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Les derniers abstracts de la revue Hepatology :


    Date de mise en ligne : Jeudi 30 mars 2017
    Pramod Kumar, Sunil Taneja, Virendra Singh
    Do the dose and type of NSBBs really matter?
    n/a


    Date de mise en ligne : Jeudi 30 mars 2017
    Alessandro Soria, Massimiliano Fabbiani, Giuseppe Lapadula, Andrea Gori
    Unexpected viral relapses in HCV‐infected patients diagnosed with hepatocellular carcinoma during treatment with DAAs
    n/a


    Date de mise en ligne : Jeudi 30 mars 2017
    Marco Cassano, Sandra Offner, Evarist Planet, Alessandra Piersigilli, Suk Min Jang, Hugues Henry, Markus B. Geuking, Catherine Mooser, Kathy D. McCoy, Andrew J. Macpherson, Didier Trono
    Polyphenic trait promotes liver cancer in a model of epigenetic instability
    Hepatocellular carcinoma (HCC) represents the fifth most common form of cancer worldwide and carries a high mortality rate due to lack of effective treatment. Males are eight times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28hep‐/‐ mice display sex‐specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and ageing precipitate alterations of TRIM28‐dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male‐restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances and altered responses to gut microbiota in the pathogenesis of Trim28hep‐/‐‐associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high‐fat diet challenge. Conclusion: This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer‐prone state, and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota and cancer. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 30 mars 2017
    Robert P. Perrillo
    HBV Reactivation During DAA Treatment of Chronic Hepatitis C: A Hidden Danger of an Otherwise Major Success Story
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    Date de mise en ligne : Jeudi 30 mars 2017
    German Soriano, Jasmohan S. Bajaj
    Grading the range of hepatic encephalopathy from overt to covert: Animals to the Rescue!
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    Date de mise en ligne : Jeudi 30 mars 2017
    Pin Liu, Mengmeng Ge, Junjie Hu, Xiaolei Li, Li Che, Kun Sun, Lili Cheng, Yuedong Huang, Maria G. Pilo, Antonio Cigliano, Giovanni M. Pes, Rosa M. Pascale, Stefania Brozzetti, Gianpaolo Vidili, Alberto Porcu, Antonio Cossu, Giuseppe Palmieri, Maria C. Sini, Silvia Ribback, Frank Dombrowski, Junyan Tao, Diego F. Calvisi, Ligong Chen, Xin Chen
    A functional mTORC1 signaling is indispensable for c‐Myc driven hepatocarcinogenesis
    Amplification and/or activation of the c‐Myc protooncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c‐Myc has been proven experimentally by the finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c‐Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c‐Myc dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of the mTORC1 complex, strongly inhibits c‐Myc liver tumor formation. Also, p70S6K/ribosomal protein S6 (RPS6) and eukaryotic translation initiation factor 4E‐binding protein 1/eukaryotic translation initiation factor 4E (4EBP1/eIF4E) signaling cascades downstream of mTORC1 are required for c‐Myc‐driven tumorigenesis. Intriguingly, microarray expression analysis revealed the upregulation of multiple amino acid transporters, including SLC1A5 and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c‐Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1, as their inhibition suppressed mTORC1 in c‐Myc tumor cells. In human HCC specimens, levels of c‐Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion: Our current study indicates that an intact mTORC1 axis is required for c‐Myc‐driven hepatocarcinogenesis. Thus, targeting mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of HCC with activated c‐Myc signaling. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 30 mars 2017
    Samer Tohme, Hamza O Yazdani, Yao Liu, Patricia Loughran, Dirk J van der Windt, Hai Huang, Richard L Simmons, Sruti Shiva, Sheng Tai, Allan Tsung
    Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth via HMGB1 and TLR9 interaction
    The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator‐activated receptor gamma (PGC‐1α) and upregulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC‐1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular High Mobility Group Box (HMGB)‐1 protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC‐1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced ATP production and decreased cellular proliferation and increased apoptosis. In a diethynitrosamine (DEN)‐induced murine model of HCC, genetic blocking of HMGB1 in the hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that, during hypoxia, HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll‐like receptor (TLR)‐9. This binding leads to the activation of p38 and subsequent phosphorylation of PGC‐1α with resultant upregulation of mitochondrial biogenesis. Conclusion: Taken together, our findings suggest that during hypoxia HMGB1 upregulates mitochondrial biogenesis in HCC cancer cells promoting tumor survival and proliferation. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 30 mars 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 non‐inferior efïŹcacy to TDF plus entecavir (ETV) combination therapy in patients with HBV resistant to multiple drugs, including ETV and adefovir, respectively. 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 TDF‐TDF group and 68.0% in 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 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 six 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 six retained some of their baseline resistance mutations of HBV. No patients developed additional resistance mutations throughout the study period. In 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 25 mars 2017
    Guadalupe Garcia‐Tsao, Juan G. Abraldes, Annalisa Berzigotti, Jaime Bosch
    Reply to: Does the dose and type of NSBBs really matter?
    n/a


    Date de mise en ligne : Mercredi 22 mars 2017
    Seong‐Jun Kim, Jae Young Jang, Eun‐Jung Kim, Eun Kyung Cho, Dae Gyun Ahn, Chonsaeng Kim, Han Seul Park, Soung Won Jeong, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Hong Soo Kim, Boo Sung Kim, Ji‐Hyung Lee, Aleem Siddiqui
    Ginsenoside Rg3 Restores Hepatitis C Virus‐Induced Aberrant Mitochondrial Dynamics and Inhibits Virus Propagation
    Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct‐acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their treatment of patients with chronic hepatitis C in interferon‐sparing regimens occasionally produces undesirable side effects such as fatigue, migraine and other conditions, which may be linked to mitochondrial dysfunction. Here we show that clinically prescribed DAAs, including Sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV‐ and DAA‐induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of the mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only One of the compounds, ginsenoside Rg3 (G‐Rg3), exhibited the notable and promising anti‐HCV potential. Treatment of HCV‐infected cells with G‐Rg3 increased HCV core protein‐mediated reduction in the expression level of cytosolic p21 required for increasing the cyclin‐dependent kinase 1 (CDK1) activity, which catalyzes Ser616 phosphorylation of dynamin‐related protein 1 (Drp1). The HCV‐induced mitophagy, which follows mitochondrial fission, was also rescued by G‐Rg3 treatment. CONCLUSIONS: G‐Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV‐induced Drp1‐mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 20 mars 2017
    Alain Braillon
    Screening for hepatocellular carcinoma: A drug safety issue
    n/a


    Date de mise en ligne : Lundi 20 mars 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 HBV‐ and HCV‐related cirrhosis: A population‐based study
    Background & Aim: Statin decreased the risk of decompensation and mortality in veteran patients with cirrhosis due to hepatitis C virus (HCV). Whether this beneficial effect can be extended to cirrhosis in general population or cirrhosis with other causes, such as hepatitis B virus (HBV) infection and alcohol, remains unknown. Statin also decreased 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 already with cirrhosis. We aimed to determine the statin effect on decreasing decompensation, mortality and HCC in HBV‐, HCV‐ and alcohol‐related cirrhosis. Methods: Cirrhotic patients were identified from a representative cohort of Taiwan National Health Insurance beneficiaries from 2000‐2013. Statin users, defined as having a cumulative defined daily dose (cDDD) ≄ 28, were selected and served as the case cohort. Statin non‐users (< 28 cDDD) were matched through propensity scores. The association between statin use and the risk of decompensation, mortality, and HCC were estimated Results: A total of 1,350 cirrhotic patients were enrolled. Among patients with cirrhosis, statin use had decreased the risk of decompensation, mortality and HCC in a dose dependent manner (p for trend: < .0001, < .0001, and 0.009). Regression analysis showed a lower risk of decompensation among statin users with cirrhosis due to chronic HBV (adjusted hazard ratio [95% confidence interval], 0.39 [0.25‐0.62]) or HCV infection (0.51 [0.29‐0.93]). The lowered risk of decompensation was of borderline significance among statin users with alcohol‐related cirrhosis (0.69 [0.45‐1.07]). Conclusions: 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 20 mars 2017
    Pierre Nahon, Olivier Seror, Isabelle Durand‐Zaleski
    Reply to: «Screening for Hepatocellular carcinoma: A drug safety issue»
    n/a


    Date de mise en ligne : Lundi 20 mars 2017
    Duminda Suraweera, Sammy Saab
    Hepatitis C Treatment Threshold in Patients with Decompensated Liver Disease
    n/a


    Date de mise en ligne : Lundi 20 mars 2017
    Amy EL Stone, Michael Gale
    Beyond Sensing: RIG‐I continues to expand its antiviral effector functions
    n/a


    Date de mise en ligne : Lundi 20 mars 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 (HCC). 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) towards fibrosis. In this study, we examined cross‐talk between macrophages and HSCs following HCV infection. Primary human HSCs and immortalized HSCs (LX2 cells) were incubated with conditioned medium (CM) derived from HCV exposed human macrophages. The expression of inflammasome and fibrosis related genes in these cells were examined and demonstrated an increased expression of inflammatory (NLRP3, IL‐1ÎČ, IL‐6 and CCL5) and profibrogenic (TGFÎČ1, COL4A1, MMP2 and α‐SMA) markers. Further investigation suggested that CCL5, secreted from HCV exposed macrophages, activates inflammasome and fibrosis makers in HSCs, and 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 20 mars 2017
    Marianna Hösel, Anke Huber, Susanne Bohlen, Julie Lucifora, Giuseppe Ronzitti, Francesco Puzzo, Florence Boisgerault, Ulrich T. Hacker, Wilhelmus J. Kwanten, Nora Klöting, Matthias BlĂŒher, Alexander Gluschko, Michael Schramm, Olaf Utermöhlen, Wilhelm Bloch, Federico Mingozzi, Oleg Krut, Hildegard BĂŒning
    Autophagy Determines Efficiency of Liver‐directed Gene Therapy with Adeno‐associated Viral Vectors
    Use of Adeno‐associated viral (AAV) vectors for liver‐directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)‐dependent autophagy in human hepatocytes. This cell response was crucially required for efficient transduction because under condition of impaired autophagy (pharmacological inhibition, siRNA knock‐down of autophagic proteins or suppression by food intake), rAAV‐mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependency, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter or AAV serotype, and was subsequently confirmed in vivo. Specifically, short‐term treatment with a single dose of torin 1 significantly increased vector‐mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, co‐administration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid‐α‐glucosidase in non‐human primates. Conclusion: We identified autophagy as a pivotal cell response determining the efficiency of AAV's intracellular processing in hepatocytes and thus the outcome of liver‐directed gene therapy using AAV vectors, and showed in a proof‐of‐principle study how this newly identified virus‐host‐interaction can be employed to enhance efficacy of this vector system. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 20 mars 2017
    Kyle S. McCommis, Jerry R. Colca, Brian N. Finck
    Reply to correspondence: Targeting mitochondrial pyruvate carrier (MPC) in NASH: Growing evidence and future challenges
    n/a


    Date de mise en ligne : Lundi 20 mars 2017
    Giovanni Musso, Roberto Gambino
    Targeting mitochondrial pyruvate carrier (MPC) in NASH: Growing evidence and future challenges
    n/a


    Date de mise en ligne : Lundi 20 mars 2017
    SĂžren MĂžller, Jens D. Hove
    Assessment of systolic function in the evaluation of patients with cirrhosis
    n/a


    Date de mise en ligne : Lundi 20 mars 2017
    Ângelo Zambam de Mattos, Suelen Aparecida da Silva Miozzo, Cristiane Valle Tovo, Angelo Alves de Mattos
    Risks of proton pump inhibitors for cirrhotic patients – the controversy remains
    n/a


    Date de mise en ligne : Mercredi 15 mars 2017
    Pasquale Piccolo, Patrizia Annunziata, Leandro R. Soria, Sergio Attanasio, Anna Barbato, Raffaele Castello, Annamaria Carissimo, Luca Quagliata, Luigi M. Terracciano, Nicola Brunetti‐Pierri
    Downregulation of HNF‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin
    α1‐antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of α1‐antitrypsin (ATZ) is a prototype of conformational disorder due to misfolding of protein with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing the human ATZ have altered expression of a network of hepatocyte transcriptional factors including HNF4‐α, that is early downregulated and induces a transcriptional repression of ATZ expression. Reduced HNF‐4α was associated with activation of ÎČ‐catenin that regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Downregulation of HNF‐4α expression and defective zonation in livers have not been yet recognized as features of the liver disease caused by ATZ and are likely responsible for metabolic disturbances and for the increased risks of hepatocellular carcinoma in patients with AAT deficiency. In conclusion, these findings are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effect on metabolic liver functions. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 14 mars 2017
    Chad Walesky, Wolfram Goessling
    WNTing no RASt for HCC
    n/a


    Date de mise en ligne : Lundi 13 mars 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 ALT 5x upper limits normal (ULN) appearing within 3 months of drug initiation, after alternative causes are excluded. Upon withdrawing the suspect drug, ALT generally decreases by 50% or more. With drug readministration, a positive rechallenge has recently been defined by an ALT 3‐5xULN or greater. Nearly 50 drugs are associated with positive rechallenge after drug‐induced liver injury (DILI): antimicrobials, 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 enable safer drug rechallenge with weekly liver chemistry monitoring during the high risk period and exclusion of patients with hypersensitivity. Yet, high positive rechallenge rates with other innovative therapeutics suggest caution with rechallenge of high risk drugs. Conclusion: For critical medicines, drug rechallenge may be appropriate, when no safer alternatives are available, the objective benefit exceeds the risk, and 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 is needed from controlled clinical trials, prospective registries, and large healthcare databases. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 mars 2017
    Yong He, Dechun Feng, Man Li, Yanhang Gao, Teresa Ramirez, Haixia Cao, Seung‐Jin Kim, Yang Yang, Yan Cai, Cynthia Ju, Hua Wang, Jun Li, Bin Gao
    Hepatic mtDNA‐TLR9‐microRNA‐223 forms a negative feedback loop to limit neutrophil over‐activation and acetaminophen hepatotoxicity
    Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, in which mitochondrial DNA (mtDNA) released by damaged hepatocytes activates neutrophils via the binding of TLR9, further aggravating liver injury. Here, we demonstrated that mtDNA/TLR9 also activates a negative feedback pathway via the induction of microRNA‐223 (miR‐223) to limit neutrophil over‐activation and liver injury. After injection of APAP in mice, levels of miR‐223, the most abundant miRNAs in neutrophils, were highly elevated in neutrophils. Disruption of the miR‐223 gene exacerbated APAP‐induced hepatic neutrophil infiltration, oxidative stress, and injury, and enhanced TLR9 ligand‐mediated activation of pro‐inflammatory mediators in neutrophils. An additional deletion of the intercellular adhesion molecule 1 (ICAM‐1) gene ameliorated APAP‐induced neutrophil infiltration and liver injury in miR‐223 knockout mice. In vitro experiments revealed that miR‐223‐deficient neutrophils were more susceptible to TLR9 agonist‐mediated induction of pro‐inflammatory mediators and NF‐ÎșB signaling; whereas overexpression of miR‐223 attenuated these effects in neutrophils. Moreover, inhibition of TLR9 signaling via either treatment with a TLR9 inhibitor or via the disruption of TLR9 gene partially but significantly suppressed miR‐223 expression in neutrophils post APAP injection. In contrast, activation of TLR9 upregulated miR‐223 expression in neutrophils in vivo and in vitro. Mechanistically, activation of TLR9 upregulated miR‐223 by enhancing NF‐ÎșB binding on miR‐223 promoter; while miR‐223 attenuated TLR9/NF‐ÎșB‐mediated inflammation by targeting IKKα expression. Collectively, upregulation of miR‐223 plays a key role in terminating the acute neutrophilic response and is a therapeutic target for the treatment of APAP‐induced liver failure. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 mars 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 inflammatory related to multiple hepatic adenomas that completely resolved after cessation of the oral contraceptive pill and associated adenoma regression. This represents the first case of such dramatic symptoms to resolve after estrogen withdrawal alone. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 mars 2017
    Yingyun Yang, Ye Zhou, Jin Hou, Chunmei Bai, Zhenyang Li, Jia Fan, Irene O.L. Ng, Weiping Zhou, Huichuan Sun, Qiongzhu Dong, Joyce M.F. Lee, Chung‐Mau Lo, Kwan Man, Yun Yang, Nan Li, Guoshan Ding, Yizhi Yu, Xuetao Cao
    Hepatic IFIT3 predicts interferon‐α therapeutic response in patients of hepatocellular carcinoma
    Adjuvant interferon‐α (IFN‐α) therapy is used to control certain types of cancer in clinics. For hepatocellular carcinoma (HCC), IFN‐α therapy is effective in only a subgroup of HCC patients, therefore identifying biomarkers to predict the response to IFN‐α therapy is of high significance and clinical utility. As the induced IFN‐stimulated genes (ISGs) expression following IFN‐α treatment plays pivotal roles in IFN‐α effects, we screened ISGs expression in HCC tissues and found several ISGs were significantly decreased in HCC. Interestingly, expressions of IFN‐induced proteins with tetratricopeptide repeats (IFIT) family members, including IFIT1, IFIT2, IFIT3, and IFIT5, were all decreased in HCC tissues. We further analyzed the expressions of IFIT family members in HCC and their roles in patients' responses to IFN‐α therapy in two independent randomized controlled IFN‐α therapy clinical trials of HCC patients. We found that higher expression of IFIT3, but not other IFITs, in HCC tissues predicts better response to IFN‐α therapy, suggesting that IFIT3 may be a useful predictor of the response to IFN‐α therapy in HCC patients. Mechanistically, IFIT3 enhanced the antitumor effects of IFN‐α by promoting IFN‐α effector responses both in vitro and in vivo. IFIT3 could bind signal transducer and activator of transcription 1 (STAT1) and STAT2 to enhance STAT1/STAT2 hetero‐dimerization and nuclear translocation upon IFN‐α treatment, thus promoting IFN‐α effector signaling. Conclusion: Higher IFIT3 expression in HCC tissues predicts better response to IFN‐α therapy in HCC patients. IFIT3 promotes IFN‐α effector responses and therapeutic effects by strengthening IFN‐α effector signaling in HCC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 mars 2017
    Anna D. Kosinska, Leila Pishraft‐Sabet, Weimin Wu, Zhong Fang, Marzena Lenart, Jieliang Chen, Kirsten K. Dietze, Cong Wang, Thekla Kemper, Yong Lin, Shiou‐Hwei Yeh, Jia Liu, Ulf Dittmer, Zhenghong Yuan, Michael Roggendorf, Mengji Lu
    Low hepatitis B virus‐specific T‐cell response in males correlates with high regulatory T‐cell numbers in murine models
    Hepatitis B virus (HBV) infection shows significant gender‐related differences in pathogenesis, disease progression, and development of hepatocellular carcinoma. The gender‐associated differences in HBV replication and viral protein levels may be associated with distinct HBV‐specific immune responses in the host. In the present study, we examined the impact of gender on HBV‐specific immune responses in two different mouse models representing transient and persistent hepadnaviral infection; hydrodynamic injection (HI) with the HBV genome mimicked acute HBV infection, whereas the efficacy of therapeutic vaccination was studied in the woodchuck hepatitis virus (WHV) transgenic (Tg) mouse model. Consistent with previous reports, significantly higher HBV DNA and protein levels were detected in male compared to female mice. Although HI with the HBV genome resulted in similar numbers of intrahepatic HBV‐specific CD8+ T‐cells, their functionality was significantly reduced in males and correlated with higher numbers of intrahepatic regulatory T‐cells (Tregs). Similar effects were observed in WHV Tg mice immunized with a DNA prime‐recombinant adenovirus boost vaccination protocol. Male mice showed functionally suppressed WHV‐specific CD8+ T‐cell responses in the liver and significantly higher numbers of intrahepatic Tregs compared to females. Blockade of Treg responses in male mice led to augmented effector functions of specific CD8+ T‐cells and subsequently improved virus control in both models of transient and persistent hepadnaviral infection. Conclusion: The functionality of virus‐specific CD8+ T‐cells in male mice was suppressed by intrahepatic Tregs and inversely correlated with levels of hepadnaviral DNA and viral protein. The induction of intrahepatic Tregs by viral replication and/or protein levels may explain the gender‐related differences in the outcomes of HBV infection and limit the success of immunotherapeutic strategies in male patients. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 mars 2017
    Fernando Bril, Kenneth Cusi
    Reply to: Liver Fat Accumulation as a Barometer of Insulin Responsiveness Again Points to Adipose Tissue as the Culprit
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    Date de mise en ligne : Samedi 11 mars 2017
    Femke Stelma, Meike H van der Ree, Marjan J Sinnige, Anthony Brown, Leo Swadling, J Marleen L de Vree, Sophie B Willemse, Marc van der Valk, Paul Grint, Steven Neben, Paul Klenerman, Eleanor Barnes, Neeltje A Kootstra, Hendrik W Reesink
    Immune phenotype and function of NK and T cells in chronic hepatitis C patients who received a single dose of anti‐miR‐122, RG‐101
    MicroRNA‐122 (miR‐122) is an important host factor for the hepatitis C (HCV) virus. Treatment with RG‐101, a GalNAc conjugated anti‐miR‐122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic hepatitis C (CHC) infection. Here, we analyzed the effects of RG‐101 therapy on antiviral immunity. 32 CHC patients HCV genotype 1, 3 and 4 received a single subcutaneous administration with RG‐101 at 2 mg/kg (n=14), 4 mg/kg (n=14) or placebo (n=2 per dosing group). Plasma and PBMCs were collected at multiple time points and comprehensive immunological analyses were performed. Following RG‐101 administration, HCV RNA declined in all patients (mean decline at week 2: 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma IP‐10 levels declined significantly upon dosing with RG‐101. Furthermore, the frequency of NK cells increased, the proportion of NK cells expressing activating receptors normalized and NK cell IFN‐γ production decreased, after RG‐101 dosing. Functional HCV‐specific IFN‐γ‐T cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post RG‐101 injection. No increase in the magnitude of HCV‐specific T cell responses was observed at later time points, including 3 patients who were HCV RNA negative 76 weeks post dosing. Conclusions: Dosing with RG‐101 is associated with a restoration of NK cell proportions and a decrease of NK cells expressing activation receptors. However, the magnitude and functionality of ex vivo HCV‐specific T cell responses did not increase following RG‐101 injection. Our data suggests that NK cells, but not HCV adaptive immunity may contribute to HCV viral control following RG‐101 therapy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 10 mars 2017
    Luigia Florimonte, Massimo Iavarone, Massimo Castellani, MariaGiulia Longo, Francesco Pallotti, Lorenzo Maffioli, Eva Orunesu, Riccardo Benti
    Uncommon extrahepatic metastases from hepatocellular carcinoma
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    Date de mise en ligne : Mercredi 08 mars 2017
    Lei Wang, Wen Zhang, Chang‐Hui Ge, Rong‐Hua Yin, Xiao Yang, Yi‐Qun Zhan, Miao Yu, Chang‐Yan Li, Zhi‐Qiang Ge, Xiao‐Ming Yang
    TLR5 signaling restrains T/NKT cell activation and protects against concanavalin A‐induced hepatic injury
    TLR5 signaling regulates the immune privileged status of the liver and is involved in hepatic immune disorders. However, the role of TLR5 has not yet been investigated in experimental models of Con A‐mediated liver injury. Here, we show that TLR5 is highly upregulated in the hepatic mononuclear cells (MNCs) of mice during Con A‐induced hepatitis. Increased mortality and liver histopathology of TLR5‐deficient mice correlated with excessive production of pro‐inflammatory cytokines, suggesting that TLR5 knockout mice were more susceptible to Con A‐induced hepatitis. We also reported for the first time that administration of CBLB502, an exogenous TLR5 agonist, substantially alleviated Con A‐mediated hepatitis in wild‐type mice as shown by increased survival rates, reduced aminotransferase and pro‐inflammatory cytokine production, impaired lymphocyte infiltration and ameliorated hepatocyte necrosis and/or apoptosis. Mechanistic studies revealed that CBLB502 acts as a negative regulator in limiting T/NKT cell activity and cytokine production in the Con A‐hepatitis model. Bone marrow transplantation experiments showed that TLR5 in bone marrow–derived cells contributed to the hepatoprotective efficacy of CBLB502 against Con A‐induced liver injury. Moreover, IL‐6 elevation induced by CBLB502 is an important protective factor against Con A‐induced liver injury. In addition, we demonstrated that CBLB502 suppresses α‐Galcer‐induced NKT cell‐dependent inflammatory liver injury. Conclusions: The TLR5 signaling pathway plays an important role in T cell‐mediated hepatic injury and may be exploited for therapeutic treatment of inflammatory liver diseases. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 08 mars 2017
    Francesca Campagna, Sara Montagnese, Lorenzo Ridola, Marco Senzolo, Sami Schiff, Michele De Rui, Chiara Pasquale, Silvia Nardelli, Ilaria Pentassuglio, Carlo Merkel, Paolo Angeli, Oliviero Riggio, Piero Amodio
    The animal naming test: An easy tool for the assessment of hepatic encephalopathy
    Background and aims. Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (MHE/grade I HE) is important. We examined if the animal naming test (ANT1) (maximum number of animals listed in one minute) is useful in this context. Methods. In total, 208 healthy controls, 40 controls with inflammatory bowel disease (IBD) and 327 consecutive patients with cirrhosis underwent the ANT1. The patients were tested for MHE by the psychometric hepatic encephalopathy score (PHES), and 146 were assessed by electroencephalography (EEG); 202 patients were followed up regarding the occurrence of overt HE and death. Results. In the healthy controls, ANT1 was influenced by limited education (<8 years) and advanced age (>80 years; p<0.001). Using an age and education adjusting procedure, the simplified ANT1 (S‐ANT1) was obtained. A S‐ANT1 of <10 animals was abnormal. Of the patients, 169 were considered unimpaired, 32 as having HE ≄ grade 2, and 126 as having MHE/grade 1 HE. This group had lower S‐ANT1 than unimpaired patients (12±0.4 vs. 16±0.7; p<0.001) and higher S‐ANT1 than those with HE≄ grade 2 (4±0.9). In grade 1 HE the S‐ANT1 was lower than in MHE. Following ROC analysis (Youden's index), 15 animals discriminated unimpaired from MHE/grade I HE patients. Thus, a three‐level score (‘0' for S‐ANT1≄15, ‘1' for 10≀S‐ANT1<15, ‘2' for S‐ANT1<10) was obtained. This score was correlated both to PHES (p<0.0001) and EEG (p=0.007). By sample random split validation, both S‐ANT1 and S‐ANT1 score resulted to have prognostic value regarding the one‐year risk of overt HE and death. No IBD control had S‐ANT < 15. Conclusions. S‐ANT1 is an easily obtainable measure useful for the assessment of HE. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 08 mars 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 LncRNA H19 in gender disparity of cholestatic liver injury in Mdr2‐/‐ mice
    The multi‐drug 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 (TCA) in 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 non‐coding 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‐day‐old), but not in aged‐matched male Mdr2‐/‐ mice. During the early stages of cholestasis, H19 expression was minimal. We further determined that the hepatic H19 was mainly expressed in cholangiocytes, not hepatocytes. Both TCA and estrogen significantly activated the ERK1/2 signaling pathway and induced H19 expression in cholangiocytes. Knocking down H19 not only significantly reduced TCA/estrogen‐induced expression of fibrotic genes and sphingosine 1‐phosphate receptor 2 (S1PR2) in cholangiocytes, but also markedly reduced cholestatic injury in female Mdr2‐/‐ mice. Furthermore, the expression of small heterodimer partner was substantially inhibited at advanced stages of liver fibrosis, which was reversed by H19 shRNA in female Mdr2‐/‐ mice. Similar findings were obtained in human PSC 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 07 mars 2017
    Brian E. Hsu, Peter M. Siegel
    Expanding the armamentarium for neutrophil‐mediated angiogenesis
    n/a


    Date de mise en ligne : Vendredi 03 mars 2017
    Paramananda Saikia, Damien Bellos, Megan R. McMullen, Katherine A. Pollard, Carol de la Motte, Laura E. Nagy
    miR181b‐3p and its target importin α5 regulate TLR4 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 ∌35kD (HA35) on ethanol‐induced sensitization of Kupffer cells, as well as ethanol‐induced liver injury in mice. Un‐biased analysis of microRNA (miRNA) expression in Kupffer cells identified miRNAs regulated by both ethanol and HA35. 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 miRNA181b‐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 LPS‐stimulated TNFα 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 non‐parenchymal cells. Treatment with HA35 normalized these changes and also protected mice from ethanol‐induced liver and intestinal injury. Conclusions: 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. To our knowledge, this study is the first to identify a miR181b‐3p→importin α5 axis in regulating inflammatory signaling pathways in hepatic macrophages. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 03 mars 2017
    Aijaz Ahmed, Stevan A. Gonzalez, George Cholankeril, Ryan B. Perumpail, Justin McGinnis, Sammy Saab, Rachel Beckerman, Zobair M. Younossi
    Treatment of Patients Waitlisted for Liver Transplant with an All‐Oral DAAs is a Cost‐Effective Treatment Strategy in the United States
    Background and Objective: All‐oral direct acting antivirals (DAAs) have been shown to have high safety and efficacy in treating patients with Hepatitis C (HCV) awaiting liver transplant (LT). However, there is limited empirical evidence comparing the health and economic outcomes associated with treating patients pre‐ vs. post‐LT. The objective of this study was to analyze the cost‐effectiveness of pre‐ vs. post‐LT treatment with an all‐oral DAA regimen among HCV patients with HCC (hepatocellular carcinoma) or DCC (decompensated cirrhosis). Methods: We constructed decision‐analytic Markov models of the natural disease progression of HCV in HCC patients and DCC patients waitlisted (WL) for LT. The model followed hypothetical cohorts of 1,000 patients with a mean age 50 over a 30 year time horizon from a third‐party US payer perspective, and estimated their health and cost outcomes based on pre‐ vs. post‐LT treatment with an all‐oral DAA regimen. Transition probabilities and utilities were based on the literature and hepatologist consensus. Sustained viral response (SVR) rates were sourced from ASTRAL‐4 and SOLAR‐1, ‐2. Costs were sourced from RedBook, Medicare fee schedules, and published literature. Results: In the HCC analysis, the pre‐LT treatment strategy resulted in 11.48 per‐patient quality‐adjusted life years (QALYs) and $365,948 per patient lifetime costs vs. 10.39 and $283,696 in the post‐LT arm. In the DCC analysis, the pre‐LT treatment strategy results in 9.27 per‐patient QALYs and $304,800 per patient lifetime costs vs. 8.7 and $283,789 in the post‐LT arm. As such, the pre‐LT treatment strategy was found to be the most cost‐effective in both populations with an incremental cost‐effectiveness ratio of $74,255 (HCC) and $36,583 (DCC). Sensitivity and scenario analyses showed results were most sensitive to the utility of patients post‐LT, treatment SVR rates, LT costs, and baseline MELD score (DCC analysis only). Conclusion: The timing of initiation of antiviral treatment for HCV patients with HCC or DCC relative to LT is an important area of clinical and policy research. Our results indicate that pre‐LT treatment with a highly effective, all‐oral DAA regimen provides the best health outcomes and is the most cost‐effective strategy for the treatment of HCV patients with HCC or DCC waitlisted for LT. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 03 mars 2017
    Irwin M. Arias
    Coming of Age and Building of Bridges
Reflections on the Past, Present and, hesitatingly, the Future
    n/a


    Date de mise en ligne : Vendredi 03 mars 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 after treatment (SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100/107 patients (93.5%) achieved SVR12, 6 patients relapsed, and 1 was lost to follow‐up. SVR12 was achieved in 94.7% (18/19), 97.6% (40/41) and 89.4% (42/47) 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 with those receiving placebo. 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 03 mars 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 (WT) or NK‐1R knockout (NK‐1R‐/‐) mice that received BDL or sham surgery and Mdr2‐/‐ mice treated with either an NK‐1R antagonist (L‐733,060) or saline were used. Additionally, WT mice were treated with SP or saline intraperitoneally. In vivo, there was increased expression of TAC1 (coding SP) and NK‐1R in both BDL and Mdr2‐/‐ mice compared to WT mice. The expression of TAC1 and NK‐1R was significantly higher in liver samples from PSC 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 cholangiocytes 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 (HSCs) and decreased senescence of cholangiocytes. In vitro, L‐733,060 inhibited SP‐induced expression of fibrotic genes in HSCs and cholangiocytes. Treatment with L‐733,060 partially reversed SP‐induced decrease of senescence genes expression in cultured HSCs and SP‐induced increase of senescence‐related genes expression in cultured cholangiocytes. Collectively, our results demonstrated the regulatory effects of the SP/NK‐1R axis on liver fibrosis through changes in cellular senescence during cholestatic liver injury. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 01 mars 2017
    Andreas Geier, Daniel Jahn, Heike Hermanns
    Interleukin‐6 ‐ the dark side of liver regeneration in chronic liver disease
    n/a


    Date de mise en ligne : Mardi 28 février 2017
    Zhiwen Fan, Luyang Li, Min Li, Xinjian Zhang, Chenzhi Hao, Liming Yu, Sheng Zeng, Huihui Xu, Mingming Fang, Aiguo Shen, Thomas Jenuwein, Yong Xu
    The histone methyltransferase Suv39h2 contributes to non‐alcoholic steatohepatitis in mice
    Uncontrolled inflammatory response highlights the central theme of non‐alcoholic steatohepatitis (NASH), a growing global pandemic. Hepatocytes and macrophages represent two major sources of hepatic inflammation during NASH pathogenesis contributing to excessive synthesis of pro‐inflammatory mediators. The epigenetic mechanism that accounts for the activation of hepatocytes and macrophages in this process remains obscure. Here we report that compared to wild type (WT) littermates, mice with a deficiency in the histone H3K9 methyltransferase Suv39h2 (KO) exhibited a less severe form of NASH induced by feeding with high‐fat high‐carbohydrate diet (HFD). Pro‐NASH stimuli increased Suv39h2 expression in cell culture, in mice, and in human livers. In hepatocytes, Suv39h2 bound to the Sirt1 gene promoter and repressed Sirt1 transcription. Suv39h2 deficiency normalized Sirt1 expression allowing NF‐ÎșB/p65 to become hypo‐acetylated thus dampening NF‐ÎșB‐dependent transcription of pro‐inflammatory mediators. In macrophages, Suv39h2‐mediated repression of PPARÎł transcription favored a pro‐inflammatory M1 phenotype over an anti‐inflammatory M2 phenotype thereby elevating hepatic inflammation. Conclusion: Suv39h2 plays a pivotal role in the regulation of inflammatory response in hepatocytes and macrophages contributing to NASH pathogenesis. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 27 février 2017
    Pamela S. Belperio, Troy A. Shahoumian, Larry A. Mole, Lisa I. Backus
    Evaluation of Hepatitis B Reactivation among 62,920 Veterans treated with Oral Hepatitis C Antivirals
    Reactivation of hepatitis B virus (HBV) has been reported in hepatitis C virus (HCV) infected individuals receiving direct‐acting antiviral (DAA) therapy. The overall risk among patients with current or prior HBV infection in the context of DAA treatment is unknown. The aim of this evaluation was to identify and characterize HBV reactivation among veterans treated with oral DAA therapy. This retrospective evaluation included 62,290 HCV‐infected veterans completing oral DAA treatment. Baseline HBV infection status for each veteran was identified from HBV laboratory data performed prior to DAA initiation. To assess for HBV reactivation and hepatitis we identified all HBsAg, HBV DNA and ALT results obtained while on DAA treatment or seven days after. HBV reactivation was defined as a >3 log increase in HBV DNA or HBsAg detection in a person who was previously negative. Prior to DAA treatment 85.5% (53,784/62,920) had HBsAg testing and 0.70% (377/53,784) were positive; 84.6% (53,237/62,920) had an anti‐HBs test of which 42.2% (22,479/53,237) were positive. In all, 9 of 62,290 patients treated with DAAs had evidence of HBV reactivation occurring while on DAA treatment. Eight occurred in patients known to be HBsAg positive and 1 occurred in a patient known to be isolated anti‐HBc positive. Seventeen other patients had small increases (<3 log) in HBV DNA levels that did not qualify as HBV reactivation. Only 3 of the 9 patients identified with HBV reactivation in this cohort exhibited peak ALT elevations >2 times the upper limit of normal. Conclusions: HBV reactivation of varying severity, even in the setting of isolated anti‐HBc, with or without accompanying hepatitis can occur –though the occurrence of accompanying severe hepatitis was rare. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 25 février 2017
    Fang Yan, Yi Wang, Wencheng Zhang, Mingyang Chang, Zhiying He, Jinbo Xu, Changzhen Shang, Tao Chen, Jiang Liu, Xin Wang, Xuetao Pei, Yunfang Wang
    Human ES Cell‐derived Hepatoblasts are an Optimal Lineage Stage for HCV Infection
    Maturation of hepatic cells can be gradually acquired through multiple stages of hepatic lineage specification, while little is known if the dynamics of HCV infection are maturationally lineage dependent. We investigated the susceptibility to HCV at multiple stages comprising human embryonic stem cells (hESCs), definitive endodermal cells (hDECs), hepatic stem cells (hHpSCs), hepatoblasts (hHBs) and mature hepatocytes (hHeps). Susceptibility to infection occurred initially at the stage of hHpSC, however, hHBs proved to have the highest permissiveness and infectivity compared with all other stages. The HBs' susceptibility to HCV correlated with the translocation of occludin (OCLN), as HCV receptor, from cytoplasm to plasma membrane of HBs. Vascular endothelial cell growth factor (VEGF) enhanced the HCV susceptibility of hHBs through re‐arrangement of OCLN by dephosphorylation of OCLN; this minimized hHB's polarization and prevented hHBs from further maturation. The transcription profiles of different hepatic lineage stages indicated that expression of innate immune response genes were correlated with hepatic maturation; interferon ÎČ (IFNÎČ) played an important role in protecting hHBs from HCV infection. HCV‐infected hHBs were able to engraft and integrate into the livers of Fah‐/‐Rag2‐/‐ (F/R) mice and maintained at hHB phenotype for over 12 weeks during the time when HCV antigen was evident. After suppression of IFNÎČ in hHBs, HCV infection was significantly enhanced in the engrafted humanized liver tissue of host mice. Conclusions: hESC‐derived HBs are the optimal hosts for HCV infectivity. The realization that HCV entry and replication occurs primarily at a particular hepatic lineage stage enables us to understand HCV infection factors, life cycle, and infection dynamics that are facets of the pathogenesis as well as suggesting targets for anti‐HCV treatments by pharmaceutical industries. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 25 février 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 via Epigenetic Repression of cccDNA Transcription and Interference with pgRNA 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 obscured. 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 the cell culture‐based models for HBV infection and the liver tissues of patients with chronic HBV infection, we found that symmetric dimethylation of arginine 3 on H4 (H4R3me2s) on cccDNAwas a repressive marker of cccDNA transcription and was regulated by PRMT5 depending on its methyltransferase domain. Moreover, PRMT5‐triggered H4R3me2s on the cccDNA minichromosome involved an interaction with the HBV core protein and the Brg1‐based hSWI/SNF chromatin remodeler, which resulted in the downregulation of the binding of RNA Pol II to cccDNA. In addition to the inhibitory effect on cccDNA transcription, PRMT5 inhibited HBV core particle DNA production independent of its methyltransferase activity. Further study revealed that PRMT5 interfered with pre‐genomic RNA (pgRNA) encapsidation by preventing its interaction with viral polymerase protein through binding to the RT‐RH region of polymerase which is crucial for the polymerase‐pgRNA interaction. Conclusion: PRMT5 restricts HBV replication via two‐part mechanisms including epigenetic suppression of cccDNA transcription and interference with pgRNA encapsidation. These findings improve the understanding of epigenetic regulation of HBV transcription and host‐HBV interaction, thus provide new insights into targeted therapeutic intervention. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 21 février 2017
    Wei Wang, Ming‐Jiang Xu, Yan Cai, Zhou Zhou, Haixia Cao, Partha Mukhopadhyay, Pal Pacher, Shusen Zheng, Frank J Gonzalez, Bin Gao
    Inflammation is independent of steatosis in a murine model of steatohepatitis
    Obesity and alcohol consumption synergistically promote steatohepatitis, and neutrophil infiltration is believed to be associated with steatosis. However, the underlying mechanisms remain obscure. Peroxisome proliferator‐activated receptor‐gamma (PPARÎł) plays a complex role in lipid metabolism and inflammation, therefore, the purpose of this study was to dissect its role in regulating steatosis and neutrophil infiltration in a clinically relevant mouse steatohepatitis model of 3‐month high‐fat diet (HFD) feeding plus a binge of ethanol (HFD ‐plus‐binge ethanol). Hepatocyte‐specific Pparg disruption reduced liver steatosis, but surprisingly increased hepatic neutrophil infiltration after HFD‐plus‐binge ethanol. Knockout or knockdown of the PPARÎł target gene, fat‐specific protein 27 (Fsp27), reduced steatosis without affecting neutrophil infiltration in this model. Moreover, hepatocyte‐specific deletion of the Pparg gene but not the Fsp27 gene markedly upregulated hepatic levels of Cxcl1 (a chemokine for neutrophil infiltration) in HFD‐plus‐binge ethanol‐fed mice. In vitro, deletion of the Pparg gene also highly augmented palmitic acid or TNF‐α induction of Cxcl1 in mouse hepatocytes. In contrast, activation of PPARÎł with a PPARÎł agonist attenuated Cxcl1 expression in hepatocytes. Palmitic acid also upregulated IL‐8 (a key chemokine for human neutrophil recruitment) expression in human hepatocytes, which was attenuated and enhanced by co‐treatment with a PPARÎł agonist and antagonist, respectively. Finally, acute ethanol binge markedly attenuated HFD‐induced hepatic PPARÎł activation, which contributed to the upregulation of hepatic Cxcl1 expression post HFD‐plus‐bigne ethanol. In conclusion, hepatic PPARÎł plays an opposing role in controlling steatosis and neutrophil infiltration, leading to dissociation between steatosis and inflammation. Acute ethanol gavage attenuates hepatic PPARÎł activation and subsequently upregulates hepatic CXCL1/IL‐8 expression, thereby exacerbating hepatic neutrophil infiltration. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 21 février 2017
    Eric Lawitz, Fred Poordad, Jennifer Wells, Robert H. Hyland, Yin Yang, Hadas Dvory‐Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Carmen Landaverde, Julio Gutierrez
    Sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin in DAA‐experienced patients with genotype 1 HCV
    The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1‐infected patients who fail direct‐acting antiviral (DAA)–based regimens remains unknown. In this phase 2, open‐label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virologic response on a DAA‐based regimen were randomized to receive treatment with a fixed‐dose combination tablet of sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin for 12 weeks. Patients were stratified by their cirrhosis and prior NS5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with sustained virologic response at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [95% CI], 86% to 100%) receiving sofosbuvir‐velpatasvir‐voxilaprevir alone, and 24 of 25 patients (96%; 95% CI, 80% to 100%) receiving the same treatment with ribavirin. None of the patients discontinued sofosbuvir‐velpatasvir‐voxilaprevir therapy due to an adverse event (AE). The most commonly reported AEs with sofosbuvir‐velpatasvir‐voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir‐velpatasvir‐voxilaprevir plus ribavirin were fatigue, anemia, gastroenteritis, and nausea. Conclusion: A fixed‐dose combination of sofosbuvir‐velpatasvir‐voxilaprevir was well‐tolerated and effective at achieving virologic response in patients with HCV genotype 1 infection and prior DAA treatment experience. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 21 février 2017
    Gitte Dam, Hendrik Vilstrup, Hugh Watson, Peter Jepsen
    Reply to letter from de Mattos and colleagues: Risks of proton pump inhibitors for cirrhotic patients – the controversy remains
    n/a


    Date de mise en ligne : Lundi 20 février 2017
    Shintaro Ichikawa, Utaroh Motosugi, Mitsuhiko Oguri, Hiroshi Onishi
    Magnetic resonance elastography for prediction of radiation‐induced liver disease after stereotactic body radiation therapy
    n/a


    Date de mise en ligne : Vendredi 17 février 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 (HEP‐16‐2474.R1)
    Focal segmental glomerulosclerosis (FSGS) presents as proteinuric kidney disease and is associated with poor long‐term renal outcomes. Here we describe three patients with solid organ transplants and normal baseline kidney function who developed FSGS during direct acting antiviral therapy for hepatitis C virus infection. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 17 février 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
    n/a


    Date de mise en ligne : Mercredi 15 février 2017
    Ruud M Buijs, Natali Guerrero Vargas
    Synchrony between Suprachiasmatic nucleus driven signals and the light dark cycle is essential for liver homeostasis
    n/a


    Date de mise en ligne : Mardi 14 février 2017
    Xavier Forns
    Juan Rodés, Obituary
    n/a


    Date de mise en ligne : Mardi 14 février 2017
    Hao Li, Zun‐Qiang Zhou, Zhang‐Ru Yang, Da‐Nian Tong, Jiao Guan, Bao‐Jie Shi, Jia Nie, Xian‐Ting Ding, Bin Li, Guang‐Wen Zhou, Zheng‐Yun Zhang
    MicroRNA‐191 acts as a tumor promoter by modulating the TET1‐p53 pathway in intrahepatic cholangiocarcinoma
    Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miRNA‐191, play an important role in tumorigenesis, but expression and biological functions of miRNA‐191 in ICC remain to be established. This study aimed to investigate the functions and underlying mechanisms of miRNA‐191 in ICC. ICC miRNA profiles were generated in 5 pairs of ICC and matched to normal bile duct tissues by next‐generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative reverse transcription PCR (qRT‐PCR). The miR‐191‐associated mechanisms in ICC were investigated in vitro and in vivo and clinical outcomes associated with miR‐191 were correlated in 84 patients. Our results showed miR‐191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (p<0.001). Overexpression of miR‐191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR‐191 expression reduced the expression level of ten‐eleven translocation 1 (TET1)—a direct target gene of miR‐191 in ICC, which catalyzes demethylation. The reduced TET1 expression level let the methylated CpG‐rich regions at the p53 gene transcription start site (TSS) stay methylated, leading to the reduced p53 expression level, which compromises the p53 anti‐cancer vigor. Finally, miR‐191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival: HR, 3.742; 95%CI, 2.080‐6.733; p<0.001; disease‐free survival: HR, 2.331; 95%CI, 1.346‐4.037; p=0.003). Conclusion: Our results suggest that overexpressed miR‐191 is associated with ICC progression through the miR‐191/TET1/p53 pathway. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 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 (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 towards the establishment for 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 mouse, rat, dog, pig, rhesus and cynomolgus macaque were transduced with adeno‐associated viral (AAV) vectors encoding hNTCP and subsequently infected with HBV. Cells were analysed for Myrcludex B binding, taurocholate uptake, HBV cccDNA formation and expression of all HBV markers. Ntcps from the respective species were cloned and analysed 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 macaque, rhesus macaques and pig became fully susceptible to HBV upon hNTCP expression with efficiencies comparable to human hepatocytes. Analysis of cloned Ntcps from all species revealed a pronounced role of the human homologue to support HBV and HDV infection. Conclusions: Ntcp is the key host factor limiting HBV infection in cynomolgus and rhesus macaque 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Filipe S. Cardoso, Rui Pereira, Gonçalo Alexandrino, Luís Bagulho
    Futility of care in patients with acute‐on‐chronic liver failure
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    Date de mise en ligne : Lundi 13 février 2017
    Dana JT Bruden, Brian J. McMahon, Lisa Townshend‐Bulson, Prabhu Gounder, Jim Gove, Julia Plotnik, Chriss Homan, Annette Hewitt, Youssef Barbour, Philip R. Spradling, Brenna C. Simons, Susan McArdle, Michael Bruce
    Risk of End Stage Liver Disease, Hepatocellular Carcinoma and Liver‐Related Death By Fibrosis Stage in the Hepatitis C Alaska Cohort
    Long‐term prospective studies of the outcomes associated with HCV infection are rare and critical for assessing the potential impact of HCV treatment. Using liver biopsy as a start point, we looked at development of end stage liver disease (ESLD), hepatocellular carcinoma (HCC) and liver‐related death (LRD) according to fibrosis stage, among a cohort of American Indian/Alaska Native persons in Alaska. Persons were classified as having no/mild (Ishak=0,1), moderate (Ishak=2), or severe (Ishak=3,4) fibrosis or cirrhosis (Ishak=5,6). We examined time until development of ESLD, HCC and LRD and report survival probabilities at 3, 5, 7 and 10‐years. Of 407 persons, 39%(n = 150) had no/mild fibrosis, 32%(n = 131) had moderate fibrosis, 22%(n = 88) had severe fibrosis and 9%(n = 38) had cirrhosis. The average time of follow‐up was 7.3 years. Within 5 years of biopsy, 1.7% (95% confidence interval (CI):0.4,6.8) of persons with none/mild fibrosis developed ESLD compared to 7.9% (CI:4.0,15.2), 16.4% (CI:9.6,27.2) and 49.0% (CI:33.0,67.7) with moderate, severe fibrosis, and cirrhosis, respectively (p<0.01). The 5‐year outcome of HCC was 1.0% (CI:0.1,7.0), 1.0% (CI 0.1,6.6), 1.1% (CI:0.2,7.7) and 13.4% (CI:4.4,36.7) among persons with none/mild, moderate fibrosis, severe fibrosis and cirrhosis, respectively (p<0.01). Five years following biopsy, 0.0% (CI:0.0,14.8) of persons with none/mild fibrosis had suffered an LRD compared to 1.0% (CI:0.2,7.5) of persons with moderate fibrosis, 4.7% (CI:1.5,14.1) with severe fibrosis and 16.3% (CI:7.0,35.1) with cirrhosis (p<0.01). Conclusion For prevention of HCC, LRD and ESLD in the short‐term, HCV therapy should target those with more than mild fibrosis. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 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 non‐apoptotic 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 (BMDMs). 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 BMDMs. Interestingly, Slc7a11, a known ferroptosis‐related gene, was significantly upregulated 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 BMDMs isolated from Slc7a11‐/‐ mice fed a high‐iron diet. 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. These results also suggest that ferroptosis may be a promising target for treating hemochromatosis‐related tissue damage. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Aynur Unalp‐Arida, Constance E. Ruhl
    Liver fibrosis scores predict liver disease mortality in the United States population
    Background and rationale. Fatty liver disease is common in the United States and worldwide due to changing lifestyles and can progress to fibrosis and cirrhosis contributing to premature death. We examined whether liver fibrosis scores were associated with increased overall and disease‐specific mortality in a U.S. population‐based prospective survey with up to 23 years of linked‐mortality data. Methods. Data were analyzed from 14,841 viral hepatitis negative adult participants in the third National Health and Nutrition Examination Survey, 1988‐1994. Liver fibrosis was predicted using the aspartate aminotransferase to platelet ratio index (APRI), fibrosis‐4 (FIB‐4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and Forns score. Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to National Death Index records through 2011. Hazard rate ratios (HR) for mortality were calculated using Cox proportional hazards regression to adjust for mortality risk factors. Results. During follow‐up, cumulative mortality was 28.0% from all causes and 0.82% with liver disease, including primary liver cancer. Elevated liver disease mortality was found with an intermediate‐high APRI (HR, 9.44; 95% CI, 5.02‐17.73), intermediate (HR, 3.15; 95% CI, 1.33‐7.44) or high (HR, 25.14; 95% CI, 8.38‐75.40) FIB‐4, high NFS (HR, 6.52; 95% CI, 2.30‐18.50), and intermediate (HR, 3.58; 95% CI, 1.78‐7.18) or high (HR, 63.13; 95% CI, 22.16‐179.78) Forns score. Overall mortality was also greater with higher fibrosis scores. Conclusion. In the U.S. population, higher liver fibrosis scores were associated with increased liver disease and overall mortality. Liver health management with common clinical measures of fibrosis risk stratification merits further investigation. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Matthew A. Goldsworthy, Ian A. Rowe
    Patient understanding of hepatocellular carcinoma surveillance
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    Date de mise en ligne : Jeudi 30 mars 2017
    Kyle S. McCommis, Wesley T. Hodges, Elizabeth M. Brunt, Ilke Nalbantoglu, William G. McDonald, Christopher Holley, Hideji Fujiwara, Jean E. Schaffer, Jerry R. Colca, Brian N. Finck
    Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis
    Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin‐sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose‐limiting side effects thought to be due to activation of the peroxisome proliferator–activated receptor γ. We sought to determine whether a next‐generation thiazolidinedione with markedly diminished ability to activate peroxisome proliferator–activated receptor γ (MSDC‐0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated through an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC‐0602. We found that MSDC‐0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans‐fatty acids, fructose, and cholesterol. Moreover, mice with liver‐specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC‐0602 directly reduced hepatic stellate cell activation in vitro, and MSDC‐0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. Conclusion: Collectively, these data demonstrate the effectiveness of MSDC‐0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. (Hepatology 2017).


    Date de mise en ligne : Jeudi 30 mars 2017
    Erfan Ayubi, Saeid Safiri, Mohadeseh Sani, Amin Doosti‐Irani, Ali Sanjari Moghaddam
    Effect of metabolic syndrome on cardiovascular, hepatic events, and death in chronic hepatitis B patients: Methodological issues
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    Date de mise en ligne : Jeudi 30 mars 2017
    CĂ ndid Villanueva, Isabel Graupera, Carles Aracil, Edilmar Alvarado, Josep Miñana, Ángela Puente, Virginia Hernandez‐Gea, Alba Ardevol, Oana Pavel, Alan Colomo, Mar ConcepciĂłn, MarĂ­a Poca, Xavier Torras, Josep M. Reñe, Carlos Guarner
    A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis
    Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG‐guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute ÎČ‐blocker response were evaluated at baseline and HVPG measurements were repeated at 2‐4 weeks to determine chronic response. In the HVPG‐guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between‐group baseline characteristics were similar. During long‐term follow‐up (median of 24 months), mortality was lower in the HVPG‐guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35‐0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29‐0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46‐0.99). The survival probability was higher with HVPG‐guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32‐1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23‐0.99). HVPG‐guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). Conclusion: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using ÎČ‐blockers and ligation. HVPG‐guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017).


    Date de mise en ligne : Jeudi 30 mars 2017
    David E. Kleiner
    On beyond staging and grading: Liver biopsy evaluation in a posttreatment world
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    Date de mise en ligne : Jeudi 30 mars 2017
    Benjamin Lelouvier, Florence Servant, Michael Courtney, RĂ©my Burcelin, Jacques Amar
    Reply:
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    Date de mise en ligne : Jeudi 30 mars 2017
    Jenny Yeuk‐Ki Cheng, Yee‐Kit Tse, Grace Lai‐Hung Wong
    Reply
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    Date de mise en ligne : Jeudi 30 mars 2017
    Tammy T. Chang
    Reply
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    Date de mise en ligne : Jeudi 30 mars 2017
    Jan Görtzen, Jonel Trebicka
    Rho‐kinase inhibition is beneficial in fibrosis
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    Date de mise en ligne : Jeudi 30 mars 2017
    Tian Yang, Han Zhang, Jun Han, Meng‐Chao Wu, Feng Shen
    Reply
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    Date de mise en ligne : Jeudi 30 mars 2017
    Solùne Denolly, François‐Loïc Cosset
    A master regulator of tight junctions involved in hepatitis C virus entry and pathogenesis
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    Date de mise en ligne : Jeudi 30 mars 2017
    Gonzalo Sapisochin, Jordi Bruix
    Reply:
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    Date de mise en ligne : Jeudi 30 mars 2017
    Payal Arora, Amartya Basu, M. Lee Schmidt, Geoffrey J. Clark, Howard Donninger, Daniel B. Nichols, Diego F. Calvisi, Neerja Kaushik‐Basu
    Nonstructural protein 5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication
    Hepatitis C virus (HCV) infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here, we show that the HCV protein, nonstructural protein (NS) 5B, directly binds to the tumor suppressor, NORE1A (RASSF5), and promotes its proteosomal degradation. In addition, we show that NORE1A colocalizes to sites of HCV viral replication and suppresses the replication process. Thus, NORE1A has antiviral activity, which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV‐induced liver cancer by shifting Ras signaling away from prosenescent/proapoptotic signaling pathways. Conclusion: HCV uses NS5B to specifically suppress NORE1A, facilitating viral replication and elevated Ras signaling. (Hepatology 2017).


    Date de mise en ligne : Jeudi 30 mars 2017
    Javier MartĂ­nez, Luis TĂ©llez, Agustin Albillos
    Acute variceal bleeding in patients on primary prophylaxis with nonselective beta‐blockers: A poor prognosis factor?
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    Date de mise en ligne : Jeudi 30 mars 2017
    Lei Hei, Jin Zhong
    Laboratory of genetics and physiology 2 (LGB2) plays an essential role in hepatitis C virus infection‐induced interferon responses
    Retinoic acid‐inducible gene I (RIG‐I)‐like receptors are cytosolic pattern recognition receptors (PRRs) that detect non‐self‐RNA and activate downstream interferon (IFN) signaling. One of the RIG‐I‐like receptors, laboratory of genetics and physiology 2 (LGP2), was originally thought to be a negative feedback regulator in the RIG‐I signaling pathway, but growing evidence indicates that LGP2 is one cofactor of melanoma differentiation‐associated protein 5 (MDA5) in MDA5‐mediated IFN signaling activation. Our previous work showed that MDA5 was the major PRR to sense hepatitis C virus (HCV) infection in hepatocytes, but the role of LGP2 in HCV infection‐induced IFN signaling has not been elucidated. In this study, we reported that LGP2 was a positive regulator of HCV infection‐induced IFN signaling. Knockout of LGP2 in hepatocytes significantly diminished IFN production in response to HCV infection, but not to HCV 3'untranslated region RNA transfection. Mechanistic studies showed that LGP2 exerted its function at a step upstream of MDA5 in the IFN signaling. HCV infection promoted the molecular interaction between LGP2 and MDA5, which, in turn, enhanced MDA5/HCV RNA association. Finally, we demonstrated that the ATPase activity of LGP2 was critical for assisting MDA5/HCV RNA interaction and activating IFN signaling during HCV infection. Conclusion: Our work demonstrated that LGP2 plays an essential role in activating IFN signaling against HCV infection by promoting MDA5 recognition of HCV pathogen‐associated molecular patterns. (Hepatology 2017)


    Date de mise en ligne : Jeudi 23 mars 2017
    Yi‐Ling Qiu, Jing‐Yu Gong, Jia‐Yan Feng, Ren‐Xue Wang, Jun Han, Teng Liu, Yi Lu, Li‐Ting Li, Mei‐Hong Zhang, Jonathan A. Sheps, Neng‐Li Wang, Yan‐Yan Yan, Jia‐Qi Li, Lian Chen, Christoph H. Borchers, Bence Sipos, A.S. Knisely, Victor Ling, Qing‐He Xing, Jian‐She Wang
    Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ‐glutamyltransferase cholestasis
    Hereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11 of 38 vs. 0 of 13). Conclusion: MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017).


    Date de mise en ligne : Jeudi 23 mars 2017
    Tali Lanton, Anat Shriki, Yael Nechemia‐Arbely, Rinat Abramovitch, Orr Levkovitch, Revital Adar, Nofar Rosenberg, Mor Paldor, Daniel Goldenberg, Amir Sonnenblick, Amnon Peled, Stefan Rose‐John, Eithan Galun, Jonathan H. Axelrod
    Interleukin 6–dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis
    Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For patients with liver cancer, surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long‐term survival of these patients. We have shown that partial hepatectomy in multidrug resistance 2 knockout (Mdr2–/–) mice, a model of chronic inflammation‐associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the postsurgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2–/– mice by perioperative pharmacological inhibition of interleukin‐6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following partial hepatectomy without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2–/– mice contain hepatocytes with a notable persistent DNA damage response (γH2AX, 53BP1) due to chronic inflammation. We show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei, a marker of genomic instability, which is suppressed by IL6 blockade. Conclusion: Our findings indicate that genomic instability derived during the IL6‐mediated liver regenerative response within a milieu of chronic inflammation links partial hepatectomy to accelerated hepatocarcinogenesis; this suggests a new therapeutic approach through the usage of an anti‐IL6 treatment to extend the tumor‐free survival of patients undergoing surgical resection. (Hepatology 2017)


    Date de mise en ligne : Mercredi 22 mars 2017
    Elizabeth A. O'Hare, Rongze Yang, Laura M. Yerges‐Armstrong, Urmila Sreenivasan, Rebecca McFarland, Carmen C. Leitch, Meredith H. Wilson, Shilpa Narina, Alexis Gorden, Kathy A. Ryan, Alan R. Shuldiner, Steve A. Farber, G. Craig Wood, Christopher D. Still, Glenn S. Gerhard, Janet D. Robishaw, Carole Sztalryd, Norann A. Zaghloul
    TM6SF2 rs58542926 impacts lipid processing in liver and small intestine
    The transmembrane 6 superfamily member 2 (TM6SF2) loss‐of‐function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride‐rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride‐rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high‐fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco‐2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. Conclusions: These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride‐rich lipoproteins. (Hepatology 2017).


    Date de mise en ligne : Mercredi 22 mars 2017
    Dan Li, Xuefeng Liu, Jian Zhou, Jie Hu, Dongdong Zhang, Jing Liu, Yanyan Qiao, Qimin Zhan
    Long noncoding RNA HULC modulates the phosphorylation of YB‐1 through serving as a scaffold of extracellular signal–regulated kinase and YB‐1 to enhance hepatocarcinogenesis
    Dysregulated expression of long noncoding RNAs has been reported in many types of cancers, indicating that it may play a critical role in tumorigenesis. The long noncoding RNA highly up‐regulated in liver cancer (HULC) was first characterized in hepatocellular carcinoma. However, the detailed mechanisms of HULC remain unclear. Here, we demonstrate a novel mechanism by which long noncoding RNA plays oncogenic roles through modulating the phosphorylation status of its interaction protein. First, we validated the markedly increased expression levels of HULC in hepatocellular carcinoma tissues compared to their adjacent noncancerous tissues. Furthermore, up‐regulation of HULC was correlated with grading and overall survival. Meanwhile, HULC could promote cell proliferation, migration, and invasion in vitro and inhibit cisplatin‐induced apoptosis. Moreover, we show that HULC specifically binds to Y‐box binding protein 1 (YB‐1) protein both in vitro and in vivo. YB‐1 is a major component of translationally inactive messenger ribonucleoprotein particles which keeps mRNA in a silent state. Our study further demonstrated that HULC could promote the phosphorylation of YB‐1 protein, which leads to the release of YB‐1 from its bound mRNA. As a consequence, translation of silenced oncogenic mRNAs would be activated, including cyclin D1, cyclin E1, and matrix metalloproteinase 3. In addition, we found that HULC promotes the phosphorylation of YB‐1 protein mainly through extracellular signal–regulated kinase. Conclusion: We demonstrate that HULC promotes the phosphorylation of YB‐1 through the extracellular signal–regulated kinase pathway, in turn regulates the interaction of YB‐1 with certain oncogenic mRNAs, and consequently accelerates the translation of these mRNAs in the process of tumorigenesis. (Hepatology 2016)


    Date de mise en ligne : Mercredi 22 mars 2017
    Kasper S. Wang, Greg Tiao, Lee M. Bass, Paula M. Hertel, Douglas Mogul, Nanda Kerkar, Matthew Clifton, Colleen Azen, Laura Bull, Philip Rosenthal, Dylan Stewart, Riccardo Superina, Ronen Arnon, Molly Bozic, Mary L. Brandt, Patrick A. Dillon, Annie Fecteau, Kishore Iyer, Binita Kamath, Saul Karpen, Frederick Karrer, Kathleen M. Loomes, Cara Mack, Peter Mattei, Alexander Miethke, Kyle Soltys, Yumirle P. Turmelle, Karen West, Jessica Zagory, Cat Goodhue, Benjamin L. Shneider,
    Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis
    To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis‐1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ‐glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder‐to‐colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. Conclusion: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017).


    Date de mise en ligne : Mercredi 22 mars 2017
    Jin‐Kyu Park, Mingjie Shao, Moon Young Kim, Soon Koo Baik, Mee Yon Cho, Teruo Utsumi, Ayano Satoh, Xinsho Ouyang, Chuhan Chung, Yasuko Iwakiri
    An endoplasmic reticulum protein, Nogo‐B, facilitates alcoholic liver disease through regulation of kupffer cell polarization
    Nogo‐B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo‐B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo‐B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild‐type (WT) and Nogo‐B knockout (KO) mice fed a control or Lieber‐DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo‐B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo‐B positive Kupffer cells and disease severity in ALD patients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo‐B–positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = −0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo‐B KO mice in response to chronic ethanol feeding. Nogo‐B in Kupffer cells promoted M1 polarization, whereas absence of Nogo‐B increased ER stress and M2 polarization in Kupffer cells. Conclusion: Nogo‐B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo‐B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017).


    Date de mise en ligne : Mercredi 22 mars 2017
    Wai‐Kay Seto, Thomas Sau‐Yan Chan, Yu‐Yan Hwang, Danny Ka‐Ho Wong, James Fung, Kevin Sze‐Hang Liu, Harinder Gill, Yuk‐Fai Lam, Eric H.Y. Lau, Ka‐Shing Cheung, Albert K.W. Lie, Ching‐Lung Lai, Yok‐Lam Kwong, Man‐Fung Yuen
    Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study
    Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)–negative, antibody to hepatitis B core antigen (anti‐HBc)–positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) has not been prospectively studied. HBsAg‐negative, anti‐HBc–positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≄10 IU/mL). Secondary endpoints included overall survival, HBsAg positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg‐negative, anti‐HBc–positive, of whom 62 were recruited and monitored for a median of 48 (4‐104) weeks. The 2‐year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8‐100) weeks. Multivariate analysis showed that age ≄50 years (P = 0.004, hazard ratio = 8.2) and chronic graft‐versus‐host disease (P = 0.010, hazard ratio = 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline antibody to HBsAg status, serial changes in antibody to HBsAg levels, and donor serology, were not associated with HBV reactivation. Patients <50 years old and without chronic graft‐versus‐host disease, compared with the remaining patient cohort, had a significantly lower 2‐year cumulative HBV reactivation rate (5.6% versus 65.0%, P = 0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with no cases developing biochemical hepatitis. Conclusion: HBsAg‐negative, anti‐HBc–positive patients had a high rate of HBV reactivation after allogeneic HSCT, with determinants of HBV reactivation including age ≄50 years and chronic graft‐versus‐host disease; treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649.) (Hepatology 2017).


    Date de mise en ligne : Mercredi 22 mars 2017
    Manuela Sabelli, Giuliana Montosi, Cinzia Garuti, Angela Caleffi, Stefania Oliveto, Stefano Biffo, Antonello Pietrangelo
    Human macrophage ferroportin biology and the basis for the ferroportin disease
    Ferroportin (FPN1) is the sole iron exporter in mammals, but its cell‐specific function and regulation are still elusive. This study examined FPN1 expression in human macrophages, the cells that are primarily responsible on a daily basis for plasma iron turnover and are central in the pathogenesis of ferroportin disease (FD), the disease attributed to lack‐of‐function FPN1 mutations. We characterized FPN1 protein expression and traffic by confocal microscopy, western blotting, gel filtration, and immunoprecipitation studies in macrophages from control blood donors (donor) and patients with either FPN1 p.A77D, p.G80S, and p.Val162del lack‐of‐function or p.A69T gain‐of‐function mutations. We found that in normal macrophages, FPN1 cycles in the early endocytic compartment does not multimerize and is promptly degraded by hepcidin (Hepc), its physiological inhibitor, within 3‐6 hours. In FD macrophages, endogenous FPN1 showed a similar localization, except for greater accumulation in lysosomes. However, in contrast with previous studies using overexpressed mutant protein in cell lines, FPN1 could still reach the cell surface and be normally internalized and degraded upon exposure to Hepc. However, when FD macrophages were exposed to large amounts of heme iron, in contrast to donor and p.A69T macrophages, FPN1 could no longer reach the cell surface, leading to intracellular iron retention. Conclusion: FPN1 cycles as a monomer within the endocytic/plasma membrane compartment and responds to its physiological inhibitor, Hepc, in both control and FD cells. However, in FD, FPN1 fails to reach the cell surface when cells undergo high iron turnover. Our findings provide a basis for the FD characterized by a preserved iron transfer in the enterocytes (i.e., cells with low iron turnover) and iron retention in cells exposed to high iron flux, such as liver and spleen macrophages. (Hepatology 2017)


    Date de mise en ligne : Mercredi 22 mars 2017
    Feng‐Juan Yan, Xiao‐Jing Zhang, Wen‐Xin Wang, Yan‐Xiao Ji, Pi‐Xiao Wang, Yang Yang, Jun Gong, Li‐Jun Shen, Xue‐Yong Zhu, Zan Huang, Hongliang Li
    The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis
    Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, is closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high‐fat diet or a genetic deficiency (ob/ob). Using gain‐of‐function and loss‐of‐function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte‐specific TRIM8 overexpression, whereas deletion or down‐regulation of TRIM8 in hepatocytes led to a completely opposite phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates transforming growth factor‐beta–activated kinase 1, thus promoting its phosphorylation and the activation of downstream c‐Jun N‐terminal kinase/p38 and nuclear factor ÎșB signaling. Importantly, the participation of TRIM8 in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of nonalcoholic steatohepatitis–related metabolic disorders. Conclusion: The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on transforming growth factor‐beta–activated kinase 1. (Hepatology 2017)


    Date de mise en ligne : Mercredi 22 mars 2017
    Yameng Sun, Jialing Zhou, Lin Wang, Xiaoning Wu, Yongpeng Chen, Hongxin Piao, Lungen Lu, Wei Jiang, Youqing Xu, Bo Feng, Yuemin Nan, Wen Xie, Guofeng Chen, Huanwei Zheng, Hai Li, Huiguo Ding, Hui Liu, Fudong Lv, Chen Shao, Tailing Wang, Xiaojuan Ou, Bingqiong Wang, Shuyan Chen, Aileen Wee, Neil D. Theise, Hong You, Jidong Jia
    New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment
    Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis caused by hepatitis B virus. However, current evaluation systems mainly focus on the severity of, but not the dynamic changes in, fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation); predominately regressive (delicate/thin/dense/splitting septa); and indeterminate, which displayed an overall balance between progressive and regressive scarring. Then, we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir‐based therapy for 78 weeks. Progressive, indeterminate, and regressive were observed in 58%, 29%, and 13% of patients before treatment versus in 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and, more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. Conclusion: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017)


    Date de mise en ligne : Jeudi 16 mars 2017
    Yan‐Dan Ren, Zhen‐Shi Ye, Liu‐Zhu Yang, Li‐Xin Jin, Wen‐Jun Wei, Yong‐Yue Deng, Xiao‐Xiao Chen, Chuan‐Xing Xiao, Xiao‐Fang Yu, Hong‐Zhi Xu, Li‐Zhu Xu, Yun‐Na Tang, Fei Zhou, Xue‐Lian Wang, Mei‐Ya Chen, Li‐Gang Chen, Mei‐Zhu Hong, Jian‐Lin Ren, Jin‐Shui Pan
    Fecal microbiota transplantation induces hepatitis B virus e‐antigen (HBeAg) clearance in patients with positive HBeAg after long‐term antiviral therapy
    n/a


    Date de mise en ligne : Jeudi 16 mars 2017
    Umberto Cillo, Alessandro Vitale, Marina Polacco, Elisa Fasolo
    Liver transplantation for hepatocellular carcinoma through the lens of transplant benefit
    n/a


    Date de mise en ligne : Mardi 14 mars 2017
    Laurent Savale, Caroline Sattler, Audrey Coilly, FilomĂ©na Conti, SĂ©bastien Renard, Claire Francoz, HĂ©lĂšne Bouvaist, Cyrille Feray, Patrick Borentain, Xavier JaĂŻs, David Montani, Florence Parent, Caroline O'Connell, Philippe HervĂ©, Marc Humbert, GĂ©rald Simonneau, Didier Samuel, Yvon Calmus, Christophe Duvoux, François Durand, Jean Charles Duclos‐VallĂ©e, Olivier Sitbon
    Long‐term outcome in liver transplantation candidates with portopulmonary hypertension
    Portopulmonary hypertension (PoPH) is diagnosed in 2‐6% of liver transplantation (LT) candidates. We studied outcomes of candidates for LT suffering from PoPH. Data were collected retrospectively from a prospective registry. Pulmonary hemodynamic variables were collected at the time of PoPH diagnosis, at last evaluation before LT, and within 6 months and beyond 6 months after LT. Forty‐nine patients (35 males, 48 ± 8 years) were analyzed (median Model for End‐Stage Liver Disease score 20). At baseline, mean pulmonary artery pressure (mPAP) was 44 ± 10 mm Hg (range 26‐73 mm Hg), cardiac index was 3.5 ± 0.9 L/min/m2, and pulmonary vascular resistance was 5.6 ± 2.8 Wood units. Hemodynamic reassessment performed in 35 patients who were treated with pulmonary arterial hypertension–targeted therapies before LT resulted in significant decreases in both mPAP (36 ± 7 versus 47 ± 10 mm Hg, P < 0.0001) and pulmonary vascular resistance (3.0 ± 1.4 versus 6.1 ± 3.1 Wood units, P < 0.0001). Fourteen patients (29%) died without having had access to LT. Thirty‐five patients underwent LT and were followed up for a median of 38 months. Eight patients (23%) died after LT including 5 due to PoPH (after 1 day to 6 months). Among survivors (n = 27), all patients treated with intravenous epoprostenol were weaned off post‐LT, and endothelin receptor antagonist or phosphodiesterase type 5 inhibitors were continued in 15/27 patients (55%). At last evaluation, 20/27 patients (74%) had mPAP <35 mm Hg and 8 of them (30%) had mPAP <25 mm Hg. Overall survival estimates after LT were 80%, 77%, and 77% at 6 months, 1 year, and 3 years, respectively. Conclusion: Stabilization or reversibility of PoPH seems to be an attainable goal using the combination of pulmonary arterial hypertension–targeted therapies and LT in patients who are transplantation candidates. (Hepatology 2016).


    Date de mise en ligne : Jeudi 09 février 2017
    Marina Artemova, Dzhamal Abdurakhmanov, Tatiana Ignatova, Nikolay Mukhin
    Persistent hepatitis C virus–associated cryoglobulinemic vasculitis following virus eradication after direct‐acting antiviral therapy
    n/a


    Date de mise en ligne : Lundi 06 février 2017
    Junyan Tao, Rong Zhang, Sucha Singh, Minakshi Poddar, Emily Xu, Michael Oertel, Xin Chen, Shanthi Ganesh, Marc Abrams, Satdarshan P. Monga
    Targeting ÎČ‐catenin in hepatocellular cancers induced by coexpression of mutant ÎČ‐catenin and K‐Ras in mice
    Recently, we have shown that coexpression of hMet and mutant‐ÎČ‐catenin using sleeping beauty transposon/transposase leads to hepatocellular carcinoma (HCC) in mice that corresponds to around 10% of human HCC. In the current study, we investigate whether Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant‐ÎČ‐catenin. We also tested therapeutic efficacy of targeting ÎČ‐catenin in an HCC model. We show that mutant‐K‐Ras (G12D), which leads to Ras activation, cooperates with ÎČ‐catenin mutants (S33Y, S45Y) to yield HCC in mice. Affymetrix microarray showed > 90% similarity in gene expression in mutant‐K‐Ras‐ÎČ‐catenin and Met‐ÎČ‐catenin HCC. K‐Ras‐ÎČ‐catenin tumors showed up‐regulation of ÎČ‐catenin targets like glutamine synthetase (GS), leukocyte cell‐derived chemotaxin 2, Regucalcin, and Cyclin‐D1 and of K‐Ras effectors, including phosphorylated extracellular signal‐regulated kinase, phosphorylated protein kinase B, phosphorylated mammalian target of rapamycin, phosphorylated eukaryotic translation initiation factor 4E, phosphorylated 4E‐binding protein 1, and p‐S6 ribosomal protein. Inclusion of dominant‐negative transcription factor 4 at the time of K‐Ras‐ÎČ‐catenin injection prevented HCC and downstream ÎČ‐catenin and Ras signaling. To address whether targeting ÎČ‐catenin has any benefit postestablishment of HCC, we administered K‐Ras‐ÎČ‐catenin mice with EnCore lipid nanoparticles (LNP) loaded with a Dicer substrate small interfering RNA targeting catenin beta 1 (CTNNB1; CTNNB1‐LNP), scrambled sequence (Scr‐LNP), or phosphate‐buffered saline for multiple cycles. A significant decrease in tumor burden was evident in the CTNNB1‐LNP group versus all controls, which was associated with dramatic decreases in ÎČ‐catenin targets and some K‐Ras effectors, leading to reduced tumor cell proliferation and viability. Intriguingly, in relatively few mice, non‐GS‐positive tumors, which were evident as a small subset of overall tumor burden, were not affected by ÎČ‐catenin suppression. Conclusion: Ras activation downstream of c‐Met is sufficient to induce clinically relevant HCC in cooperation with mutant ÎČ‐catenin. ÎČ‐catenin suppression by a clinically relevant modality is effective in treatment of ÎČ‐catenin‐positive, GS‐positive HCCs. (Hepatology 2016)


    Date de mise en ligne : Vendredi 03 février 2017
    Rahul Gupta, Jyoti Gupta
    Strategies to improve survival of patients with intrahepatic cholangiocarcinoma undergoing liver transplantation
    n/a


    Date de mise en ligne : Vendredi 03 février 2017
    Demetrios Moris, Evangelos Felekouras
    Ignore reality but not the consequences of its ignorance: Broaden guidelines in surgery of hepatocellular carcinoma
    n/a


    Date de mise en ligne : Mardi 31 janvier 2017
    Zongxin Ling, Xia Liu, Yiwen Cheng, Li Shao, Haiyin Jiang, Lanjuan Li
    Blood microbiota as a potential noninvasive diagnostic biomarker for liver fibrosis in severely obese patients: Choose carefully
    n/a


    Date de mise en ligne : Vendredi 06 janvier 2017
    Daimin Xiang, Zhuo Cheng, Hui Liu, Xue Wang, Tao Han, Wen Sun, Xiaofeng Li, Wen Yang, Cheng Chen, Mingyang Xia, Na Liu, Shengyong Yin, Guangzhi Jin, Terence Lee, Liwei Dong, Heping Hu, Hongyang Wang, Jin Ding
    Shp2 promotes liver cancer stem cell expansion by augmenting ÎČ‐catenin signaling and predicts chemotherapeutic response of patients
    Src‐homology 2 domain–containing phosphatase 2 (Shp2) has been reported to play an important role in the maintenance and self‐renewal of embryonic and adult stem cells, but its role in cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of Shp2 in both chemoresistant hepatocellular carcinomas (HCCs) and recurrent HCCs from patients. A remarkable increase of Shp2 was detected in sorted epithelial cell adhesion molecule–positive or cluster of differentiation 133–positive liver CSCs and in CSC‐enriched hepatoma spheroids from patients. Up‐regulated Shp2 facilitated liver CSC expansion by promoting the dedifferentiation of hepatoma cells and enhancing the self‐renewal of liver CSCs. Mechanistically, Shp2 dephosphorylated cell division cycle 73 in the cytosol of hepatoma cells, and the dephosphorylated cell division cycle 73 bound ÎČ‐catenin and facilitated the nuclear translocation of ÎČ‐catenin, which promoted the dedifferentiation of hepatoma cells. Shp2 increased ÎČ‐catenin accumulation by inhibiting glycogen synthase kinase 3ÎČ–mediated ÎČ‐catenin degradation in liver CSCs, thereby enhancing the self‐renewal of liver CSCs. Blockage of ÎČ‐catenin abolished the discrepancy in liver CSC proportion and the self‐renewal capacity between Shp2‐depleted hepatoma cells and control cells, which further confirmed that ÎČ‐catenin is required in Shp2‐promoted liver CSC expansion. More importantly, HCC patients with low Shp2 levels benefited from transcatheter arterial chemoembolization or sorafenib treatment, but patients with high Shp2 expression did not, indicating the significance of Shp2 in personalized HCC therapy. Conclusion: Shp2 could promote HCC cell dedifferentiation and liver CSC expansion by amplifying ÎČ‐catenin signaling and may be useful in predicting patient response to chemotherapeutics. (Hepatology 2017).


    Date de mise en ligne : Mardi 03 janvier 2017
    Lin Wang, Jiabao Geng
    Acute hepatitis E virus infection in patients with acute liver failure in China: Not quite an uncommon cause
    n/a


    Date de mise en ligne : Vendredi 30 décembre 2016
    Micol RavĂ , Aleco D'Andrea, Mirko Doni, Theresia R. Kress, Renato Ostuni, Valerio Bianchi, Marco J. Morelli, Agnese Collino, Serena Ghisletti, Paola Nicoli, Camilla Recordati, Maria Iascone, Aurelio Sonzogni, Lorenzo D'Antiga, Ruchi Shukla, Geoffrey J. Faulkner, Gioacchino Natoli, Stefano Campaner, Bruno Amati
    Mutual epithelium‐macrophage dependency in liver carcinogenesis mediated by ST18
    The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo, as well as coculture with macrophages in vitro. Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in pre‐established tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumor‐associated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18‐depleted tumors before involution revealed down‐regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B–dependent transcription. Conclusion: ST18 expression in epithelial cells is induced by tumor‐associated macrophages, contributing to the reciprocal feed‐forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18‐dependent epithelium–macrophage interactions in a therapeutic setting. (Hepatology 2016).


    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).


    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 2016).


    Date de mise en ligne : Mardi 09 août 2016
    Raj Vuppalanchi, Romil Saxena, Anna Maria V. Storniolo, Naga Chalasani
    Pseudocirrhosis and liver failure in patients with metastatic breast cancer after treatment with palbociclib
    n/a


    Date de mise en ligne : Mardi 21 mars 2017
    Masthead
    Masthead
    n/a


    Date de mise en ligne : Mardi 21 mars 2017
    Table of contents
    Table of contents
    n/a


    Date de mise en ligne : Mardi 21 mars 2017
    Jean‐François Dufour
    Hepatology Highlights
    1083


    Date de mise en ligne : Vendredi 03 mars 2017
    Grace L. Su, Robert J. Fontana
    Introducing the AASLD president: Anna S.F. Lok
    1087


    Date de mise en ligne : Vendredi 03 mars 2017
    Yaron Rotman, Brent A. Neuschwander‐Tetri
    Liver fat accumulation as a barometer of insulin responsiveness again points to adipose tissue as the culprit
    1090


    Date de mise en ligne : Vendredi 03 mars 2017
    Einar S. Björnsson, Jon Gunnlaugur Jonasson
    Idiosyncratic drug‐induced liver injury associated with bile duct loss and vanishing bile duct syndrome: Rare but has severe consequences
    1093


    Date de mise en ligne : Samedi 25 février 2017
    Kris V. Kowdley, Vinay Sundaram, Christie Y. Jeon, Kamran Qureshi, Nyan L. Latt, Amandeep Sahota, Stephen Lott, Michael P. Curry, Naoky Tsai, Nathorn Chaiyakunapruk, Yoori Lee, Jorg Petersen, Peter Buggisch
    Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection
    Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus–infected patients who are treatment‐naive, do not have cirrhosis, and have a pretreatment viral load <6,000,000 IU/mL. The effectiveness of this regimen, however, has not been fully confirmed by real‐world experience. Using data from real‐world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we used individual patient data from the IFI (Institut fĂŒr InterdisziplinĂ€re Medizin), Burman's Pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography, or serum biomarkers. We also performed a systematic review and meta‐analysis of six additional real‐world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of whom all had outcomes of cure or relapse without loss to follow‐up. Per protocol rates of sustained virologic response at 12 weeks were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment‐eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta‐analysis of six additional real‐world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (relative risk = 0.99, 95% confidence interval 0.98‐1.00). Conclusion: An 8‐week duration of treatment with LDV/SOF is highly effective in properly selected patients; greater use of this regimen is recommended. (Hepatology 2017;65:1094‐1103)


    Date de mise en ligne : Mardi 17 janvier 2017
    Senko Tsukuda, Koichi Watashi, Taichi Hojima, Masanori Isogawa, Masashi Iwamoto, Katsumi Omagari, Ryosuke Suzuki, Hideki Aizaki, Soichi Kojima, Masaya Sugiyama, Akiko Saito, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau, Takaji Wakita
    A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins
    Introduction of direct‐acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral‐targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell‐based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP‐mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan‐genotypic anti‐HBV activity and was also effective against a clinically relevant nucleoside analog‐resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more‐potent anti‐HBV activity over PAC. Conclusion: PAC and its analogs represent a new class of anti‐HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well‐tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2017;65:1104‐1116).


    Date de mise en ligne : Mardi 14 février 2017
    Patricia T. Vietheer, Irene Boo, Jun Gu, Kathleen McCaffrey, Stirling Edwards, Catherine Owczarek, Matthew P. Hardy, Louis Fabri, Rob J. Center, Pantelis Poumbourios, Heidi E. Drummer
    The core domain of hepatitis C virus glycoprotein E2 generates potent cross‐neutralizing antibodies in guinea pigs
    A vaccine that prevents hepatitis C virus (HCV) infection is urgently needed to support an emerging global elimination program. However, vaccine development has been confounded because of HCV's high degree of antigenic variability and the preferential induction of type‐specific immune responses with limited potency against heterologous viral strains and genotypes. We showed previously that deletion of the three variable regions from the E2 receptor‐binding domain (Δ123) increases the ability of human broadly neutralizing antibodies (bNAbs) to inhibit E2‐CD81 receptor interactions, suggesting improved bNAb epitope exposure. In this study, the immunogenicity of Δ123 was examined. We show that high‐molecular‐weight forms of Δ123 elicit distinct antibody specificities with potent and broad neutralizing activity against all seven HCV genotypes. Antibody competition studies revealed that immune sera raised to high‐molecular‐weight Δ123 was poly specific, given that it inhibited the binding of human bNAbs directed to three major neutralization epitopes on E2. By contrast, the immune sera raised to monomeric Δ123 predominantly blocked the binding of a non‐neutralizing antibody to Δ123, while having reduced ability to block bNAb binding to E2, and neutralization was largely toward the homologous genotype. This increased ability of oligomeric Δ123 to generate bNAbs correlates with occlusion of the non‐neutralizing face of E2 in this glycoprotein form. Conclusion: The results from this study reveal new information on the antigenic and immunogenic potential of E2‐based immunogens and provide a pathway for the development of a simple, recombinant protein‐based prophylactic vaccine for HCV with potential for universal protection. (Hepatology 2017;65:1117‐1131).


    Date de mise en ligne : Samedi 25 février 2017
    Fernando Bril, Diana Barb, Paola Portillo‐Sanchez, Diane Biernacki, Romina Lomonaco, Amitabh Suman, Michelle H. Weber, Jeffrey T. Budd, Maria E. Lupi, Kenneth Cusi
    Metabolic and histological implications of intrahepatic triglyceride content in nonalcoholic fatty liver disease
    The cut‐off point of intrahepatic triglyceride (IHTG) content to define nonalcoholic fatty liver disease (NAFLD) by proton magnetic resonance spectroscopy (1H‐MRS) was established based on the 95th percentile in a group of healthy individuals (i.e., ≄5.56%). Whether this threshold correlates with metabolic and histological changes and whether a further accumulation of IHTG is associated with worsening of these parameters has not been properly assessed in a large cohort of patients. In this cross‐sectional study, 352 subjects were carefully characterized with the following studies: liver 1H‐MRS; euglycemic insulin clamp with measurement of glucose turnover; oral glucose tolerance test; and a liver biopsy. Hepatic insulin sensitivity (suppression of endogenous glucose production by insulin) was affected early on after IHTG content was ∌1.5% and remained uniformly impaired (∌40%‐45%), regardless of further IHTG accumulation. Skeletal muscle insulin sensitivity showed a gradual impairment at low degrees of IHTG accumulation, but remained unchanged after IHTG content reached the ∌6 ± 2% threshold. A similar pattern was observed for metabolic changes typically associated with NAFLD, such as hypertriglyceridemia and low high‐density lipoprotein cholesterol (HDL‐C). In contrast, adipose tissue insulin sensitivity (suppression of free fatty acids by insulin) showed a continuous worsening across the spectrum of IHTG accumulation in NAFLD (r = –0.38; P < 0.001). Histological severity of liver disease (inflammation, ballooning, and fibrosis) was not associated with the amount of IHTG content. Conclusion: IHTG accumulation is strongly associated with adipose tissue insulin resistance (IR), supporting the current theory of lipotoxicity as a driver of IHTG accumulation. Once IHTG accumulation reaches ∌6 ± 2%, skeletal muscle IR, hypertriglyceridemia, and low HDL‐C become fully established. Histological activity appears to have an early threshold and is not significantly influenced by increasing amounts of IHTG accumulation. (Hepatology 2017;65:1132‐1144).


    Date de mise en ligne : Samedi 05 novembre 2016
    Salvatore Petta, Vincent Wai‐Sun Wong, Calogero Cammà, Jean‐Baptiste Hiriart, Grace Lai‐Hung Wong, Fabio Marra, Julien Vergniol, Anthony Wing‐Hung Chan, Vito Di Marco, Wassil Merrouche, Henry Lik‐Yuen Chan, Marco Barbara, Brigitte Le‐Bail, Umberto Arena, Antonio Craxì, Victor de Ledinghen
    Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values
    Liver stiffness measurement (LSM) frequently overestimates the severity of liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Controlled attenuation parameter (CAP) is a new parameter provided by the same machine used for LSM and associated with both steatosis and body mass index, the two factors mostly affecting LSM performance in NAFLD. We aimed to determine whether prediction of liver fibrosis by LSM in NAFLD patients is affected by CAP values. Patients (n = 324) were assessed by clinical and histological (Kleiner score) features. LSM and CAP were performed using the M probe. CAP values were grouped by tertiles (lower 132‐298, middle 299‐338, higher 339‐400 dB/m). Among patients with F0‐F2 fibrosis, mean LSM values, expressed in kilopascals, increased according to CAP tertiles (6.8 versus 8.6 versus 9.4, P = 0.001), and along this line the area under the curve of LSM for the diagnosis of F3‐F4 fibrosis was progressively reduced from lower to middle and further to higher CAP tertiles (0.915, 0.848‐0.982; 0.830, 0.753‐0.908; 0.806, 0.723‐0.890). As a consequence, in subjects with F0‐F2 fibrosis, the rates of false‐positive LSM results for F3‐F4 fibrosis increased according to CAP tertiles (7.2% in lower versus 16.6% in middle versus 18.1% in higher). Consistent with this, a decisional flowchart for predicting fibrosis was suggested by combining both LSM and CAP values. Conclusions: In patients with NAFLD, CAP values should always be taken into account in order to avoid overestimations of liver fibrosis assessed by transient elastography. (Hepatology 2017;65:1145‐1155).


    Date de mise en ligne : Mardi 21 février 2017
    Matthew J. Klebanoff, Kathleen E. Corey, Jagpreet Chhatwal, Lee M. Kaplan, Raymond T. Chung, Chin Hur
    Bariatric surgery for nonalcoholic steatohepatitis: A clinical and cost‐effectiveness analysis
    Nonalcoholic steatohepatitis (NASH) affects 2%‐3% of the US population and is expected to become the leading indication for liver transplantation in the next decade. Bariatric surgery may be an effective but expensive treatment for NASH. Using a state‐transition model, our analysis assessed the effectiveness and cost‐effectiveness of surgery to manage NASH. We simulated the benefits and harms of laparoscopic Roux‐en‐Y gastric bypass surgery in patients defined by weight class (overweight, mild obesity, moderate obesity, and severe obesity) and fibrosis stage (F0‐F3). Comparators included intensive lifestyle intervention (ILI) and no treatment. Quality‐adjusted life years (QALYs), costs, and incremental cost‐effectiveness ratios were calculated. Our results showed that surgery and ILI in obese patients (with F0‐F3) increased QALYs by 0.678‐2.152 and 0.452‐0.618, respectively, compared with no treatment. Incremental cost‐effectiveness ratios for surgery in all F0‐F3 patients with mild, moderate, or severe obesity were $48,836/QALY, $24,949/QALY, and $19,222/QALY, respectively. In overweight patients (with F0‐F3), surgery increased QALYs by 0.050‐0.824 and ILI increased QALYs by 0.031‐0.164. In overweight patients, it was cost‐effective to reserve treatment only for F3 patients; the incremental cost‐effectiveness ratios for providing surgery or ILI only to F3 patients were $30,484/QALY and $25,367/QALY, respectively. Conclusions: Surgery was both effective and cost‐effective for obese patients with NASH, regardless of fibrosis stage; in overweight patients, surgery increased QALYs for all patients regardless of fibrosis stage, but was cost‐effective only for patients with F3 fibrosis; our results highlight the promise of bariatric surgery for treating NASH and underscore the need for clinical trials in this area. (Hepatology 2017;65:1156‐1164).


    Date de mise en ligne : Lundi 06 février 2017
    Zoe Hall, Nicholas J. Bond, Tom Ashmore, Francis Sanders, Zsuzsanna Ament, Xinzhu Wang, Andrew J. Murray, Elena Bellafante, Sam Virtue, Antonio Vidal‐Puig, Michael Allison, Susan E. Davies, Albert Koulman, Michele Vacca, Julian L. Griffin
    Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease
    Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA‐containing lipids. This results in a cycle of AA‐enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. Conclusion: NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165‐1180)


    Date de mise en ligne : Vendredi 03 février 2017
    Clara Jana‐Lui Busch, Tim Hendrikx, David Weismann, Sven JĂ€ckel, Sofie M.A. Walenbergh, AndrĂ© F. Rendeiro, Juliane Weißer, Florian Puhm, Anastasiya Hladik, Laura Göderle, Nikolina Papac‐Milicevic, Gerald Haas, Vincent Millischer, Saravanan Subramaniam, Sylvia Knapp, Keiryn L. Bennett, Christoph Bock, Christoph Reinhardt, Ronit Shiri‐Sverdlov, Christoph J. Binder
    Malondialdehyde epitopes are sterile mediators of hepatic inflammation in hypercholesterolemic mice
    Diet‐related health issues such as nonalcoholic fatty liver disease and cardiovascular disorders are known to have a major inflammatory component. However, the exact pathways linking diet‐induced changes (e.g., hyperlipidemia) and the ensuing inflammation have remained elusive so far. We identified biological processes related to innate immunity and oxidative stress as prime response pathways in livers of low‐density lipoprotein receptor‐deficient mice on a Western‐type diet using RNA sequencing and in silico functional analyses of transcriptome data. The observed changes were independent of the presence of microbiota and thus indicative of a role for sterile triggers. We further show that malondialdehyde (MDA) epitopes, products of lipid peroxidation and markers for enhanced oxidative stress, are detectable in hepatic inflammation predominantly on dying cells and stimulate cytokine secretion as well as leukocyte recruitment in vitro and in vivo. MDA‐induced cytokine secretion in vitro was dependent on the presence of the scavenger receptors CD36 and MSR1. Moreover, in vivo neutralization of endogenously generated MDA epitopes by intravenous injection of a specific MDA antibody results in decreased hepatic inflammation in low‐density lipoprotein receptor‐deficient mice on a Western‐type diet. Conclusion: Accumulation of MDA epitopes plays a major role during diet‐induced hepatic inflammation and can be ameliorated by administration of an anti‐MDA antibody. (Hepatology 2017;65:1181‐1195)


    Date de mise en ligne : Lundi 19 décembre 2016
    Omair Atiq, Jasmin Tiro, Adam C. Yopp, Adam Muffler, Jorge A. Marrero, Neehar D. Parikh, Caitlin Murphy, Katharine McCallister, Amit G. Singal
    An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis
    Although surveillance ultrasound and alpha fetoprotein (AFP) tests have minimal direct harm, downstream harms from follow‐up tests must be weighed against surveillance benefits when determining the value of hepatocellular carcinoma (HCC) screening programs. Our study's aims were to characterize prevalence and correlates of surveillance benefits and harms in cirrhosis patients undergoing HCC surveillance. We conducted a retrospective cohort study among patients with cirrhosis followed at a safety‐net health system between July 2010 and July 2013. We recorded surveillance‐related benefits, defined as early tumor detection and curative treatment, and surveillance‐related physical harms, defined as computed tomography or magnetic resonance imaging scans, biopsies, or other procedures performed for false‐positive or indeterminate surveillance results. Sociodemographic and clinical correlates of surveillance harms were evaluated using multivariable logistic regression. We identified 680 patients with cirrhosis, of whom 78 (11.5%) developed HCC during the 3‐year study period. Of the 48 (61.5%) HCCs identified by surveillance, 43.8% were detected by ultrasound, 31.2% by AFP, and 25.0% by both surveillance tests. Surveillance‐detected patients had a higher proportion of early HCC (70.2% vs. 40.0%; P = 0.009), with no difference in tumor stage between ultrasound‐ and AFP‐detected tumors (P = 0.53). Surveillance‐related physical harms were observed in 187 (27.5%) patients, with a higher proportion of ultrasound‐related harm than AFP‐related harm (22.8% vs. 11.4%; P < 0.001). Surveillance‐related harms were associated with elevated ALT (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.26‐2.76), thrombocytopenia (OR, 2.06; 95% CI, 1.26‐3.38), and hepatology subspecialty care (OR, 1.63; 95% CI, 1.09‐2.42). Conclusion: Over one fourth of patients with cirrhosis experience physical harm for false‐positive or indeterminate surveillance tests—more often related to ultrasound than AFP. Interventions are needed to reduce surveillance‐related harm to increase the value of HCC screening programs in clinical practice. (Hepatology 2017;65:1196‐1205).


    Date de mise en ligne : Lundi 19 décembre 2016
    Wang‐Yu Cai, Ling‐Yun Lin, Han Hao, Sai‐Man Zhang, Fei Ma, Xin‐Xin Hong, Hui Zhang, Qing‐Feng Liu, Guo‐Dong Ye, Guang‐Bin Sun, Yun‐Jia Liu, Sheng‐Nan Li, Yuan‐Yuan Xie, Jian‐Chun Cai, Bo‐An Li
    Yes‐associated protein/TEA domain family member and hepatocyte nuclear factor 4‐alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice
    Great progress has been achieved in the study of Hippo signaling in regulating tumorigenesis; however, the downstream molecular events that mediate this process have not been completely defined. Moreover, regulation of Hippo signaling during tumorigenesis in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we systematically investigated the relationship between Yes‐associated protein/TEA domain family member (YAP‐TEAD) and hepatocyte nuclear factor 4‐alpha (HNF4α) in the hepatocarcinogenesis of HCC cells. Our results indicated that HNF4α expression was negatively regulated by YAP1 in HCC cells by a ubiquitin proteasome pathway. By contrast, HNF4α was found to directly associate with TEAD4 to compete with YAP1 for binding to TEAD4, thus inhibiting the transcriptional activity of YAP‐TEAD and expression of their target genes. Moreover, overexpression of HNF4α was found to significantly compromise YAP‐TEAD‐induced HCC cell proliferation and stem cell expansion. Finally, we documented the regulatory mechanism between YAP‐TEAD and HNF4α in rat and mouse tumor models, which confirmed our in vitro results. Conclusion: There is a double‐negative feedback mechanism that controls TEAD‐YAP and HNF4α expression in vitro and in vivo, thereby regulating cellular proliferation and differentiation. Given that YAP acts as a dominant oncogene in HCC and plays a crucial role in stem cell homeostasis and tissue regeneration, manipulating the interaction between YAP, TEADs, and HNF4α may provide a new approach for HCC treatment and regenerative medicine. (Hepatology 2017;65:1206‐1221).


    Date de mise en ligne : Vendredi 20 janvier 2017
    Abhisek Mitra, Jun Yan, Xueqing Xia, Shouhao Zhou, Jian Chen, Lopa Mishra, Shulin Li
    IL6‐mediated inflammatory loop reprograms normal to epithelial‐mesenchymal transition+ metastatic cancer stem cells in preneoplastic liver of transforming growth factor beta–deficient ÎČ2‐spectrin+/− mice
    Hepatocellular carcinoma (HCC) is the second‐leading cause of cancer‐related deaths worldwide with a poor survival rate. As many as 40% of HCCs are clonal, with alteration of key tumor‐suppressor pathways in stem cells as the primary cause of HCC initiation. However, mechanisms that generate metastatic stem cells in preneoplastic liver tissue are not well understood. We hypothesized that chronic inflammation is a major driver of the transformation of genetically defective liver stem cells (LSCs) into highly metastatic liver cancer cells in premalignant liver tissue. We developed models of chronic inflammation in wild‐type (WT) and ÎČ2‐spectrin (ÎČ2SP)+/− (SPTBN1) mice. CD133+ LSCs derived from preneoplastic livers of ÎČ2SP+/− mice treated with interleukin‐6 (pIL6; IL6ÎČ2SP+/− LSCs) were highly tumorigenic and metastatic, whereas those derived from WT mice treated with pIL6 (IL6WT LSCs) had significantly less proliferation and no tumorigenic properties. IL6ÎČ2SP+/− LSCs not only exhibited nuclear localization of Twist and Slug, markers of epithelial‐mesenchymal transition (EMT), but also constitutive activation of nuclear factor kappa B (NFÎșB; RELA). Knockdown of NFÎșB decreased the EMT phenotypes and metastatic capacity of these cells. NFÎșB in IL6ÎČ2SP+/− LSCs was activated by transforming growth factor ÎČ (TGFÎČ)‐activated kinase 1 (TAK1; MAP3K7), which is associated with poor survival in HCC and interleukin‐6 (IL6) expression. The amount of constitutively activated NFÎșB increased dramatically from normal to cirrhotic to HCC tissues from human patients. Conclusion: IL6‐mediated inflammation programs constitutive activation of the TAK1‐NFÎșB signaling cascade in CD133+ LSCs, and this program interacts with deficient TGFÎČ signaling, thereby accelerating the transformation of normal LSCs to metastatic cancer stem cells (mCSCs). Indeed, this study delineates the development of EMT‐positive mCSCs in HCC‐free liver tissue upon chronic inflammation. (Hepatology 2017;65:1222‐1236).


    Date de mise en ligne : Mercredi 08 février 2017
    Benjamin Cadier, Julie Bulsei, Pierre Nahon, Olivier Seror, Alexis Laurent, Isabelle Rosa, Richard Layese, Charlotte Costentin, Carole Cagnot, Isabelle Durand‐Zaleski, Karine Chevreul,
    Early detection and curative treatment of hepatocellular carcinoma: A cost‐effectiveness analysis in France and in the United States
    Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. Patients outside clinical trials seldom benefit from evidence‐based monitoring. The objective of this study was to estimate the cost‐effectiveness of complying with HCC screening guidelines. The economic evaluation compared surveillance of patients with cirrhosis as recommended by the guidelines (“gold‐standard monitoring”) to “real‐life monitoring” from the health care system perspective. A Markov model described the history of the disease and treatment course including current first‐line curative treatment: liver resection, radiofrequency ablation (RFA), and liver transplantation. Transition probabilities were derived mainly from two French cohorts, CIRVIR and CHANGH. Costs were computed using French and U.S. tariffs. Effectiveness was measured in life years gained (LYG). An incremental cost‐effectiveness ratio (ICER) was calculated for a 10‐year horizon and tested with one‐way and probabilistic sensitivity analyses. The cost difference between the two groups was $648 ($87,476 in the gold‐standard monitoring group vs. $86,829 in the real‐life monitoring group) in France and $11,965 ($93,795 vs. $81,829) in the United States. Survival increased by 0.37 years (7.18 vs. 6.81 years). The ICER was $1,754 per LYG in France and $32,415 per LYG in the United States. The health gain resulted from earlier diagnosis and access to first‐line curative treatments, among which RFA provided the best value for money. Conclusion: Our results indicate that gold‐standard monitoring for patients with cirrhosis is cost‐effective, attributed to a higher probability of benefiting from a curative treatment and so a higher survival probability. (Hepatology 2017;65:1237‐1248)


    Date de mise en ligne : Mardi 31 janvier 2017
    Wei Fan, Heping Yang, Ting Liu, Jiaohong Wang, Tony W.H. Li, Nirmala Mavila, Yuanyuan Tang, JinWon Yang, Hui Peng, Jian Tu, Alagappan Annamalai, Mazen Noureddin, Anuradha Krishnan, Gregory J. Gores, Maria L. MartĂ­nez‐Chantar, JosĂ© M. Mato, Shelly C. Lu
    Prohibitin 1 suppresses liver cancer tumorigenesis in mice and human hepatocellular and cholangiocarcinoma cells
    Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone, and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α1 (MATα1) have lower PHB1 expression, and we reported that c‐MYC interacts directly with both proteins. Furthermore, c‐MYC and MATα1 exert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1, and c‐MYC and PHB1's role in liver tumorigenesis. We found that PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down‐regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1 expression correlates inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c‐MYC, MAFG, and c‐MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E‐box element, and repress E‐box promoter activity. PHB1 promoter contains a repressive E‐box element and is occupied mainly by MAX, MNT, and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c‐MYC, c‐MAF, and MAFG in cancer cells and human HCC/CCA. All 8‐month‐old liver‐specific Phb1 knockout mice developed HCC, and one developed CCA. Five‐month‐old Phb1 heterozygotes, but not Phb1 flox mice, developed aberrant bile duct proliferation; and one developed CCA 3.5 months after left and median bile duct ligation. Phb1 heterozygotes had a more profound fall in the expression of glutathione synthetic enzymes and higher hepatic oxidative stress following left and median bile duct ligation. Conclusion: We have identified that PHB1, down‐regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E‐box and positively regulates MAT1A while suppressing c‐MYC, MAFG, and c‐MAF expression; in mice, reduced PHB1 expression predisposes to the development of cholestasis‐induced CCA. (Hepatology 2017;65:1249‐1266).


    Date de mise en ligne : Mardi 07 février 2017
    Herbert L. Bonkovsky, David E. Kleiner, Jiezhun Gu, Joseph A. Odin, Mark W. Russo, Victor M. Navarro, Robert J. Fontana, Marwan S. Ghabril, Huiman Barnhart, Jay H. Hoofnagle,
    Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements
    Bile duct loss during the course of drug‐induced liver injury is uncommon, but can be an indication of vanishing bile duct syndrome (VBDS). In this work, we assess the frequency, causes, clinical features, and outcomes of cases of drug‐induced liver injury with histologically proven bile duct loss. All cases of drug‐induced liver injury enrolled into a prospective database over a 10‐year period that had undergone liver biopsies (n = 363) were scored for the presence of bile duct loss and assessed for clinical and laboratory features, causes, and outcomes. Twenty‐six of the 363 patients (7%) with drug‐, herbal‐, or dietary‐supplement–associated liver injury had bile duct loss on liver biopsy, which was moderate to severe (<50% of portal areas with bile ducts) in 14 and mild (50%‐75%) in 12. The presenting clinical features of the 26 cases varied, but the most common clinical pattern was a severe cholestatic hepatitis. The implicated agents included amoxicillin/clavulanate (n = 3), temozolomide (n = 3), various herbal products (n = 3), azithromycin (n = 2), and 15 other medications or dietary supplements. Compared to those without, those with bile duct loss were more likely to develop chronic liver injury (94% vs. 47%), which was usually cholestatic and sometimes severe. Five patients died and 2 others underwent liver transplantation for progressive cholestasis despite treatment with corticosteroids and ursodiol. The most predictive factor of poor outcome was the degree of bile duct loss on liver biopsy. Conclusion: Bile duct loss during acute cholestatic hepatitis is an ominous early indicator of possible VBDS, for which at present there are no known means of prevention or therapy. (Hepatology 2017;65:1267‐1277)


    Date de mise en ligne : Mardi 10 janvier 2017
    Sujit K. Mohanty, Bryan Donnelly, Inna Lobeck, Ashley Walther, Phylicia Dupree, Abigail Coots, Jaroslaw Meller, Monica McNeal, Karol Sestak, Greg Tiao
    The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia
    Biliary atresia (BA) is a neonatal obstructive cholangiopathy that progresses to end‐stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that the RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Using rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA. We identified the amino acid sequence on VP4 and its cholangiocyte binding protein, finding that the sequence is specific to those rotavirus strains that cause obstructive cholangiopathy. Pretreatment of murine and human cholangiocytes with this VP4‐derived peptide (TRTRVSRLY) significantly reduced the ability of RRV to bind and infect cells. However, the peptide did not block cholangiocyte binding of TUCH and Ro1845, strains that do not induce murine BA. The SRL sequence within TRTRVSRLY is required for cholangiocyte binding and viral replication. The cholangiocyte membrane protein bound by SRL was found to be Hsc70. Inhibition of Hsc70 by small interfering RNAs reduced RRV's ability to infect cholangiocytes. This virus‐cholangiocyte interaction is also seen in vivo in the murine model of BA, where inoculation of mice with TRTRVSRLY peptide significantly reduced symptoms and mortality in RRV‐injected mice. Conclusion: The tripeptide SRL on RRV VP4 binds to the cholangiocyte membrane protein Hsc70, defining a novel binding site governing VP4 attachment. Investigations are underway to determine the cellular response to this interaction to understand how it contributes to the pathogenesis of BA. (Hepatology 2017;65:1278‐1292)


    Date de mise en ligne : Lundi 06 mars 2017
    Annalisa Berzigotti, AgustĂ­n Albillos, Candid Villanueva, Joan GenescĂĄ, Alba Ardevol, Salvador AugustĂ­n, Jose Luis Calleja, Rafael Bañares, Juan Carlos GarcĂ­a‐PagĂĄn, Francisco Mesonero, Jaime Bosch,
    Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The SportDiet study
    Obesity increases the risk of clinical decompensation in cirrhosis, possibly by increasing portal pressure. Whether weight reduction can be safely achieved through lifestyle (LS) changes (diet and exercise) in overweight/obese patients with cirrhosis, and if weight loss reduces portal pressure in this setting, is unknown. This prospective, multicentric, uncontrolled pilot study enrolled patients with compensated cirrhosis, portal hypertension (hepatic venous pressure gradient [HVPG] ≄6 mm Hg), and body mass index (BMI) ≄26 kg/m2 in an intensive 16‐week LS intervention program (personalized hypocaloric normoproteic diet and 60 min/wk of supervised physical activity). We measured HVPG, body weight (BW) and composition, adipokines, health‐related quality of life, and safety data before and after the intervention. Changes in HVPG and BW were predefined as clinically relevant if ≄10% and ≄5%, respectively. Safety and BW were reassessed after 6 months. 60 patients were included and 50 completed the study (56 ± 8 years old; 62% male; nonalcoholic steatohepatitis etiology 24%; BMI 33.3 ± 3.2 kg/m2; Child A 92%; HVPG ≄10 mm Hg, 72%). LS intervention significantly decreased BW (average, –5.0 ± 4.0 kg; P < 0.0001), by ≄5% in 52% and ≄10% in 16%. HVPG also significantly decreased (from 13.9 ± 5.6 to 12.3 ± 5.2 mm Hg; P < 0.0001), by ≄10% in 42% and ≄20% in 24%. A ≄10% BW loss was associated with a greater decrease in HVPG (–23.7 ± 19.9% vs. –8.2 ± 16.6%; P = 0.024). No episodes of clinical decompensation occurred. Weight loss achieved at 16 weeks was maintained at 6 months; Child and Model for End‐Stage Liver Disease scores did not change. Conclusion: Sixteen weeks of diet and moderate exercise were safe and reduced BW and portal pressure in overweight/obese patients with cirrhosis and portal hypertension. (Hepatology 2017;65:1293‐1305).


    Date de mise en ligne : Mardi 07 mars 2017
    Anna Hadjihambi, Francesco Chiara, Patrick S. Hosford, Abeba Habtetion, Anastassios Karagiannis, Nathan Davies, Alexander V. Gourine, Rajiv Jalan
    Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease
    The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte‐neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia‐lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia‐induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. Conclusion: The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel‐mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306‐1318)


    Date de mise en ligne : Samedi 25 février 2017
    Prakash Baligar, Veena Kochat, Shailendra K. Arindkar, Zaffar Equbal, Snehashish Mukherjee, Swati Patel, Perumal Nagarajan, Sujata Mohanty, Jeffrey H. Teckman, Asok Mukhopadhyay
    Bone marrow stem cell therapy partially ameliorates pathological consequences in livers of mice expressing mutant human α1‐antitrypsin
    Alpha‐1‐antitrypsin (AAT) deficiency (AATD) is a genetic disease, caused by mutation of the AAT gene. Accumulation of mutated AAT protein aggregates in hepatocytes leads to endoplasmic reticulum stress, resulting in impairment of liver functions and, in some cases, hepatocellular carcinoma, whereas decline of AAT levels in sera is responsible for pulmonary emphysema. In advanced liver disease, the only option for treatment is liver transplantation, whereas AAT replacement therapy is therapeutic for emphysema. Given that hepatocytes are the primary affected cells in AATD, we investigated whether transplantation of bone marrow (BM)‐derived stem cells in transgenic mice expressing human AATZ (the Z variant of AAT) confers any competitive advantages compared to host cells that could lead to pathological improvement. Mouse BM progenitors and human mesenchymal stem cells (MSCs) appeared to contribute in replacement of 40% and 13% host hepatocytes, respectively. Transplantation of cells resulted in decline of globule‐containing hepatocytes, improvement in proliferation of globule‐devoid hepatocytes from the host‐derived hepatocytes, and apparently, donor‐derived cells. Further analyses revealed that transplantation partially improves liver pathology as reflected by inflammatory response, fibrosis, and apoptotic death of hepatocytes. Cell therapy was also found to improve liver glycogen storage and sera glucose level in mice expressing human AATZ mice. These overall improvements in liver pathology were not restricted to transplantation of mouse BM cells. Preliminary results also showed that following transplantation of human BM‐derived MSCs, globule‐containing hepatocytes declined and donor‐derived cells expressed human AAT protein. Conclusion: These results suggest that BM stem cell transplantation may be a promising therapy for AATD‐related liver disease. (Hepatology 2017;65:1319‐1335).


    Date de mise en ligne : Vendredi 03 mars 2017
    Katherine J. Brempelis, Sebastian Y. Yuen, Nicole Schwarz, Isaac Mohar, Ian N. Crispe
    Central role of the TIR‐domain‐containing adaptor‐inducing interferon‐ÎČ (TRIF) adaptor protein in murine sterile liver injury
    Multiple pathways drive the sterile injury response in the liver; however, it is unclear how the type of cells injured or the mechanism of injury activates these pathways. Here, we use a model of selective hepatocyte death to investigate sterile liver injury. In this model, the TIR‐domain‐containing adaptor‐inducing interferon‐ÎČ (TRIF) was a central mediator of the resulting intrahepatic inflammatory response that was independent of both upstream Toll‐like receptor (TLR) 4 signaling and downstream type I interferon (IFN) signaling. TRIF was required for induction of interleukin (IL)‐10, IL‐6, and IL‐1ÎČ cytokines. Conversely, although induction of C‐C motif chemokine ligand (CCL) 2 and C‐X‐C motif chemokine ligand (CXCL) 1 chemokines and up‐regulation of chemokine (Ccl2, Ccl7, Cxcl1, Cxcl2, and Cxcl10) and cell‐adhesion (intracellular adhesion molecule 1 and vascular cell adhesion molecule 1) genes involved in myeloid cell recruitment was reduced in a majority of TRIF–/– mice, a subset of TRIF–/– mice showed breakthrough inflammation and the ability to induce these genes and proteins, indicating that redundant pathways exist to respond to hepatocyte death. Furthermore, we found that hepatocytes themselves were the main responders to hepatocyte death, increasing transcription of genes involved in myeloid cell recruitment more than either liver sinusoidal endothelial cells or Kupffer cells. Conclusion: Our studies define a TRIF‐dependent, TLR4‐ and type I IFN‐independent pathway of sterile liver injury in which hepatocytes are both the targets of damage and the principal responding cell type. (Hepatology 2017;65:1336‐1351).


    Date de mise en ligne : Mardi 21 février 2017
    Lucille Morzyglod, MichĂšle CaĂŒzac, Lucie Popineau, Pierre‐Damien Denechaud, Lluis Fajas, Bruno Ragazzon, VĂ©ronique Fauveau, Julien Planchais, Mireille Vasseur‐Cognet, Laetitia Fartoux, Olivier Scatton, Olivier Rosmorduc, Sandra Guilmeau, Catherine Postic, Chantal Desdouets, ChristĂšle Desbois‐Mouthon, Anne‐Françoise Burnol
    Growth factor receptor binding protein 14 inhibition triggers insulin‐induced mouse hepatocyte proliferation and is associated with hepatocellular carcinoma
    Metabolic diseases such as obesity and type 2 diabetes are recognized as independent risk factors for hepatocellular carcinoma (HCC). Hyperinsulinemia, a hallmark of these pathologies, is suspected to be involved in HCC development. The molecular adapter growth factor receptor binding protein 14 (Grb14) is an inhibitor of insulin receptor catalytic activity, highly expressed in the liver. To study its involvement in hepatocyte proliferation, we specifically inhibited its liver expression using a short hairpin RNA strategy in mice. Enhanced insulin signaling upon Grb14 inhibition was accompanied by a transient induction of S‐phase entrance by quiescent hepatocytes, indicating that Grb14 is a potent repressor of cell division. The proliferation of Grb14‐deficient hepatocytes was cell‐autonomous as it was also observed in primary cell cultures. Combined Grb14 down‐regulation and insulin signaling blockade using pharmacological approaches as well as genetic mouse models demonstrated that Grb14 inhibition–mediated hepatocyte division involved insulin receptor activation and was mediated by the mechanistic target of rapamycin complex 1–S6K pathway and the transcription factor E2F1. In order to determine a potential dysregulation in GRB14 gene expression in human pathophysiology, a collection of 85 human HCCs was investigated. This revealed a highly significant and frequent decrease in GRB14 expression in hepatic tumors when compared to adjacent nontumoral parenchyma, with 60% of the tumors exhibiting a reduced Grb14 mRNA level. Conclusion: Our study establishes Grb14 as a physiological repressor of insulin mitogenic action in the liver and further supports that dysregulation of insulin signaling is associated with HCC. (Hepatology 2017;65:1352‐1368).


    Date de mise en ligne : Mardi 07 février 2017
    Eleanna Kaffe, Aggeliki Katsifa, Nikos Xylourgidis, Ioanna Ninou, Markella Zannikou, Vaggelis Harokopos, Pelagia Foka, Alexios Dimitriadis, Kostas Evangelou, Anargyros N. Moulas, Urania Georgopoulou, Vassilis G. Gorgoulis, George N. Dalekos, Vassilis Aidinis
    Hepatocyte autotaxin expression promotes liver fibrosis and cancer
    Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth‐factor–like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte‐specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. Conclusion: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369‐1383).


    Date de mise en ligne : Lundi 06 mars 2017
    George K. Michalopoulos
    Hepatostat: Liver regeneration and normal liver tissue maintenance
    In contrast to all other organs, liver‐to‐body‐weight ratio needs to be maintained always at 100% of what is required for body homeostasis. Adjustment of liver size to 100% of what is required for homeostasis has been called “hepatostat.” Removal of a portion of any other organ is followed with local regeneration of a limited degree, but it never attempts to reach 100% of the original size. The complex mechanisms involved in this uniquely hepatic process encompass a variety of regenerative pathways that are specific to different types of injury. The most studied form of liver regeneration (LR) is that occurring after loss of hepatocytes in a single acute injury, such as rodent LR after two‐thirds partial hepatectomy or administration of damaging chemicals (CCl4, acetaminophen, etc.). Alternative regenerative pathways become activated when normal regeneration is thwarted and trigger the appearance of “progenitor” cells. Chronic loss of hepatocytes is associated with regenerative efforts characterized by continual hepatocyte proliferation and often has adverse consequences (development of cirrhosis or liver cancer). Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood. (Hepatology 2017;65:1384‐1392)


    Date de mise en ligne : Mardi 07 mars 2017
    Michael Trauner, Claudia Daniela Fuchs, Emina Halilbasic, Gustav Paumgartner
    New therapeutic concepts in bile acid transport and signaling for management of cholestasis
    The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA‐induced gut hormones, fibroblast growth factor 19 and glucagon‐like peptide 1, and the BA transport systems, apical sodium‐dependent bile acid transporter and Na+‐taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393‐1404).


    Date de mise en ligne : Mardi 07 mars 2017
    Cynthia Levy
    Primary biliary cholangitis: Treatment options finally expand
    1407


    Date de mise en ligne : Mardi 21 mars 2017
    Naim Alkhouri, Ariel E. Feldstein
    Treating nonalcoholic steatohepatitis in children: Not a cinch task
    1409


    Date de mise en ligne : Vendredi 03 février 2017
    Marcial Sebode, Sören Weidemann, Malte Wehmeyer, Ansgar W. Lohse, Christoph Schramm
    Anti‐TNF‐α for necrotizing sarcoid granulomatosis of the liver
    We present a case of hepatosplenic necrotizing sarcoid granulomatosis, a variant form of “classical” sarcoidosis, that became clinically apparent in the form of multiple hepatic and splenic masses mimicking malignancy. Flow cytometry of intrahepatic T cells isolated from liver biopsy led to the targeted treatment with anti‐tumor necrosis factor‐alpha, which was highly effective in inducing remission. (Hepatology 2017;65:1410‐1412)


    Date de mise en ligne : Mardi 21 mars 2017
    Robert Driver, Ian A. Rowe
    What is the benefit of early follow‐up after hospitalization for patients with cirrhosis?
    1413


    Date de mise en ligne : Mardi 21 février 2017
    Antoni Sabate, Annabel Blasi
    Thromboelastography and blood product usage in cirrhosis with severe coagulopathy
    1414


    Date de mise en ligne : Samedi 10 décembre 2016
    Gin‐Ho Lo
    The interval of endoscopic variceal ligation: The shorter the better?
    1415


    Date de mise en ligne : Vendredi 30 décembre 2016
    Ulku Saritas, Yucel Ustundag
    One‐ or two‐week interval for variceal banding after bleeding: Which one to choose?
    1416


    Date de mise en ligne : Mardi 29 novembre 2016
    Sarah Sheibani, Loren Laine
    Reply
    1417


    Date de mise en ligne : Lundi 28 novembre 2016
    Silvia Sookoian, Carlos J. Pirola
    Nonalcoholic fatty liver disease: Biomarkers support decisions around pharmacological intervention
    1419


    Date de mise en ligne : Mardi 29 novembre 2016
    Astrid Marot, HĂ©lĂšne Vandenbulcke, Jean‐François Knebel, Christopher Doerig, Christophe Moreno, Pierre Deltenre
    External validation of the nomogram for individualized prediction of hepatocellular carcinoma occurrence in patients with hepatitis C virus–related compensated cirrhosis
    1421


    Date de mise en ligne : Mardi 03 janvier 2017
    Haider Altaii, Sadeer G. Al‐Kindi, Guilherme H. Oliveira, Zaid Yaqoob, Carlos Romero‐Marrero
    Aspirin use and risk of cholangiocarcinoma: External validation with big data
    1422


    Date de mise en ligne : Jeudi 29 décembre 2016
    Jonggi Choi, Roongruedee Chaiteerakij, Lewis R. Roberts
    Reply
    1423


    Date de mise en ligne : Mardi 21 février 2017
    Anand V. Kulkarni, Shiv K. Sarin, Ashok Choudhury, S.M. Shashthry, Karan Kumar, Lovkesh Anand
    Role of microRNA in acute cellular rejection
    1424


    Date de mise en ligne : Lundi 06 mars 2017
    Anders Boyd, Patrick Miailhes, Karine Lacombe, Fabien Zoulim
    Potential effect of lamivudine‐induced S gene mutations on liver‐related pathogenesis in hepatitis D virus infection
    1426


    Date de mise en ligne : Vendredi 03 mars 2017
    Correction
    Correction
    1427


    Date de mise en ligne : Vendredi 03 mars 2017
    Correction
    Correction
    1427


    Date de mise en ligne : Mardi 21 mars 2017
    Notices
    Notices
    n/a


    Date de mise en ligne : Mardi 21 mars 2017
    Instructions to authors and Information for readers
    Instructions to authors and Information for readers
    n/a