%) had CFLD at a median age of 36.6 years (interquartile range 26.5‐43.2). By the new criteria, those with CFLD had higher median alanine aminotransferase (42 versus 27, P = 0.005), aspartate aminotransferase (AST; 26 versus 21, P = 0.01), direct bilirubin (0.13 versus 0.1, P = 0.01), prothrombin time (14.4 versus 12.4, P = 0.002), and AST‐to‐platelet ratio index (0.31 versus 0.23, P = 0.003) over the last 2 years of follow‐up. Subjects with a FibroScan >6.8 kPa had higher alanine aminotransferase (42 versus 28U/L, P = 0.02), AST (35 versus 25U/L, P = 0.02), AST‐to‐platelet ratio index (0.77 versus 0.25, P = 0.0004), and Fibrosis‐4 index (2.14 versus 0.74, P = 0.0003) and lower platelet counts (205 versus 293, P = 0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group (from 310 to 230 U/L, P = 0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD (143 versus 258 U/L, P = 0.004) or those deceased with no CFLD (143 versus 327U/L, P = 0.006). Conclusion: Adult‐onset CFLD may be more prevalent than previously described, which suggests a later wave of CFLD that impacts morbidity; routine liver tests, radiologic imaging, noninvasive fibrosis markers, and FibroScan can be used algorithmically to identify adult CFLD; and further evaluation in other CF cohorts should be performed for validation. (Hepatology 2017;66:591–601).


    Date de mise en ligne : Mardi 04 juillet 2017
    Paramananda Saikia, Damien Bellos, Megan R. McMullen, Katherine A. Pollard, Carol de la Motte, Laura E. Nagy
    MicroRNA 181b‐3p and its target importin α5 regulate toll‐like receptor 4 signaling in Kupffer cells and liver injury in mice in response to ethanol
    Increased inflammatory signaling by Kupffer cells contributes to alcoholic liver disease (ALD). Here we investigated the impact of small, specific‐sized hyaluronic acid of 35 kD (HA35) on ethanol‐induced sensitization of Kupffer cells, as well as ethanol‐induced liver injury in mice. Unbiased analysis of microRNA (miRNA) expression in Kupffer cells identified miRNAs regulated by both ethanol and HA35. Toll‐like receptor 4 (TLR4)‐mediated signaling was assessed in primary cultures of Kupffer cells from ethanol‐ and pair‐fed rats after treatment with HA35. Female C57BL6/J mice were fed ethanol or pair‐fed control diets and treated or not with HA35. TLR4 signaling was increased in Kupffer cells by ethanol; this sensitization was normalized by ex vivo treatment with HA35. Next generation sequencing of Kupffer cell miRNA identified miRNA 181b‐3p (miR181b‐3p) as sensitive to both ethanol and HA35. Importin α5, a protein involved in p65 translocation to the nucleus, was identified as a target of miR181b‐3p; importin α5 protein was increased in Kupffer cells from ethanol‐fed rats, but decreased by HA35 treatment. Overexpression of miR181b‐3p decreased importin α5 expression and normalized lipopolysaccharide‐stimulated tumor necrosis factor α expression in Kupffer cells from ethanol‐fed rats. In a mouse model of ALD, ethanol feeding decreased miR181b‐3p in liver and increased expression of importin α5 in nonparenchymal cells. Treatment with HA35 normalized these changes and also protected mice from ethanol‐induced liver and intestinal injury. Conclusion: miR181b‐3p is dynamically regulated in Kupffer cells and mouse liver in response to ethanol and treatment with HA35. miR181b‐3p modulates expression of importin α5 and sensitivity of TLR4‐mediated signaling. This study identifies a miR181b‐3p–importin α5 axis in regulating inflammatory signaling pathways in hepatic macrophages. (Hepatology 2017;66:602–615).


    Date de mise en ligne : Lundi 26 juin 2017
    Christian Loeffelholz, Stefanie Lieske, Frank NeuschĂ€fer‐Rube, Diana M. Willmes, Nathanael Raschzok, Igor M. Sauer, Jörg König, Martin F. Fromm, Paul Horn, Antonios Chatzigeorgiou, Andrea Pathe‐NeuschĂ€fer‐Rube, Jens Jordan, Andreas F.H. Pfeiffer, Geltrude Mingrone, Stefan R. Bornstein, Peter Stroehle, Christoph Harms, F. Thomas Wunderlich, Stephen L. Helfand, Michel Bernier, Rafael Cabo, Gerald I. Shulman, Triantafyllos Chavakis, Gerhard P. PĂŒschel, Andreas L. Birkenfeld
    The human longevity gene homolog INDY and interleukin‐6 interact in hepatic lipid metabolism
    Reduced expression of the Indy (“I am Not Dead, Yet”) gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane–associated citrate transporter expressed highly in the liver, protects mice from high‐fat diet–induced and aging‐induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin‐resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2‐year high‐fat, high‐sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin‐6 (IL‐6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL‐6 markedly induced mIndy transcription through the IL‐6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL‐6–signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL‐6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL‐6 and determine novel functions of IL‐6 through mINDY. Conclusion: Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616–630).


    Date de mise en ligne : Lundi 19 juin 2017
    Shanshan Liu, Yu Sun, Ming Jiang, Yangkai Li, Ye Tian, Weili Xue, Ninghe Ding, Yue Sun, Cheng Cheng, Jianshuang Li, Xiaoping Miao, Xinran Liu, Ling Zheng, Kun Huang
    Glyceraldehyde‐3‐phosphate dehydrogenase promotes liver tumorigenesis by modulating phosphoglycerate dehydrogenase
    Up‐regulated glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is observed in multiple cancers with unclear mechanism. Using GAPDH transgenic mouse and a mouse model of diethylnitrosamine‐induced hepatocellular carcinoma (HCC), here we show that GAPDH overexpression aggravated tumor development by activating cell proliferation and inflammation. In cultured hepatic cells, overexpression of GAPDH or a catalytic domain‐deleted GAPDH (GAPDHΔCD) affected metabolism, up‐regulated phosphoglycerate dehydrogenase (PHGDH), increased histone methylation levels, and promoted proliferation. Consistently, inhibition of GAPDH by short hairpin RNA reprogrammed metabolism down‐regulated PHGDH and histone methylation, and inhibited proliferation. The xenograft study suggested that HepG2 cells overexpressing GAPDH or GAPDHΔCD similarly promoted tumor development, whereas knockdown PHGDH in GAPDH overexpressing cells significantly inhibited tumor development. In liver sections of HCC patients, increased GAPDH staining was found to be positively correlated with PHGDH and histone methylation staining. Conclusion: GAPDH increases histone methylation levels by up‐regulating PHGDH, promoting diversion from glycolysis to serine biosynthesis, and consequently accelerating HCC development. (Hepatology 2017;66:631–645).


    Date de mise en ligne : Lundi 26 juin 2017
    Christine M. Hunt, Julie I. Papay, Vid Stanulovic, Arie Regev
    Drug rechallenge following drug‐induced liver injury
    Drug‐induced hepatocellular injury is identified internationally by alanine aminotransferase (ALT) levels equal to or exceeding 5× the upper limit of normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decrease by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT level of 3‐5× ULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug‐induced liver injury (DILI): antimicrobials; and central nervous system, cardiovascular and oncology therapeutics. Drugs associated with high rates of positive rechallenge exhibit multiple risk factors: daily dose >50 mg, an increased incidence of ALT elevations in clinical trials, immunoallergic clinical injury, and mitochondrial impairment in vitro. These drug factors interact with personal genetic, immune, and metabolic factors to influence positive rechallenge rates and outcomes. Drug rechallenge following drug‐induced liver injury is associated with up to 13% mortality in prospective series of all prescribed drugs. In recent oncology trials, standardized systems have enabled safer drug rechallenge with weekly liver chemistry monitoring during the high‐risk period and exclusion of patients with hypersensitivity. However, high positive rechallenge rates with other innovative therapeutics suggest that caution should be taken with rechallenge of high‐risk drugs. Conclusion: For critical medicines, drug rechallenge may be appropriate when 1) no safer alternatives are available, 2) the objective benefit exceeds the risk, and 3) patients are fully informed and consent, can adhere to follow‐up, and alert providers to hepatitis symptoms. To better understand rechallenge outcomes and identify key risk factors for positive rechallenge, additional data are needed from controlled clinical trials, prospective registries, and large health care databases. (Hepatology 2017;66:646–654).


    Date de mise en ligne : Jeudi 22 juin 2017
    Daniel Azoulay, Eylon Lahat, Chady Salloum, Philippe Compagnon, Cyrille Feray
    Heterotopic liver retransplantation for impossible former graft explantation
    657


    Date de mise en ligne : Jeudi 22 juin 2017
    Jonathan J. Hogan, Mary Ann Lim, Matthew B. Palmer, Roy D. Bloom, Raymond T. Chung, Meghan E. Sise
    Development of proteinuria and focal segmental glomerulosclerosis during direct‐acting antiviral therapy for hepatitis C virus infection
    660


    Date de mise en ligne : Samedi 24 juin 2017
    Behnam Saberi, Alia S. Dadabhai, Christine M. Durand, Benjamin Philosophe, Andrew M. Cameron, Mark S. Sulkowski, Ahmet Gurakar
    Challenges in treatment of hepatitis C among patients with hepatocellular carcinoma
    663


    Date de mise en ligne : Jeudi 22 juin 2017
    Shintaro Ichikawa, Utaroh Motosugi, Mitsuhiko Oguri, Hiroshi Onishi
    Magnetic resonance elastography for prediction of radiation‐induced liver disease after stereotactic body radiation therapy
    665


    Date de mise en ligne : Mardi 04 juillet 2017
    Marcin Krawczyk, Monika Rau, Frank GrĂŒnhage, Jörn M. Schattenberg, Heike Bantel, Anita Pathil, MĂŒnevver Demir, Johannes Kluwe, Tobias Boettler, Andreas Geier, Frank Lammert,
    The ABCB4 p.T175A variant as potential modulator of hepatic fibrosis in patients with chronic liver diseases: Looking beyond the cholestatic realm
    667


    Date de mise en ligne : Mardi 04 juillet 2017
    Andreas Geier, Daniel Jahn, Heike M. Hermanns
    Interleukin‐6: The dark side of liver regeneration in chronic liver disease
    668


    Date de mise en ligne : Mardi 04 juillet 2017
    Ewan Forrest
    Clinical criteria are critical to diagnosing alcoholic hepatitis
    669


    Date de mise en ligne : Mardi 04 juillet 2017
    Heng Fan, Jian‐hua Zhu
    FABP1 as a novel potential biomarker for predicting mortality in acetaminophen‐induced acute liver failure
    670


    Date de mise en ligne : Mardi 04 juillet 2017
    Constantine J. Karvellas, Jaime L. Speiser, MĂ©lanie Tremblay, William M. Lee, Christopher F. Rose,
    REPLY:
    671


    Date de mise en ligne : Mardi 04 juillet 2017
    Han Zhang, Zhen‐Li Li, Hao Xing, Meng‐Chao Wu, Tian Yang
    Hepatocellular carcinoma surveillance: Sometimes just specialists' incidental behavior?
    672


    Date de mise en ligne : Mercredi 28 juin 2017
    Thomas Pembroke, Giada Sebastiani
    Hepatic steatosis, hepatitis C, and human immunodeficiency viruses: A complex interplay
    674


    Date de mise en ligne : Mercredi 28 juin 2017
    Jennifer C. Price, Phyllis C. Tien
    Reply
    675


    Date de mise en ligne : Mercredi 28 juin 2017
    Takashi Kokudo, Kiyoshi Hasegawa, Norihiro Kokudo
    Assessment of preoperative liver function based on indocyanine green clearance
    676


    Date de mise en ligne : Mercredi 28 juin 2017
    Tatehiro Kagawa, Yukihiko Adachi
    Reply
    676


    Date de mise en ligne : Mercredi 28 juin 2017
    Antonio Ponzetto, Guillermo I. Perez‐Perez, Natale Figura
    Alpha1‐antitrypsin deficiency and c‐JUN
    677


    Date de mise en ligne : Mercredi 28 juin 2017
    Nunzia Pastore, Sergio Attanasio, Nicola Brunetti‐Pierri
    Reply
    678


    Date de mise en ligne : Mercredi 28 juin 2017
    Hanna K. Sanoff, YunKyung Chang, Jennifer L. Lund, Bert H. O'Neil, Stacie B. Dusetzina
    Immortal time bias or sorafenib effect in elderly patients with HCC?
    679


    Date de mise en ligne : Mercredi 28 juin 2017
    Neehar D. Parikh, Amit G. Singal, Anna S. Lok, Rajesh Balkrishnan, Vahakn Shahinian, Vincent D. Marshall
    Reply
    680


    Date de mise en ligne : Mercredi 28 juin 2017
    Chia‐Chi Wang, Jia‐Horng Kao
    Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: A cohort study
    681


    Date de mise en ligne : Mardi 04 juillet 2017
    Eun‐Jeong Joo, Yoosoo Chang, Seungho Ryu
    Reply:
    682


    Date de mise en ligne : Mercredi 19 juillet 2017
    Notices
    Notices
    n/a


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