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  • External validation of the ITA.LI.CA prognostic system for patients with hepatocellular carcinoma: A multicenter cohort study. (HEP-17-0903)
    Hepatology (IF 13.246) Pub Date : 2017-11-22
    Mauro Borzio; Elena Dionigi; Angelo Rossini; Massimo Marignani; Rodolfo Sacco; Ilario De Sio; Emanuela Bertolini; Giampiero Francica; Anna Giacomin; Giancarlo Parisi; Susanna Vicari; Anna Toldi; Andrea Salmi; Sergio Boccia; Mario Mitra; Fabio Fornari

    Several staging systems for HCC have been developed. BCLC is considered the best in predicting survival, although limitations have emerged. Recently the Italian-Liver-Cancer (ITA.LI.CA) prognostic system, integrating the ITA.LI.CA tumor-staging (stages 0, A, B1-3; C) with Child-Pugh score, ECOG-PST, and AFP with a strong ability to predict survival was proposed. Aim of our study was to provide an external validation of the ITA.LI.CA system in an independent real-life occidental cohort of HCCs.

    更新日期:2017-11-22
  • Interaction between alcohol consumption and metabolic syndrome in predicting severe liver disease in the general population
    Hepatology (IF 13.246) Pub Date : 2017-11-22
    Fredrik Åberg; Jaana Helenius‐Hietala; Pauli Puukka; Martti Färkkilä; Antti Jula

    The metabolic syndrome and alcohol risk use are both associated with high prevalence of hepatic steatosis, but only a minority develop liver failure or liver cancer. Few general population studies have analyzed metabolic predictors of such severe liver complications. We studied which metabolic factors best predict severe liver complications, stratified by alcohol consumption. 6732 individuals without baseline liver disease who participated in the Finnish population-based Health 2000 Study (2000-2001), a nationally representative cohort. Follow-up data from national registers until 2013 were analyzed for liver-related admissions, mortality, and liver cancer. Baseline alcohol use and metabolic factors were analyzed by backward stepwise Cox regression analysis. 84 subjects experienced a severe liver event during follow-up. In the final multivariate model, factors predictive of liver events were age (HR 1.02, 95%CI 1.004-1.04), gender (women HR 0.55, 0.34-0.91), alcohol use (HR 1.002, 1.001-1.002), diabetes (HR 2.73, 1.55-4.81), LDL cholesterol (HR 0.74, 0.58-0.93), and HOMA-IR (HR 1.01, 1.004-1.02). Among alcohol risk users (average alcohol use ≥210 g/week for men, ≥140 g/week for women), diabetes (HR 6.79, 95%CI 3.18-14.5) was the only significant predictor. Among non-risk drinkers, age, alcohol use, smoking, waist circumference, low LDL cholesterol and HOMA-IR were significant independent predictors. The total cholesterol-to-LDL cholesterol-ratio and waist circumference-to-BMI-ratio emerged as additional independent predictors.

    更新日期:2017-11-22
  • Patients with advanced hepatocellular carcinoma need a personalized management: A lesson from clinical practice
    Hepatology (IF 13.246) Pub Date : 2017-11-21
    Edoardo G. Giannini; Laura Bucci; Francesca Garuti; Matteo Brunacci; Barbara Lenzi; Matteo Valente; Eugenio Caturelli; Giuseppe Cabibbo; Fabio Piscaglia; Roberto Virdone; Martina Felder; Francesca Ciccarese; Francesco Giuseppe Foschi; Rodolfo Sacco; Gianluca Svegliati Baroni; Fabio Farinati; Gian Lodovico Rapaccini; Andrea Olivani; Antonio Gasbarrini; Maria Di Marco; Filomena Morisco; Marco Zoli; Alberto Masotto; Franco Borzio; Luisa Benvegnù; Fabio Marra; Antonio Colecchia; Gerardo Nardone; Mauro Bernardi; Franco Trevisani

    The Barcelona Clinic Liver Cancer advanced stage (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population, where sorafenib alone is the recommended treatment. In this study our aim was to assess treatment and overall survival (OS) of BCLC C patients sub-classified according to clinical features (Performance Status [PS], macro-vascular invasion [MVI], extra-hepatic spread [EHS] or MVI+EHS) determining their allocation to this stage. From the Italian Liver Cancer database, we analysed 835 consecutive BCLC C patients diagnosed between 2008 and 2014. Patients were sub-classified as: PS1 alone (n=385, 46.1%), PS2 alone (n=146, 17.5%), MVI (n=224, 26.8%), EHS (n=51, 6.1%) and MVI+EHS (n=29, 3.5%). MVI, EHS and MVI+EHS patients had larger and multifocal/massive HCCs and higher alpha-fetoprotein levels than PS1 and PS2 patients. Median OS significantly declined from PS1 (38.6 months) to PS2 (22.3 months), EHS (11.2 months), MVI (8.2 months) and MVI+EHS (3.1 months) (P<0.001). Among MVI patients, OS was longer in those with peripheral than with central (portal trunk) MVI (11.2 vs 7.1 months, P=0.005). The most frequent treatments were: curative approaches in PS1 (39.7%), supportive therapy in PS2 (41.8%), sorafenib in MVI (39.3%) and EHS (37.3%), and best supportive care in MVI+EHS patients (51.7%). Independent prognostic factors were: Model for End-stage Liver Disease score, Child-Pugh class, ascites, platelet count, albumin, tumour size, MVI, EHS, alpha-fetoprotein levels and treatment type.

    更新日期:2017-11-21
  • Using the Icelandic Genealogical Database to define the familial risk of primary biliary cholangitis
    Hepatology (IF 13.246) Pub Date : 2017-11-21
    K.T. Örnolfsson; S. Olafsson; O.M. Bergmann; M.E. Gershwin; E.S. Björnsson

    Hereditary factors in primary biliary cholangitis (PBC) have been well defined in genome wide-association studies but there is not much direct data available that define the relative risk for family members with an affected proband. An increased risk in first-degree relatives has been demonstrated in a variety of studies but data have been lacking on further detailed associations for subsequent generations. The objective of the study was to use the unique Icelandic genealogical database to study the familiality of PBC. All patients with positive anti-mitochondrial antibodies measurements in Iceland during the period of 1991-2015, fulfilling diagnostic criteria for PBC were included. The Icelandic Genealogical Database was used to assess familial relations. For each case of PBC, 10,000 control subjects matched for age, gender and number of known relatives were randomly chosen from this database to calculate the familial relative risk of PBC. The average kinship coefficient (KC) of the patients was calculated and compared to the average kinship coefficient of controls. Overall 222 PBC patients were identified, 182 females and 40 males, median age 62 years. First-, second- and third-degree relatives of the PBC patients had a high relative risk of the disease: 9.13 (p<0.0001), 3.61 (p=0.014) and 2.59 (p=0.008), respectively. In fourth- and fifth-degree relatives the relative risk was also increased, with 1.66 (p=0.08) and 1.42 (p=0.08), respectively. The average kinship coefficient of the patients was also higher than that of the control subjects, with 21.34 x10-5 vs. 9.56 x10-5 (p<0.0001). In conclusion relatives of PBC patients had markedly higher risk for development of the disease compared with controls and importantly our data demonstrate that the risk was significantly increased even in second- and third-degree relatives. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-21
  • C/EBPα-dependent pre-neoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer
    Hepatology (IF 13.246) Pub Date : 2017-11-21
    Ashley Cast; Leila Valanejad; Mary Wright; Phuong Nguyen; Anita Gupta; Liqin Zhu; Soona Shin; Nikolai Timchenko

    Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes; while hepatocellular carcinoma (HCC) is caused by the de-differentiation of hepatocytes into Cancer Stem Cells (CSCs). However, the mechanisms of aggressive HBL and mechanisms that cause de-differentiation of hepatocytes into CSCs are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of de-differentiation of hepatocytes into CSCs. In both cases of liver cancer, the de-phosphorylation of tumor suppressor protein, C/EBPα, at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that de-ph-C/EBPα creates pre-neoplastic foci with CSC that give rise to HCC and aggressive HBL. C/EBPα-dependent de-differentiation of hepatocytes into CSCs includes increased proliferation of hepatocytes followed by generation of multi-nucleated hepatocytes and subsequent appearance of hepatocytes with DLK1-positive intra-nuclear inclusions. We further isolated C/EBPα-dependent multi-nucleated hepatocytes and found that they possess characteristics of tumor initiating cells, including elevation of stem cell markers. C/EBPα-dependent CSCs are observed in patients with aggressive hepatoblastoma and in patients with a predisposition for liver cancer. Conclusion: The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include the conversion of the tumor suppressor C/EBPα into an oncogenic isoform which further creates pre-neoplastic foci where hepatocytes de-differentiate into cancer cells, giving rise to liver cancer. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-21
  • Modulation of the intestinal bile acid–FXR–FGF15 axis improves alcoholic liver disease in mice
    Hepatology (IF 13.246) Pub Date : 2017-11-21
    Phillipp Hartmann; Katrin Hochrath; Angela Horvath; Peng Chen; Caroline T. Seebauer; Cristina Llorente; Lirui Wang; Yazen Alnouti; Derrick E. Fouts; Peter Stärkel; Rohit Loomba; Sally Coulter; Christopher Liddle; Ruth T. Yu; Lei Ling; Stephen J. Rossi; Alex M. DePaoli; Michael Downes; Ronald M. Evans; David A. Brenner; Bernd Schnabl

    Alcoholic liver disease is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine. Bile acid analysis confirmed an increased amount of unconjugated bile acids in the small intestine after ethanol administration. Mediated by a lower farnesoid x receptor (FXR) activity in enterocytes, lower fibroblast growth factor (FGF)-15 protein secretion was associated with increased hepatic cytochrome P450 enzyme (Cyp)-7a1 protein expression and circulating bile acid levels. Depletion of the commensal microbiota with non-absorbable antibiotics attenuated hepatic Cyp7a1 expression and reduced alcoholic liver disease in mice, suggesting that increased bile acid synthesis is dependent on gut bacteria. To restore intestinal FXR activity, we used a pharmacological intervention with the intestine-restricted FXR agonist fexaramine, which protected mice from ethanol-induced liver injury. While bile acid metabolism was only minimally altered, fexaramine treatment stabilized the gut barrier and significantly modulated hepatic genes involved in lipid metabolism. To link the beneficial metabolic effect to FGF15, a non-tumorigenic FGF19 variant – a human FGF15 ortholog – was overexpressed in mice using adeno-associated viruses. FGF19 treatment showed similarly beneficial metabolic effects and ameliorated alcoholic steatohepatitis. Taken together, alcohol-associated metagenomic changes result in alterations of bile acid profiles. Targeted interventions improve bile acid–FXR–FGF15 signaling by modulation of hepatic Cyp7a1 and lipid metabolism, and reduce ethanol-induced liver disease in mice. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-21
  • Glecaprevir/Pibrentasvir in Patients with HCV Genotype 1 or 4 and Prior Direct-acting Antiviral Treatment Failure
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Fred Poordad; Stanislas Pol; Armen Asatryan; Maria Buti; David Shaw; Christophe Hézode; Franco Felizarta; Robert W Reindollar; Stuart C Gordon; Stephen Pianko; Michael W Fried; David E Bernstein; Joel Gallant; Chih‐Wei Lin; Yang Lei; Teresa I Ng; Preethi Krishnan; Sarah Kopecky‐Bromberg; Jens Kort; Federico Mensa

    Methods: MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and prior virologic failure on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12).

    更新日期:2017-11-21
  • New insights into diagnosis and therapeutic options for proliferative hepatoblastoma
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Katarzyna B. Hooks; Jérôme Audoux; Helena Fazli; Sarah Lesjean; Tony Ernault; Nathalie‐Dugot Senant; Thierry Leste‐Lasserre; Martin Hagedorn; Benoit Rousseau; Coralie Danet; Sophie Branchereau; Laurence Brugières; Sophie Taque; Catherine Guettier; Monique Fabre; Anne Rullier; Marie‐Annick Buendia; Thérèse Commes; Christophe F. Grosset; Anne‐Aurélie Raymond

    Surgery and cisplatin-based treatment of hepatoblastoma (HB) currently guarantee the survival of 70-80% of patients. However, some important challenges remain in diagnosing high risk tumors and identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of hepatoblastoma tumors have been described, namely C1 and C2; C2 being the subgroup with the poorest prognosis, a more advanced tumor stage and the worst overall survival rate. An associated 16-gene signature to discriminate the two tumoral subgroups was proposed but it has not been transferred into clinical routine. To address these issues we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A and C2B, identifiable by a concise four-gene signature: HSD17B6, ITGA6, TOP2A and VIM, with TOP2A being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by RT-qPCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in Fanconi Anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, an FDA-approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway associated double-strand DNA repair and significantly impedes HB growth in vivo.

    更新日期:2017-11-21
  • Cytoplasmic localization of the cell polarity factor Scribble supports liver tumor formation and tumor cell invasiveness
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Shan Wan; Anne‐Sophie Meyer; Sofia Maria Elisabeth Weiler; Christian Rupp; Marcell Tóth; Carsten Sticht; Stephan Singer; Stefan Thomann; Stephanie Roessler; Marina Schorpp‐Kistner; Jennifer Schmitt; Norbert Gretz; Peter Angel; Darjus Felix Tschaharganeh; Jens Marquardt; Peter Schirmacher; Federico Pinna; Kai Breuhahn

    The loss of epithelial cell polarity plays an important role in the development and progression of liver cancer. However, the specific molecular mechanisms supporting tumor initiation and progression are poorly understood. In this study, transcriptome data and immunofluorescence stains of tissue samples derived from hepatocellular carcinoma (HCC) patients revealed that overexpression associated with cytoplasmic localization of the baso-lateral cell polarity complex protein Scribble (Scrib) correlated with poor prognosis of HCC patients. In comparison to HCC cells stably expressing wildtype Scrib (ScribWT), mutated Scrib with enforced cytoplasmic enrichment (ScribP305L) induced AKT signaling through the destabilization of phosphatase and tensin homolog (PTEN) and PH domain and leucine rich repeat protein phosphatase 1 (PHLPP1). Cytoplasmic ScribP305L stimulated a gene signature and a phenotype, which were characteristic for epithelial to mesenchymal transition (EMT) and HCC cell invasiveness. ScribP305L-dependent invasion was mediated by the AP-1 constituents ATF2 and JunB via induction of paracrine-acting secreted protein acidic and cysteine rich (SPARC). Co-expression of ScribP305L and the oncogene c-MYC via hydrodynamic gene delivery in mouse livers promoted tumor formation and increased pAKT, pATF2, and SPARC abundance in comparison to controls. Lastly, cytoplasmic Scrib localization correlated with AKT and ATF2 phosphorylation in human HCC tissues and the ScribP305L-dependent gene signature was enriched in cancer patients with poor prognosis.

    更新日期:2017-11-21
  • Development and Validation of a Primary Sclerosing Cholangitis-Specific Patient-Reported Outcomes Instrument: The PSC PRO
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Zobair M. Younossi; Arian Afendy; Maria Stepanova; Andrei Racila; Fatema Nader; Rachel Gomel; Ricky Safer; William R. Lenderking; Anne Skalicky; Leah Kleinman; Robert P. Myers; G. Mani Subramanian; John G. McHutchison; Cynthia Levy; Christopher L. Bowlus; Kris Kowdley; Andrew J. Muir

    Background: PSC is a chronic liver disease associated with inflammation and biliary fibrosis that leads to cholangitis, cirrhosis, and impaired quality of life. Our objective was to develop and validate a PSC-specific PRO instrument.

    更新日期:2017-11-21
  • Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The lowr HDV – 1 study
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Cihan Yurdaydin; Onur Keskin; Çağdaş Kalkan; Fatih Karakaya; Aysun Çalişkan; Ersin Karatayli; Senem Karatayli; A Mithat Bozdayi; Christopher Koh; Theo Heller; Ramazan Idilman; Jeffrey S Glenn

    Background and rationale: In a proof-of-concept (POC) study, the oral prenylation inhibitor lonafarnib (LNF) decreased HDV RNA during 4 weeks of treatment. Here we explored optimal LNF regimens. Methods: 15 patients (5 groups; 3 per group) completed dosing as follows: 1) LNF 200 mg BID (12 weeks); 2) LNF 300 mg BID (12 weeks); 3) LNF 100 mg TID (5 weeks); 4) LNF 100 mg BID + pegylated interferon alfa (PEG-IFNα) 180 mcg QW (8 weeks); and 5) LNF 100 mg BID + ritonavir (RTV) 100 mg QD (8 weeks). Tolerability and efficacy were assessed. Results: Higher LNF monotherapy doses had greater decreases in HDV viral load than achieved in the original POC study. However, this was associated with increased gastrointestinal adverse events. Addition of RTV 100 mg QD to a LNF 100 mg BID regimen yielded better antiviral responses than LNF 300 mg BID monotherapy, and with less side effects. A similar improvement was observed with LNF 100 mg BID + PEG-IFNα 180 mcg QW. 2/6 patients who received 12 weeks of LNF experienced transient post-treatment ALT increases resulting in HDV RNA negativity and ALT normalization. Conclusions: The CYP3A4 inhibitor RTV allows a lower LNF dose to be used while achieving higher levels of post-absorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG-IFNα achieved more substantial and rapid HDV RNA reduction, compared to historical responses with PEG-IFNα alone. 12 weeks of LNF can result in post-treatment HDV RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-21
  • β-Catenin Deficiency in Hepatocytes Aggravates Hepatocarcinogenesis Driven by Oncogenic β-Catenin and MET
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Yan Liang; Yun Feng; Min Zong; Xufu Wei; Jin Lee; Yukuan Feng; Hairi Li; Guangshun Yang; Zhong‐Jun Wu; Xiang‐Dong Fu; Gen‐Sheng Feng

    Both activating and inactivating mutations in ctnnb1, encoding β-catenin, have been implicated in liver tumorigenesis in humans and mice, although the underlying mechanisms are not fully understood. Herein we show that deletion of endogenous β-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of β-catenin (CAT) in combination with HGF receptor MET. Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the β-catenin-deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9+ cells, and upregulation of pro-tumorigenic cytokines including IL-6 and TGF-β1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in β-catenin-deficient livers, featured by upregulation of Erk, Akt and Wnt/β-catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. These data argue that while dominantly activating mutants of β-catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro-oncogenic microenvironment, which may facilitate HCC recurrence following a targeted therapy of the primary tumor. Therefore, an effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and also suppression of the secondary tumor-promoting stromal effects in the liver microenvironment. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-21
  • Prospero-related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating interleukin-8 expression
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Yanfeng Liu; Yonglong Zhang; Shenghao Wang; Qiong‐Zhu Dong; Zhongliang Shen; Wei Wang; Shuai Tao; Chenjian Gu; Jing Liu; Youhua Xie; Lun‐Xiu Qin

    Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. Conclusions: We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894–1909)

    更新日期:2017-11-21
  • Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell–intrinsic PD-1
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Hui Li; Xiaoqiang Li; Shuang Liu; Lei Guo; Bo Zhang; Jubo Zhang; Qinghai Ye

    Inhibitors of programmed cell death 1 (PD-1) administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti-PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppresses tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mammalian target of rapamycin effectors eukaryotic initiation factor 4E and ribosomal protein S6, thus promoting their phosphorylation. Moreover, combining mammalian target of rapamycin inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. Conclusion: Targeting mammalian target of rapamycin pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. (Hepatology 2017;66:1920–1933)

    更新日期:2017-11-21
  • Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    José Altamirano; Hugo López‐Pelayo; Javier Michelena; Patricia D. Jones; Lluisa Ortega; Pere Ginès; Juan Caballería; Antoni Gual; Ramón Bataller; Anna Lligoña

    Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short-term prognosis, whereas factors associated with long-term survival are largely unknown. The aims of our study were to (1) determine the impact of complete abstinence from alcohol on long-term survival and (2) identify prognostic factors at admission capable of predicting abstinence during long-term follow-up in patients with AH. One hundred forty-two patients with biopsy-proven AH that survived the first episode were included. Demographic, psychiatric, and biochemical variables at admission and drinking status during follow-up were obtained. Cox regression, logistic regression, and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow-up of 55 months. During follow-up, complete abstinence was reported in 39% and was associated with better long-term survival (hazard ratio, 0.53; P = 0.03). After adjustment for baseline prognostic scoring systems (Model for End-Stage Liver Disease and age, bilirubin, international normalized ratio, creatinine scores), complete abstinence was independently associated with survival (P < 0.05). Age and lack of past alcoholism treatments were independently associated with complete abstinence (P < 0.001 and P = 0.02, respectively) during follow-up. CART analysis generated a simple and practical algorithm based on the combination of past alcoholism treatments and age. Using CART analysis, we stratified 2 subgroups of patients with high (65%) and low (26%-29%) rates of complete abstinence after an episode of AH. Conclusion: Complete abstinence after an episode of AH positively impacts long-term survival. The combination of 2 variables easily obtained at admission might be useful to predict long-term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842–1853)

    更新日期:2017-11-21
  • Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Xiaoming Cheng; Yuchen Xia; Elisavet Serti; Peter Daniel Block; Michelle Chung; Kazuaki Chayama; Barbara Rehermann; T. Jake Liang

    Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune-mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell-culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV-infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high-level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779–1793)

    更新日期:2017-11-21
  • Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Jasmohan S. Bajaj; Zain Kassam; Andrew Fagan; Edith A. Gavis; Eric Liu; I. Jane Cox; Raffi Kheradman; Douglas Heuman; Jessica Wang; Thomas Gurry; Roger Williams; Masoumeh Sikaroodi; Michael Fuchs; Eric Alm; Binu John; Leroy R. Thacker; Antonio Riva; Mark Smith; Simon D. Taylor‐Robinson; Patrick M Gillevet

    Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusion: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727–1738)

    更新日期:2017-11-21
  • A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus–infected mongolians
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Xiaohua Chen; Odgerel Oidovsambuu; Ping Liu; Rosslyn Grosely; Menashe Elazar; Virginia D. Winn; Benjamin Fram; Zhang Boa; Hongjie Dai; Bekhbold Dashtseren; Dahgwahdorj Yagaanbuyant; Zulkhuu Genden; Naranbaatar Dashdorj; Andreas Bungert; Naranjargal Dashdorj; Jeffrey S. Glenn

    Hepatitis delta virus (HDV) causes the most severe form of human viral hepatitis. HDV requires a hepatitis B virus (HBV) coinfection to provide HDV with HBV surface antigen envelope proteins. The net effect of HDV is to make the underlying HBV disease worse, including higher rates of hepatocellular carcinoma. Accurate assessments of current HDV prevalence have been hampered by the lack of readily available and reliable quantitative assays, combined with the absence of a Food and Drug Administration–approved therapy. We sought to develop a convenient assay for accurately screening populations and to use this assay to determine HDV prevalence in a population with abnormally high rates of hepatocellular carcinoma. We developed a high-throughput quantitative microarray antibody capture assay for anti-HDV immunoglobulin G wherein recombinant HDV delta antigen is printed by microarray on slides coated with a noncontinuous, nanostructured plasmonic gold film, enabling quantitative fluorescent detection of anti-HDV antibody in small aliquots of patient serum. This assay was then used to screen all HBV-infected patients identified in a large randomly selected cohort designed to represent the Mongolian population. We identified two quantitative thresholds of captured antibody that were 100% predictive of the sample either being positive on standard western blot or harboring HDV RNA detectable by real-time quantitative PCR. Subsequent screening of the HBV+ cohort revealed that a remarkable 57% were RNA+ and an additional 4% were positive on western blot alone. Conclusion: The quantitative microarray antibody capture assay's unique performance characteristics make it ideal for population screening; its application to the Mongolian HBV surface antigen–positive population reveals an apparent ∼60% prevalence of HDV coinfection among these HBV-infected Mongolian subjects, which may help explain the extraordinarily high rate of hepatocellular carcinoma in Mongolia. (Hepatology 2017;66:1739–1749)

    更新日期:2017-11-21
  • Polo-like-kinase 1 is a proviral host factor for hepatitis B virus replication
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Ahmed Diab; Adrien Foca; Floriane Fusil; Thomas Lahlali; Pascal Jalaguier; Fouzia Amirache; Lia N'Guyen; Nathalie Isorce; François‐Loïc Cosset; Fabien Zoulim; Ourania Andrisani; David Durantel

    Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for chronic hepatitis B and HCC are suboptimal. Herein, we identified cellular serine/threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy. To this end, we employed physiologically relevant HBV infection models of primary human hepatocytes (PHHs) and differentiated HepaRG cells in conjunction with pharmacologic PLK1 inhibitors, small interfering RNA (siRNA)-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1CA). In addition, a humanized liver Fah−/−/Rag2−/−/Il2rg−/− (FRG) mouse model was used to determine the antiviral effect of PLK1 inhibitor BI-2536 on HBV infection in vivo. Finally, in vitro PLK1 kinase assays and site-directed mutagenesis were employed to demonstrate that HBV core protein (HBc) is a PLK1 substrate. We demonstrated that HBV infection activated cellular PLK1 in PHHs and differentiated HepaRG cells. PLK1 inhibition by BI-2536 or siRNA-mediated knockdown suppressed HBV DNA biosynthesis, whereas overexpression of PLK1CA increased it, suggesting that the PLK1 effects on viral biosynthesis are specific and that PLK1 is a proviral cellular factor. Significantly, BI-2536 administration to HBV-infected humanized liver FRG mice strongly inhibited HBV infection, validating PLK1 as an antiviral target in vivo. The proviral action of PLK1 is associated with the biogenesis of the nucleocapsid, as BI-2536 leads to its decreased intracellular formation/accumulation. In this respect, our studies identified HBc as a PLK1 substrate in vitro, and mapped PLK1 phosphorylation sites on this protein. Conclusion: PLK1 is a proviral host factor that could be envisaged as a target for combined antiviral and antitumoral strategies against HBV infection and HBV-mediated carcinogenesis. (Hepatology 2017;66:1750–1765)

    更新日期:2017-11-21
  • Hepatitis C virus–induced tumor-initiating cancer stem–like cells activate stromal fibroblasts in a xenograft tumor model
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Reina Sasaki; Pradip Devhare; Ratna B. Ray; Ranjit Ray

    Hepatitis C virus (HCV) often causes persistent infection and is an increasingly important factor in the etiology of fibrosis/cirrhosis and hepatocellular carcinoma, although the mechanisms for the disease processes remain unclear. We have shown previously that HCV infection generates an epithelial–mesenchymal transition state and tumor-initiating cancer stem–like cells in human hepatocytes. In this study, we investigated whether HCV-induced tumor-initiating cancer stem–like cells when implanted into mice activate stromal fibroblasts. A number of fibroblast activation markers, including matrix metalloproteinase 2, were significantly increased at the mRNA or protein level in the xenograft tumors, suggesting the presence of tumor-associated fibroblasts. Fibroblast activation markers of murine origin were specifically increased in tumor, suggesting that fibroblasts migrate to form stroma. Next, we demonstrated that conditioned medium from HCV-infected human hepatocytes activates fibrosis-related markers in hepatic stellate cells. We further observed that these HCV-infected hepatocytes express transforming growth factor beta, which activates stromal fibroblast markers. Subsequent analysis suggested that anti–transforming growth factor beta neutralizing antibody, when incubated with conditioned medium from HCV-infected hepatocytes, inhibits fibrosis marker activation in primary human hepatic stellate cells. Conclusion: HCV-infected hepatocytes induce local fibroblast activation by secretion of transforming growth factor beta, and a preneoplastic or tumor state of the hepatocytes influences the network for the tumor-associated fibroblast environment. (Hepatology 2017;66:1766–1778)

    更新日期:2017-11-21
  • Hepatitis B virus evades innate immunity of hepatocytes but activates cytokine production by macrophages
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Xiaoming Cheng; Yuchen Xia; Elisavet Serti; Peter Daniel Block; Michelle Chung; Kazuaki Chayama; Barbara Rehermann; T. Jake Liang

    Hepatitis B virus (HBV) infects hepatocytes specifically and causes immune-mediated liver damage. How HBV interacts with the innate immunity at the early phase of infection, either with hepatocytes or other cells in the liver, remains controversial. To address this question, we utilized various human cell-culture models and humanized Alb-uPA/SCID mice. All these models were unable to mount an interferon (IFN) response despite robust HBV replication. To elucidate the mechanisms involved in the lack of IFN response, we examined whether HBV actively inhibits innate immune functions of hepatocytes. By treating HBV-infected cells with known inducers of the IFN signaling pathway, we observed no alteration of either sensing or downstream IFN response by HBV. We showed that the DNA innate sensing pathways are poorly active in hepatocytes, consistent with muted innate immune recognition of HBV. Upon exposure to high-level HBV, human macrophages could be activated with increased inflammatory cytokine expressions. Conclusion: HBV behaves like a “stealth” virus and is not sensed by, nor actively interferes with, the intrinsic innate immunity of infected hepatocytes. Macrophages are capable of sensing HBV, but require exposure to high HBV titers, potentially explaining the long “window period” during acute infection and HBV's propensity to chronic infection. (Hepatology 2017;66:1779–1793)

    更新日期:2017-11-21
  • Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    David Wyles; Heiner Wedemeyer; Ziv Ben‐Ari; Edward J. Gane; Jesper Bach Hansen; Ira M. Jacobson; Alex L. Laursen; Annie Luetkemeyer; Ronald Nahass; Stephen Pianko; Stefan Zeuzem; Patricia Jumes; Hsueh‐Cheng Huang; Joan Butterton; Michael Robertson; Janice Wahl; Eliav Barr; Hee‐Koung Joeng; Elizabeth Martin; Lawrence Serfaty

    People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor–containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor–containing therapy. (Hepatology 2017;66:1794–1804)

    更新日期:2017-11-21
  • Impact of an electronic health record alert in primary care on increasing hepatitis c screening and curative treatment for baby boomers
    Hepatology (IF 13.246) Pub Date : 2017-09-14
    Monica A. Konerman; Mary Thomson; Kristen Gray; Meghan Moore; Hetal Choxi; Elizabeth Seif; Anna S.F. Lok

    Despite effective treatment for chronic hepatitis C, deficiencies in diagnosis and access to care preclude disease elimination. Screening of baby boomers remains low. The aims of this study were to assess the impact of an electronic health record–based prompt on hepatitis C virus (HCV) screening rates in baby boomers in primary care and access to specialty care and treatment among those newly diagnosed. We implemented an electronic health record–based “best practice advisory” (BPA) that prompted primary care providers to perform HCV screening for patients seen in primary care clinic (1) born between 1945 and 1965, (2) who lacked a prior diagnosis of HCV infection, and (3) who lacked prior documented anti-HCV testing. The BPA had associated educational materials, order set, and streamlined access to specialty care for newly diagnosed patients. Pre-BPA and post-BPA screening rates were compared, and care of newly diagnosed patients was analyzed. In the 3 years prior to BPA implementation, 52,660 baby boomers were seen in primary care clinics and 28% were screened. HCV screening increased from 7.6% for patients with a primary care provider visit in the 6 months prior to BPA to 72% over the 1 year post-BPA. Of 53 newly diagnosed patients, all were referred for specialty care, 11 had advanced fibrosis or cirrhosis, 20 started treatment, and 9 achieved sustained virologic response thus far. Conclusion: Implementation of an electronic health record–based prompt increased HCV screening rates among baby boomers in primary care by 5-fold due to efficiency in determining needs for HCV screening and workflow design. Streamlined access to specialty care enabled patients with previously undiagnosed advanced disease to be cured. This intervention can be easily integrated into electronic health record systems to increase HCV diagnosis and linkage to care. (Hepatology 2017;66:1805–1813)

    更新日期:2017-11-21
  • Modeling cost-effectiveness and health gains of a “universal” versus “prioritized” hepatitis C virus treatment policy in a real-life cohort
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Loreta A. Kondili; Federica Romano; Francesca Romana Rolli; Matteo Ruggeri; Stefano Rosato; Maurizia Rossana Brunetto; Anna Linda Zignego; Alessia Ciancio; Alfredo Di Leo; Giovanni Raimondo; Carlo Ferrari; Gloria Taliani; Guglielmo Borgia; Teresa Antonia Santantonio; Pierluigi Blanc; Giovanni Battista Gaeta; Antonio Gasbarrini; Luchino Chessa; Elke Maria Erne; Erica Villa; Donatella Ieluzzi; Francesco Paolo Russo; Pietro Andreone; Maria Vinci; Carmine Coppola; Liliana Chemello; Salvatore Madonia; Gabriella Verucchi; Marcello Persico; Massimo Zuin; Massimo Puoti; Alfredo Alberti; Gerardo Nardone; Marco Massari; Giuseppe Montalto; Giuseppe Foti; Maria Grazia Rumi; Maria Giovanna Quaranta; Americo Cicchetti; Antonio Craxì; Stefano Vella

    We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virus–infected patients: policy 1, “universal,” treat all patients, regardless of fibrosis stage; policy 2, treat only “prioritized” patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus–infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies’ cost-effectiveness. The patients’ age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of €30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 post–sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (€15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis.

    更新日期:2017-11-21
  • Genetic diversity and worldwide distribution of the deltavirus genus: A study of 2,152 clinical strains
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Frédéric Le Gal; Ségolène Brichler; Tudor Drugan; Chakib Alloui; Dominique Roulot; Jean‐Michel Pawlotsky; Paul Dény; Emmanuel Gordien

    Hepatitis delta virus (HDV) is responsible for the most severe form of acute and chronic viral hepatitis. We previously proposed that the Deltavirus genus is composed of eight major clades. However, few sequences were available to confirm this classification. Moreover, little is known about the structural and functional consequences of HDV variability. One practical consequence is the failure of most quantification assays to properly detect or quantify plasmatic HDV RNA. Between 2001 and 2014, 2,152 HDV strains were prospectively collected and genotyped in our reference laboratory by means of nucleotide sequencing and extensive phylogenetic analyses of a 400-nucleotide region of the genome (R0) from nucleotides 889 to 1289 encompassing the 3′ end of the delta protein–coding gene. In addition, the full-length genome sequence was generated for 116 strains selected from the different clusters, allowing for in-depth characterization of the HDV genotypes and subgenotypes. This study confirms that the HDV genus is composed of eight genotypes (HDV-1 to HDV-8) defined by an intergenotype similarity >85% or >80%, according to the partial or full-length genome sequence, respectively. Furthermore, genotypes can be segregated into two to four subgenotypes, characterized by an intersubgenotype similarity >90% (>84% for HDV-1) over the whole genome sequence. Systematic analysis of genome and protein sequences revealed highly conserved functional nucleotide and amino acid motifs and positions across all (sub)genotypes, indicating strong conservatory constraints on the structure and function of the genome and the protein. Conclusion: This study provides insight into the genetic diversity of HDV and a clear view of its geographical localization and allows speculation as to the worldwide spread of the virus, very likely from an initial African origin. (Hepatology 2017;66:1826–1841)

    更新日期:2017-11-21
  • Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    José Altamirano; Hugo López‐Pelayo; Javier Michelena; Patricia D. Jones; Lluisa Ortega; Pere Ginès; Juan Caballería; Antoni Gual; Ramón Bataller; Anna Lligoña

    Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short-term prognosis, whereas factors associated with long-term survival are largely unknown. The aims of our study were to (1) determine the impact of complete abstinence from alcohol on long-term survival and (2) identify prognostic factors at admission capable of predicting abstinence during long-term follow-up in patients with AH. One hundred forty-two patients with biopsy-proven AH that survived the first episode were included. Demographic, psychiatric, and biochemical variables at admission and drinking status during follow-up were obtained. Cox regression, logistic regression, and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow-up of 55 months. During follow-up, complete abstinence was reported in 39% and was associated with better long-term survival (hazard ratio, 0.53; P = 0.03). After adjustment for baseline prognostic scoring systems (Model for End-Stage Liver Disease and age, bilirubin, international normalized ratio, creatinine scores), complete abstinence was independently associated with survival (P < 0.05). Age and lack of past alcoholism treatments were independently associated with complete abstinence (P < 0.001 and P = 0.02, respectively) during follow-up. CART analysis generated a simple and practical algorithm based on the combination of past alcoholism treatments and age. Using CART analysis, we stratified 2 subgroups of patients with high (65%) and low (26%-29%) rates of complete abstinence after an episode of AH. Conclusion: Complete abstinence after an episode of AH positively impacts long-term survival. The combination of 2 variables easily obtained at admission might be useful to predict long-term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842–1853)

    更新日期:2017-11-21
  • Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Oludemilade Akinrotimi; Ryan Riessen; Philip VanDuyne; Jung Eun Park; Yoon Kwang Lee; Lee‐Jun Wong; Ann M. Zavacki; Kristina Schoonjans; Sayeepriyadarshini Anakk

    Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr –/– Shp–/– double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator-activated receptor gamma 2 and lipid-droplet protein fat-specific protein 27 beta. Conclusion: These data suggest that Fxr and Shp inactivation may be beneficial to combat diet-induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854–1865)

    更新日期:2017-11-21
  • USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Shimin An; Ling‐Ping Zhao; Li‐Jun Shen; Siyuan Wang; Kuo Zhang; Yu Qi; Jilin Zheng; Xiao‐Jing Zhang; Xue‐Yong Zhu; Rong Bao; Ling Yang; Yue‐Xin Lu; Zhi‐Gang She; Yi‐Da Tang

    Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down-regulated in the livers of nonalcoholic steatohepatitis patients and high-fat diet (HFD)–induced or genetically obese mice. When challenged with HFD, hepatocyte-specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18–hepatocyte-specific transgenic mice and promoted in USP18–hepatocyte-specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18–hepatocyte-specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis. Conclusion: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (Hepatology 2017;66:1866–1884)

    更新日期:2017-11-21
  • Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Salvatore Petta; Luca Valenti; Antonino Tuttolomondo; Paola Dongiovanni; Rosaria Maria Pipitone; Calogero Cammà; Daniela Cabibi; Vito Di Marco; Anna Ludovica Fracanzani; Sara Badiali; Valerio Nobili; Silvia Fargion; Stefania Grimaudo; Antonio Craxì

    The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). Conclusion: The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885–1893)

    更新日期:2017-11-21
  • Prospero-related homeobox 1 drives angiogenesis of hepatocellular carcinoma through selectively activating interleukin-8 expression
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Yanfeng Liu; Yonglong Zhang; Shenghao Wang; Qiong‐Zhu Dong; Zhongliang Shen; Wei Wang; Shuai Tao; Chenjian Gu; Jing Liu; Youhua Xie; Lun‐Xiu Qin

    Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero-related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin-specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin-8 (IL-8) by epigenetically stimulating the IL-8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti-IL-8 monoclonal antibody. Conclusions: We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti-IL-8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894–1909)

    更新日期:2017-11-21
  • Intention-to-treat survival benefit of liver transplantation in patients with hepatocellular cancer
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Quirino Lai; Alessandro Vitale; Samuele Iesari; Armin Finkenstedt; Gianluca Mennini; Gabriele Spoletini; Maria Hoppe‐Lotichius; Giovanni Vennarecci; Tommaso M. Manzia; Daniele Nicolini; Alfonso W. Avolio; Anna Chiara Frigo; Ivo Graziadei; Massimo Rossi; Emmanouil Tsochatzis; Gerd Otto; Giuseppe M. Ettorre; Giuseppe Tisone; Marco Vivarelli; Salvatore Agnes; Umberto Cillo; Jan Lerut

    The debate about the best approach to select patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT) is still ongoing. This study aims to identify the best variables allowing to discriminate between “high-” and “low-benefit” patients. To do so, the concept of intention-to-treat (ITT) survival benefit of LT has been created. Data of 2,103 adult HCC patients consecutively enlisted during the period 1987-2015 were analyzed. Three rigorous statistical steps were used in order to create the ITT survival benefit of LT: the development of an ITT LT and a non-LT survival model, and the individual prediction of the ITT survival benefit of LT defined as the difference between the median ITT survival with (based on the first model) and without LT (based on the second model) calculated for each enrolled patient. Four variables (Model for End-Stage Liver Disease, alpha-fetoprotein, Milan-Criteria status, and radiological response) displayed a high effect in terms of delta benefit. According to these risk factors, four benefit groups were identified. Patients with three to four factors (“no-benefit group”; n = 405 of 2,103; 19.2%) had no benefit of LT compared to alternative treatments. Conversely, patients without any risk factor (“large-benefit group”; n = 108; 5.1%) yielded the highest benefit from LT reaching 60 months. Conclusion: The ITT transplant survival benefit presented here allows physicians to better select HCC patients waiting for LT. The obtained stratification may lead to an improved and more equitable method of organ allocation. Patients without benefit should be de-listed, whereas patients with large benefit ratio should be prioritized for LT. (Hepatology 2017;66:1910–1919)

    更新日期:2017-11-21
  • Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell–intrinsic PD-1
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Hui Li; Xiaoqiang Li; Shuang Liu; Lei Guo; Bo Zhang; Jubo Zhang; Qinghai Ye

    Inhibitors of programmed cell death 1 (PD-1) administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti-PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppresses tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mammalian target of rapamycin effectors eukaryotic initiation factor 4E and ribosomal protein S6, thus promoting their phosphorylation. Moreover, combining mammalian target of rapamycin inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. Conclusion: Targeting mammalian target of rapamycin pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. (Hepatology 2017;66:1920–1933)

    更新日期:2017-11-21
  • Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Xiao‐Feng Li; Cheng Chen; Dai‐Min Xiang; Le Qu; Wen Sun; Xin‐Yuan Lu; Teng‐Fei Zhou; Shu‐Zhen Chen; Bei‐Fang Ning; Zhuo Cheng; Ming‐Yang Xia; Wei‐Feng Shen; Wen Yang; Wen Wen; Terence Kin Wah Lee; Wen‐Ming Cong; Hong‐Yang Wang; Jin Ding

    The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6–positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6–positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. Conclusion: Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934–1951)

    更新日期:2017-11-21
  • MicroRNA-206 prevents the pathogenesis of hepatocellular carcinoma by modulating expression of met proto-oncogene and cyclin-dependent kinase 6 in mice
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Heng Wu; Junyan Tao; Xiaolei Li; Tianpeng Zhang; Lei Zhao; Yao Wang; Lei Zhang; Jun Xiong; Zhi Zeng; Na Zhan; Clifford J. Steer; Li Che; Mingjie Dong; Xiaomei Wang; Junqi Niu; Zhuoyu Li; Guiqing Yan; Xin Chen; Guisheng Song

    Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present tremendous therapeutic potential. Here, we report that microRNA-206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell-cycle progression and the cMet signaling pathway. MicroRNA-206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto-oncogene), cyclin D1 (CCND1), and cyclin-dependent kinase 6 (CDK6) as functional targets of microRNA-206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA-206 delayed cell-cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA-206 completely prevented HCC development in both cMyc and V-Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA-206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA-206 on the development of HCC. MicroRNA-206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. Conclusion: In summary, this study defines a potentially critical role of microRNA-206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952–1967)

    更新日期:2017-11-21
  • A point-based prediction model for cardiovascular risk in orthotopic liver transplantation: The CAR-OLT score
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Lisa B. VanWagner; Hongyan Ning; Maureen Whitsett; Josh Levitsky; Sarah Uttal; John T. Wilkins; Michael M. Abecassis; Daniela P. Ladner; Anton I. Skaro; Donald M. Lloyd‐Jones

    Cardiovascular disease (CVD) complications are important causes of morbidity and mortality after orthotopic liver transplantation (OLT). There is currently no preoperative risk-assessment tool that allows physicians to estimate the risk for CVD events following OLT. We sought to develop a point-based prediction model (risk score) for CVD complications after OLT, the Cardiovascular Risk in Orthotopic Liver Transplantation risk score, among a cohort of 1,024 consecutive patients aged 18-75 years who underwent first OLT in a tertiary-care teaching hospital (2002-2011). The main outcome measures were major 1-year CVD complications, defined as death from a CVD cause or hospitalization for a major CVD event (myocardial infarction, revascularization, heart failure, atrial fibrillation, cardiac arrest, pulmonary embolism, and/or stroke). The bootstrap method yielded bias-corrected 95% confidence intervals for the regression coefficients of the final model. Among 1,024 first OLT recipients, major CVD complications occurred in 329 (32.1%). Variables selected for inclusion in the model (using model optimization strategies) included preoperative recipient age, sex, race, employment status, education status, history of hepatocellular carcinoma, diabetes, heart failure, atrial fibrillation, pulmonary or systemic hypertension, and respiratory failure. The discriminative performance of the point-based score (C statistic = 0.78, bias-corrected C statistic = 0.77) was superior to other published risk models for postoperative CVD morbidity and mortality, and it had appropriate calibration (Hosmer-Lemeshow P = 0.33). Conclusion: The point-based risk score can identify patients at risk for CVD complications after OLT surgery (available at www.carolt.us); this score may be useful for identification of candidates for further risk stratification or other management strategies to improve CVD outcomes after OLT. (Hepatology 2017;66:1968–1979)

    更新日期:2017-11-21
  • Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Salvador Augustin; Mònica Pons; James B. Maurice; Christophe Bureau; Horia Stefanescu; Michel Ney; Hélène Blasco; Bogdan Procopet; Emmanuel Tsochatzis; Rachel H. Westbrook; Jaime Bosch; Annalisa Berzigotti; Juan G. Abraldes; Joan Genescà

    Patients with compensated advanced chronic liver disease (cACLD) can safely avoid screening endoscopy with a platelet count >150 × 109 cells/L and a liver stiffness measurement (LSM) <20 kPa (Baveno VI criteria). However, the total number of avoided endoscopies using this rule is relatively low. We aimed at expanding the Baveno VI criteria and validating them in additional cohorts. Patients from the Anticipate cohort (499 patients with cACLD of different etiologies) were used to study the performance of different thresholds of platelets and LSM for the identification of patients at very low risk (<5%) of having varices needing treatment (VNT). The new criteria (Expanded-Baveno VI) were validated in two additional cohorts from London (309 patients) and Barcelona (117 patients). The performance of the new criteria by etiology of cACLD was also assessed. The best new expanded classification rule was platelet count >110 × 109 cells/L and LSM <25 kPa. This was validated in the two additional cohorts. Overall, the Expanded-Baveno VI criteria would potentially spare 367 (40%) endoscopies (21% with Baveno VI criteria) with a risk of missing VNT of 1.6% (95% confidence interval, 0.7%-3.5%) in patients within the criteria and 0.6% (95% confidence interval, 0.3%-1.4%) in the overall population of 925 patients evaluated. The Expanded-Baveno VI criteria performed well in patients with cACLD with hepatitis C virus and alcoholic and nonalcoholic steatohepatitis. Conclusion: The new Expanded-Baveno VI criteria spare more endoscopies than the original criteria with a minimal risk of missing VNT in most of the main etiologies of cACLD. (Hepatology 2017;66:1980–1988)

    更新日期:2017-11-21
  • Hepatic stimulator substance resists hepatic ischemia/reperfusion injury by regulating Drp1 translocation and activation
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Chao Zhang; Jing Huang; Wei An

    Ischemia/reperfusion injury, induced by abnormal mitochondrial fission–related apoptosis, is a major concern in liver transplantation settings. Our previous studies have demonstrated that hepatic stimulator substance (HSS) is an antiapoptotic effector and could protect liver from ischemia/reperfusion injury. However, the underlying mechanism remains unclear. In the present study, we report that in vitro and in vivo HSS could regulate mitochondrial fission and hepatocyte apoptosis during liver ischemia/reperfusion injury by orchestrating the translocation and activation of dynamin-related protein 1 (Drp1). Using a mouse model of ischemia/reperfusion-induced liver injury, we found that HSS-haploinsufficient (HSS+/−) mice displayed exacerbated liver damage based on their increased serum aminotransferase levels, cell structural destruction, and apoptosis levels compared to wild-type (HSS+/+) littermates. Disruption of HSS markedly increased cyclin-dependent kinase 1 (CDK1) and Bax expression, accompanied by elevated phosphorylated Drp1 and release of cytochrome c. In parallel in vitro studies, we found that HSS could inhibit the expression of CDK1 and that HSS inhibits hepatocyte apoptosis through its suppression of CDK1/cyclin B–mediated phosphorylation at Ser-616 of Drp1, thereby decreasing Drp1 accumulation in mitochondria and Drp1-mediated activation of the mitochondrial fission program. On the contrary, knockdown of HSS increased CDK1 as well as Drp1 phosphorylation and aggravated hepatocellular apoptosis. Mechanistic investigation showed that HSS was able to reduce the stability and translation of CDK1 mRNA by modulating the expression of several microRNAs (miRs), including miR-410-3p, miR-490-3p, and miR-582-5p. Conclusion: Our data reveal a novel mechanism for HSS in regulating the mitochondrial fission machinery and further suggest that modulation of HSS may provide a therapeutic approach for combating liver damage. (Hepatology 2017;66:1989–2001)

    更新日期:2017-11-21
  • Pericentral hepatocytes produce insulin-like growth factor-2 to promote liver regeneration during selected injuries in mice
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Junlai Liu; Xiao Hu; Jie Chen; Xinqi Li; Lu Wang; Binbin Wang; Wenbo Peng; Cuiwei Yang; Zhijie Li; Yan Chen; Yue J. Wang; Chuanjiang Li; Xiajun Li; Fang Yan; Yunfang Wang; Changzhen Shang; Xin Wang; Tao Chen; Pengyu Huang

    Liver regeneration (LR) happens after various types of injuries. Unlike the well-studied LR caused by partial hepatectomy (PHx), there is accumulating evidence suggesting that LR during other injuries may result from unknown mechanisms. In this study, we found that insulin-like growth factor 2 (IGF-2) was drastically induced following the liver injuries caused by tyrosinemia or long-term treatments of CCl4. However, this was not observed during the early phase of acute liver injuries after PHx or single treatment of CCl4. Remarkably, most IGF-2-expressing hepatocytes were located at the histological area around the central vein of the liver lobule after the liver injuries caused either in fumarylacetoacetate hydrolase–deficient mice or in CCl4 chronically treated mice. Hepatocyte proliferation in vivo was significantly promoted by induced IGF-2 overexpression, which could be inhibited by adeno-associated virus–delivered IGF-2 short hairpin RNAs or linsitinib, an inhibitor of IGF-2 signaling. Proliferating hepatocytes in vivo responded to IGF-2 through both insulin receptor and IGF-1 receptor. IGF-2 also significantly promoted DNA synthesis of primary hepatocytes in vitro. More interestingly, the significantly induced IGF-2 was also found to colocalize with glutamine synthetase in the region enriched with proliferating hepatocytes for the liver samples from patients with liver fibrosis. Conclusion: IGF-2 is produced by pericentral hepatocytes to promote hepatocyte proliferation and repair tissue damage in the setting of chronic liver injury, which is distinct from the signaling that occurs post-PHx. (Hepatology 2017;66:2002–2015)

    更新日期:2017-11-21
  • Argininosuccinate synthase 1 (ASS1): A marker of unclassified hepatocellular adenoma and high bleeding risk
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Elodie Henriet; Aya Abou Hammoud; Jean‐William Dupuy; Benjamin Dartigues; Zakaria Ezzoukry; Nathalie Dugot‐Senant; Thierry Leste‐Lasserre; Nestor Pallares‐Lupon; Macha Nikolski; Brigitte Le Bail; Jean‐Frédéric Blanc; Charles Balabaud; Paulette Bioulac‐Sage; Anne‐Aurélie Raymond; Frédéric Saltel

    Hepatocellular adenomas (HCAs) are rare benign tumors divided into three main subgroups defined by pathomolecular features, HNF1A (H-HCA), mutated β-catenin (b-HCA), and inflammatory (IHCA). In the case of unclassified HCAs (UHCAs), which are currently identified by default, a high risk of bleeding remains a clinical issue. The objective of this study was to explore UHCA proteome with the aim to identify specific biomarkers. Following dissection of the tumoral (T) and nontumoral (NT) tissue on formalin-fixed, paraffin-embedded HCA tissue sections using laser capture methodology, we performed mass spectrometry analysis to compare T and NT protein expression levels in H-HCA, IHCA, b-HCA, UHCA, and focal nodular hyperplasia. Using this methodology, we searched for proteins which are specifically deregulated in UHCA. We demonstrate that proteomic profiles allow for discriminating known HCA subtypes through identification of classical biomarkers in each HCA subgroup. We observed specific up-regulation of the arginine synthesis pathway associated with overexpression of argininosuccinate synthase (ASS1) and arginosuccinate lyase in UHCA. ASS1 immunohistochemistry identified all the UHCA, of which 64.7% presented clinical bleeding manifestations. Interestingly, we demonstrated that the significance of ASS1 was not restricted to UHCA, but also encompassed certain hemorrhagic cases in other HCA subtypes, particularly IHCA. Conclusion: ASS1 + HCA combined with a typical hematoxylin and eosin stain aspect defined a new HCA subgroup at a high risk of bleeding. (Hepatology 2017;66:2016–2028)

    更新日期:2017-11-21
  • YAP suppresses gluconeogenic gene expression through PGC1α
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Yue Hu; Dong‐Ju Shin; Hui Pan; Zhiqiang Lin; Jonathan M. Dreyfuss; Fernando D. Camargo; Ji Miao; Sudha B. Biddinger

    Cell growth and proliferation are tightly coupled to metabolism, and dissecting the signaling molecules which link these processes is an important step toward understanding development, regeneration, and cancer. The transcriptional regulator Yes-associated protein 1 (YAP) is a key regulator of liver size, development, and function. We now show that YAP can also suppress gluconeogenic gene expression. Yap deletion in primary hepatocytes potentiates the gluconeogenic gene response to glucagon and dexamethasone, whereas constitutively active YAP suppresses it. The effects of YAP are mediated by the transcriptional coactivator peroxisome proliferator–activated receptor-gamma coactivator 1. YAP inhibits its ability to bind to and activate transcription from the promoters of its gluconeogenic targets, and the effects of YAP are blunted upon its knockdown. In vivo, constitutively active YAP lowers plasma glucose levels and increases liver size.

    更新日期:2017-11-21
  • Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Brenda S. Hijmans; Andreas Boss; Theo H. van Dijk; Maud Soty; Henk Wolters; Elodie Mutel; Albert K. Groen; Terry G.J. Derks; Gilles Mithieux; Arend Heerschap; Dirk‐Jan Reijngoud; Fabienne Rajas; Maaike H. Oosterveer

    It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase–independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc–/– mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc–/– mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc–/– mice. It also showed increased glycogen phosphorylase flux in L-G6pc–/– mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6pc−/− mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. Conclusion: Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042–2054)

    更新日期:2017-11-21
  • Sarcopenia in hiding: The risk and consequence of underestimating muscle dysfunction in nonalcoholic steatohepatitis
    Hepatology (IF 13.246) Pub Date : 2017-10-30
    Rahima A. Bhanji; Praveena Narayanan; Alina M. Allen; Harmeet Malhi; Kymberly D. Watt

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Up to one third of individuals with NAFLD will develop nonalcoholic steatohepatitis (NASH), which is associated with progression to cirrhosis and is rapidly becoming the leading indication for liver transplantation. Sarcopenia is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. It is observed in up to 60% of patients with end-stage liver disease and portends a poor prognosis. Recent studies have shown that sarcopenia is a novel risk factor for developing NAFLD. Pathophysiological mechanisms relating sarcopenia and NASH may include insulin resistance (IR) and increased inflammation. IR leads to accumulation of triglycerides in both muscle tissue and the liver. It also exacerbates proteolysis and leads to muscle depletion. Chronic inflammation leads to liver injury and progression of fibrosis. The inflammatory milieu also stimulates protein catabolism. Viewing skeletal muscle as an endocrine organ that secretes various salutary myokines may help us understand its role in the development of steatosis. A better understanding of the pathophysiology will aid in developing physical and pharmacological therapeutic interventions. In this review, we will explore the complex inter-relationships between sarcopenia and NASH. We will discuss the impact of sarcopenia in patients with NASH and therapeutic options for the management of sarcopenia. (Hepatology 2017;66:2055–2065)

    更新日期:2017-11-21
  • Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B
    Hepatology (IF 13.246) Pub Date : 2017-11-06
    Xupeng Hong; Elena S. Kim; Haitao Guo

    Hepatitis B virus (HBV) infection represents a significant public health burden worldwide. Although current therapeutics manage to control the disease progression, lifelong treatment and surveillance are required because drug resistance develops during treatment and reactivations frequently occur following medication cessation. Thus, the occurrence of hepatocellular carcinoma is decreased, but not eliminated. One major reason for failure of HBV treatment is the inability to eradicate or inactivate the viral covalently closed circular DNA (cccDNA), which is a stable episomal form of the viral genome decorated with host histones and nonhistone proteins. Accumulating evidence suggests that epigenetic modifications of cccDNA contribute to viral replication and the outcome of chronic HBV infection. Here, we summarize current progress on HBV epigenetics research and the therapeutic implications for chronic HBV infection by learning from the epigenetic therapies for cancer and other viral diseases, which may open a new venue to cure chronic hepatitis B. (Hepatology 2017;66:2066–2077)

    更新日期:2017-11-21
  • Diabetes, Metabolic Comorbidities and Risk of Hepatocellular Carcinoma: Results from Two Prospective Cohort Studies
    Hepatology (IF 13.246) Pub Date : 2017-11-20
    Tracey G. Simon; Lindsay Y. King; Dawn Q. Chong; Long Nguyen; Yanan Ma; Trang VoPham; Edward L. Giovannucci; Charles S. Fuchs; Jeffrey A. Meyerhardt; Kathleen E. Corey; Hamed Khalili; Raymond T. Chung; Xuehong Zhang; Andrew T. Chan

    Background: Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk.

    更新日期:2017-11-20
  • The liver–gut microbiota axis modulates hepatotoxicity of tacrine in the rat
    Hepatology (IF 13.246) Pub Date : 2017-11-19
    Lian Yee Yip; Chiu Cheong Aw; Sze Han Lee; Yi Shuen Hong; Han Chen Ku; Winston Hecheng Xu; Jessalyn Mei Xuan Chan; Eleanor Jing Yi Cheong; Kern Rei Chng; Amanda Hui Qi Ng; Niranjan Nagarajan; Ratha Mahendran; Yuan Kun Lee; Edward R. Browne; Eric Chun Yong Chan

    The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver–gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher β-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. Conclusion: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2017).

    更新日期:2017-11-20
  • A functional characteristic of cysteine-rich protein 61: Modulation of myeloid-derived suppressor cells in liver inflammation
    Hepatology (IF 13.246) Pub Date : 2017-11-17
    Haiyan Zhang; Min Lian; Jun Zhang; Zhaolian Bian; Ruqi Tang; Qi Miao; Yanshen Peng; Jingyuan Fang; Zhengrui You; Pietro Invernizzi; Qixia Wang; M. Eric Gershwin; Xiong Ma

    There is increasing awareness of the immunologic roles of liver mononuclear populations, including myeloid-derived suppressor cells (MDSCs). We took advantage of a large well-defined cohort of 148 patients with liver inflammation and 45 healthy controls to focus on the qualitative and quantitative characteristics of MDSCs. We investigated the frequency, phenotype, and functional capacities of MDSCs by using peripheral blood MDSCs in a cohort of 55 patients with primary biliary cholangitis (PBC), 40 with autoimmune hepatitis, 39 with chronic hepatitis B, 14 with nonalcoholic fatty liver disease, and 45 healthy controls. This was followed by a liver-targeted determination in 27 patients with PBC, 27 with autoimmune hepatitis, 20 with chronic hepatitis B, 14 with nonalcoholic fatty liver disease, and 6 controls. We then focused on mechanisms of this expansion with PBC as an example, using both ursodeoxycholic acid-naive and treated patients. HLA-DR−/lowCD33+CD11b+CD14+CD15− monocytic MDSCs were elevated in diseases characterized by liver inflammation compared to healthy controls. Using PBC as a focus, there was a significant correlation between levels of circulating MDSCs and disease-related biochemical markers (alkaline phosphatase, total bilirubin). We found higher amounts of MDSCs in patients with PBC who were responsive to ursodeoxycholic acid. MDSCs from PBC were found to manifest a potent immunosuppressive function. There was a significant correlation in the accumulation of hepatic MDSCs in the inflamed lesions of PBC with histologic changes, such as fibrosis. We also found that cysteine-rich protein 61 (CCN1), a highly expressed protein in impaired cholangiocytes and hepatocytes, contributes to MDSC expansion and MDSC inducible nitric oxide synthase-associated immune suppression. Conclusion: CCN1 modulates expansion and a suppressive function of MDSCs. Our data highlight the potential functions of CCN1 on MDSCs and suggest therapeutic implications in inflammatory liver diseases. (Hepatology 2017).

    更新日期:2017-11-19
  • Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance
    Hepatology (IF 13.246) Pub Date : 2017-11-17
    Melania Gaggini; Fabrizia Carli; Chiara Rosso; Emma Buzzigoli; Milena Marietti; Veronica Della Latta; Demetrio Ciociaro; Maria Lorena Abate; Roberto Gambino; Maurizio Cassader; Elisabetta Bugianesi; Amalia Gastaldelli

    Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography–mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR = endogenous glucose production × insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2017).

    更新日期:2017-11-19
  • HMGB1 Controls Liver Cancer Initiation through YAP-dependent Aerobic Glycolysis
    Hepatology (IF 13.246) Pub Date : 2017-11-17
    Ruochan Chen; Shan Zhu; Xue‐Gong Fan; Haichao Wang; Michael T. Lotze; Herbert J. Zeh; Timothy R. Billiar; Rui Kang; Daolin Tang

    Emerging studies have suggested that the Hippo pathway is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the key regulator of the Hippo pathway in liver tumor metabolic reprogramming remains elusive. Here, we provide evidence to support that high mobility group box 1 (HMGB1), a chromosomal protein, plays a role in the regulation of the Hippo pathway during liver tumorigenesis. Cre/loxP recombination-mediated HMGB1 depletion in hepatocytes blocks diethylnitrosamine-induced liver cancer initiation in mice, whereas shRNA-mediated gene silencing of HMGB1 inhibits HCC cell proliferation. Mechanistically, the binding of HMGB1 to GA-binding protein alpha (GABPα) promotes the expression of yes-associated protein (YAP), a major downstream effector of the Hippo pathway, which contributes to liver tumorigenesis by inducing hypoxia-inducible factor 1α (HIF1α)-dependent aerobic glycolysis. Like wild type YAP-cDNA, YAP-5SA-S94A can restore HIF1α DNA binding activity, glycolysis-associated gene expression, and HIF1α-YAP complex formation in YAP-knockdown HCC cell lines. In contrast, verteporfin, a reagent targeting the interface between YAP and TEA domain transcription factor (TEAD), has the ability to block YAP-HIF1α complex formation. Notably, genetic or pharmacological inhibition of the HMGB1-YAP-HIF1α pathway confers protection against excessive glycolysis and tumor growth in mice. Conclusion: These findings uncover that HMGB1 plays a novel role in modulating the YAP-dependent HIF1α pathway and sheds light on the development of metabolism-targeting therapeutics for HCC chemoprevention. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-17
  • Perioperative Von Willebrand Factor Dynamics are Associated with Liver Regeneration and Predict Outcome after Liver Resection
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Patrick Starlinger; David Pereyra; Stefanie Haegele; Paul Braeuer; Lukas Oehlberger; Florian Primavesi; Andreas Kohler; Florian Offensperger; Thomas Reiberger; Arnulf Ferlitsch; Barbara Messner; Guido Beldi; Stefan Staettner; Christine Brostjan; Thomas Gruenberger

    Von Willebrand Factor (vWF) was found to mediate platelet influx during the early phase of liver regeneration in mice. Further, increased vWF-antigen (vWF-Ag) levels were shown to be predictive for outcome of patients with chronic liver disease. Accordingly, we aimed to assess the relevance of perioperative vWF-Ag dynamics in terms of liver regeneration and clinical outcome in patients undergoing liver resection (LR). Accordingly, we observed that vWF-Ag and its activity – estimated via ristocetin cofactor measurement – increased immediately after induction of liver regeneration and was associated with platelet accumulation within the liver. However, a significant vWF-Ag burst was only observed in patients with unaffected postoperative liver regeneration. E-selectin, as an established marker for endothelial cell activation, was found to correlate with vWF-Ag in the liver vein after induction of liver regeneration (P=0.022). Preoperative vWF-Ag levels significantly predicted postoperative liver dysfunction (LD) (N=95, AUC:0.725, P=0.009). Furthermore, a cut-off of vWF-Ag≥182% was defined to identify patients with a higher risk for postoperative LD or morbidity. This was confirmed within an independent mulitcenter validation cohort (N=133). Ultimately, multivariable analysis revealed that vWF-Ag was an independent predictor of postoperative LD and morbidity.

    更新日期:2017-11-16
  • lncRNA H19 interacts with polypyrimidine tract-binding protein 1 to reprogram hepatic lipid homeostasis
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Chune Liu; Zhihong Yang; Jianguo Wu; Li Zhang; Sangmin Lee; Dong‐Ju Shin; Melanie Tran; Li Wang

    H19 is an imprinted long non-coding RNA abundantly expressed in embryonic liver and repressed after birth. Here we show that H19 serves as a lipid sensor by synergizing with RNA-binding protein PTBP1 to modulate hepatic metabolic homeostasis. H19RNA interacts with PTBP1 to facilitate its association with SREBP1c mRNA and protein, leading to increased stability and nuclear transcriptional activity. H19 and PTBP1 are upregulated by fatty acids in hepatocytes and in diet-induced fatty liver, which further augments lipid accumulation. Ectopic expression of H19 induces steatosis and pushes the liver into a “pseudo fed” state in response to fasting by promoting SREBP1c protein cleavage and nuclear translocation. Deletion of H19 or knockdown of PTBP1 abolishes high-fat and high-sucrose (HFHS) diet-induced steatosis. Our study unveils a H19/PTBP1/SREBP1 feedforward amplifying signaling pathway to exacerbate the development of fatty liver. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-16
  • β-catenin and IL-1β dependent CXCL10 production drives progression of disease in a mouse model of Congenital Hepatic Fibrosis
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Eleanna Kaffe; Romina Fiorotto; Francesca Pellegrino; Valeria Mariotti; Mariangela Amenduni; Massimiliano Cadamuro; Luca Fabris; Mario Strazzabosco; Carlo Spirli

    Congenital Hepatic Fibrosis (CHF), a genetic disease caused by mutations in the PKHD1 gene, encoding for the protein fibrocystin (FPC), is characterized by biliary dysgenesis, progressive portal fibrosis, and by a PKA-mediated activating phosphorylation of β-Catenin at Ser675. Biliary structures of Pkhd1del4/del4 mice, a mouse model of CHF, secrete CXCL10 a chemokine able to recruit macrophages. The aim of this study is to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF/CD and to understand the mechanisms leading to increased CXCL10 secretion. We demonstrate that treatment of Pkhd1del4/del4 mice for three-month with AMG-487, an inhibitor of CXCR3 the cognate receptor of CXCL10, reduces the peribiliary recruitment of M2 macrophages (CD45+F4/80+ cells), spleen size, liver fibrosis (Sirius red), and cyst growth (K19+ area), consistent with a pathogenetic role of CXCL10. Furthermore, we show that in FPC-defective cholangiocytes, isolated from Pkhd1del4/del4 mice, CXCL10 production is mediated by JAK/STAT3, in response to IL-1β and β-Catenin. Specifically, IL-1β promotes STAT3 phosphorylation whereas β-Catenin promotes its nuclear translocation. Increased pro-IL-1β was regulated by NF-kB and increased secretion of active IL-1β was mediated by the activation of NLRP3 inflammasome (increased expression of caspase 1 and NLRP33). Conclusions: In FPC-defective cholangiocytes, β-Catenin and IL-1β are responsible for STAT3-dependent secretion of CXCL10. In vivo experiments show CXCL10/CXCR3 axis prevents the recruitment of macrophages, reduces inflammation and halts the progression of the disease. The increased production of IL-1β highlights the autoinflammatory nature of CHF and may open novel therapeutic avenues. This article is protected by copyright. All rights reserved.

    更新日期:2017-11-16
  • MicroRNA-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation
    Hepatology (IF 13.246) Pub Date : 2017-11-16
    Céline Demarez; Claude Gérard; Sabine Cordi; Alexis Poncy; Younes Achouri; Nicolas Dauguet; David A. Rosa; Patrick T. Gunning; Isabelle Manfroid; Frédéric P. Lemaigre

    Transcriptional networks control the differentiation of the hepatocyte and cholangiocyte lineages from embryonic liver progenitor cells and their subsequent maturation to the adult phenotype. However, how relative levels of hepatocyte and cholangiocyte gene expression are determined during differentiation remains poorly understood. Here, we identify microRNA (miR)-337-3p as a regulator of liver development. miR-337-3p stimulates expression of cholangiocyte genes and represses hepatocyte genes in undifferentiated progenitor cells in vitro and in embryonic mouse livers. Beyond the stage of lineage segregation, miR-337-3p controls the transcriptional network dynamics of developing hepatocytes and balances both cholangiocyte populations that constitute the ductal plate. miR-337-3p requires Notch and transforming growth factor-β signaling and exerts a biphasic control on the hepatocyte transcription factor hepatocyte nuclear factor 4α by modulating its activation and repression. With the help of an experimentally validated mathematical model, we show that this biphasic control results from an incoherent feedforward loop between miR-337-3p and hepatocyte nuclear factor 4α. Conclusion: Our results identify miR-337-3p as a regulator of liver development and highlight how tight quantitative control of hepatic cell differentiation is exerted through specific gene regulatory network motifs. (Hepatology 2017).

    更新日期:2017-11-16
  • The contribution of health risk behaviors to excess mortality in American adults with chronic hepatitis C: A population cohort-study
    Hepatology (IF 13.246) Pub Date : 2017-11-16
    Hamish Innes; Andrew McAuley; Maryam Alavi; Heather Valerio; David Goldberg; Sharon J. Hutchinson

    In resource-rich countries, chronic hepatitis C (CHC) infection is associated with a sizeable excess mortality risk. The extent to which this is due to (1) the biological sequelae of CHC infection versus (2) a high concomitant burden of health risk behaviors (HRBs) is unclear. We used data from the 1999-2010 U.S. National Health and Nutritional Examination Surveys (NHANES), which include detailed information on HRBs and CHC infection status. We calculated the prevalence of the five major HRBs—alcohol use; cigarette smoking, physical inactivity, unhealthy diet, and illicit drug use—according to CHC after adjusting for sociodemographic differences. Mortality status after survey interview was ascertained by linkage to the U.S. National Death Index. To assess the contribution of HRBs to the excess mortality risk, we determined the all-cause mortality rate ratio (MRR) for individuals with CHC relative to individuals without, and then calculated the attenuation in this MRR following adjustment for HRBs. This analysis included 27,468 adult participants of NHANES of which 363 tested positive for CHC. All HRBs were markedly more prevalent among individuals with CHC versus individuals without. CHC was associated with a 2.4-fold higher mortality rate after adjustment for sociodemographic factors (MRR, 2.36; 95% CI, 1.60-3.49). Subsequent adjustment for all five HRBs attenuated this ratio by 50.7% to MRR 1.67 (95% CI, 1.14-2.44). Higher levels of attenuation (69.1%) were observed among individuals aged 45-70 years, who form the target demographic for U.S. birth cohort screening. Conclusion: At least half the excess mortality risk for individuals with CHC in the United States may be attributed to HRBs rather than CHC. The remedial response to hepatitis C must not neglect action on HRBs if it is to fully resolve the high mortality problem in this population. (Hepatology 2017).

    更新日期:2017-11-16
  • Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Yang‐Hsiang Lin; Meng‐Han Wu; Ya‐Hui Huang; Chau‐Ting Yeh; Mei‐Ling Cheng; Hsiang‐Cheng Chi; Chung‐Ying Tsai; I‐Hsiao Chung; Ching‐Ying Chen; Kwang‐Huei Lin

    Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3′ untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Conclusion: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2017)

    更新日期:2017-11-16
  • Curative salvage liver transplantation in patients with cirrhosis and hepatocellular carcinoma: An intention-to-treat analysis
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Robbert J. de Haas; Chetana Lim; Prashant Bhangui; Chady Salloum; Philippe Compagnon; Cyrille Feray; Julien Calderaro; Alain Luciani; Daniel Azoulay

    The salvage liver transplantation (SLT) strategy was conceived for initially resectable and transplantable (R&T) hepatocellular carcinoma (HCC) patients, to try to obviate upfront liver transplantation, with the “safety net” of SLT in case of postresection recurrence. The SLT strategy is successful or curative when patients are recurrence free following primary resection alone, or after SLT for recurrence. The aim of the current study was to determine the SLT strategy's potential for cure in R&T HCC patients, and to identify predictors for its success. From 1994 to 2012, all R&T HCC patients with cirrhosis were enrolled in the SLT strategy. An intention-to-treat (ITT) analysis was used to determine this strategy's outcomes and predictors of success according to the above definition. In total, 110 patients were enrolled in the SLT strategy. Sixty-three patients (57%) had tumor recurrence after initial resection, and in 30 patients SLT could be performed (recurrence transplantability rate = 48%). From the time of initial resection, ITT 5-year overall and disease-free survival rates were 69% and 60%, respectively. The SLT strategy was successful in 60 patients (56%), either by resection alone (36%), or by SLT for recurrence (19%). Preresection predictors of successful SLT strategy at multivariate analysis included Model for End-Stage Liver Disease (MELD) score >10, and absence of neoadjuvant transarterial chemoembolization (TACE). Additional postresection predictive factors were absence of postresection morbidity, and T-stage 1-2 at the resection specimen. Conclusion: The SLT strategy is curative in only 56% of cases. Higher MELD score at inception of the strategy and no pre-resection TACE are predictors of successful SLT strategy. (Hepatology 2017).

    更新日期:2017-11-16
  • Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient data-based meta-analysis
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Eva Herrmann; Victor de Lédinghen; Christophe Cassinotto; Winnie C.‐W. Chu; Vivian Y.‐F. Leung; Giovanna Ferraioli; Carlo Filice; Laurent Castera; Valérie Vilgrain; Maxime Ronot; Jérôme Dumortier; Aymeric Guibal; Stanislas Pol; Jonel Trebicka; Christian Jansen; Christian Strassburg; Rongqin Zheng; Jian Zheng; Sven Francque; Thomas Vanwolleghem; Luisa Vonghia; Emanuel K. Manesis; Pavlos Zoumpoulis; Ioan Sporea; Maja Thiele; Aleksander Krag; Claude Cohen‐Bacrie; Aline Criton; Joel Gay; Thomas Deffieux; Mireen Friedrich‐Rust

    Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of liver fibrosis in small to moderate-sized clinical trials. We aimed at running a larger-scale meta-analysis of individual data. Centers which have worked with Aixplorer ultrasound equipment were contacted to share their data. Retrospective statistical analysis used direct and paired receiver operating characteristic and area under the receiver operating characteristic curve (AUROC) analyses, accounting for random effects. Data on both 2D-SWE and liver biopsy were available for 1,134 patients from 13 sites, as well as on successful transient elastography in 665 patients. Most patients had chronic hepatitis C (n = 379), hepatitis B (n = 400), or nonalcoholic fatty liver disease (n = 156). AUROCs of 2D-SWE in patients with hepatitis C, hepatitis B, and nonalcoholic fatty liver disease were 86.3%, 90.6%, and 85.5% for diagnosing significant fibrosis and 92.9%, 95.5%, and 91.7% for diagnosing cirrhosis, respectively. The AUROC of 2D-SWE was 0.022-0.084 (95% confidence interval) larger than the AUROC of transient elastography for diagnosing significant fibrosis (P = 0.001) and 0.003-0.034 for diagnosing cirrhosis (P = 0.022) in all patients. This difference was strongest in hepatitis B patients. Conclusion: 2D-SWE has good to excellent performance for the noninvasive staging of liver fibrosis in patients with hepatitis B; further prospective studies are needed for head-to-head comparison between 2D-SWE and other imaging modalities to establish disease-specific appropriate cutoff points for assessment of fibrosis stage. (Hepatology 2017).

    更新日期:2017-11-16
  • Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during hepatitis C virus infection
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Dustin A. Cobb; Ok‐Kyung Kim; Lucy Golden‐Mason; Hugo R. Rosen; Young S. Hahn

    Hepatitis C virus (HCV) is a global health concern that can cause severe liver disease, such as cirrhosis and hepatocellular carcinoma. Control of HCV requires vigorous T-cell responses, yet CD4+ T cells in chronic HCV patients are dysfunctional. T follicular regulatory (Tfr) cells are a subset of regulatory T cells that suppress T follicular helper (Tfh) cells and the generation of high affinity antibody-producing B cells. In this study, we examined the accumulation of Tfr cells in the liver compartment during chronic HCV infection and defined the cellular and molecular mechanisms underlying their expansion. Our analysis revealed a substantial population of Tfr cells in livers of chronic HCV patients that is absent in liver tissues from nonviral hepatitis or healthy subjects. Coculture of PBMCs from healthy subjects with HCV-infected hepatoma cells resulted in preferential expansion of circulating Tfr cells, leading to suppression of Tfh cells. Additionally, coculture of tonsillar cells with infected hepatoma cells lead to an expansion of germinal center Tfr. Notably, expansion was mediated by transforming growth factor beta (TGF-β)-containing exosomes released from HCV-infected hepatocytes given that blockade of exosome-associated TGF-β or inhibition of exosome release abrogated Tfr expansion. Conclusion: These results show that liver-derived exosomes play a pivotal role in the accumulation of Tfr cells, likely leading to suppression of Tfh responses in HCV-infected patients. Our study identifies a novel pathway in which HCV infection in hepatocytes exacerbates Tfr cell responses to subvert antiviral immunity. (Hepatology 2017)

    更新日期:2017-11-16
  • Recombinant covalently closed circular DNA of hepatitis B virus induces long-term viral persistence with chronic hepatitis in a mouse model
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Gaiyun Li; Yuanfei Zhu; Dianhui Shao; Hao Chang; Xiaoming Zhang; Dongming Zhou; Yueqiu Gao; Ke Lan; Qiang Deng

    Covalently closed circular DNA of hepatitis B virus (HBV) is critical for viral persistence in vivo. We recently reported a technique involving recombinant covalently closed circular DNA (rcccDNA) of HBV by site-specific DNA recombination. Using hydrodynamic injection, rcccDNA induces a temporarily prolonged HBV antigenemia in immunocompetent mice, similar to acute resolving HBV infection. In this study, we simulated the pathophysiological impact of chronic hepatitis to reproduce rcccDNA persistence in mouse models. We showed that rcccDNA achieved long-lasting persistence in the presence of a compromised immune response or when transcriptional activity was repressed. To closely mimic chronic hepatitis, we used a replication-defective recombinant adenoviral vector to deliver rcccDNA to the liver, which led to prominent HBV persistence throughout the experiment duration (>62 weeks) in transgenic mice expressing Cre recombinase under the albumin promoter. A sustained necroinflammatory response and fibrosis were identified in mouse livers, with dysplastic lesions commonly seen during the late stage of viral persistence, analogous to the progressive pathology of clinical chronic hepatitis. Conclusion: rcccDNA was intrinsically stable in vivo, enabling long-term persistence in the context of chronic hepatitis, and viral persistence, in turn, may promote progression of chronic liver disease; our study also presented a surrogate model of HBV cccDNA persistence in mice that could advance our understanding of the pathogenesis of chronic hepatitis B. (Hepatology 2017).

    更新日期:2017-11-15
  • Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Michitaka Matsuda; Shinya Tsurusaki; Naoko Miyata; Eiko Saijou; Hitoshi Okochi; Atsushi Miyajima; Minoru Tanaka

    Fibrosis is an important wound-healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up-regulated the expression of fibrogenic factors, such as transforming growth factor-β and platelet-derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence-activated cell sorting analyses using OSM-HTVi and OSM knockout mice have revealed that bone-marrow–derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM-induced fibrosis. Conclusion: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (Hepatology 2017).

    更新日期:2017-11-15
  • Long noncoding RNA TSLNC8 is a tumor suppressor that inactivates the interleukin-6/STAT3 signaling pathway
    Hepatology (IF 13.246) Pub Date : 2017-11-15
    Jiwei Zhang; Zhe Li; Longzi Liu; Qifeng Wang; Shengli Li; Di Chen; Zhixiang Hu; Tao Yu; Jie Ding; Jinjun Li; Ming Yao; Shenglin Huang; Yingjun Zhao; Xianghuo He

    Long noncoding RNAs can serve as oncogenes or tumor suppressors in human cancer; however, their biological functions and underlying mechanism in hepatocarcinogenesis are largely unknown. Here, we report a novel tumor suppressor long noncoding RNA on chromosome 8p12 (termed TSLNC8) that is frequently deleted and down-regulated in hepatocellular carcinoma (HCC) tissues. The loss of TSLNC8 is highly associated with the malignant features of HCC and serves as a prognostic indicator for HCC patients. TSLNC8 significantly suppresses the proliferation and metastasis of HCC cells in vitro and in vivo. TSLNC8 exerts its tumor suppressive activity by competitively interacting with transketolase and signal transducer and activator of transcription 3 (STAT3) and modulating the STAT3-Tyr705 and STAT3-Ser727 phosphorylation levels and STAT3 transcriptional activity, thus resulting in inactivation of the interleukin-6–STAT3 signaling pathway in HCC cells. Conclusion: TSLNC8 is a promising prognostic predictor for patients with HCC, and the TSLNC8–transketolase–STAT3 axis is a potential therapeutic target for HCC treatment. (Hepatology 2017).

    更新日期:2017-11-15
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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