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Les derniers abstracts de la revue Hepatology :


    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
    n/a


    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
    n/a


    Date de mise en ligne : Lundi 13 février 2017
    Yasuko Iwakiri
    Reply to the Letter to the Editor in regards to the commentary on “The lymphatic system: A new frontier in hepatology”
    n/a


    Date de mise en ligne : Lundi 13 février 2017
    David E. Kleiner
    On Beyond Staging and Grading: Liver Biopsy Evaluation in a Post‐Treatment World
    n/a


    Date de mise en ligne : Lundi 13 février 2017
    Lucy Golden‐Mason, Hugo R. Rosen
    Galectin‐9: Diverse Roles in Hepatic Immune Homeostasis and Inflammation
    Glycan‐binding proteins which include galectins are involved at all stages of immunity and inflammation, ranging from initiation through resolution. Galectin‐9 (Gal‐9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal‐9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal‐9 is evident in hepatocellular carcinoma (HCC) where loss of expression in hepatocytes promotes tumor growth and metastasis whereas overexpression by Kupffer cells and endothelial cells inhibits the anti‐tumor immune response. In non‐alcoholic fatty liver disease (NAFLD), Gal‐9 is involved indirectly in the expansion of protective NKT cell populations. In ischemic liver injury, hepatocyte‐derived Gal‐9 is both diagnostic and cytoprotective. In drug‐induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal‐9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune‐mediated diseases and to develop new therapeutic interventions using glycan‐binding proteins. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Raquel Yotti, Cristina Ripoll, Yolanda Benito, Maria Vega Catalina, Jaime ElĂ­zaga, Diego RincĂłn, Francisco FernĂĄndez‐AvilĂ©s, Javier Bermejo, Rafael Bañares
    Left ventricular systolic function is associated to sympathetic nervous activity and markers of inflammation in cirrhosis
    An accurate evaluation of cardiac function in patients with cirrhosis remains a challenge. We used robust echocardiographic indices to characterize LV systolic function and its relationship to activation of the sympathetic nervous system (SNS) and inflammation in 59 patients cirrhosis and 59 age‐matched controls. Aditionally, in eleven patients we withdrew betablockers and diuretics and used phenylephrine and albumin infusion to evaluate the response to acute afterload and preload changes (interventional substudy). Measures of systolic LV function such as the ejection intraventricular pressure difference (EIVPD) and the systolic strain‐rate were higher in patients with cirrhosis than in controls (median [1st ‐ 3rd quartile]: 4.0 [3.1 ‐ 5.1] vs. 2.9 [2.4 ‐ 3.6] mmHg and ‐1.3 [‐1.6 to ‐1.1] vs. ‐1.2 [‐1.6 to ‐1.1)] s−1, respectively; p< 0.05 for both). EIVPD was related to the severity of liver disease (MELD: rho= 0.45, p< 0.001), the degree of SNS activation (noradrenaline: rho= 0.26, p=0.05; heart‐rate variability: rho= ‐0.43 p=0.003), and treatment with beta‐blockers (p=0.001). In the interventional substudy, EIPVD was higher in patients with ascites (6.5 [5.4‐8.5] vs. 4.0 [3.9‐5.1] mmHg, p=0.045). The decrease in EIVPD induced by phenylephrine was inversely related to baseline systolic function (p< 0.05), and associated to markers of systemic vasodilatation (nitric oxide: rho=‐0.66, p=0.06; diastolic blood‐pressure: rho 0.68, p=0.04) and inflammation (interleukin‐1 beta: rho=‐0.80, p=0.009). Conclusion: LV systolic function is enhanced in cirrhosis due to augmented adrenergic tone and is modulated by treatment with beta‐blockers. Acute afterload stress induces a deeper impairment of systolic function in patients with more advanced degrees of vasodilatation and inflammation. These changes in LV function related to cirrhosis can be assessed using robust echocardiographic methods. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Guofeng Chen, Cheng Wang, Jing Chen, Dong Ji, Yudong Wang, Vanessa Wu, J Karlberg, George Lau
    Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and meta‐analysis
    There is an increased awareness of hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients coinfected with HBV treated with pan‐oral direct‐acting antivirals (DAAs). We performed a systematic review and meta‐analysis to compare the rate of HBV reactivation in CHC patients coinfected with overt HBV (hepatitis B surface antigen [HBsAg] positive) and occult HBV (HBsAg negative with positive HBV DNA) infection separately, treated with interferon (IFN)‐based therapy to those with pan‐oral DAAs. The primary outcome was HBV reactivation and the secondary outcomes included hepatitis due to HBV reactivation, sustained virologic response (SVR) for CHC, loss of HBV DNA and HBsAg seroclearance. Although the pooled incidence rate of HBV reactivation, among CHC patients with overt HBV (n=779), was similar among those treated with IFN‐based therapy (14.5%, p<0.001) and DAAs (12.2%, p=0.03; p=0.91 for heterogeneity between sub‐groups), it was reported to occur much earlier in those treated with DAAs (4‐12 weeks during treatment) than IFN‐based therapies (most at the end of treatment and some during follow‐up). Also, studies with DAAs‐based therapies were more likely to report incidence of hepatitis due to HBV reactivation (12.2% in DAAs vs. 0% in IFN, p=0.009 for heterogeneity between sub‐groups). HBV reactivation and hepatitis due to HBV reactivation also occurred though less frequently in CHC patients with occult HBV infection. CHC SVR was not affected by HBV reactivation (p=0.27). Conclusions: HBV reactivation occurs earlier and is clinically more significant in those CHC patients coinfected with overt and occult HBV, treated with pan‐oral DAAs compared to IFN‐based therapy. It is hence important to have all patients screened for evidence of overt or occult HBV infection and managed during pan‐oral DAAs therapy. (PROSPERO registration number: CRD42016046760) This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Avinash Kumar, Gangarao Davuluri, Rafaella Nasciemento deSilva, Marielle PKJ Engelen, Gabrie TenHave, Richard Prayson, Nicolaas EP Deutz, Srinivasan Dasarathy
    Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis
    n/a


    Date de mise en ligne : Lundi 13 février 2017
    Lei Xu, Wenshi Wang, Yunlong Li, Xinying Zhou, Yuebang Yin, Yijin Wang, Robert A. de Man, Luc J. W. van der Laan, Fen Huang, Nassim Kamar, Maikel P. Peppelenbosch, Qiuwei Pan
    RIG‐I Is A Key Antiviral Interferon‐Stimulated Gene Against Hepatitis E Virus Dispensable Of Interferon Production
    Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of interferon‐stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of individual ISG. The mechanism‐of‐action of the key anti‐HEV ISG was further studied. We identified RIG‐I, MDA5 and IRF1 as the key anti‐HEV ISGs. We found that basal expression of RIG‐I restricts HEV infection. Pharmacological activation of the RIG‐I pathway by its natural ligand 5'pppRNA potently inhibits HEV replication. Overexpression of RIG‐I activates the transcription of a wide range of ISGs. RIG‐I also mediates but does not overlap with IFN‐α initiated ISG transcription. Although it is classically recognized that RIG‐I exerts antiviral activity through the induction of IFN production via IRF3 and IRF7, we now revealed an IFN‐independent antiviral mechanism of RIG‐I in combating HEV infection. We found that activation of RIG‐I stimulates an antiviral response independent of IRF3 and IRF7 and dispensable of IFN production. However, it is partially through the activation of the JAK‐STAT cascade of the IFN signaling. RIG‐I activated two distinct categories of ISGs, one class of JAK‐STAT‐dependent and the other of JAK‐STAT‐independent, which coordinately contribute to the anti‐HEV activity. Conclusion: We identified RIG‐I as an important anti‐HEV ISG that can be pharmacologically activated. Activation of RIG‐I stimulates the cellular innate immunity against HEV dispensable of IFN production, but partially through the JAK‐STAT cascade of the IFN signaling. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 13 février 2017
    Thierry Gustot, Javier Fernandez, Elisabet Garcia, Marco Pavesi, Vicente Arroyo
    Reply to “Futility of care in patients with acute‐on‐chronic liver failure”
    n/a


    Date de mise en ligne : Lundi 13 février 2017
    Lionel Arrivé, Sanaù El Mouhadi
    Letter to the editor
    n/a


    Date de mise en ligne : Mercredi 08 février 2017
    Solùne Denolly, François‐Loïc Cosset
    A master regulator of tight junctions involved in hepatitis C virus entry and pathogenesis
    n/a


    Date de mise en ligne : Mercredi 08 février 2017
    Marcin Krawczyk, Monika Rau, Frank GrĂŒnhage, Jörn M. Schattenberg, Heike Bantel, Anita Pathil, MĂŒnevver Demir, Johannes Kluwe, Tobias Boettler, Andreas Geier, Frank Lammert,
    The ABCB4 p.T175A variant as potential modulator of hepatic fibrosis in patients with chronic liver diseases: Looking beyond the cholestatic realm
    n/a


    Date de mise en ligne : Mardi 07 février 2017
    Carlos FernĂĄndez Carrillo, Sabela Lens, Elba Llop, Juan Manuel Pascasio, Javier Crespo, Juan Arenas, Inmaculada FernĂĄndez, Carme Baliellas, JosĂ© Antonio CarriĂłn, Manuel de la Mata, Maria Buti, LluĂ­s Castells, AgustĂ­n Albillos, Manuel Romero, Juan Turnes, Clara Pons, JosĂ© MarĂ­a Moreno‐Planas, JosĂ© Javier Moreno‐Palomares, Conrado FernĂĄndez‐Rodriguez, Javier GarcĂ­a‐Samaniego, MartĂ­n Prieto, Miguel FernĂĄndez Bermejo, Javier SalmerĂłn, Ester Badia, Magdalena Salcedo, JosĂ© Ignacio Herrero, Rafael Granados, Michel BlĂ©, Zoe Mariño, JosĂ© Luis Calleja
    Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of MELD: Analysis of data from the Hepa‐C registry
    Direct‐acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus (HCV) infection, including those with compensated cirrhosis. However, fewer data are available in patients with more advanced liver disease. Our retrospective, non‐interventional, national, multi‐center study in patients from the Spanish Hepa‐C registry investigated the effectiveness and safety of interferon‐free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 cirrhotic patients (Child A, n=564; Child B/C, n=175), 90% achieved sustained virologic response 12 weeks post‐treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between Child A and Child B/C patients (94% vs. 78%, and 4% vs. 14%, respectively; both P<0.001). Serious adverse events (SAEs) were more common in Child B/C vs. Child A patients (50% vs. 12%, respectively; P<0.001). Incident decompensation was the most common SAE (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among Child B/C vs. Child A patients (6.4% vs. 0.9%; P<0.001). Baseline Model for End‐Stage Liver Disease (MELD) score alone (cut‐off 18) was the best predictor of survival. Conclusions Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≄18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 07 février 2017
    S. Mueller, P. Nahon, V. Rausch, T. Peccerella, I. Silva, E. Yagmur, B.K. Straub, C. Lackner, H.K. Seitz, P. Rufat, A. Sutton, H. Bantel, T. Longerich
    Caspase‐cleaved K18 fragments increase during alcohol withdrawal and predict liver‐related death in patients with ALD
    Non‐invasive assessment of disease activity in patients with non‐alcoholic (NALFD) and alcoholic liver disease (ALD) is still unsettled but essential for the evaluation of disease progression. We here studied the association of total (M65) and caspase‐cleaved (M30) serum keratin‐18 fragments (n=204) with histological parameters (n=106) in heavy drinkers primarily admitted for alcohol withdrawal before and after alcohol detoxification. An age, gender and fibrosis‐stage matched NAFLD cohort (n=30) was used for comparison. The prognostic value of M30 and M65 levels were assessed in an additional prospectively followed‐up cohort of 230 patients with alcoholic cirrhosis using competing risk analyses. Among the histological parameters, both M30/65 correlated significantly and better than any other serum marker with apoptosis and liver damage such as ballooning (r=0.65, P<0.001), followed by lobular inflammation (0.48, P<0.001), steatosis (0.46, P<0.001) but less with fibrosis (0.24, P<0.001). AUROCs to detect ballooning, steatosis or steatohepatitis were slightly better for M30 (P<0.005). Optimal M30 cut‐off values for mild and severe ballooning were 330 and 420 U/L, and 290 and 330 U/L for steatohepatitis grade 1 and 2. No significant differences of M30/65 were found between the matched NAFLD and ALD cohort. In contrast to AST and M65, M30 levels increased significantly from 391 to 518 U/L during alcohol detoxification. Moreover, levels of M30 and M65 predicted non‐HCC liver‐related mortality in patients with alcoholic cirrhosis during a mean observation interval of 67.2 months. In conclusion, our data suggest M30 as highly specific marker of liver apoptosis both in ALD and NAFLD. In addition, hepatocellular apoptosis as determined by M30 levels occur during alcohol withdrawal and survival data point towards a novel underestimated role of apoptosis in patients with ALD. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 07 février 2017
    Min Woo Lee, Steven S. Raman, Nazanin H. Asvadi, Surachate Siripongsakun, Robert M. Hicks, Jeffrey Chen, Akeanong Worakitsitisatorn, Justin McWilliams, Myron J. Tong, Richard S. Finn, Vatche G. Agopian, Ronald W. Busuttil, David S.K. Lu
    Radiofrequency Ablation of Hepatocellular Carcinoma as Bridge Therapy to Liver Transplantation: A Ten Year Intention‐to‐treat Analysis
    In a long‐term (10 years) study of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) as bridging therapy in patients listed for orthotopic liver transplantation (LT), we evaluated the impact of RFA on waiting list dropout rate, post‐LT tumor recurrence, and long‐term intention to treat, disease‐specific survival. From March 2004 to October 2014, RFA was performed as the initial stand‐alone bridge therapy to LT for 121 patients (male:female = 83:38; mean age, 60.0 years) with 156 de‐novo HCCs (mean size: 2.4 cm). Follow‐up period from initial RFA ranged from 1.3 to 128.0 months (median: 42.9 months). We assessed the overall and tumor specific waiting list dropout rates, post‐LT tumor recurrence, and the 10‐year post‐LT and intention‐to‐treat survival rates. Drop out from the waiting list due to tumor progression occurred in 7.4% of patients. HCC recurrence after LT occurred in 5.6% of patients. Post‐LT overall survival (OS) and recurrence‐free survival (RFS) rates at 5 and 10 years were 75.8% and 42.2%, and 71.1% and 39.6% respectively. Intention‐to‐treat OS, RFS, and disease‐specific survival (DSS) rates for the entire study population at 5 and 10 years were 63.5% and 41.2%, 60.8% and 37.7%, and 89.5% and 89.5%, respectively. Conclusion: In the largest and longest intention‐to‐treat study to date of HCC treated by RFA as first line stand‐alone bridge therapy to LT, long term overall and tumor specific survivals were excellent, with low dropout rate from tumor progression despite long wait list times, and sustained low tumor recurrence rate upon follow up post LT up to 10 years. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 04 février 2017
    Leah D.B. Carter, and Andrew Aronsohn
    Overcoming Injustice: A Roadmap to Improve Access to HCV Therapy for Our Medicaid Patients
    n/a


    Date de mise en ligne : Jeudi 02 février 2017
    Catarina Oliveira, Carole Fournier, VĂ©ronique Descamps, Virginie Morel, Corey A. Scipione, Rocco Romagnuolo, Marlys L. Koschinsky, AgnĂšs Boullier, Paulo Marcelo, Jean‐Marc Domon, Etienne Brochot, Gilles Duverlie, Catherine Francois, Sandrine Castelain, Francois Helle
    Apolipoprotein(a) Inhibits Hepatitis C Virus Entry Through Interaction With Infectious Particles
    The development of different cell culture models has greatly contributed to improve the knowledge of the hepatitis C virus (HCV) life cycle. However, it is still challenging to grow HCV clinical isolates in cell culture. This would open new perspectives to study HCV biology, including drug resistant variants emerging with new antiviral therapies. In this study we hypothesized that this hurdle could be due to the presence of inhibitory factors in patient serum. Combining polyethylene glycol precipitation, iodixanol gradient and size‐exclusion chromatography, we obtained a purified fraction enriched in inhibitory factors from HCV seronegative sera. Mass spectrometry analysis identified apolipoprotein(a) (apo(a)) as a potential inhibitor of HCV entry. Apo(a) consists of ten kringle IV domains (KIVs), one kringle V domain (KV) and an inactive protease domain. The ten KIVs are present in a single copy with the exception of KIV type 2 (KIV2), which is encoded in a variable number of tandemly repeated copies, giving rise to numerous apo(a) size isoforms. In addition, apo(a) covalently links to the apolipoprotein B component of a low density lipoprotein via a disulfide bridge to form lipoprotein(a). Using a recombinant virus derived from the JFH1 strain we confirmed that plasma‐derived and recombinant lipoprotein(a) as well as purified recombinant apo(a) variants were able to specifically inhibit HCV by interacting with infectious particles. Our results also suggest that small isoforms are less inhibitory than the large ones. Finally, we observed that the lipoprotein moiety of HCV lipoviroparticles was essential for the inhibition whereas functional lysine‐binding sites in KIV7, KIV8 and KIV10 were not required. Conclusions: Altogether, our results identify apo(a) as an additional component of the lipid metabolism modulating HCV infection. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 02 février 2017
    Yaron Rotman, Brent A. Neuschwander‐Tetri
    Liver Fat Accumulation as a Barometer of Insulin Responsiveness Again Points to Adipose Tissue as the Culprit
    n/a


    Date de mise en ligne : Mardi 31 janvier 2017
    Edoardo G. Giannini, Vincenzo Savarino
    Non‐invasive Assessment of Varices Needing Treatment in Patients with Advanced Chronic Liver Disease: No One Should Be Left Behind
    n/a


    Date de mise en ligne : Mardi 31 janvier 2017
    Marina Vilaseca, HĂ©ctor GarcĂ­a‐CalderĂł, Erica Lafoz, Oihane GarcĂ­a‐Irigoyen, MatĂ­as Avila, Joan Carles Reverter, Jaume Bosch, Virginia HernĂĄndez‐Gea, Jordi Gracia‐Sancho, Joan Carles GarcĂ­a‐PagĂĄn
    The anticoagulant Rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells
    Background & aims: In cirrhosis, increased intrahepatic vascular resistance (IHVR) is the primary factor for portal hypertension development. Hepatic Stellate Cells (HSC) play a major role increasing IHVR as when activated are contractile and promote fibrogenesis. Protease activated receptors (PARs) can activate HSC, through thrombin and factor Xa which are known PARs agonists, and cause microthrombosis in liver microcirculation. This study investigates the effects of the oral anticoagulant rivaroxaban, a direct anti‐factor Xa, on HSC phenotype, liver fibrosis, liver microthrombosis and portal hypertension in cirrhotic rats. Methods: Hepatic and systemic hemodynamic, NO bioavailability, liver fibrosis, HSC activation and microthrombosis were evaluated in CCl4 and thioacetamide‐cirrhotic rats treated with rivaroxaban (20 mg/kg/day) or its vehicle for two weeks. Results: Rivaroxaban significantly decreased portal pressure in both models of cirrhosis without changes in portal blood flow, suggesting a reduction in IHVR. Rivaroxaban reduced oxidative stress, improved NO bioavailability and ameliorated endothelial dysfunction. Rivaroxaban deactivated HSC, with decreased α‐SMA and mRNA expression of other HSC activation markers. Despite this marked improvement in HSC phenotype, no significant changes in liver fibrosis were identified. Rivaroxaban markedly reduced fibrin deposition suggesting reduced intrahepatic microthrombosis. Summary and conclusion: Rivaroxaban decreases portal pressure in two rat models of cirrhosis. This effect is mostly associated to decreased IHVR, enhanced NO bioavailability, HSC deactivation and reduced intrahepatic microthrombosis. Our findings suggest that rivaroxaban deserves further evaluation as a potential treatment for cirrhotic portal hypertension. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 30 janvier 2017
    Christian von Loeffelholz, Stefanie Lieske, Frank NeuschĂ€fer‐Rube, Diana M. Willmes, Nathanael Raschzok, Igor M. Sauer, Jörg König, Martin Fromm, Paul Horn, Antonis Chatzigeorgiou, Andrea Pathe‐NeuschĂ€fer‐Rube, Jens Jordan, Andreas F. H. Pfeiffer, Geltrude Mingrone, Stefan R. Bornstein, Peter Stroehle, Christoph Harms, F. Thomas Wunderlich, Stephen. L. Helfand, Michel Bernier, Rafael de Cabo, Gerald I. Shulman, Triantafyllos Chavakis, Gerhard P. PĂŒschel, Andreas. L. Birkenfeld
    The Human Longevity Gene Homolog INDY and Interleukin‐6 Interact in Hepatic Lipid Metabolism
    Reduced expression of the Indy (‘I am Not Dead, Yet') gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane associated citrate transporter expressed highly in the liver, protects mice from high‐fat diet and aging‐induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We aimed to study a possible role of mIndy in human hepatic fat metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In non‐human primates, a two year high fat, high sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin‐6 (IL‐6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL‐6 markedly induced mIndy transcription via the IL‐6‐receptor (IL‐6R) and activation of the transcription factor Stat3 and a putative start site of the human mIndy promoter was determined. Activation of the IL‐6‐Stat3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL‐6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and non‐human primates with NALFD. Moreover, our data identify mIndy as a target gene of IL‐6 and determine novel functions of IL‐6 via mINDY. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 30 janvier 2017
    Yan Wang, Robert Vincent, Jinlian Yang, Amon Asgharpour, Xieer Liang, Michael O. Idowu, Melissa J. Contos, Kalyani Daitya, Mohammed S. Siddiqui, Faridoddin Mirshahi, Arun J. Sanyal
    Dual photon microscopy based quantitation of fibrosis‐related parameters (q‐FP) to model disease progression in steatohepatitis
    There is a need for further refinement of current histological systems for assessment of hepatic fibrosis in nonalcoholic fatty liver disease (NAFLD). This study evaluated hepatic fibrosis in NAFLD using dual photon microscopy based quantitation of fibrosis‐related parameters (q‐FPs). Fifty (test cohort) and 42 (validation cohort) subjects with NAFLD and the full spectrum of fibrosis were studied. Q‐FPs were measured in specific predefined regions of interest (general, vessel, perisinusoid and vascular septa). Seventy q‐FPs had inter‐ and intra‐observer concordance ≄0.8 and were related to the NASH CRN fibrosis staging. Of these, 16 q‐FPs with the strongest correlations (p<0.001 for all) were entered in a principal component analysis model (Odds ratio [OR] 7.8, p<0.001), which separated any stage of fibrosis versus no fibrosis, and cirrhosis versus earlier stages with the areas under receiver‐operating‐characteristic curves of 0.88 and 0.93 (p≀0.01 for both), respectively. In an independent multivariable analysis, four q‐FPs including the number of collagen strands (OR 8.5, p=0.004), strand length (OR 12.0, p=0.02), strand eccentricity (OR 8.3, p=0.004), and strand solidity (OR 8.0, p=0.003) were independently associated with fibrosis stages and were used to model fibrosis along a continuous linear scale using Desirability functions; this linear scale of fibrosis measurement was also related to fibrosis stage (p˂0.0001). The robustness of both the multivariable model and the linear scale of measurement was confirmed in the validation cohort. Conclusion: Q‐FPs model provides an accurate reproducible method to evaluate fibrosis in NAFLD along a quantitative and continuous scale. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 30 janvier 2017
    Alex N. Gordon‐Weeks, Su Y. Lim, Arseniy E. Yuzhalin, Keaton Jones, Bostjan Markelc, Jon N. Buzelli, Emmanouil Fokas, Yunhong Cao, Sean Smart, Ruth Muschel
    Neutrophils Promote Hepatic Metastasis Growth Through fibroblast growth factor (FGF)2‐dependent Angiogenesis
    Hepatic metastases are amenable to ablation, however many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both pro‐ and anti‐ tumor effects. Here, neutrophils promoted the growth of hepatic metastases, as depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization Metastasis‐associated neutrophils expressed substantially more FGF2 than naïve neutrophils indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density and branching. Conclusion. Here we show using FGF2 as an example, that identification of factors responsible for the pro‐tumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 28 janvier 2017
    Juan G Abraldes, Annalisa Berzigotti,
    Reply to LTE HEP 16‐2397
    n/a


    Date de mise en ligne : Samedi 28 janvier 2017
    Parambir S. Dulai, Siddharth Singh, Janki Patel, Meera Soni, Larry J. Prokop, Zobair Younossi, Giada Sebastiani, Mattias Ekstedt, Hannes Hagstrom, Patrik Nasr, Per Stal, Vincent Wai‐Sun Wong, Stergios Kechagias, Rolf Hultcrantz, Rohit Loomba
    Increased risk of mortality by fibrosis stage in non‐alcoholic fatty liver disease: Systematic Review and Meta‐analysis
    Background: Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage‐specific risk of all‐cause and liver‐related mortality in NAFLD. Methods: Through a systematic review and meta‐analysis, we identified 5 adult NAFLD cohort studies reporting fibrosis stage specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage‐specific mortality rate ratios (MRR) with 95% confidence intervals (CI), for all‐cause and liver‐related mortality, were estimated. The study is reported according to the PRISMA statement. Results: 1,495 NAFLD patients with 17,452 patient years of follow‐up were included. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality and this risk increased with increase in the stage of fibrosis: stage 1, MRR, 1.58 (95% CI 1.19‐2.11); stage 2, MRR, 2.52 (95% CI 1.85‐3.42); stage 3, MRR, 3.48 (95% CI 2.51‐4.83), and stage 4, MRR, 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with increase in the stage of fibrosis: stage 1, MRR, 1.41 (95% CI 0.17‐11.95); stage 2, MRR, 9.57 (95% CI 1.67‐54.93); stage 3, MRR, 16.69 (95% CI 2.92‐95.36); and stage 4, MRR, 42.30 (95% CI 3.51‐510.34). Limitations: Inability to adjust for co‐morbid conditions or demographics known to impact fibrosis progression in NAFLD, and the inclusion of patients with simple steatosis and NASH without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage. These data have important implications in assessing utility of each stage and benefits of regression of fibrosis from one stage to another. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 28 janvier 2017
    Julie Heimbach, Laura M. Kulik, Richard Finn, Claude B. Sirlin, Michael Abecassis, Lewis R. Roberts, Andrew Zhu, M. Hassan Murad, Jorge Marrero
    Aasld guidelines for the treatment of hepatocellular carcinoma
    n/a


    Date de mise en ligne : Vendredi 27 janvier 2017
    Sonali Paul, Aaron Dickstein, Akriti Saxena, Norma Terrin, Kathleen Viveiros, Ethan M. Balk, John B. Wong
    Role of Surface Antibody in Hepatitis B Reactivation in Patients with Resolved Infection and Hematologic Malignancy: A Meta‐Analysis
    Patients with resolved hepatitis B virus (HBV) infection who are treated for hematological malignancies remain at risk for HBV reactivation. Because of conflicting studies about whether the antibody to hepatitis B surface antigen (anti‐HBs) protects against reactivation in patients with resolved infection (hepatitis B surface antigen negative) receiving chemotherapy for hematological malignancies, we conducted a meta‐analysis to determine if anti‐HBs reduces HBV reactivation risk. We sought English language studies through March 1, 2016 in Medline and other sources that examined reactivation in patients with resolved HBV infection receiving chemotherapy for hematologic malignancies. The absolute risks and odds ratio (OR) of reactivation with versus without anti‐HBs were estimated in random‐effects model meta‐analyses. In 20 studies involving 1672 patients not receiving antiviral prophylaxis, the reactivation risk was 14% (95% CI 9.4 – 19%) in 388 patients who had antibodies to hepatitis B core antigen (anti‐HBc) only versus 5.0% (95% CI 3.0 – 7.0%) in 1284 patients who also had anti‐HBs. Anti‐HBs reduced reactivation risk with a pooled OR of 0.21 (95% CI 0.14‐0.32) versus patients with anti‐HBc only. Similar results were found when limiting the analysis to rituximab chemotherapy (OR 0.19, 95% CI 0.11 – 0.32) and lymphoma (OR 0.18, 95% CI 0.11 – 0.28). Conclusion: In patients with resolved HBV receiving chemotherapy for hematological malignancies without antiviral prophylaxis, anti‐HBs‐positivity is associated with a decreased risk of reactivation. HBV screening in this patient population should include the routine use of anti‐HBs and those that are anti‐HBs negative should receive antiviral prophylaxis. Future studies should examine the effect of anti‐HBs serum titers, the potential role for booster vaccinations, and antiviral prophylaxis prior to chemotherapy in this patient population. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 27 janvier 2017
    Fred Poordad, Franco Felizarta, Armen Asatryan, Mark S. Sulkowski, Robert W. Reindollar, Charles S. Landis, Stuart C. Gordon, Steven L. Flamm, Michael W. Fried, David E. Bernstein, Chih‐Wei Lin, Ran Liu, Sandra S. Lovell, Teresa I. Ng, Jens Kort, Federico J. Mensa
    Glecaprevir and Pibrentasvir for 12 Weeks for HCV Genotype 1 Infection and Prior Direct‐acting Antiviral Treatment
    Although direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA‐containing regimens, particularly those with NS5A inhibitors, are limited, and remain an area of unmet medical need. This phase 2, open‐label study (MAGELLAN‐1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1‐infected patients with prior virologic failure to HCV DAA‐containing therapy. A total of 50 non‐cirrhotic patients were randomized to three arms: 200 mg GLE + 80 mg PIB (Arm A), 300 mg GLE + 120 mg PIB with 800 mg once‐daily RBV (Arm B), or 300 mg GLE + 120 mg PIB without RBV (Arm C). By intent‐to‐treat analysis, sustained virologic response at post‐treatment week 12 (SVR12) was achieved in 100% (6/6, 95% CI 61 – 100), 95% (21/22, 95% CI 78 – 99), and 86% (19/22, 95% CI 67 – 95) of patients in Arms A, B, and C, respectively. Virologic failure occurred in no patients in Arm A, and 1 patient each in Arms B and C (two patients lost to follow‐up in Arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin, were observed. Conclusion: The combination of GLE and PIB was highly efficacious and well‐tolerated in patients with HCV GT1 infection and prior failure to DAA‐containing therapy; RBV coadministration did not improve efficacy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 24 janvier 2017
    Julien Bissonnette, JosĂ© Altamirano, CĂ©cile Devue, Olivier Roux, Audrey PayancĂ©, Didier Lebrec, Pierre Bedossa, Dominique Valla, François Durand, Hafid Ait Oufella, Pau Sancho‐Bru, Joan Caballeria, Pere GinĂšs, Chantal M Boulanger, Ramon Bataller, Pierre‐Emmanuel Rautou
    A Prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis
    The diagnosis of alcoholic hepatitis (AH) often requires a transjugular liver biopsy (TJLB), a procedure not always readily accessible. We analyzed plasma biomarkers to estimate the presence of histological features of AH among patients with clinical suspicion of AH. Using ELISA, we tested M65 and M30 (circulating fragments of cytokeratin‐18) and their respective fraction carried by microvesicles (MVs), CCL20 and TREM1. Leukocyte, platelet and endothelial‐derived MVs were quantified by flow cytometry. Test and validation cohorts prospectively included patients with clinical features of AH undergoing TJLB. In the test cohort, 46/83 (55%) patients showed histological features of AH. ABIC score was B or C in 83%. Patients with histologically proven AH had higher levels of total and MV‐bound M65, total and MV‐bound M30 and CCL20 than those without (p<0.001 for all tests). Levels of TREM‐1 and of subpopulations of MVs were not different between groups. M65 and M30 both had AUROCs of 0.84 to estimate the presence of AH. For M65, a cutoff of 2000 IU/L had a positive predictive value of 91%, while a cutoff of 641 IU/L had a negative predictive value of 88%. In the validation cohort, AH was histologically confirmed in 48/68 (71%) patients. ABIC score was B or C in 69%. For M65, the above cutoffs had a diagnostic accuracy of 81%. Even better results were obtained in patients with suspicion of severe AH (ABIC B or C) in both cohorts. Conclusion: Plasma levels of cytokeratin‐18 fragments are reliable non‐invasive markers of AH. Using the proposed cutoffs for M65, two thirds of TJLB can be avoided, which can be useful in centers where this technique is not readily available. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 24 janvier 2017
    Daniel Azoulay, Eylon Lahat, Chady Salloum, Philippe Compagnon, Cyrille Feray
    Heterotopic Liver Re‐Transplantation For Impossible Former Graft Explantation
    n/a


    Date de mise en ligne : Mardi 24 janvier 2017
    Carolin Lackner, Ramon Bataller, Alastair Burt, Rosa Miquel, Detlef Schuppan, Dina Tiniakos, Michael Trauner
    Fibrosis evaluation by transient elastography in alcoholic liver disease ‐ is the histological scoring system impacting cut‐off values?
    n/a


    Date de mise en ligne : Mardi 24 janvier 2017
    Yongqing Wang, Hiroaki Aoki, Jing Yang, Kesong Peng, Runping Liu, Xiaojiaoyang Li, Xiaoyan Qiang, Lixin Sun, Emily C Gurley, Guanhua Lai, Luyong Zhang, Guang Liang, Masayuki Nagahashi, Kazuaki Takabe, William M Pandak, Phillip B. Hylemon, Huiping Zhou
    The role of S1PR2 in bile acid‐induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice
    Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the AKT and ERK1/2 signaling pathways via the sphingosine 1‐phosphate receptor 2 (S1PR2) in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)‐induced apoptosis. However, the role of S1PR2 in bile acid‐mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA‐ and S1P‐induced activation of ERK1/2 and AKT were inhibited by JTE‐013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA‐ and S1P‐induced cell proliferation and migration were inhibited by JTE‐013 and a specific shRNA of S1PR2 as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, the expression of S1PR2 was upregulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL‐induced cholangiocyte proliferation and cholestatic injury as indicated by significant reduction of inflammation and liver fibrosis in S1PR2‐/‐ mice. Treatment of BDL mice with JTE‐013 significantly reduced total bile acid levels in the serum and cholestatic liver injury. This study suggests that the CBA‐induced activation of S1PR2‐mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 24 janvier 2017
    Yutaka Shimizu, Nieves Peltzer, Alexandra Sevko, Elodie Lafont, Aida Sarr, Helena Draberova, Henning Walczak
    The linear ubiquitin chain assembly complex acts as a liver tumor suppressor and inhibits hepatocyte apoptosis and hepatitis
    Linear ubiquitination is a key post‐translational modification that regulates immune signaling and cell death pathways, notably TNFR1 signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date is the linear ubiquitin chain assembly complex (LUBAC), of which the catalytic core component is HOIP. To understand the underlying mechanisms of maintenance of liver homeostasis and the role of linear ubiquitination specifically in liver parenchymal cells, we investigated the physiological role of HOIP in the liver parenchyma. To do so, we created mice harboring liver parenchymal cell‐specific deletion of HOIP (HoipΔhep mice) by crossing Hoip‐floxed mice with albumin‐cre mice. HOIP deficiency in liver parenchymal cells triggered tumorigenesis at eighteen months of age preceded by spontaneous hepatocyte apoptosis and liver inflammation within the first month of life. In line with the emergence of inflammation, HoipΔhep mice displayed enhanced liver regeneration and DNA damage. In addition, consistent with increased apoptosis, HOIP‐deficient hepatocytes showed enhanced caspase activation and endogenous formation of a death‐inducing signaling complex which activated caspase‐8. Unexpectedly, exacerbated caspase activation and apoptosis were not dependent on TNFR1, whereas ensuing liver inflammation and tumorigenesis were promoted by TNFR1 signaling. Conclusion: LUBAC serves as a previously undescribed tumor suppressor in the liver, restraining TNFR1‐independent apoptosis in hepatocytes which, in its absence, is causative of a TNFR1‐mediated inflammation resulting in hepatocarcinogenesis. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 24 janvier 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 IFN signaling. TRIF was required for the induction of IL‐10, IL‐6, and IL‐1ÎČ cytokines. Conversely, although the induction of CCL2 and CXCL1 chemokines and the up‐regulation of chemokine (Ccl2, Ccl7, Cxcl1, Cxcl2, and Cxcl10) and cell‐adhesion (Icam1 and Vcam1) 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 (LSECs) or Kupffer cells (KCs). 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 24 janvier 2017
    Laura Hargrove, Lindsey Kennedy, Jennifer Demieville, Hannah Jones, Fanyin Meng, Sharon DeMorrow, Walker Karstens, Taronish Madeka, John Greene, Heather Francis
    BDL‐induced biliary hyperplasia, hepatic injury and fibrosis are reduced in mast cell deficient Kitw‐sh mice
    Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL) increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC deficient mice. Methods: WT and KitW‐sh mice were subjected to sham or BDL for up to 7 days and KitW‐sh mice were injected with cultured mast cells or 1X PBS before collecting serum, liver blocks and cholangiocytes. Liver damage was assessed by H&E and ALT levels. IBDM was detected by CK‐19 expression and proliferation by Ki‐67 immunohistochemistry. Fibrosis was detected by immunohistochemistry, hydroxyproline content and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and TGF‐ÎČ1 expression/secretion were evaluated. HDC and histamine receptor (HR) expression were detected by qPCR and HA secretion by EIA. To evaluate vascular cells, Von Willebrand (vWF) and VEGF‐C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and α‐SMA measured. Results: BDL‐induced liver damage was reduced in the BDL KitW‐sh mice, whereas injection of MCs did not mimic BDL‐induced damage. In BDL KitW‐sh mice, IBDM, proliferation, HSC activation/fibrosis and TGF‐ÎČ1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW‐sh mice. vWF and VEGF‐C expression decreased in BDL KitW‐sh mice. In KitW‐sh mice injected with MCs, IBDM, proliferation, fibrosis and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW‐sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW‐sh mice. Conclusion: MCs promote hyperplasia, fibrosis and vascular cell activation. Knockout of MCs decreases BDL‐induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 21 janvier 2017
    Caroline Steinmetz, Anubha Kashyap, Nataliya Zhivkova, Henry Alizor, Isabell Ernst, Daniela Gottfried‐Brand, Henning Janssen, Andreas Teufel, Henning Schulze‐Bergkamen, Johannes Lotz, JĂŒrgen Kuball, Matthias Theobald, Michael Heise, Hauke Lang, Peter R. Galle, Dennis Strand, Susanne Strand
    Activation of SIRT1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation
    The incidence and prevalence of inflammatory liver diseases has increased over the last years but therapeutic options are limited. Pregnancy induces a state of immune tolerance, which can result in spontaneous improvement of clinical symptoms of certain autoimmune diseases including autoimmune hepatitis (AIH). We investigated the immune suppressive mechanisms of the human pregnancy hormone chorionic gonadotropin (hCG) in the liver. HCG signaling activates SIRT1, which deacetylates FOXO3a, leading to repression of pro‐apoptotic gene expression. As immunosuppressive consequence due to the absence of Caspase‐3 activity hepatocellular IL‐16 is no longer processed and released. Thus serum levels of IL‐16, a key chemotactic factor for CD4+ lymphocytes, were reduced and migration to injured hepatocytes prevented. Further, elevated IL‐16 levels are found in the sera from patients with autoimmune hepatitis, HBV, HCV and NASH. Conclusion: Here we report that hCG regulates the SIRT1/FOXO3a axis in hepatocytes resulting in immune suppression by attenuating Caspase‐3 dependent IL‐16 processing and release, which concomitantly prevents auto‐aggressive T cell infiltration to the liver. Considering the low toxicity profile of hCG in humans, interrupting the inflammatory cycle by hCG opens new perspectives for therapeutic intervention of inflammatory liver diseases. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 21 janvier 2017
    Anthony Cousien, Viet Chi Tran, Sylvie Deuffic‐Burban, Marie Jauffret‐Roustide, Jean‐StĂ©phane Dhersin, Yazdan Yazdanpanah
    Reply to “Addressing opioid use disorder in modeling hepatitis C transmission among persons who inject drugs”
    n/a


    Date de mise en ligne : Samedi 21 janvier 2017
    Jacob Smith, Josiah Rich
    Addressing opioid use disorder in modeling hepatitis C transmission among persons who inject drugs
    n/a


    Date de mise en ligne : Samedi 21 janvier 2017
    Juan Berenguer, Elena RodrĂ­guez‐Castellano, Ana Carrero, Miguel A. Von Wichmann, Marta Montero, MarĂ­a J. Galindo, Josep Mallolas, Manuel Crespo, MarĂ­a J. TĂ©llez, Carmen Quereda, JosĂ© Sanz, Carlos Barros, Cristina Tural, Ignacio Santos, Federico Pulido, Josep M. Guardiola, Rafael Rubio, Enrique Ortega, MarĂ­a L. Montes, Juan J. Jusdado, Gabriel Gaspar, Herminia Esteban, JosĂ© M. BellĂłn, Juan GonzĂĄlez‐GarcĂ­a,
    Eradication of HCV and non–liver‐related non–AIDS‐related events in HIV/HCV coinfection
    We assessed non–liver‐related non–AIDS‐related (NLR‐NAR) events and mortality in a cohort of HIV/HCV‐coinfected patients treated with interferon and ribavirin between 2000 and 2008. The censoring date was May 31, 2014. Cox regression analysis was performed to assess the adjusted hazard rate (HR) of overall death in responders and non‐responders. Fine and Gray regression analysis was conducted to determine the adjusted sub‐hazard rate (sHR) of NLR deaths and NLR‐NAR events considering death as the competing risk. The NLR‐NAR events analyzed included diabetes mellitus, chronic renal failure, cardiovascular events, NLR‐NAR cancer, bone events, and non–AIDS‐related infections. The variables for adjustment were age, sex, prior AIDS, HIV‐transmission category, nadir CD4+ T‐cell count, antiretroviral therapy, HIV‐RNA, liver fibrosis, HCV genotype, and exposure to specific anti‐HIV drugs. Of the 1,625 patients included, 592 (36%) had a sustained viral response (SVR). After a median five‐year follow‐up, SVR was found to be associated with a significant decrease in the hazard of diabetes mellitus (sHR 0.57 [95% CI, 0.35 ‐ 0.93] P= .024) and decline in the hazard of chronic renal failure close to the threshold of significance (sHR 0.43 [95% CI, 0.17 ‐ 1.09], P=.075). Conclusion: Our data suggest that eradication of HCV in coinfected patients is associated not only with a reduction in the frequency of death, HIV progression, and liver‐related events, but also with a reduced hazard of diabetes mellitus and possibly of chronic renal failure. These findings argue for the prescription of HCV therapy in coinfected patients regardless of fibrosis stage. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Samedi 21 janvier 2017
    Grace Su
    Introducing the AASLD President
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    Date de mise en ligne : Vendredi 20 janvier 2017
    Khaled Thabet, Henry Lik Yuen Chan, Salvatore Petta, Alessandra Mangia, Thomas Berg, Andre Boonstra, Willem P Brouwer, Maria Lorena Abate, Vincent Wai‐Sun Wong, Maiiada Nazmy, Janett Fischer, Christopher Liddle, Jacob George, Mohammed Eslam
    The MBOAT7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B
    Chronic hepatitis B (CHB) is characterized by hepatic inflammation that promotes progression to cirrhosis and predisposes to the development of hepatocellular carcinoma (HCC). Subtle inter‐individual genetic variation, viral and environmental factors interact to determine the disease progression between individuals. Recently, the rs641738 Membrane Bound O‐Acyltransferase Domain Containing 7 (MBOAT7) polymorphism was demonstrated to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease and hepatitis C, but no data are available for CHB. We evaluated rs641738 influence on disease severity in a cohort of 1101 patients with CHB. Forty two patients underwent gene expression analysis to assess the functional consequences of rs641738 on hepatic MBOAT7 expression. The minor allele (T) of rs641738 was associated with greater inflammation (OR: 1.45, 95% CI: 1.06‐1.95, p=0.001) and fibrosis (OR=1.31, 95% CI: 1.19‐1.92, p=0.01). The risk allele frequency in Caucasians (0.43) was greater than in Chinese (0.24), translating to a larger size effect in the former. The rs641738 (T) allele was associated with lower hepatic MBOAT7 expression (p=0.008) and the latter was associated with serum liver enzymes and inflammation. Neither PNPLA3 rs738409, nor TM6SF2 rs58542926 polymorphisms influenced disease severity. In patients with CHB, MBOAT7 rs641738 influences hepatic inflammation and fibrosis stage. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 20 janvier 2017
    Angels Escorsell, Oana Pavel, Andres Cardenas, Elba Llop, Candid Villanueva, Carlos Juan
    REPLY TO HEP‐16‐2222
    n/a


    Date de mise en ligne : Jeudi 19 janvier 2017
    Salvatore Petta, Vincent Way‐Sun Wong, Victor de Ledinghen
    Response to Dr Karlas and colleagues
    n/a


    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)


    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).


    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 2016).


    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 2016).


    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 2016).


    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
    n/a


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


    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 2016)


    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 2016).


    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 : 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 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
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    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 2016)


    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 2016)


    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 : 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 2016).


    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 2016).


    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 2016).


    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 2016)


    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
    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
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    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
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    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 : Vendredi 30 décembre 2016
    Ulku Saritas, Yucel Ustundag
    One‐ or two‐week interval for variceal banding after bleeding: Which one to choose?
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    Date de mise en ligne : Jeudi 29 décembre 2016
    Jonggi Choi, Roongruedee Chaiteerakij, Lewis R. Roberts
    Reply
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    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 : 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 2016).


    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: We identified 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 2016).


    Date de mise en ligne : Samedi 10 décembre 2016
    Gin‐Ho Lo
    The interval of endoscopic variceal ligation: The shorter the better?
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    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
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    Date de mise en ligne : Mardi 29 novembre 2016
    Sarah Sheibani, Loren Laine
    Reply
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    Date de mise en ligne : Lundi 28 novembre 2016
    Silvia Sookoian, Carlos J. Pirola
    Nonalcoholic fatty liver disease: Biomarkers support decisions around pharmacological intervention
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    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 : 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 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 février 2017
    Masthead
    Masthead
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    Date de mise en ligne : Mardi 21 février 2017
    Table of contents
    Table of contents
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    Date de mise en ligne : Mardi 21 février 2017
    Jean‐François Dufour
    Hepatology Highlights
    762


    Date de mise en ligne : Lundi 06 février 2017
    Elizabeth C. Verna
    The dynamic landscape of liver transplant in the era of effective hepatitis C virus therapy
    766


    Date de mise en ligne : Lundi 06 février 2017
    Dieter HĂ€ussinger, Verena Keitel
    Dual role of the bile acid receptor Takeda G‐protein‐coupled receptor 5 for hepatic lipid metabolism in feast and famine
    770


    Date de mise en ligne : Mardi 31 janvier 2017
    Ruben Hernaez, Hashem B. El‐Serag
    Hepatocellular carcinoma surveillance: The road ahead
    773


    Date de mise en ligne : Mardi 17 janvier 2017
    Lindsey Kennedy, Heather Francis
    Defining the relationship between farsenoid X receptor, hepatitis B virus X protein and hepatocellular carcinoma: It's complicated
    776


    Date de mise en ligne : Vendredi 06 janvier 2017
    Jagpreet Chhatwal, Sumeyye Samur, Brian Kues, Turgay Ayer, Mark S. Roberts, Fasiha Kanwal, Chin Hur, Drew Michael S. Donnell, Raymond T. Chung
    Optimal timing of hepatitis C treatment for patients on the liver transplant waiting list
    The availability of oral direct‐acting antivirals has altered the hepatitis C virus (HCV) treatment paradigm for both pre–liver transplant (LT) and post‐LT patients. There is a perceived trade‐off between pre‐LT versus post‐LT treatment of HCV—treatment may improve liver function but potentially decrease the likelihood of a necessary LT. Our objective was to identify LT‐eligible patients with decompensated cirrhosis who would benefit (and not benefit) from pre‐LT treatment based on their Model for End‐Stage Liver Disease (MELD) scores. We simulated a virtual trial comparing long‐term outcomes of pre‐LT versus post‐LT HCV treatment with oral direct‐acting antivirals for patients with MELD scores between 10 and 40. We developed a Markov‐based microsimulation model, which simulated the life course of patients on the transplant waiting list and after LT. Simulation of LT integrated data from recent trials of oral direct‐acting antivirals (SOLAR 1 and 2), the United Network for Organ Sharing (UNOS), and other studies. The outcomes of the model included life expectancy, 1‐year and 5‐year patient survival, and mortality. Model‐predicted patient survival was validated with UNOS data. We found that, at the national level, treating HCV before LT increased life expectancy if MELD was ≀27 but could decrease life expectancy at higher MELD scores. Depending on the UNOS region, the threshold MELD score to treat HCV pre‐LT varied between 23 and 27 and was lower for UNOS regions 3, 10, and 11 and higher for regions 1, 2, 4, 5, 8, and 9. Sensitivity analysis showed that the thresholds were stable. Conclusion: Our findings suggest that the optimal MELD threshold below which decompensated cirrhosis patients should receive HCV treatment while awaiting LT is between 23 and 27, depending on the UNOS region. (Hepatology 2017;65:777‐788)


    Date de mise en ligne : Vendredi 03 février 2017
    Pierre L. LĂ©vy, Sarah Duponchel, Hannah Eischeid, Jennifer Molle, Maud Michelet, GaĂ«lle Diserens, Martina Vermathen, Peter Vermathen, Jean‐Francois Dufour, Hans‐Peter Dienes, Hans‐Michael Steffen, Margarete Odenthal, Fabien Zoulim, Birke Bartosch
    Hepatitis C virus infection triggers a tumor‐like glutamine metabolism
    Chronic infection with hepatitis C virus (HCV) is one of the main causes of hepatocellular carcinoma. However, the molecular mechanisms linking the infection to cancer development remain poorly understood. Here we used HCV‐infected cells and liver biopsies to study how HCV modulates the glutaminolysis pathway, which is known to play an important role in cellular energetics, stress defense, and neoplastic transformation. Transcript levels of glutaminolytic factors were quantified in Huh7.5 cells or primary human hepatocytes infected with the Japanese fulminant hepatitis 1 HCV strain as well as in biopsies of chronic HCV patients. Nutrient deprivation, biochemical analysis, and metabolite quantification were performed with HCV–infected Huh7.5 cells. Furthermore, short hairpin RNA vectors and small molecule inhibitors were used to investigate the dependence of HCV replication on metabolic changes. We show that HCV modulates the transcript levels of key enzymes of glutamine metabolism in vitro and in liver biopsies of chronic HCV patients. Consistently, HCV infection increases glutamine use and dependence. We finally show that inhibiting glutamine metabolism attenuates HCV infection and the oxidative stress associated with HCV infection. Conclusion: Our data suggest that HCV establishes glutamine dependence, which is required for viral replication, and, importantly, that glutamine addiction is a hallmark of tumor cells. While HCV induces glutaminolysis to create an environment favorable for viral replication, it predisposes the cell to transformation. Glutaminolytic enzymes may be interesting therapeutic targets for prevention of hepatocarcinogenesis in chronic hepatitis C. (Hepatology 2017;65:789‐803).


    Date de mise en ligne : Samedi 24 décembre 2016
    Jennifer A. Flemming, W. Ray Kim, Carol L. Brosgart, Norah A. Terrault
    Reduction in liver transplant wait‐listing in the era of direct‐acting antiviral therapy
    Direct‐acting antiviral (DAA) therapy, recently approved for patients with decompensated cirrhosis (DC) secondary to hepatitis C virus (HCV), is associated with improved hepatic function. We analyzed trends in liver transplant (LT) wait‐listing (WL) to explore potential impact of effective medical therapy on WL registration. This is a cohort study using the Scientific Registry of Transplant Recipients database from 2003 to 2015. A total of 47,591 adults wait‐listed for LT from HCV, hepatitis B virus (HBV), and nonalcoholic steatohepatitis (NASH) were identified. LT indication was defined as DC if the Model for End‐Stage Liver Disease (MELD) at WL was ≄15 or hepatocellular carcinoma (HCC). Era of listing was divided into interferon (IFN; 2003‐2010), protease inhibitor (PI; 2011‐2013), and direct‐acting antiviral (DAA; 2014‐2015). Annual standardized incidence rates of WL were analyzed using Poisson regression. Adjusted incidences of LT WL for DC in HCV patients decreased by 5% in the PI era (P = 0.004) and 32% in the DAA era (P < 0.001) compared to the IFN era. Listing for DC in HBV also decreased in the PI (–17%; P = 0.002) and DAA eras (–24%; P < 0.001). Conversely, WL for DC in NASH increased by 41% in the PI era (P < 0.001) and 81% in the DAA era (P < 0.001). WL for HCC in both the HCV and NASH populations increased in both the PI and DAA eras (P < 0.001 for all) whereas HCC WL in HBV remained stable (P > 0.05 for all). Conclusion: The rate of LT WL for HCV complicated by DC has decreased by over 30% in the era of DAA therapy. Further reductions in WL are anticipated with increased testing, linkage to care, and access to DAA therapy. (Hepatology 2017;65:804‐812).


    Date de mise en ligne : Samedi 30 juillet 2016
    Ajay C. Donepudi, Shannon Boehme, Feng Li, John Y.L. Chiang
    G‐protein‐coupled bile acid receptor plays a key role in bile acid metabolism and fasting‐induced hepatic steatosis in mice
    Bile acids are signaling molecules that play a critical role in regulation of hepatic metabolic homeostasis by activating nuclear farnesoid X receptor (Fxr) and membrane G‐protein‐coupled receptor (Takeda G‐protein‐coupled receptor 5; Tgr5). The role of FXR in regulation of bile acid synthesis and hepatic metabolism has been studied extensively. However, the role of TGR5 in hepatic metabolism has not been explored. The liver plays a central role in lipid metabolism, and impaired response to fasting and feeding contributes to steatosis and nonalcoholic fatty liver and obesity. We have performed a detailed analysis of gallbladder bile acid and lipid metabolism in Tgr5−/− mice in both free‐fed and fasted conditions. Lipid profiles of serum, liver and adipose tissues, bile acid composition, energy metabolism, and messenger RNA and protein expression of the genes involved in lipid metabolism were analyzed. Results showed that deficiency of the Tgr5 gene in mice alleviated fasting‐induced hepatic lipid accumulation. Expression of liver oxysterol 7α‐hydroxylase in the alternative bile acid synthesis pathway was reduced. Analysis of gallbladder bile acid composition showed marked increase of taurocholic acid and decrease of tauro‐α and ÎČ‐muricholic acid in Tgr5−/− mice. Tgr5−/− mice had increased hepatic fatty acid oxidation rate and decreased hepatic fatty acid uptake. Interestingly, fasting induction of fibroblast growth factor 21 in liver was attenuated. In addition, fasted Tgr5−/− mice had increased activation of hepatic growth hormone‐signal transducer and activator of transcription 5 (GH‐Stat5) signaling compared to wild‐type mice. Conclusion: TGR5 may play a role in determining bile acid composition and in fasting‐induced hepatic steatosis through a novel mechanism involving activation of the GH‐Stat5 signaling pathway. (Hepatology 2017;65:813‐827)


    Date de mise en ligne : Vendredi 30 décembre 2016
    Eun‐Jeong Joo, Yoosoo Chang, Joon‐Sup Yeom, Seungho Ryu
    Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: A cohort study
    The presence of an association between chronic hepatitis B virus (HBV) infection and fatty liver is controversial. We examined the association between HBV infection and the development of nonalcoholic fatty liver disease (NAFLD). We conducted a cohort study of 83,339 participants without NAFLD at baseline who underwent serologic testing for hepatitis B surface antigen (HBsAg) between 2002 and 2006 and were followed annually or biennially until December 2014. NAFLD was defined as the presence of ultrasonographic fatty liver in the absence of excessive alcohol use or other identifiable causes. We used a parametric Cox model to estimate adjusted hazard ratios with 95% confidence intervals of incident NAFLD. During 484,736.1 person‐years of follow‐up, 20,200 incident NAFLD cases were identified. In models adjusted for age, sex, year of visit, smoking status, alcohol intake, regular exercise, education level, and body mass index, the adjusted hazard ratio (95% confidence interval) for incident NAFLD comparing HBsAg‐positive to HBsAg‐negative participants was 0.83 (0.73‐0.94). After introducing HBV infection and confounders (including homeostasis model assessment of insulin resistance and metabolic factors) as time‐dependent exposures, the association between HBV infection and decreased risk of incident NAFLD was attenuated but persisted. These associations were consistently observed across clinically relevant, prespecified subgroups. Conclusion: In this large cohort of apparently healthy Korean adults, HBsAg seropositivity was associated with lower risk of developing NAFLD, indicating a possible effect of HBV infection on the pathogenesis of NAFLD development. (Hepatology 2017;65:828‐835).


    Date de mise en ligne : Jeudi 19 janvier 2017
    Elizabeth P. Newberry, Yan Xie, Susan M. Kennedy, Mark J. Graham, Rosanne M. Crooke, Hui Jiang, Anping Chen, Daniel S. Ory, Nicholas O. Davidson
    Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice
    Blocking hepatic very low‐density lipoprotein secretion through genetic or pharmacologic inhibition of microsomal triglyceride transfer protein (Mttp) causes hepatic steatosis, yet the risks for developing hepatic fibrosis are poorly understood. We report that liver‐specific Mttp knockout mice (Mttp‐LKO) exhibit both steatosis and fibrosis, which is exacerbated by a high‐transfat/fructose diet. When crossed into germline liver fatty acid (FA) binding protein null mice (Mttp‐LKO, i.e., double knockout mice) hepatic steatosis was greatly diminished and fibrosis prevented, on both low‐fat and high‐fat diets. The mechanisms underlying protection include reduced long chain FA uptake, shifts in FA distribution (lipidomic profiling), and metabolic turnover, specifically decreased hepatic 18:2 FA and triglyceride species and a shift in 18:2 FA use for oxidation versus incorporation into newly synthesized triglyceride. Double knockout mice were protected against fasting‐induced hepatic steatosis (a model of enhanced exogenous FA delivery) yet developed steatosis upon induction of hepatic de novo lipogenesis with fructose feeding. Mttp‐LKO mice, on either the liver FA binding protein null or Apobec‐1 null background (i.e., apolipoprotein B100 only) exhibited only subtle increases in endoplasmic reticulum stress, suggesting that an altered unfolded protein response is unlikely to account for the attenuated phenotype in double knockout mice. Acute, antisense‐mediated liver FA binding protein knockdown in Mttp‐LKO mice also reduced FA uptake, increased oxidation versus incorporation of 18:2 species with complete reversal of hepatic steatosis, increased hepatic injury, and worsened fibrosis. Conclusion: Perturbing exogenous hepatic FA use modulates both hepatic steatosis and fibrosis in the setting of hepatic Mttp deletion, adding new insight into the pathophysiological mechanisms and consequences of defective very low‐density lipoprotein secretion. (Hepatology 2017;65:836‐852).


    Date de mise en ligne : Vendredi 03 février 2017
    Jennifer C. Price, Yifei Ma, Rebecca Scherzer, Natalie Korn, Kyle Tillinghast, Marion G. Peters, Susan M. Noworolski, Phyllis C. Tien
    Human immunodeficiency virus–infected and uninfected adults with non–genotype 3 hepatitis C virus have less hepatic steatosis than adults with neither infection
    Hepatic steatosis (HS) is common in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections, but the independent contributions of HCV and HIV to HS are unclear. Magnetic resonance imaging and spectroscopy were used to measure visceral adipose tissue (VAT) and liver fat fraction (LFF) (total lipids/[total lipids + water]) in 356 adults: 57 with HCV monoinfection, 70 with HIV/HCV coinfection, 122 with HIV monoinfection, and 107 with neither infection. Participants who were infected with HCV genotype 3 were excluded because of the genotype's reported steatogenic effects. For prevalence estimates, HS was defined as LFF ≄ 0.05. We estimated the association of HIV and HCV status with LFF using multivariable linear regression, adjusting for demographics, lifestyle, and metabolic factors including the homeostasis model assessment estimate of insulin resistance (HOMA‐IR) and liver fibrosis defined using the aspartate aminotransferase‐to‐platelet ratio index (APRI). The prevalence of HS was highest in the uninfected (33%) and HIV‐monoinfected (28%), followed by the HCV‐monoinfected (19%) and HIV/HCV‐coinfected (11%) (P = 0.003 across groups). Compared with uninfected participants—and after adjusting for demographics, lifestyle, and metabolic factors—HIV monoinfection, HCV monoinfection, and HIV/HCV coinfection were associated with 19% (95% confidence interval [CI], −39% to 6%), 38% (95% CI, −55% to −12%), and 42% (95% CI, −59% to −18%) lower LFF, respectively. HCV monoinfection and HIV/HCV coinfection remained strongly associated with lower LFF after further adjusting for APRI, and results were unchanged after excluding subjects with suspected cirrhosis. Among the entire cohort, Hispanic ethnicity, male sex, VAT, and HOMA‐IR were independently associated with greater LFF. Conclusion: Contrary to expectations, HIV/HCV‐coinfected and HCV‐monoinfected adults had significantly less liver fat than uninfected adults, even after adjusting for demographics, lifestyle, metabolic factors, and hepatic fibrosis. Our findings suggest that non–genotype 3 HCV infection may be protective against HS. The mechanisms by which this occurs and the impact of HCV treatment on HS requires further investigation. (Hepatology 2017;65:853‐863)


    Date de mise en ligne : Mercredi 05 octobre 2016
    David S. Goldberg, Tamar H. Taddei, Marina Serper, Rajni Mehta, Eric Dieperink, Ayse Aytaman, Michelle Baytarian, Rena Fox, Kristel Hunt, Marcos Pedrosa, Christine Pocha, Adriana Valderrama, David E Kaplan
    Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis
    Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in cirrhosis patients. This provides an opportunity to target the highest‐risk population, yet surveillance rates in the United States and Europe range from 10% to 40%. The goal of this study was to identify barriers to HCC surveillance, using data from the Veterans Health Administration, the largest provider of liver‐related health care in the United States. We included all patients 75 years of age or younger who were diagnosed with cirrhosis from January 1, 2008, until December 31, 2010. The primary outcome was a continuous measure of the percentage of time up‐to‐date with HCC surveillance (PTUDS) based on abdominal ultrasound (secondary outcomes included computed tomography and magnetic resonance imaging). Among 26,577 patients with cirrhosis (median follow‐up = 4.7 years), the mean PTUDS was 17.8 ± 21.5% (ultrasounds) and 23.3 ± 24.1% when any liver imaging modality was included. The strongest predictor of increased PTUDS was the number of visits to a specialist (gastroenterologist/hepatologist and/or infectious diseases) in the first year after cirrhosis diagnosis; the association between visits to a primary care physician and increasing surveillance was very small. Increasing distance to the closest Veterans Administration center was associated with decreased PTUDS. There was an inverse association between ultrasound lead time (difference between the date an ultrasound was ordered and requested exam date) and the odds of it being performed: odds ratio = 0.77, 95% confidence interval 0.72‐0.82 when ordered > 180 days ahead of time; odds ratio = 0.90, 95% confidence interval 0.85‐0.94 if lead time 91‐180 days. Conclusions: The responsibility for suboptimal surveillance rests with patients, providers, and the overall health care system; several measures can be implemented to potentially increase HCC surveillance, including increasing patient–specialist visits and minimizing appointment lead time. (Hepatology 2017;65:864‐874).


    Date de mise en ligne : Samedi 01 octobre 2016
    Sherean Farvardin, Jaimin Patel, Maleka Khambaty, Olutola A. Yerokun, Huram Mok, Jasmin A. Tiro, Adam C. Yopp, Neehar D. Parikh, Jorge A. Marrero, Amit G. Singal
    Patient‐reported barriers are associated with lower hepatocellular carcinoma surveillance rates in patients with cirrhosis
    Over 20% of patients with cirrhosis are nonadherent with hepatocellular carcinoma (HCC) surveillance recommendations; however, few studies have evaluated the impact of patient‐level factors on surveillance receipt. We characterized the association between HCC surveillance receipt and patient knowledge, attitudes, and perceived barriers in a racially diverse and socioeconomically disadvantaged cohort of patients with cirrhosis. Patients with cirrhosis followed at a large urban hospital were invited to complete a survey about HCC surveillance between August 2014 and December 2015. Multivariable logistic regression was performed to identify factors associated with HCC surveillance receipt during the 12‐month period preceding and 6‐month period after survey administration. We achieved a response rate of 71.8% (n = 541 of 753). Patients demonstrated high levels of HCC‐related knowledge (summary score, 77.7%); however, 48.6% believed that eating a healthy diet precluded the need for HCC surveillance, and 34.0% believed that HCC surveillance was not necessary if they had a normal physical exam and/or lacked clinical symptoms. Patients expressed worry about developing and dying from HCC, but nearly half (49.9%) of patients reported barriers to receiving HCC surveillance, including difficulty with the scheduling process (30.5%), costs of surveillance testing (25.3%), and transportation difficulties (17.3%). HCC surveillance receipt was significantly higher in patients who knew cirrhosis is a risk factor for developing HCC (odds ratio [OR], 3.09; 95% confidence interval [CI], 1.25‐7.62) and significantly lower in those reporting barriers to surveillance (OR, 0.42; 95% CI, 0.25‐0.70). Conclusion: Patients with cirrhosis are knowledgeable and interested in HCC surveillance; however, patient‐reported barriers are associated with lower surveillance rates in clinical practice and represent potential intervention targets to improve HCC surveillance effectiveness. (Hepatology 2017;65:875‐884).


    Date de mise en ligne : Vendredi 30 septembre 2016
    Anna Törner, Knut Stokkeland, Åke Svensson, Paul W. Dickman, Rolf Hultcrantz, Scott Montgomery, Ann‐Sofi Duberg
    The underreporting of hepatocellular carcinoma to the cancer register and a log‐linear model to estimate a more correct incidence
    The Cancer Register (CR) in Sweden has reported that the incidence of primary liver cancer (PLC) has slowly declined over the last decades. Even though all cancers, irrespective of diagnostic method, should be reported to the CR, the PLC incidence may not reflect the true rate. Improved diagnostic tools have enabled diagnosis of hepatocellular carcinoma based on noninvasive methods without histological verification, possibly associated with missed cancer reports or misclassification in the CR. Our objective was to study the completeness and assess the underreporting of PLC to the CR and to produce a more accurate estimate based on three registers. The CR, the Cause of Death Register, and the Patient Register were investigated. Differences and overlap were examined, the incidence was estimated by merging data from the registers, and the number reported to none of the registers was estimated using a log‐linear capture‐recapture model. The results show that 98% of the PLCs reported to the CR were histologically verified; 80% were hepatocellular carcinoma and 20% were intrahepatic cholangiocarcinoma. Unspecified liver cancer decreased over time and constituted <10% of all reported liver cancers. The CR may underestimate the liver cancer incidence by 37%‐45%, primarily due to missed cancer reports. The estimated annual number of liver cancers increased over time, but the standardized incidence was stable around 11 per 100,000. Hepatitis C‐associated liver cancer increased and constituted 20% in 2010. Conclusion: There was an underreporting of PLC diagnosed by noninvasive methods; the incidence was considerably higher than estimated by the CR, with a stable incidence over time; reporting needs to improve and combining registers is recommended when studying incidence. (Hepatology 2017;65:885‐892).


    Date de mise en ligne : Jeudi 19 janvier 2017
    Yongdong Niu, Meishu Xu, Betty L. Slagle, Haihua Huang, Song Li, Grace L. Guo, Ganggang Shi, Wenxin Qin, Wen Xie
    Farnesoid X receptor ablation sensitizes mice to hepatitis b virus X protein–induced hepatocarcinogenesis
    Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti‐inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx‐induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR‐responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx–FXR interaction was confirmed by coimmunoprecipitation and glutathione S‐transferase pull‐down assays, and the FXR activation function 1 domain was mapped to bind to the third α helix in the C terminus of HBx. We also found that the C‐terminally truncated variants of HBx, which were found in clinical HCC, were not effective at transactivating FXR. Interestingly, recruitment of the full‐length HBx, but not the C‐terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx‐induced hepatocarcinogenesis. Conclusions: We propose that transactivation of FXR by full‐length HBx may represent a protective mechanism to inhibit HCC and that this inhibition may be compromised upon the appearance of C‐terminally truncated HBx or when the expression and/or activity of FXR is decreased. (Hepatology 2017;65:893‐906)


    Date de mise en ligne : Mercredi 11 janvier 2017
    Elisabeth M. G. de Vries, Manon de Krijger, Martti FĂ€rkkilĂ€, Johanna Arola, Peter Schirmacher, Daniel Gotthardt, Benjamin Goeppert, Palak J. Trivedi, Gideon M. Hirschfield, Henriette Ytting, Ben Vainer, Henk R. van Buuren, Katharina Biermann, Maren H. Harms, Olivier Chazouilleres, Dominique Wendum, Astrid D. Kemgang, Roger W. Chapman, Lai Mun Wang, Kate D. Williamson, Annette S. H. Gouw, Valerie Paradis, Christine Sempoux, Ulrich Beuers, Stefan G. HĂŒbscher, Joanne Verheij, Cyriel Y. Ponsioen
    Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study
    Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC‐related death and liver transplantation), 2 (liver transplantation), and 3 (liver‐related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow‐up was 142 months. During follow‐up, 31 patients died (20 PSC‐related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver‐related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49‐6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17‐3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10‐2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10‐1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19‐5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09‐3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22‐3.77). Interobserver agreement was moderate for Nakanuma stage (Îș = 0.56) and substantial for Nakanuma component fibrosis (Îș = 0.67), Ishak stage (Îș = 0.64), and Ludwig stage (Îș = 0.62). Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system—incorporating features of chronic biliary disease—again showed the strongest predictive value. (Hepatology 2017;65:907‐919).


    Date de mise en ligne : Mardi 17 janvier 2017
    Sumeyye Samur, Matthew Klebanoff, Reiner Banken, Daniel S. Pratt, Rick Chapman, Daniel A. Ollendorf, Anne M. Loos, Kathleen Corey, Chin Hur, Jagpreet Chhatwal
    Long‐term clinical impact and cost‐effectiveness of obeticholic acid for the treatment of primary biliary cholangitis
    Primary biliary cholangitis (PBC) is a chronic, progressive autoimmune liver disease that mainly affects middle‐aged women. Obeticholic acid (OCA), which was recently approved by the Food and Drug Administration for PBC treatment, has demonstrated positive effects on biochemical markers of liver function. Our objective was to evaluate the long‐term clinical impact and cost‐effectiveness of OCA as a second‐line treatment for PBC in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA. We developed a mathematical model to simulate the lifetime course of PBC patients treated with OCA+UDCA versus UDCA alone. Efficacy data were derived from the phase 3 PBC OCA International Study of Efficacy trial, and the natural history of PBC was informed by published clinical studies. Model outcomes were validated using the PBC Global Study. We found that in comparison with UDCA, OCA+UDCA could decrease the 15‐year cumulative incidences of decompensated cirrhosis from 12.2% to 4.5%, hepatocellular carcinoma from 9.1% to 4.0%, liver transplants from 4.5% to 1.2%, and liver‐related deaths from 16.2% to 5.7% and increase 15‐year transplant‐free survival from 61.1% to 72.9%. The lifetime cost of PBC treatment would increase from $63,000 to $902,000 (1,330% increment). The discounted quality‐adjusted life years with UDCA and OCA+UDCA were 10.74 and 11.78, respectively, and the corresponding costs were $142,300 and $633,900, resulting in an incremental cost‐effectiveness ratio of $473,400/quality‐adjusted life year gained. The results were most sensitive to the cost of OCA. Conclusion: OCA is a promising new therapy to substantially improve the long‐term outcomes of PBC patients, but at its current annual price of $69,350, it is not cost‐effective using a willingness‐to‐pay threshold of $100,000/quality‐adjusted life year; pricing below $18,450/year is needed to make OCA cost‐effective. (Hepatology 2017;65:920‐928).


    Date de mise en ligne : Vendredi 06 janvier 2017
    Gro Askgaard, David A. Leon, Mette S. KjĂŠr, Thomas Deleuran, Thomas A. Gerds, Janne S. Tolstrup
    Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study
    Alcoholic liver cirrhosis is usually preceded by many years of heavy drinking, in which cessation in drinking could prevent the disease. Alcohol problems are not consistently managed in hospital patients. We followed all Danish patients with an initial hospital contact with alcohol problems (intoxication, harmful use, or dependence) during 1998‐2002 for alcoholic liver cirrhosis development (n = 36,044). In this registry‐based cohort, we identified predictors of the absolute risk for alcoholic liver cirrhosis. Incidence rate ratios (IRRs) were estimated as the incidence rate of alcoholic liver cirrhosis in these patients relative to the general population. Age and alcohol diagnosis were significant predictors of alcoholic liver cirrhosis risk in men and women, whereas civil status, education, and type of hospital care were not. In men, the 15‐year absolute risk was 0.7% (95% confidence interval [CI], 0.4, 0.8) for 20‐29 years, 5.5% (95% CI, 4.9, 6.2) for 30‐39 years, 9.8% (95% CI, 9.0, 11) for 40‐49 years, 8.9% (95% CI, 8.1, 9.8) for 50‐59 years, 6.2% (95% CI, 5.1, 7.2) for 60‐69 years, and 2.5% (95% CI, 1.7, 3.3) for 70‐84 years. According to alcohol diagnosis in men, the 15‐year absolute risk was 2.6% (95% CI, 2.3, 2.9) for intoxication, 7.7% (95% CI, 6.4, 7.9) for harmful use, and 8.8% (95% CI, 8.2, 9.4) for dependence. The IRR for alcoholic liver cirrhosis in the cohort relative to the general population was 11 (95% CI, 10, 12) in men and 18 (95% CI, 15, 21) in women. Conclusion: Hospital patients with alcohol problems had a much greater risk for alcoholic liver cirrhosis compared to the general population. The risk was particularly increased for patients 40‐59 years and for patients diagnosed with harmful use or dependence. (Hepatology 2017;65:929‐937).


    Date de mise en ligne : Jeudi 19 janvier 2017
    Constantine J. Karvellas, Jaime L. Speiser, MĂ©lanie Tremblay, William M. Lee, Christopher F. Rose,
    Elevated FABP1 serum levels are associated with poorer survival in acetaminophen‐induced acute liver failure
    Acetaminophen (APAP)‐induced acute liver failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Serum liver‐type fatty acid binding protein (FABP1) early (day 1) or late (day 3‐5) levels are associated with 21‐day mortality in the absence of liver transplant. Serum samples from 198 APAP‐ALF patients (nested case–control study with 99 survivors, 99 nonsurvivors) were analyzed by enzyme‐linked immunosorbent assay with clinical data from the US Acute Liver Failure Study Group registry (1998‐2014). APAP‐ALF survivors had significantly lower serum FABP1 levels early (238.6 versus 690.8 ng/mL, P < 0.0001) and late (148.4 versus 612.3 ng/mL, P < 0.0001) compared with nonsurvivors. FABP1 > 350 ng/mL was associated with significantly higher risk of death at early (P = 0.0004) and late (P < 0.0001) time points. Increased serum FABP1 early (log FABP1 odds ratio = 1.31, P = 0.027) and late (log FABP1 odds ratio = 1.50, P = 0.005) were associated with significantly increased 21‐day mortality after adjusting for significant covariates (Model for End‐Stage Liver Disease, vasopressor use). Areas under the receiver operating characteristic curve for early and late multivariable models were 0.778 and 0.907, respectively. The area under the receiver operating characteristic curve of the King's College criteria (early, 0.552 alone, 0.711 with FABP1; late, 0.604 alone, 0.797 with FABP1) and the Acute Liver Failure Study Group prognostic index (early, 0.686 alone, 0.766 with FABP1; late, 0.711 alone, 0.815 with FABP1) significantly improved with the addition of FABP1 (P < 0.002 for all). Conclusion: In patients with APAP‐ALF, FABP1 may have good potential to discriminate survivors from nonsurvivors and may improve models currently used in clinical practice; validation of FABP1 as a clinical prediction tool in APAP‐ALF warrants further investigation. (Hepatology 2017;65:938‐949)


    Date de mise en ligne : Lundi 30 janvier 2017
    M. Pilar Valdecantos, Virginia Pardo, Laura Ruiz, Luis Castro‐SĂĄnchez, Borja LanzĂłn, Elisa FernĂĄndez‐MillĂĄn, Carmelo GarcĂ­a‐MonzĂłn, Ana I. Arroba, Águeda GonzĂĄlez‐RodrĂ­guez, Fernando EscrivĂĄ, Carmen Álvarez, Francisco J. RupĂ©rez, Coral Barbas, Anish Konkar, Jacqui Naylor, David Hornigold, Ana Dos Santos, Maria Bednarek, Joseph Grimsby, Cristina M. Rondinone, Ángela M. Valverde
    A novel glucagon‐like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice
    Because nonalcoholic steatohepatitis (NASH) is associated with impaired liver regeneration, we investigated the effects of G49, a dual glucagon‐like peptide‐1/glucagon receptor agonist, on NASH and hepatic regeneration. C57Bl/6 mice fed chow or a methionine and choline–deficient (MCD) diet for 1 week were divided into 4 groups: control (chow diet), MCD diet, chow diet plus G49, and M+G49 (MCD diet plus G49). Mice fed a high‐fat diet (HFD) for 10 weeks were divided into groups: HFD and H+G49 (HFD plus G49). Following 2 (MCD groups) or 3 (HFD groups) weeks of treatment with G49, partial hepatectomy (PH) was performed, and all mice were maintained on the same treatment schedule for 2 additional weeks. Analysis of liver function, hepatic regeneration, and comprehensive genomic and metabolic profiling were conducted. NASH was ameliorated in the M+G49 group, manifested by reduced inflammation, steatosis, oxidative stress, and apoptosis and increased mitochondrial biogenesis. G49 treatment was also associated with replenishment of intrahepatic glucose due to enhanced gluconeogenesis and reduced glucose use through the pentose phosphate cycle and oxidative metabolism. Following PH, G49 treatment increased survival, restored the cytokine‐mediated priming phase, and enhanced the proliferative capacity and hepatic regeneration ratio in mice on the MCD diet. NASH markers remained decreased in M+G49 mice after PH, and glucose use was shifted to the pentose phosphate cycle and oxidative metabolism. G49 administered immediately after PH was also effective at alleviating the pathological changes induced by the MCD diet. Benefits in terms of liver regeneration were also found in mice fed HFD and treated with G49. Conclusion: Dual‐acting glucagon‐like peptide‐1/glucagon receptor agonists such as G49 represent a novel therapeutic approach for patients with NASH and particularly those requiring PH. (Hepatology 2017;65:950‐968).


    Date de mise en ligne : Vendredi 30 décembre 2016
    Veronica L. Massey, Christine E. Dolin, Lauren G. Poole, Shanice V. Hudson, Deanna L. Siow, Guy N. Brock, Michael L. Merchant, Daniel W. Wilkey, Gavin E. Arteel
    The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice
    The extracellular matrix (ECM) consists of diverse components that work bidirectionally with surrounding cells to create a responsive microenvironment. In some contexts (e.g., hepatic fibrosis), changes to the ECM are well recognized and understood. However, it is becoming increasingly accepted that the hepatic ECM proteome (i.e., matrisome) responds dynamically to stress well before fibrosis. The term “transitional tissue remodeling” describes qualitative and quantitative ECM changes in response to injury that do not alter the overall architecture of the organ; these changes in ECM may contribute to early disease initiation and/or progression. The nature and magnitude of these changes to the ECM in liver injury are poorly understood. The goals of this work were to validate analysis of the ECM proteome and compare the impact of 6 weeks of ethanol diet and/or acute lipopolysaccharide (LPS). Liver sections were processed in a series of increasingly rigorous extraction buffers to separate proteins by solubility. Extracted proteins were identified using liquid chromatography/tandem mass spectrometry (LC‐MS/MS). Both ethanol and LPS dramatically increased the number of matrisome proteins ∌25%. The enhancement of LPS‐induced liver damage by ethanol preexposure was associated with unique protein changes. Conclusion: An extraction method to enrich the hepatic ECM was characterized. The results demonstrate that the hepatic matrisome responds dynamically to both acute (LPS) and chronic (ethanol) stresses, long before more‐dramatic fibrotic changes to the liver occur. The changes to the mastrisome may contribute, at least in part, to the pathological responses to these stresses. It is also interesting that several ECM proteins responded similarly to both stresses, suggesting a common mechanism in both models. Nevertheless, there were responses that were unique to the individual and combined exposures. (Hepatology 2017;65:969‐982).


    Date de mise en ligne : Samedi 31 décembre 2016
    Jessica L. Maiers, Enis Kostallari, Malek Mushref, Thiago M. deAssuncao, Haiyang Li, Nidhi Jalan‐Sakrikar, Robert C. Huebert, Sheng Cao, Harmeet Malhi, Vijay H. Shah
    The unfolded protein response mediates fibrogenesis and collagen I secretion through regulating TANGO1 in mice
    Fibrogenesis encompasses the deposition of matrix proteins, such as collagen I, by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a small interfering RNA screen, we identified Transport and Golgi organization 1 (TANGO1) as a potential participant in collagen I secretion. We investigated the role of TANGO1 in procollagen I secretion in HSCs and liver fibrogenesis. Depletion of TANGO1 in HSCs blocked collagen I secretion without affecting other matrix proteins. Disruption of secretion led to procollagen I retention within the ER, induction of the UPR, and HSC apoptosis. In wild‐type (WT) HSCs, both TANGO1 and the UPR were induced by transforming growth factor ÎČ (TGFÎČ). As the UPR up‐regulates proteins involved in secretion, we studied whether TANGO1 was a target of the UPR. We found that UPR signaling is responsible for up‐regulating TANGO1 in response to TGFÎČ, and this mechanism is mediated by the transcription factor X‐box binding protein 1 (XBP1). In vivo, murine and human cirrhotic tissue displayed increased TANGO1 messenger RNA levels. Finally, TANGO1+/– mice displayed less hepatic fibrosis compared to WT mice in two separate murine models: CCl4 and bile duct ligation. Conclusion: Loss of TANGO1 leads to procollagen I retention in the ER, which promotes UPR‐mediated HSC apoptosis. TANGO1 regulation during HSC activation occurs through a UPR‐dependent mechanism that requires the transcription factor, XBP1. Finally, TANGO1 is critical for fibrogenesis through mediating HSC homeostasis. The work reveals a unique role for TANGO1 and the UPR in facilitating collagen I secretion and fibrogenesis. (Hepatology 2017;65:983‐998).


    Date de mise en ligne : Samedi 31 décembre 2016
    Shuai Yan, Juan Tang, Yuyao Zhang, Yuanyang Wang, Shengkai Zuo, Yujun Shen, Qianqian Zhang, Di Chen, Yu Yu, Kai Wang, Sheng‐Zhong Duan, Ying Yu
    Prostaglandin E2 promotes hepatic bile acid synthesis by an E prostanoid receptor 3‐mediated hepatocyte nuclear receptor 4α/cholesterol 7α‐hydroxylase pathway in mice
    Prostaglandin E2 (PGE2) is an important lipid mediator of inflammation. However, whether and how PGE2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte‐specific deletion of EP3 receptor (EP3hep–/–) results in hypercholesterolemia and augments diet‐induced atherosclerosis in low‐density lipoprotein receptor knockout (Ldlr–/–) mice. Cholesterol 7α‐hydroxylase (CYP7A1) is down‐regulated in livers of EP3hep–/–Ldlr−/− mice, leading to suppressed hepatic bile acid (BA) biosynthesis. Mechanistically, hepatic‐EP3 deficiency suppresses CYP7A1 expression by elevating protein kinase A (PKA)‐dependent Ser143 phosphorylation of hepatocyte nuclear receptor 4α (HNF4α). Disruption of the PKA‐HNF4α interaction and BA sequestration rescue impaired BA excretion and ameliorated atherosclerosis in EP3hep–/–Ldlr−/− mice. Conclusion: Our results demonstrated an unexpected role of proinflammatory mediator PGE2 in improving hepatic cholesterol metabolism through activation of the EP3‐mediated PKA/HNF4α/CYP7A1 pathway, indicating that inhibition of this pathway may be a novel therapeutic strategy for dyslipidemia and atherosclerosis. (Hepatology 2017;65:999‐1014)


    Date de mise en ligne : Samedi 31 décembre 2016
    Bo Zhu, Lan Wei, Nicholas Rotile, Helen Day, Tyson Rietz, Christian T. Farrar, Gregory Y. Lauwers, Kenneth K. Tanabe, Bruce Rosen, Bryan C. Fuchs, Peter Caravan
    Combined magnetic resonance elastography and collagen molecular magnetic resonance imaging accurately stage liver fibrosis in a rat model
    Hepatic fibrosis is associated with an overproduction of matrix proteins and a pathological increase of liver stiffness. Noninvasive magnetic resonance (MR) quantification of matrix can be assessed with a collagen‐binding molecular MR probe and stiffness by MR elastography, complementary techniques. This study used both imaging techniques to more accurately stage hepatic fibrosis in a rat model. Thirty rats with varying levels of diethylnitrosamine‐induced liver fibrosis were imaged before and 45 minutes after injection of collagen‐specific probe EP‐3533. MR elastography was performed in the same imaging session. Changes in liver relaxation rate post–EP‐3533 and liver stiffness were compared to the collagen proportional area determined by histology and to Ishak scoring using receiver operating characteristic analysis. Collagen imaging was most sensitive to early fibrosis, while elastography was more sensitive to advanced fibrosis. This complementary feature enabled the formulation of a composite model using multivariate analysis of variance. This model incorporated the discriminating advantages of both MR techniques, resulting in more accurate staging throughout fibrotic progression. Conclusion: Collagen molecular MR imaging is complementary to MR elastography, and combining the two techniques in a single exam leads to increased diagnostic accuracy for all stages of fibrosis. (Hepatology 2017;65:1015‐1025)


    Date de mise en ligne : Vendredi 06 janvier 2017
    Estella M. Alonso, Simon P. Horslen, Edward M. Behrens, Edward Doo
    Pediatric acute liver failure of undetermined cause: A research workshop
    Pediatric acute liver failure (PALF) is a potentially devastating condition that occurs in previously healthy children of all ages and frequently leads to a rapid clinical deterioration. An identified cause for liver injury is lacking in approximately 30% of cases. Children with undetermined diagnosis have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. A single‐day workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together clinicians and basic scientists to integrate aligned research findings and develop a foundation for new mechanistic studies and future treatment trials. The clinical phenotype of indeterminate PALF shares important similarities to the hyperinflammatory state characteristic of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). A failure of cytotoxic T cells to limit or contract inflammatory responses may propagate injury and lead to a local and systemic milieu that does not support normal hepatic regeneration. Evidence was presented that bone marrow (BM)‐derived Sinusoidal endothelial cell PROgenitor Cells (sprocs) play a vital role in hepatic regeneration. Overwhelming systemic inflammatory responses may suppress mobilization of BM sprocs and dampen hepatic recovery. Conclusion: Experience gained through treatment trials of HLH and MAS in childhood may inform study design for therapy of PALF. Successful approaches to limiting neuroinflammation through reduction of systemic inflammation and standardized neuroprotection protocols that limit glial injury could significantly improve intact survival. Finally, given that PALF is a rare disease, investigative efforts must include broad multicenter collaboration and careful stewardship of biorepository specimens. (Hepatology 2017;65:1026‐1037).


    Date de mise en ligne : Mercredi 08 février 2017
    Dennis L. Shung, Guadalupe Garcia‐Tsao
    Liver Capsule: Portal Hypertension and Varices: Pathogenesis, Stages, and Management
    1038


    Date de mise en ligne : Mercredi 11 janvier 2017
    Tatiana Kisseleva
    The origin of fibrogenic myofibroblasts in fibrotic liver
    Liver fibrosis results from chronic liver injury of different etiologies. It is characterized by dysregulation of physiological remodeling, activation of myofibroblasts, and formation of a fibrous scar. Myofibroblasts develop contractile functions and secrete the extracellular matrix proteins that form this fibrous scar. Myofibroblasts are not present in the normal liver but activate and proliferate in response to injury and inflammation. This review summarizes the understanding and controversies on the contribution of cell populations to the myofibroblasts in liver fibrosis. (Hepatology 2017;65:1039‐1043).


    Date de mise en ligne : Lundi 06 février 2017
    Puneeta Tandon, Maitreyi Raman, Marina Mourtzakis, Manuela Merli
    A practical approach to nutritional screening and assessment in cirrhosis
    Malnutrition is one of the most common complications of cirrhosis, associated with an increased risk of morbidity and mortality. As a potentially modifiable condition, it is of particular importance to identify malnourished patients so that nutritional therapy can be instituted. Nutrition screening and assessment are infrequently performed in patients with cirrhosis. The reasons for this are multifactorial, including the absence of a validated “rapid” screening tool, multiple definitions of what constitutes malnutrition, and challenges with interpreting body composition and laboratory results in the setting of volume overload and liver dysfunction. This article summarizes the clinically relevant evidence and presents key issues, tools, and clinical options that are applicable to patients with cirrhosis. The definition, etiology, and clinically relevant outcomes associated with malnutrition are reviewed. Rapid nutritional screening is differentiated from more detailed nutritional assessment. Nutritional assessment in special populations, including women and the obese, and the role of inflammation are discussed. Multicenter studies using a common nutritional screening/assessment strategy are the next steps to fast‐track adoption and implementation of nutrition‐related evaluations into routine clinical practice. (Hepatology 2017;65:1044‐1057).


    Date de mise en ligne : Mardi 31 janvier 2017
    Giovanni Musso, Maurizio Cassader, Elena Paschetta, Roberto Gambino
    Pioglitazone for advanced fibrosis in nonalcoholic steatohepatitis: New evidence, new challenges
    1061


    Date de mise en ligne : Lundi 30 janvier 2017
    Yu Tahara, Shigenobu Shibata
    Abnormal tuning of the hepatic circadian metabolic rhythms in lung cancer
    1064


    Date de mise en ligne : Vendredi 06 janvier 2017
    Tatehiro Kagawa, Yukihiko Adachi, Naoaki Hashimoto, Hiroshi Mitsui, Tomohiko Ohashi, Masashi Yoneda, Izumi Hasegawa, Shunji Hirose, Kota Tsuruya, Kazuya Anzai, Tetsuya Mine
    Loss of organic anion transporting polypeptide 1B3 function causes marked delay in indocyanine green clearance without any clinical symptoms
    1068


    Date de mise en ligne : Jeudi 06 octobre 2016
    Dimitri Tchernitchko, Virginie Scotet, Thibaud Lefebvre, Carine L'Hostis, Isabelle Gourlaouen, Marie‐Christine Merour, Khadidja Rebah, Katell Peoc'h, Suzanne Assari, Claude Ferec, HervĂ© Puy, GĂ©rald Le Gac
    GNPAT polymorphism rs11558492 is not associated with increased severity in a large cohort of HFE p.Cys282Tyr homozygous patients
    1071


    Date de mise en ligne : Vendredi 03 février 2017
    Gordon D. McLaren, James C. Barton, Grant A. Ramm, Mary J. Emond, V. Nathan Subramaniam, Pradyumna D. Phatak, Paul C. Adams, Lawrie W. Powell, Lyle C. Gurrin, Gregory J. Anderson, Christine E. McLaren
    Reply:
    1073


    Date de mise en ligne : Mardi 15 novembre 2016
    Antonio Ponzetto, Radhika Sita Srinivasan
    Risk factors for hepatocellular carcinoma
    1074


    Date de mise en ligne : Mardi 29 novembre 2016
    Gang Qin, Xun Zhuang
    Cost‐effectiveness of augmenting current perinatal hepatitis B prevention program with maternal antiviral therapy
    1075


    Date de mise en ligne : Vendredi 03 février 2017
    Giovanni Brandi, Stefania De Lorenzo, Andrea Palloni, Guido Biasco, Francesco Tovoli
    Aspirin for cholangiocarcinoma prevention: New targets to shift the dogma from ascertained risk to possible prevention
    1076


    Date de mise en ligne : Mardi 03 janvier 2017
    Ahad Eshraghian
    High prevalence of nonalcoholic fatty liver disease in the middle east: Lifestyle and dietary habits
    1077


    Date de mise en ligne : Mardi 03 janvier 2017
    Marloes van Asten, Pauline Verhaegh, Ger Koek, Jef Verbeek
    The increasing burden of NAFLD fibrosis in the general population: Time to bridge the gap between hepatologists and primary care
    1078


    Date de mise en ligne : Mardi 03 janvier 2017
    Michael J. R. Desborough, Brennan C. Kahan, Simon J. Stanworth, Vipul Jairath
    Fibrinogen as an independent predictor of mortality in decompensated cirrhosis and bleeding
    1080


    Date de mise en ligne : Vendredi 30 décembre 2016
    Andreas Drolz, Valentin Fuhrmann
    Reply
    1080


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


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