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Date de mise en ligne : Vendredi 26 mai 2017
Christoph Schramm, John Eaton, Kristina I. Ringe, Sudhakar Venkatesh, Jin Yamamura,
Recommendations on the use of MRI in PSC‐A position statement from the International PSC study group
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder characterized by inflammation and fibrosis of the intra and/or extrahepatic bile ducts. Magnetic resonance imaging (MRI) is a noninvasive imaging modality that can be used to diagnose PSC and detect disease related complications. Quantitative MRI technologies also have the potential to provide valuable prognostic information. Despite the potential of this imaging technology, the clinical application of MRI in the care of PSC patients and imaging standards vary across institutions. Moreover, a unified position statement about the role of MRI in the care of PSC patients, quality imaging standards and its potential as a research tool is lacking. Conclusions: Members of the international PSC study group and radiologists from North America and Europe have compiled the following position statement to provide guidance regarding the application of MRI in the care of PSC patients, minimum imaging standards and future areas of research. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Vendredi 26 mai 2017
Edward Gane
Is HBIG still needed after liver transplantation for CHB?
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Date de mise en ligne : Vendredi 26 mai 2017
Ander Arbelaiz, Mikel Azkargorta, Marcin Krawczyk, Alvaro Santos‐Laso, Ainhoa Lapitz, Maria J. Perugorria, Oihane Erice, Esperanza Gonzalez, Raul Jimenez‐Agüero, Adelaida Lacasta, Cesar Ibarra, Alberto Sanchez‐Campos, Juan P. Jimeno, Frank Lammert, Piotr Milkiewicz, Marco Marzioni, Rocio I.R. Macias, Jose J. G. Marin, Tushar Patel, Gregory J. Gores, Ibon Martinez, Félix Elortza, Juan M. Falcon‐Perez, Luis Bujanda, Jesus M. Banales
Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma
Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with poor prognosis. Several conditions such as primary sclerosing cholangitis (PSC) are risk factors. Non‐invasive differential diagnosis between intrahepatic CCA (iCCA) and hepatocellular carcinoma (HCC) is sometimes difficult. Accurate non‐invasive biomarkers for PSC, CCA or HCC are not available. In the search of novel biomarkers, serum extracellular vesicles (EV) were isolated from CCA (n=43), PSC (n=30) or HCC (n=29) patients, and healthy individuals (control, n=32), and their protein content was characterized. By using nanoparticle tracking analysis (NTA), serum EV concentration was found higher in HCC than all the other groups. Round morphology (by transmission electron microscopy), size (∼180 nm diameter by NTA) and markers (CD9, CD63 and CD81 by immunoblot) indicated that most serum EV were exosomes. Proteome profiles (by mass spectrometry) revealed multiple differentially expressed proteins among groups. Several of these proteins showed high diagnostic values with maximum area under the ROC curve (AUC) of 0.878 for CCA vs control, 0.905 for CCA stage I‐I vs control, 0.789 for PSC vs control, 0.806 for PSC non‐cirrhotic vs control, 0.796 for CCA vs PSC, 0.956 for CCA stage I‐I vs PSC, 0.904 for HCC vs control, and 0.894 for iCCA vs HCC. The proteomic analysis of EV derived from CCA human cells in vitro revealed higher abundance of oncogenic proteins compared to EV released by normal human cholangiocytes. Orthotopic implant of CCA human cells in the liver of immunodeficient mice resulted in the release to serum of EV containing some similar human oncogenic proteins. Conclusion: novel proteomic signatures found in serum EV of CCA, PSC and HCC patients show potential usefulness as diagnostic tools. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 25 mai 2017
Daniel Markwardt, Lesca Holdt, Christian Steib, Andreas Benesic, Flemming Bendtsen, Mauro Bernardi, Richard Moreau, Daniel Teupser, Julia Wendon, Frederik Nevens, Jonel Trebicka, Elisabet Garcia, Marco Pavesi, Vicente Arroyo, Alexander L. Gerbes
Plasma Cystatin C is a predictor of renal dysfunction, ACLF and mortality in patients with acutely decompensated liver cirrhosis
Background: The development of acute‐on‐chronic liver failure (ACLF) in patients with liver cirrhosis is associated with high mortality rates. Renal failure is the most significant organ dysfunction that occurs in ACLF. So far there are no biomarkers predicting ACLF. Aim: To investigate whether Cystatin C (CysC) and neutrophil gelatinase‐associated lipocalin (NGAL) can predict development of renal dysfunction (RD), hepatorenal syndrome (HRS), ACLF and mortality, respectively. Methods: We determined the plasma levels of CysC and NGAL of 429 patients hospitalized for acute decompensation of cirrhosis in the CANONIC study. The patients were followed for 90 days. Results: Patients without RD or ACLF at inclusion, but with development of either, had significantly higher baseline concentrations of CysC and NGAL compared to patients without. CysC, but not NGAL was found to be predictive of RD (OR 9.4 [1.8; 49.7]), HRS (OR 4.2 [1.2; 14.8]) and ACLF (OR 5.9 [1.3; 25.9]). CysC at day3 was not found to be a better predictor than baseline CysC. CysC and NGAL were both predictive of 90 days mortality with hazard ratios for CysC of 3.1 (2.1; 4.7), and for NGAL of 1.9 (1.5; 2.4), respectively. Conclusions: Baseline CysC is a biomarker of renal dysfunction, HRS and ACLF and an independent predictor of mortality in patients with acutely decompensated liver cirrhosis. Determining CysC at day 3 did not provide any benefit. While NGAL is also associated with short‐term mortality, it fails to predict development of RD, HRS and ACLF. Baseline CysC may add to identify patients at risk earlier and might improve clinical management. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 25 mai 2017
Agustín Albillos, Javier Zamora, Javier Martínez, David Arroyo, Irfan Ahmad, Joaquin De‐la‐Peña, Juan‐Carlos Garcia‐Pagán, GH Lo, Shiv Sarin, Barjesh Sharma, Juan Abraldes, Jaime Bosch, Guadalupe Garcia‐Tsao,
Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta‐analysis
Endoscopic variceal ligation plus beta‐blockers (EVL+BB) is currently recommended for variceal rebleeding prophylaxis, a recommendation that extends to all patients with cirrhosis with previous variceal bleeding irrespective of prognostic stage. Individualizing patient care is relevant and, in published studies on variceal rebleeding prophylaxis, there is a lack of information regarding response to therapy by prognostic stage. This study aimed at comparing EVL plus BB with monotherapy (EVL or BB) on all‐source rebleeding and mortality in patients with cirrhosis and previous variceal bleeding stratified by cirrhosis severity (Child A vs. B/C) by means of individual time‐to‐event patient data meta‐analysis (IPD) from randomized controlled trials. The study was IPD of 389 patients from 3 trials comparing EVL plus BB vs. BB and 416 patients from 4 trials comparing EVL plus BB vs. EVL. Compared with BB alone, EVL plus BB reduced overall rebleeding in Child A (incidence rate ratio 0.40; 95%CI 0.18‐0.89; p=0.025), but not in Child B/C, without differences in mortality. The effect of EVL on rebleeding was different according to Child (p for interaction <0.001). Conversely, compared with EVL, EVL plus BB reduced rebleeding in both Child A and B/C, with a significant reduction in mortality in Child B/C (incidence rate ratio 0.46; 95%CI 0.25‐0.85; p=0.013). Conclusion: Outcomes of therapies to prevent variceal rebleeding differ depending on cirrhosis severity. In patients with preserved liver function (Child A), combination therapy is recommended since it is more effective in preventing rebleeding, without modifying survival. In patients with advanced liver failure (Child B/C), EVL alone carries an increased risk of rebleeding and death as compared with combination therapy, underlining that BB is the key element of combination therapy. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mercredi 24 mai 2017
Zheng Wang, Jun Han, Han Zhang, Meng‐Chao Wu, Tian Yang
Emphasis on Harms of Hepatocellular Carcinoma Surveillance: Just Pretending Innocent After Taking Advantages?
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Date de mise en ligne : Mercredi 24 mai 2017
John Y. L. Chiang
Linking long non‐coding RNA to control bile acid signaling and cholestatic liver fibrosis
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Date de mise en ligne : Mercredi 24 mai 2017
Omair Atiq, Jasmin Tiro, Adam C. Yopp, Adam Muffler, Jorge A. Marrero, Neehar D. Parikh, Caitlin Murphy, Katharine McCallister, Amit G. Singal
HCC Surveillance: Striving for a Better Balance of Benefits and Harms
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Date de mise en ligne : Mercredi 24 mai 2017
Xue‐Jun Xu, Huai‐Zhi Wang, Ping Bie
Unscheduled Screening Tests Cannot Be Termed as Surveillance
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Date de mise en ligne : Mercredi 24 mai 2017
Kaku A. So‐Armah, Joseph K. Lim, Vincent Lo Re, Janet P. Tate, Chung‐Chou H. Chang, Adeel A. Butt, Cynthia L. Gibert, David Rimland, Vincent C. Marconi, Matthew B. Goetz, Maria C. Rodriguez‐Barradas, Michael E. DeBakey, Matthew J. Budoff, Hilary A. Tindle, Jeffrey H. Samet, Amy C. Justice, Matthew S. Freiberg,
FIB‐4 stage of liver fibrosis predicts incident heart failure among HIV infected and uninfected patients
Liver fibrosis is common, particularly in human immunodeficiency virus infected (HIV+) people. HIV+ people have excess congestive heart failure (CHF) risk compared to uninfected people. It remains unknown if stage of liver fibrosis influences the CHF risk or if HIV or hepatitis C virus (HCV) infection modifies this association. Our objectives were to assess whether: 1) stage of liver fibrosis is independently associated with incident CHF; 2) the association between stage of liver fibrosis and incident CHF is modified by HIV/HCV status. Participants alive on or after 4/1/2003 in the Veterans Aging Cohort Study were included. Those without prevalent cardiovascular disease (CVD) were followed until their first CHF event, death, last follow‐up date or 12/31/2011. Liver fibrosis was measured by FIB‐4, calculated using age, aminotransferases and platelets. Outcome: incident CHF (ICD‐9 codes). Cox proportional hazards regression models were adjusted for CVD risk factors. Among 96,373 participants over 6.9 years, 3,844 incident CHF events occurred. FIB‐4 between 1.45‐3.25 (moderate fibrosis) and FIB‐4>3.25 (advanced fibrosis/cirrhosis) were associated with CHF (HR (95% CI)=1.17 (1.07‐1.27); 1.65(1.43‐1.92)). The association of advanced fibrosis/cirrhosis and incident CHF persisted regardless of HIV/HCV status. Conclusions: Moderate and advanced liver fibrosis/cirrhosis are associated with an increased risk of CHF. The association for advanced fibrosis/cirrhosis persists even among participants without hepatitis C and/or HIV infection. Assessing liver health may be important for reducing the risk of future CHF events, particularly among HIV and hepatitis C infected people among whom CVD risk is elevated and liver disease is common. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mardi 23 mai 2017
Tatyana V Masyuk, Anatoliy I Masyuk, Maria Lorenzo Pisarello, Brynn N Howard, Bing Q Huang, Pui‐Yuen Lee, Xavier Fung, Eduard Sergienko, Robert J Ardesky, Thomas DY Chung, Anthony B Pinkerton, Nicholas F LaRusso
TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases via cAMP/Gαs signaling
Hepatic cystogenesis in Polycystic Liver Disease (PLD) is associated with increased levels of cAMP in cholangiocytes lining liver cysts. TGR5, a G protein‐coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with PLD. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to: (i) TGR5 agonists [taurolithocholic acid (TLCA), oleanolic acid (OA) and two synthetic compounds]; (ii) a novel TGR5 antagonist (SBI‐115); and (iii) a combination of SBI‐115 and pasireotide, a somatostatin receptor (SSTR) analog. In vivo, we examined hepatic cystogenesis in OA‐treated PCK rats and after genetic elimination of TGR5 in double mutant TGR5‐/‐;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq) proteins was increased 2‐3‐fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by shRNA. OA increased cystogenesis in PCK rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5‐deficient TGR5‐/‐;Pkhd1del2/del2 mice. TGR5 expression and its co‐localization with Gαs were increased ∼2‐fold upon OA treatment. Levels of cAMP, cell proliferation and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI‐115 alone and by ∼50% when SBI‐115 was combined with pasireotide. Conclusion: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation. Our data suggest that a TGR5 antagonist alone or concurrently with SSTR agonists represents novel therapeutic approaches in PLD. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mardi 23 mai 2017
Paul H. Hayashi, Don Rockey, Robert J. Fontana, Hans L. Tillmann, Neil Kaplowitz, Huiman Barnhart, Jiezhan Gu, Naga P. Chalasani, K. Rajender Reddy, Averell H. Sherker, Jay H. Hoofnagle,
Death and Liver Transplantation within Two Years of Onset of Drug‐Induced Liver Injury
Drug‐induced liver injury (DILI) is an important cause of death and indication for liver transplantation (fatality). The role of DILI in these fatalities ispoorly characterized particularly when fatalities occur > 26 weeks after DILI onset. We analyzed patients in the U.S. Drug‐Induced Liver Injury Network prospective study having a fatal outcome within 2 years of onset. Each case was reviewed by 8 Network investigators and categorized as DILI having a primary, contributory or no role in the fatality. We subcategorized primary role cases as acute, chronic, acute‐on‐chronic or acute cholestatic liver failure. For contributory and no role cases, we assigned a primary cause of death. Among 1089 patients, 107 (9.8%) fatalities occurred within 2 years. DILI had a primary role in 68 (64%), a contributory role in 15 (14%) and no role in 22 (21%); 2 had insufficient data. Among primary role cases, 74% had acute, 13% chronic, 7% acute‐on‐chronic and 6% acute cholestatic failure. For the 15 contributory role cases, common causes of death included sepsis, malignancy and severe cutaneous reactions with multi‐organ failure. For the 22 no role cases, malignancies accounted for most fatalities. Higher bilirubin, coagulopathy, leukocytosis and thrombocytopenia were independently associated with DILI fatalities. nR Hy's Law had a higher positive predictive value for overall fatality (14% vs. 10%) and stronger independent association with DILI fatalities within 26 weeks compared to the original version of Hy's Law (HR: 6.2, CI 3.4 – 11.1 vs. 2.2, CI 1.3‐3.7). DILI leads directly or indirectly to fatality in 7.6% of cases; 40% of these have non‐acute liver failure courses. nR Hy's Law better identifies risk for death compared to the original Hy's Law. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 22 mai 2017
Stefan Wirth, Philip Rosenthal, Regino P. Gonzalez‐Peralta, Maureen M. Jonas, William F. Balistreri, Chuan‐Hao Lin, Winita Hardikar, Kathryn Kersey, Benedetta Massetto, Bittoo Kanwar, Diana M. Brainard, Jiang Shao, Evguenia Svarovskaia, Brian Kirby, Ronen Arnon, Karen F. Murray, Kathleen B. Schwarz
Sofosbuvir and Ribavirin in Adolescents 12 to 17 Years Old With Hepatitis C Virus Genotype 2 or 3 Infection
Background & Aims. Children with chronic hepatitis C virus (HCV) infection have limited treatment options. We evaluated the all‐oral combination of sofosbuvir and ribavirin in adolescents aged 12‐17 with HCV genotype 2 or 3. Methods. Fifty‐two patients received sofosbuvir 400mg once daily and weight‐based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS‐331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled, and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). Results. The median age of patients was 15 years, and 75% had genotype 3. Eighty‐three percent of patients were treatment‐naïve, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% CI, 90%‐100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for genotype 3. The single patient who did not achieve SVR12 was lost to follow‐up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in Phase 2 and 3 sofosbuvir studies, the AUCtau and Cmax for sofosbuvir and GS‐331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%‐200%. Conclusion. Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic HCV genotype 2 or 3 infection. http://ClinicalTrials.gov NCT02175758. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 22 mai 2017
Emmanuel A. Tsochatzis, Jaime Bosch
Statins in cirrhosis – ready for prime time
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Date de mise en ligne : Lundi 22 mai 2017
Eon Jeong Nam, Kazutaka Hayashida, Rafael S. Aquino, John R. Couchman, Rosemary A. Kozar, Jian Liu, Pyong Woo Park
Syndecan‐1 Limits the Progression of Liver Injury and Promotes Liver Repair in Acetaminophen‐Induced Liver Injury
Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. While mechanisms that trigger APAP‐induced liver injury are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injury in vivo remains unknown. Here, we examined the role of syndecan‐1, the major cell surface HSPG of hepatocytes, in APAP‐induced liver injury. Ablation of syndecan‐1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times after APAP overdose were unaffected by syndecan‐1, suggesting that syndecan‐1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan‐1 null (Sdc1‐/‐) mice were traced to a deficiency in Akt activation in hepatocytes, which led to a delayed increase in GSK‐3β‐mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK‐3β and caspases protected mice from APAP‐induced liver injury. Moreover, administration of purified syndecan‐1, HS, or engineered heparan compounds containing 2‐O‐sulfate groups rescued Sdc1‐/‐ mice from APAP‐induced liver injury by potentiating Akt signaling and inhibiting GSK‐3β‐mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared to N‐acetylcysteine (NAC). Conclusion: These results demonstrate that 2‐O‐sulfated domains in syndecan‐1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in APAP‐induced liver injury. We propose that syndecan‐1 is a critical endogenous factor that controls the balance between pro‐survival signaling and apoptosis in hepatocytes in APAP liver disease. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Samedi 20 mai 2017
Vasantha L. Kolachala, Sirish Palle, Ming Shen, Alayna Feng, Dmitry Shayakhmetov, Nitika A. Gupta
Loss of L‐ Selectin Guided CD8+ but not CD4+ Cells, Protects Against Ischemia Reperfusion Injury in a Steatotic Liver
Background & Aims: Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic‐reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically non‐existent. The objective of the current study was to delineate contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. Methods: RNA sequencing was performed on isolated steatotic primary hepatocytes and T cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high fat diet (HFD) fed mice. CD8‐/‐ and CD4‐/‐ mice along with CD8 and L‐selectin antibody treated mice were fed on a HFD and hepatocellular injury was assessed by histology, propidium iodide injection and ALT after IRI. Results: RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes vs. lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8+ cells, ALT and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8+/CD62L+(L‐selectin) cells in HFD fed mice after IRI. CD8‐/‐ mice and CD8 depleted C57BL/6 mice, demonstrated significant protection from injury, which was not seen in CD4‐/‐ mice. L‐selectin blockade also demonstrated significant hepatoprotection from IRI. L selectin ligand MECA‐79 was increased in HFD fed mice undergoing IRI. Conclusion: Blockade of CD8 and L‐selectin but not CD4, ameliorated hepatocellular injury, confirming that CD8+ cells are critical drivers of injury in a steatotic liver. This represents a novel therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 18 mai 2017
Jörg‐Martin Bangen, Linda Hammerich, Roland Sonntag, Maike Baues, Ute Haas, Daniela Lambertz, Thomas Longerich, Twan Lammers, Frank Tacke, Christian Trautwein, Christian Liedtke
Targeting CCl4‐induced liver fibrosis by RNA interference ‐ mediated inhibition of Cyclin E1 in mice
Initiation and progression of liver fibrosis requires proliferation and activation of resting hepatic stellate cells (HSC). Cyclin E1 (CcnE1) is the regulatory subunit of the Cyclin‐dependent Kinase 2 (Cdk2) and controls cell cycle re‐entry. We have recently shown that genetic inactivation of CcnE1 prevents activation, proliferation and survival of HSC and protects from liver fibrogenesis. The aim of the present study was to translate these findings into pre‐clinical applications using an RNAi‐based approach. CcnE1‐siRNA efficiently inhibited CcnE1 gene expression in murine and human HSC cell lines and in primary HSCs resulting in diminished proliferation and increased cell death. In C57BL/6 wildtype (WT) mice, delivery of stabilized siRNA using a liposome‐based carrier targeted approximately 95% of HSC, 70% of hepatocytes, and 40% of CD45+ cells after single injection. Acute CCl4‐mediated liver injury in WT mice induced endogenous CcnE1 expression and proliferation of surviving hepatocytes and non‐parenchymal cells including CD45+ leukocytes. Pre‐treatment with CcnE1‐siRNA reverted CcnE1 induction to baseline levels of healthy mice, which was associated with reduced liver injury, diminished proliferation of hepatocytes, leukocytes and attenuated overall inflammatory response. For induction of liver fibrosis, WT mice were challenged with CCl4 for 4‐6 weeks. Co‐treatment with CcnE1‐siRNA once a week was sufficient to continuously block CcnE1 expression and cell cycle activity of hepatocytes and non‐parenchymal cells resulting in significantly ameliorated liver fibrosis and inflammation. Importantly, CcnE1‐siRNA also prevented progression of liver fibrosis if applied after onset of chronic liver injury. Conclusion: Therapeutic targeting of CcnE1 in vivo using RNAi is feasible and has high anti‐fibrotic activity. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 18 mai 2017
Petra Hirsova, Maria Eugenia Guicciardi, Gregory J. Gores
Proapoptotic Signaling Induced by RIPK1 and TRAF2 Deletion Results in Liver Carcinogenesis
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Date de mise en ligne : Jeudi 18 mai 2017
Dan Han, Jiangxue Li, Huamin Wang, Xiaoping Su, Jin Hou, Yan Gu, Cheng Qian, Yun Lin, Xiang Liu, Mingyan Huang, Nan Li, Weiping Zhou, Yizhi Yu, Xuetao Cao
Circular RNA MTO1 acts as the sponge of miR‐9 to suppress hepatocellular carcinoma progression
Non‐coding RNAs play important roles in cancer biology, providing potential targets for cancer intervention. As a new class of endogenous non‐coding RNAs, circular RNAs (circRNAs) have been recently identified in the development, cell function and certain types of pathological responses, generally acting as microRNA (miRNA) sponge to regulate gene expression. Identifying the deregulated circRNAs and their roles in cancer has attracted much attention. However, the expression profile and function of circRNAs in human hepatocellular carcinoma (HCC) remain to be investigated. Here, we analyzed the expression profile of human circRNAs in HCC tissues and identified circMTO1 (hsa_circRNA_0007874/hsa_circRNA_104135) as one circRNA significantly downregulated in HCC tissues. HCC patients with low circMTO1 expression had shortened survival. By using biotin‐labeled circMTO1 probe to perform RNA in vivo precipitation (RIP) in HCC cells, we identified miR‐9 as the circMTO1‐associated microRNA. Furthermore, silencing of circMTO1 in HCC could downregulate p21, the target of oncogenic miR‐9, resulting in the promotion of HCC cell proliferation and invasion. In addition, the tumor‐promoting effect of circMTO1 silencing was blocked by miR9 inhibitor. Intratumoral administration of cholesterol‐conjugated circMTO1 siRNA promoted HCC tumor growth in vivo. Conclusion: circMTO1 suppresses HCC progression by acting as the sponge of oncogenic miR‐9 to promote p21 expression, suggesting that circMTO1 is a potential target in HCC treatment. The decrease of circMTO1 in HCC tissues may serve as a prognosis predictor for poor survival of patients. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 18 mai 2017
Soumik BasuRay, Eriks Smagris, Jonathan C. Cohen, Helen H. Hobbs
The PNPLA3 Variant Associated with Fatty Liver Disease (I148M) Accumulates on Lipid Droplets by Evading Ubiquitylation
A sequence variation (I148M) in patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) is strongly associated with fatty liver disease (FLD), but the underlying mechanism remains obscure. Here we used knock‐in (KI) mice (Pnpla3148M/M) to examine the mechanism responsible for accumulation of triglyceride (TG) and PNPLA3 in hepatic lipid droplets (LDs). No differences were found between Pnpla3148M/M and Pnpla3+/+ mice in hepatic TG synthesis, utilization, or secretion. These results are consistent with TG accumulation in the Pnpla3148M/M mice being caused by impaired TG mobilization from LDs. Sucrose feeding, which is required to elicit fatty liver in KI mice, led to a much larger and more persistent increase in PNPLA3 protein in the KI than in the WT mice. Inhibition of the proteasome (bortezomib), but not macroautophagy (3‐methyladenine), markedly increased PNPLA3 levels in WT mice, coincident with the appearance of ubiquitylated forms of the protein. Bortezomib did not increase PNPLA3 levels in Pnpla3148M/M mice, and only trace amounts of ubiquitylated PNPLA3 were seen in these animals. Conclusion: These results are consistent with the notion that the 148M variant disrupts ubiquitylation and proteasomal degradation of PNPLA3, resulting in accumulation of PNPLA3‐148M and impaired mobilization of TG from LDs. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 18 mai 2017
Chun‐Seok Cho, David B. Lombard, Jun Hee Lee
SIRT3 as a Regulator of Hepatic Autophagy
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Date de mise en ligne : Jeudi 18 mai 2017
Kentaro Tominaga, Kenya Kamimura, Akira Sakamaki, Shuji Terai
Intraductal Papillary Neoplasm of the Bile Duct: A Rare Liver Tumor Complicated by Malignancy
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Date de mise en ligne : Jeudi 18 mai 2017
Iván Posso‐Osorio, Tatiana Méndez‐Rayo, Carlos Andrés Jiménez, Diana Escobar, Mauricio Sepúlveda, Erika Navarro, Gabriel J. Tobón
Hepatic infiltration by silicone in a patient with asia syndrome
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Date de mise en ligne : Jeudi 18 mai 2017
Mariya L. Samoylova, Mark J. Nigrini, Jennifer L. Dodge, John P. Roberts
Biases in the reporting of hcc tumor sizes on the liver transplant waiting list
We investigate the possibility that patients with hepatocellular carcinoma (HCC) listed for liver transplant with tumors just outside Stage T2 size criteria may be inaccurately reported as just meeting the tumor size criteria for transplant. The UNOS/STAR database identified 12,958 patients listed for liver transplants with HCC exception points from 2006‐2013, 9,168 of whom were listed with one tumor. A logistic power peak function was fitted to the single‐tumor size histogram, with the fitted values representing unbiased expected values. The difference between the observed and expected tumor counts for 2.0cm and 5.0cm was 238 (22%) and 66 (57%), respectively. This suggests that up to 304 (3.0%) patients with tumors outside of transplant criteria had their measurements recorded at the margins of eligibility. A risk‐adjusted Poisson model evaluated the ratio of observed to expected (O:E) HCC recurrence by tumor size. There were 435 HCC recurrences among 6,049 transplants. Only 2.0cm tumors had O:E recurrence differing from 1 (ratio 0.73, 95%CI 0.57‐0.94), indicating a 27% lower than expected rate of recurrence. Conclusion: Higher than expected observed tumor counts at the lower transplant criteria margin were corroborated by lower than expected HCC recurrence, suggesting that tumor sizes at the margins of HCC transplant criteria may be subject to inaccurate reporting. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 18 mai 2017
Tanja Cvitanović, Matthias C Reichert, Miha Moškon, Miha Mraz, Frank Lammert, Damjana Rozman
Large‐scale computational models of liver metabolism: How far from the clinics?
Understanding the dynamics of human liver metabolism is fundamental for effective diagnosis and treatment of liver diseases in general and the metabolism of drugs in particular. This knowledge can be obtained with systems biology/medicine approaches that account for the complexity of hepatic responses and their systemic consequences in other organs. Computational modelling can reveal hidden principles of the system by classification of individual components, analysing their interactions and simulating the effects that are difficult to investigate experimentally. Herein we review the state‐of‐the‐art computational models that describe liver dynamics from the metabolic, gene regulatory and signal transduction perspectives. We focus especially on large‐scale liver models described either by genome scale metabolic networks (GSMN) or object‐oriented approach. We also discuss the benefits and limitations of each modelling approach and their value for clinical applications in diagnosis, therapy and prevention of liver diseases as well as precision medicine in hepatology. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mardi 16 mai 2017
Hanna K. Sanoff, YunKyung Chang, Jennifer L. Lund, Bert H. O'Neil, Stacie B. Dusetzina
Letter to the Editor: Immortal Time Bias or Sorafenib Effect in Elderly Patients with HCC?
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Date de mise en ligne : Mardi 16 mai 2017
Alessandra Dellavance, Maria L. G. Ferraz, Eduardo L. R. Cançado, Luís E. C. Andrade
Letter to the Editor
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Date de mise en ligne : Mardi 16 mai 2017
Yan Wang, Arun J. Sanyal
Reply
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Date de mise en ligne : Mardi 16 mai 2017
Christophe Corpechot, Géraldine Dahlqvist, Olivier Chazouillères, Catherine Johanet
Reply to Dellavance et al. HEP‐17‐0499
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Date de mise en ligne : Mardi 16 mai 2017
Saeid Safiri, Erfan Ayubi
Dual photon microscopy based quantitation of fibrosis‐related parameters (q‐FP) to model disease progression in steatohepatitis: Methodological issues
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Date de mise en ligne : Mardi 16 mai 2017
Marie‐Annick Buendia, Carolina Armengol, Stefano Cairo
Molecular classification of hepatoblastoma and prognostic value of the HB 16‐gene signature
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Date de mise en ligne : Lundi 15 mai 2017
Grace L. Guo
Why are females more susceptible to cholestasis‐induced liver injury — Could it be LncRNA H19?
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Date de mise en ligne : Lundi 15 mai 2017
Quan‐Yu Zhang, Ling‐Ping Zhao, Xiao‐Xiang Tian, Cheng‐Hui Yan, Yang Li, Yan‐Xia Liu, Pi‐Xiao Wang, Xiao‐Jing Zhang, Ya‐Ling Han
The novel intracellular protein CREG inhibits hepatic steatosis, obesity and insulin resistance
Cellular repressor of E1A‐stimulated genes (CREG), a novel cellular glycoprotein, has been identified as a suppressor of various cardiovascular diseases (CVDs) because of its capacity to reduce hyperplasia, maintain vascular homeostasis, and promote endothelial restoration. However, the effects and mechanism of CREG in metabolic disorder and hepatic steatosis remain unknown. Here, we report that hepatocyte‐specific CREG deletion dramatically exacerbates high fat diet (HFD) and leptin deficiency‐induced (ob/ob) adverse effects such as obesity, hepatic steatosis and metabolic disorders, whereas a beneficial effect is conferred by CREG overexpression. Additional experiments demonstrated that JNK1 but not JNK2 is largely responsible for the protective effect of CREG on the above mentioned pathologies. Notably, JNK1 inhibition strongly prevents the adverse effects of CREG deletion on steatosis and related metabolic disorders. Mechanistically, CREG directly interacts with apoptosis signal‐regulating kinase1 (ASK1) and inhibits its phosphorylation, thereby blocking the downstream MKK4/7‐JNK1 signaling pathway and leading to significantly alleviated obesity, insulin resistance and hepatic steatosis. Importantly, dramatically reduced CREG expression and hyper‐activated JNK1 signaling was observed in the livers of NAFLD patients, thus suggesting that CREG might be a promising therapeutic target for NAFLD and related metabolic diseases. Conclusion: The results of our study provide the first evidence that CREG is a robust suppressor of hepatic steatosis and metabolic disorders through its direct interaction with ASK1 and the resultant inactivation of ASK1‐JNK1 signaling. This study offers new insights into NAFLD pathogenesis and its complicated pathologies, such as obesity and insulin resistance, and paves the way for disease treatment through targeting CREG. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 15 mai 2017
Varun Saxena, Vandana Khungar, Elizabeth C. Verna, Josh Levitsky, Robert S. Brown, Mohamed A. Hassan, Mark S. Sulkowski, Jacqueline G. O'Leary, Farrukh Koraishy, Joseph S. Galati, Alexander A. Kuo, Monika Vainorius, Lucy Akushevich, David R. Nelson, Michael W. Fried, Norah Terrault, K.Rajender Reddy
Safety and Efficacy of Current DAA Regimens in Kidney and Liver Transplant Recipients with Hepatitis C: Results from the HCV‐TARGET Study
Background: Data outside of clinical trials with direct acting antiviral (DAA) regimens with or without ribavirin as treatment of chronic HCV in solid organ transplant recipients is limited. Methods: Liver transplant (LT), kidney transplant (KT) and dual liver kidney (DLK) transplant recipients from the HCV‐TARGET database, a multicenter, longitudinal clinical care treatment cohort, treated with DAA regimens between January 1 2014 and February 15, 2016 were included to assess safety and efficacy. Results: 443 post‐transplant patients were included (KT=60, LT =347, DLK=36); 42% had cirrhosis, 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% G1a, 27% G1b, and 8% G1 no subtype) and were treated with sofosbuvir/ledipasvir (SOF/LDV) ± RBV (85%) followed by sofosbuvir + daclatasvir (SOF + DAC) ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir (PrOD) ± RBV (6%). SVR12 rates were available on 415 patients and 397 patients (95.7%) achieved SVR12: 96.3%, 94.6% and 90.9% among LT, KT and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher eGFR and lower creatinine. Female gender, baseline albumin ≥ 3.5 g/dL, baseline total bilirubin ≤ 1.2 mg/dL, the absence of cirrhosis and hepatic decompensation predicted SVR12. Six episodes of acute rejection (n=2 KT, 4 LT) occurred during HCV treatment in 4 and after cessation of treatment in 2. Conclusion: In a large prospective observational cohort study, DAA therapy with SOF/LDV, PrOD and SOF plus DAC was efficacious and safe in, LT, KT, and DLK transplant recipients. Ribavirin did not influence SVR. Graft rejection was rare. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Vendredi 12 mai 2017
Romain Désert, Florian Rohart, Frédéric Canal, Marie Sicard, Mireille Desille, Stéphanie Renaud, Bruno Turlin, Pascale Bellaud, Christine Perret, Bruno Clément, Kim‐Anh Lê Cao, Orlando Musso
Human Hepatocellular Carcinomas with a Periportal Phenotype Have the Lowest Potential for Early Recurrence after Curative Resection
Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve and on the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well‐differentiated, potentially low‐aggressiveness tumors form the heterogeneous molecular class of non‐proliferative HCCs, characterized by an approximate 50% β‐catenin (CTNNB1) mutation rate. To define the clinical, pathological, molecular features and the outcome of non‐proliferative HCCs, we constructed an 1133‐HCC transcriptomic metadata set and validated findings in a publically available 210‐HCC RNAseq set. We show that non‐proliferative HCCs preserve the zonation program that distributes metabolic functions along the porto‐central axis in normal liver. More precisely, we identified two well‐differentiated, non‐proliferation subclasses, namely Periportal‐type (wild‐type CTNNB1) and Perivenous‐type (mutant CTNNB1), which expressed negatively correlated gene networks. The new Periportal‐type subclass represented 29% of all HCCs; expressed an HNF4A‐driven gene network, which was down‐regulated in mouse Hnf4a‐KO mice; were early‐stage tumors by BCLC, CLIP and TNM staging systems; had no macrovascular invasion and showed the lowest metastasis‐specific gene expression levels and TP53 mutation rates. Also, we identified an 8‐gene Periportal‐type HCC signature, which was independently associated with the highest 2‐year recurrence‐free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well‐differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, Periportal‐type tumors have the lowest intrinsic potential for early recurrence after curative resection. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Vendredi 12 mai 2017
Davor Slijepcevic, Reinout L. P. Roscam Abbing, Takeshi Katafuchi, Antje Blank, Joanne M. Donkers, Stéphanie van Hoppe, Dirk. R. de Waart, Dagmar Tolenaars, Jonathan H.M. van der Meer, Manon Wildenberg, Ulrich Beuers, Ronald P.J. Oude Elferink, Alfred H. Schinkel, Stan F.J. van de Graaf
Hepatic uptake of conjugated bile acids is mediated by both NTCP and OATPs and modulated by intestinal sensing of plasma bile acid levels in mice
Background & Aims: The Na+‐taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Methods: Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild‐type, OATP knockout mice (lacking Slco1a/1b‐isoforms), and human OATP1B1‐transgenic mice. Effects of FGF19 on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or AAV‐mediated overexpression. Results: NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in wild‐type mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cyp7a1 expression was strongly downregulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte‐models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. Conclusions: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP‐mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Vendredi 12 mai 2017
Edward J. Gane, Mitchell L. Shiffman, Kyle Etzkorn, Giuseppe Morelli, Catherine Stedman, Mitchell N. Davis, Federico Hinestrosa, Hadas Dvory‐Sobol, K.C. Huang, Anu Osinusi, John McNally, Diana M. Brainard, John G. McHutchison, Alex J. Thompson, Mark S. Sulkowski,
Sofosbuvir‐velpatasvir with ribavirin for 24 weeks in HCV patients previously treated with a direct‐acting antiviral regimen
The optimal retreatment strategy for patients chronically infected with hepatitis C virus (HCV) who experience virologic failure after treatment with direct‐acting antiviral (DAA)‐based therapies remains unclear. In this multicenter, open‐label, phase 2 study, we evaluated the efficacy and safety of a fixed‐dose combination of sofosbuvir‐velpatasvir (400 mg/100 mg) plus weight‐adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response (SVR) after prior treatment with DAA regimens that included the nucleotide analogue NS5B inhibitor sofosbuvir plus the NS5A inhibitor velpatasvir with or without the NS3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving SVR at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval [CI], 82‐97%) patients achieved SVR12, including 36 of 37 (97%; 95% CI, 86‐100%) patients with HCV genotype 1 infection, 13 of 14 (93%; 95% CI, 66‐100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% CI, 52‐94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all treatment due to an adverse event (irritability). Conclusion: Retreatment of patients who previously failed DAA‐based therapies with sofosbuvir‐velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with HCV genotype 1 or 2 infection. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Jeudi 11 mai 2017
Jeffrey B. Schwimmer, Cynthia Behling, Jorge Eduardo Angeles, Melissa Paiz, Janis Durelle, Jonathan Africa, Kimberly P. Newton, Elizabeth M. Brunt, Joel E. Lavine, Stephanie H. Abrams, Prakash Masand, Rajesh Krishnamurthy, Kelvin Wong, Richard L. Ehman, Meng Yin, Kevin J. Glaser, Bogdan Dzyubak, Tanya Wolfson, Anthony C. Gamst, Jonathan Hooker, William Haufe, Alexandra Schlein, Gavin Hamilton, Michael S. Middleton, Claude B. Sirlin
Magnetic Resonance Elastography Measured Shear Stiffness as a Biomarker of Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease
Magnetic Resonance Elastography (MRE) is promising for non‐invasive assessment of fibrosis, a major determinant of outcome in nonalcoholic fatty liver disease (NAFLD). However, data in children are limited. Study aims were to determine accuracy of MRE for detection of fibrosis and advanced fibrosis in children with NAFLD, and to assess agreement between manual and novel automated reading methods. We performed a prospective, multi‐center study of 2D‐MRE in children with NAFLD. MR‐elastograms were analyzed manually at 2 reading centers and using a new automated technique. Analysis using each approach was done independently. Correlations were determined between MRE analysis methods and fibrosis stage. Thresholds for classifying the presence of fibrosis and of advanced fibrosis were computed and cross‐validated. In 90 children with mean age of 13.1 ± 2.4 years, median hepatic stiffness was 2.35 kPa. Stiffness values derived by each reading center were strongly correlated with each other (r=0.83). All three analyses were significantly correlated with fibrosis stage (center 1, ρ=0.53; center 2, ρ=0.55; and automated analysis, ρ=0.52; p<0.001). Overall cross‐validated accuracy for detecting any fibrosis was the same for all methods: 72.2% (61.8 – 81.1). Overall cross‐validated accuracy for assessing advanced fibrosis varied by method: 88.9% (80.5% ‐ 94.5%) for center 1, 90.0% (81.9% – 95.3%) for center 2, and 86.7% (77.9 – 92.9) for automated analysis. Conclusions: 2D‐MRE can estimate hepatic stiffness in children with NAFLD. Further refinement and validation of automated analysis techniques will be an important step in standardizing MRE. How to best integrate MRE into clinical protocols for the assessment of NAFLD in children will need prospective evaluation. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 08 mai 2017
Chia‐Chi Wang, Jia‐Horng Kao
Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: A cohort study
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Date de mise en ligne : Lundi 08 mai 2017
Eun‐Jeong Joo, Yoosoo Chang, Seungho Ryu
Metabolic parameters and the development of non‐alcoholic fatty liver disease according to HBsAg seropositivity
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Date de mise en ligne : Mercredi 03 mai 2017
Neehar D. Parikh, Amit G. Singal, Anna S Lok, Rajesh Balkrishnan, Vahakn Shahinian, Vincent D Marshall
Author Reply
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Date de mise en ligne : Mercredi 03 mai 2017
Laurent Mailly, Mirjam B. Zeisel, Thomas F. Baumert
Towards novel immunocompetent animal models for hepatitis B virus infection
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Date de mise en ligne : Mercredi 03 mai 2017
Varun Takyar, Anand Nath, Andrea Beri, Ahmed M. Gharib, Yaron Rotman
How healthy are the “healthy volunteers”? Penetrance of NAFLD in the biomedical research volunteer pool
Introduction: Healthy volunteers are crucial for biomedical research. Inadvertent inclusion of subjects with non‐alcoholic fatty liver disease (NAFLD) as controls can compromise study validity and subject safety. Given the rising prevalence of NAFLD in the general population, we sought to identify its prevalence and potential impact in volunteers for clinical trials. Methods: Cross‐sectional study of subjects with “Healthy Volunteer” diagnosis between 2011‐2015 and no known liver disease. Subjects were defined presumed NAFLD (pNF, ALT≥20 for women or ≥31 for men and BMI>25), healthy non‐NAFLD controls (HC, normal ALT and BMI), or indeterminate. Results: 3160 subjects participated as healthy volunteers in 149 clinical trials, (1‐29 trials per subject). 1732 (55%) had BMI > 25 kg/m2 and 1382 (44%) had abnormal ALT. pNF was present in 881 subjects (27.9%) and these subjects were older than HC, and had higher triglycerides, LDL‐C, and HbA1c and lower HDL‐C (p<0.001 for all) . The 149 trials included 101 non‐interventional, 33 interventional and 15 vaccine trials. The impact on study validity of recruiting NAFLD subjects as controls was estimated as likely, probable and unlikely in 10, 41 and 98 trials, respectively. The proportion of pNF subjects (28‐29%) did not differ by impact. Only 14% of trials used both BMI and ALT for screening. ALT cut‐offs for screening were based on local reference values. Grade 3‐4 ALT elevations during the study period were rare but more common in pNF subjects than HC (4 vs. 1). Conclusion: NAFLD is common and often overlooked in volunteers for clinical trials, despite its potential impact on subject safety and validity of study findings. Increased awareness of NAFLD prevalence and stricter ALT cut‐offs may ameliorate this problem. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mercredi 03 mai 2017
Kathryn Stiede, Wenyan Miao, Heather S. Blanchette, Carine Beysen, Geraldine Harriman, H. James Harwood Jr, Heather Kelley, Rosana Kapeller, Tess Schmalbach, William F. Westlin
Acetyl‐CoA carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double‐blind, crossover study
NDI‐010976, an allosteric inhibitor of acetyl‐CoA carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double‐blind, placebo‐controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI‐010976 on hepatic DNL in overweight and/or obese, but otherwise healthy, adult male subjects. Subjects were randomized to receive either NDI‐010976 (20, 50, or 200 mg) or matching placebo in Period 1, followed by the alternate treatment in Period 2, and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1‐13C]acetate, and monitoring 13C incorporation into palmitate of circulating very low‐density lipoprotein triglyceride. Single dose administration of NDI‐010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10 hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± SD) above fasting DNL values in placebo‐treated subjects. Subjects administered single doses of NDI‐010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI‐010976 exposure was observed with greater than 90% inhibition of fractional DNL associated with plasma concentrations of NDI‐010976 greater than 4 ng/mL. Conclusions: ACC inhibition with a single dose of NDI‐010976 is well tolerated and results in a profound dose‐dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI‐010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mercredi 03 mai 2017
Toshihiro Tanaka, Weici Zhang, Ying Sun, Zongwen Shuai, Asiya Chida, Thomas P. Kenny, Guo‐Xiang Yang, Ignacio Sanz, Aftab Ansai, Christopher L. Bowlus, Gregory C. Ippolito, Ross L. Coppel, Kazuichi Okazaki, Xiao‐Song He, Patrick S.C. Leung, M. Eric Gershwin
Autoreactive Monoclonal Antibodies from Patients with Primary Biliary Cholangitis Recognize Environmental Xenobiotics
A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multi‐lineage immune responses to mitochondrial self‐antigens in primary biliary cholangitis (PBC), the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC‐E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti‐PDC‐E2 autoantibodies cross‐react with the chemical xenobiotics 2‐octynoic acid (2‐OA) and 6,8‐bis (acetylthio) octanoic acid (SAc) and further that there is a high frequency of PDC‐E2 specific peripheral plasmablasts. Herein we generated 104 recombinant mAbs based on paired heavy‐ and light‐chain variable regions of individual plasmablasts derived from PBC patients. We identified 32 mAbs reactive with native PDC‐E2, including 20 specific for PDC‐E2 and 12 cross‐reactive with both PDC‐E2 and 2‐OA and SAc. A lower frequency of replacement somatic hypermutations, indicating lower level of affinity maturation, was observed in the complementarity‐determining regions (CDR) of the cross‐reactive mAbs in comparison to mAbs exclusively recognizing PDC‐E2 or those for irrelevant antigens. In particular, when the highly mutated heavy chain gene of a cross‐reactive mAb was reverted to the germline sequence, the PDC‐E2 reactivity was reduced dramatically whereas the xenobiotics reactivity was retained. Importantly, cross‐reactive mAbs also recognized lipoic acid (LA), a mitochondrial fatty acid that is covalently bound to PDC‐E2. Our data reflect that chemically modified LA or LA itself, via molecular mimicry, is the initial target that leads to the development of PBC. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mercredi 03 mai 2017
Enpeng Zhao, Ghulam Ilyas, Francesca Cingolani, Jae Ho Choi, François Ravenelle, Kathryn E. Tanaka, Mark J. Czaja
Pentamidine Blocks Hepatotoxic Injury in Mice
Toxin‐induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti‐inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the D‐galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase‐mediated deoxyuridine triphosphate nick end‐labeling (TUNEL)‐positive cells and mortality as compared to vehicle‐injected controls. VLX103 decreased GalN/LPS induction of TNF but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS‐treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7 which resulted from reduced c‐Jun N‐terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 h after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol‐induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL‐positive cells. Conclusion: VLX103 effectively decreases toxin‐induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mardi 02 mai 2017
Steven P. O'Hara, Nicholas F. LaRusso
Cellular Senescence, Neuropeptides and Hepatic Fibrosis: Additional Insights into Increasing Complexity
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Date de mise en ligne : Mardi 02 mai 2017
Wei Li, Tohti Amet, Yanyan Xing, Dennis Yang, Suthat Liangpunsakul, Puneet Puri, Patrick Kamath, Arun Sanyal, Vijay Shah, Barry Katz, Svetlana Radaeva, David Crabb, Naga Chalasani, Qigui Yu
Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study
Alcoholic hepatitis (AH) develops only in small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty‐eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls (HC) were enrolled and followed up to 12 months. At the baseline, HDC and HC had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (TNF‐α, IL‐6, IL‐8, IP10, IL‐4, IL‐9, IL‐10, FGF‐2, IL‐7, IL‐15, and TGF‐α), but lower levels of the anti‐inflammatory macrophage‐derived chemokine (MDC). AH patients also had more activated, yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of CD38 and CD69, but low levels of HLA‐DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less IFN‐γ in response to T cell stimulation. Upregulated IL‐6, IL‐8, CD38, and CD69 and downregulated MDC, HLA‐DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL‐6, IL‐8, CD38, and CD69 were reduced, whereas levels of MDC, HLA‐DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of TNF‐α, IL‐8, IL‐10, FGF‐2, and IL‐7 remained higher. Conclusion: AH patients were in a highly immune‐dysregulated state, whereas HDC showed little evidence of immune activation. Alcohol abstinence reversed most, but not all, of the immunological abnormalities. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Samedi 29 avril 2017
Alexandre Louvet, Julien Labreuche, Florent Artru, Alexis Bouthors, Benjamin Rolland, Pierre Saffers, Julien Lollivier, Elise Lemaître, Sébastien Dharancy, Guillaume Lassailly, Valérie Canva‐Delcambre, Alain Duhamel, Philippe Mathurin
Main drivers of outcome differ between short and long‐term in severe alcoholic hepatitis: A prospective study
Understanding the mechanisms of outcome according to the time frame can help optimize the therapeutic development in severe alcoholic hepatitis (AH). Objective: to assess short‐term and long‐term survival in severe AH based on baseline disease severity, extent of therapeutic improvement, long‐term influence of alcohol relapse and their interaction. Design: Data and alcohol consumption were prospectively recorded in 398 patients treated with corticosteroids at short (from corticosteroid initiation to 6 months) and long term (from 6 months to maximum follow‐up time). Results: Cumulative incidence rate of first alcohol relapse was 25.2%, 33.7% and 35.2% at 1, 3 and 5 years, respectively. Alcohol relapse (≥30g/day) was not associated with mortality (p=0.24) during the short‐term period (1606 patients‐months at risk) but the Lille (p<0.0001) and MELD (p<0.0001) scores were independent prognostic factors. In patients who were alive at 6 months (median follow‐up: 42 months, IQR11‐88), corresponding to 10413 patients‐months at risk, alcohol consumption (≥30g/day) was associated with mortality (HR 3.9, p<0.0001). Additional analysis with abstinent patients as a reference showed a dose effect of alcohol on the HR of death: 2.36 (p=0.052) for 1‐29g/day, 3.2 (p=0.003) for 30‐49g/day, 3.51 (p<0.0001) for 50‐99g/day and 5.61 (p<0.0001) for ≥100g/day. The baseline MELD score was not predictive of long‐term outcome while Lille score (p=0.02) and alcohol relapse (p<0.0001) were independent prognostic factors. Conclusion: This study shows that new therapeutic development for severe AH must target liver injury for short term and alcohol consumption for long term. Thus, health agencies can endorse future study design adapted to the time‐frame of factors influencing mortality. With this in mind, drugs targeting mechanisms involved in liver injury should only be tested for the short‐term period. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mercredi 26 avril 2017
Yingjie Bian, Zheng Zhang, Zhichen Sun, Juanjuan Zhao, Danming Zhu, Yang Wang, Sherry Fu, Jingya Guo, Longchao Liu, Lishan Su, Fu‐sheng Wang, Yang‐Xin Fu, Hua Peng
Vaccines Targeting PreS1 Domain Overcome Immune Tolerance in HBV Carrier Mice
Strong tolerance to HBV surface antigens limits the therapeutic effect of the conventional HBsAg vaccination in both preclinical animal models and patients with chronic hepatitis B (CHB) infection. In contrast, we observed that clinical CHB patients presented less immune tolerance to the preS1 domain of HBV large surface antigen. To study whether targeting the weak tolerance of preS1 region could improve therapy gain, we explored vaccination with the long peptide of preS1 domain for HBV virions clearance. Our study showed that this preS1‐polypeptide rather than HBsAg vaccination induced robust immune responses in the HBV carrier mice. The anti‐preS1 rapidly cleared HBV virions in vivo and blocked HBV infection to hepatocytes in vitro. Intriguingly, vaccination of preS1‐polypeptide even reduced the tolerized status of HBsAg, opening a therapeutic window for the host to respond to the HBsAg vaccine. A sequential administration of antigenically distinct preS1‐polypeptide and HBsAg vaccines in HBV carrier mice could finally induce HBsAg‐HBsAb serological conversion and clear chronic HBV infection in the carrier mice. These results suggest that preS1 can function as a therapeutic vaccination for the control of CHB. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mercredi 26 avril 2017
Ahmed M. Diab, Adrien Foca, Floriane Fusil, Thomas Lahlali, Pascal Jalaguier, Fouzia Amirache, Lia N'Guyen, Nathalie Isorce, François‐Loïc Cosset, Fabien Zoulim, Ourania M Andrisani, David Durantel
Polo‐like‐kinase 1 is a proviral host‐factor for hepatitis B virus replication
Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for CHB and HCC are perfectible. 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 (PHH) and differentiated HepaRG cells, in conjunction with pharmacologic PLK1 inhibitors, siRNA‐mediated knockdown, and overexpression of constitutively active PLK1 (PLK1CA). In addition, humanized liver FRG mouse model was used to determine antiviral effect of PLK1 inhibitor BI‐2536 on HBV infection in vivo. Lastly, in vitro PLK1 kinase assays and site‐directed mutagenesis were employed to demonstrate HBV core protein (HBc) is a PLK1 substrate. We demonstrate HBV infection activated cellular PLK1 in PHH and dHepaRG cells. PLK1 inhibition by BI‐2536 or siRNA‐mediated knockdown suppressed, whereas overexpression of PLK1CA increased HBV DNA biosynthesis, supporting PLK1 effects on viral biosynthesis are specific, and PLK1 is a proviral cellular factor. Significantly, BI‐2536 administration to HBV‐infected humanized liver FRG mice strongly inhibited HBV infection, validating PLK1 as a novel 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. PLK1 is a proviral host factor that could be envisaged as a target for combined antiviral and anti‐tumoral strategies against HBV infection and HBV mediated carcinogenesis. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mardi 25 avril 2017
Jae‐Kyung Won, Su Jong Yu, Chae Young Hwang, Sung‐Hwan Cho, Sang‐Min Park, Kwangsoo Kim, Won‐Mook Choi, Hyeki Cho, Eun Ju Cho, Jeong‐Hoon Lee, Kyung Bun Lee, Yoon Jun Kim, Kyung‐Suk Suh, Ja‐June Jang, Chung Yong Kim, Jung‐Hwan Yoon, Kwang‐Hyun Cho
Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on patho‐genetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we employed a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis (GSEA) revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum (ER) stress network model combined with in vitro experiments showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low PDI expression group. Conclusion: These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Mardi 25 avril 2017
Xiaobin Zheng, Fen Xu, Hua Liang, Huanyi Cao, Mengyin Cai, Wen Xu, Jianping Weng
SIRT1/HSF1/HSPs Pathway is Essential for Exenatide‐alleviated Lipid‐induced Hepatic Endoplasmic Reticulum Stress
Recent studies have indicated lipid‐induced endoplasmic reticulum (ER) stress to be a major contributor to the progression of hepatic steatosis. Exenatide (Exendin‐4), a glucagon‐like peptide‐1 receptor agonist, is known to improve hepatic steatosis with accumulating evidence. In this study, we investigated whether exenatide could alleviate lipid‐induced hepatic ER stress through mammal sirtuin1 (SIRT1) and illustrated the detailed mechanisms. Male C57BL/6J mice challenged with a high‐fat diet (HFD) were then treated with exenatide or normal saline by intraperitoneal injection for 4 weeks. We observed that HFD feeding obviously induced hepatic ER stress as indicated by increased expression of glucose‐regulated protein 78, phosphorylated protein kinase‐like ER kinase and phosphorylated eukaryotic initiation factor 2α, while these increases were significantly inhibited by exenatide. Exenatide notably decreased the liver weight and hepatic steatosis induced by HFD challenge. Consistently, in human HepG2 cells and primary murine hepatocytes, exendin‐4 also significantly alleviated the ER stress and lipid accumulation induced by palmitate. Importantly, further studies showed exendin‐4 enhanced the binding of heat shock factor 1 (HSF1) to the promoter of heat shock protein (HSP) genes through SIRT1‐mediated deacetylation, which then increased the expression of molecular chaperones HSP70 and HSP40 to alleviate hepatic ER stress. Finally, inhibition of SIRT1 by genetically whole‐body heterozygous knockout or by lentiviral shRNA knockdown greatly diminished the effect of exenatide on deacetylating HSF1, increasing HSPs expression, and alleviating ER stress and hepatic steatosis in HFD‐fed mice. Conclusion: SIRT1/HSF1/HSPs pathway is essential for exenatide‐alleviated lipid‐induced ER stress and hepatic steatosis, which provides novel evidence for a molecular mechanism to support exenatide and incretin mimetics as promising therapeutics for obesity‐induced hepatic steatosis. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 24 avril 2017
Tatehiro Kagawa, Yukihiko Adachi
Reply (to LTE 17‐0412)
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Date de mise en ligne : Lundi 24 avril 2017
Nunzia Pastore, Sergio Attanasio, Nicola Brunetti‐Pierri
Reply Letter
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Date de mise en ligne : Lundi 24 avril 2017
Takashi Kokudo, Kiyoshi Hasegawa, Norihiro Kokudo
Assessment of preoperative liver function based on indocyanine green clearance
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Date de mise en ligne : Lundi 24 avril 2017
Antonio Ponzetto, Guillermo I Perez‐Perez, Natale Figura
Alpha1‐antitrypsin deficiency and c‐JUN
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Date de mise en ligne : Lundi 24 avril 2017
Ekaterina Kachaylo, Christoph Tschuor, Nicolas Calo, Nathalie Borgeaud, Perparim Limani, Anne‐Christine Piguet, Jean‐Francois Dufour, Michelangelo Foti, Rolf Graf, Pierre A. Clavien, Bostjan Humar
PTEN downregulation promotes β‐oxidation to fuel hypertrophic liver growth after hepatectomy in mice
In regenerating liver, hepatocytes accumulate lipids before the major wave of parenchymal growth. This transient, regeneration‐associated steatosis (TRAS) is required for liver recovery, but its purpose is unclear. The tumor suppressor PTEN is a key inhibitor of the AKT‐mTOR axis that regulates growth and metabolic adaptations after hepatectomy. In quiescent liver, PTEN causes pathological steatosis when lost, while its role in regenerating liver remains unknown. Here, we show that PTEN downregulation promotes liver growth in a TRAS‐dependent way. In wild type mice, PTEN reduction occurred after TRAS formation, persisted during its disappearance, and correlated with upregulated β‐oxidation at the expense of lipogenesis. Pharmacological modulation revealed an association of PTEN with TRAS turnover and hypertrophic liver growth. In liver‐specific Pten‐/‐ mice shortly after induction of knockout, hypertrophic regeneration was accelerated and led to hepatomegaly. The resulting surplus liver mass was functional, as demonstrated by raised survival in a lethal model of resection‐induced liver failure. Indirect calorimetry revealed lipid oxidation as the primary energy source early after hepatectomy. The shift from glucose to lipid usage was pronounced in Pten‐/‐ mice and correlated with the disappearance of TRAS. Partial inhibition of β‐oxidation led to persisting TRAS in Pten‐/‐ mice and abrogated hypertrophic liver growth. PTEN downregulation may promote β‐oxidation via β‐catenin, while hypertrophy was dependent on mTORC1. Conclusion: PTEN downregulation after hepatectomy promotes the burning of TRAS‐derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands, and emphasize the need of lipids for regeneration. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 24 avril 2017
Albert D. Min
Low‐level viremia in hepatitis B patients on antiviral treatment: Can we ignore it?
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Date de mise en ligne : Lundi 24 avril 2017
Songtao Li, Xiaobing Dou, Hua Ning, Qing Song, Wei Wei, Ximei Zhang, Chen Shen, Jiaxin Li, Changhao Sun, Zhenyuan Song
SIRT3 Acts As a Negative Regulator of Autophagy Dictating Hepatocyte Susceptibility to Lipotoxicity
Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD); however, the exact mechanism(s) remain to be fully elucidated. SIRT3 is an NAD+‐dependent deacetylase primarily located inside mitochondria. In this study, we demonstrated that a SFAs‐rich high‐fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated FAs‐rich HFD. Unexpectedly, SIRT3 expression/activity were significantly elevated in the livers of mice exposed to the SFAs‐rich HFD. Using cultured HepG2 and AML‐12 hepatocytes, we demonstrated that unlike monounsaturated FAs, SFAs upregulates SIRT3 expression/activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate‐induced cell death, which can be alleviated by SIRT3 siRNA transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, whereby enhancing the susceptibility of hepatocytes to SFAs‐induced cytotoxicity. Mechanistic investigations elucidate that SIRT3 overexpression causes manganese superoxide dismutase (MnSOD) deacetylation/activation, which depleted intracellular superoxide contents, leading to AMP‐activated protein kinase (AMPK) inhibition and mTORC1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhances autophagy flux. The similar result was observed in the liver tissue from SIRT3 knockout mice. Conclusion: our data identified SIRT3 to be a novel negative regulator of autophagy, whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. This article is protected by copyright. All rights reserved.

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Date de mise en ligne : Lundi 29 mai 2017
Marianna Hösel, Anke Huber, Susanne Bohlen, Julie Lucifora, Giuseppe Ronzitti, Francesco Puzzo, Florence Boisgerault, Ulrich T. Hacker, Wilhelmus J. Kwanten, Nora Klöting, Matthias Blüher, Alexander Gluschko, Michael Schramm, Olaf Utermöhlen, Wilhelm Bloch, Federico Mingozzi, Oleg Krut, Hildegard Büning
Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors
Use of adeno‐associated viral (AAV) vectors for liver‐directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)–dependent autophagy in human hepatocytes. This cell response was critically required for efficient transduction because under conditions of impaired autophagy (pharmacological inhibition, small interfering RNA knockdown of autophagic proteins, or suppression by food intake), recombinant AAV‐mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependence, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter, or AAV serotype and was subsequently confirmed in vivo. Specifically, short‐term treatment with a single dose of torin 1 significantly increased vector‐mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, coadministration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid‐α‐glucosidase in nonhuman primates. Conclusion: We identified autophagy as a pivotal cell response determining the efficiency of AAVs intracellular processing in hepatocytes and thus the outcome of liver‐directed gene therapy using AAV vectors and showed in a proof‐of‐principle study how this virus–host interaction can be employed to enhance efficacy of this vector system. (Hepatology 2017)

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Date de mise en ligne : Samedi 27 mai 2017
Bing‐liang Lin, Jun‐feng Chen, Wei‐hong Qiu, Ke‐wei Wang, Dong‐ying Xie, Xiao‐yong Chen, Qiu‐li Liu, Liang Peng, Jian‐guo Li, Yong‐yu Mei, Wei‐zhen Weng, Yan‐wen Peng, Hui‐juan Cao, Jun‐qiang Xie, Shi‐bin Xie, Andy Peng Xiang, Zhi‐liang Gao
Allogeneic bone marrow–derived mesenchymal stromal cells for hepatitis B virus–related acute‐on‐chronic liver failure: A randomized controlled trial
Mortality from hepatitis B virus (HBV)–related acute‐on‐chronic liver failure (ACLF) is high due to limited treatment options. Preclinical and clinical investigations have proved that treatment with mesenchymal stromal cells (MSCs) is beneficial for recovery from liver injury. We hypothesized that the outcome of HBV‐related ACLF would be improved by MSC treatment. From 2010 to 2013, 110 patients with HBV‐related ACLF were enrolled in this open‐label, nonblinded randomized controlled study. The control group (n = 54) was treated with standard medical therapy (SMT) only. The experimental group (n = 56) was infused weekly for 4 weeks with 1.0 to 10 × 105 cells/kg allogeneic bone marrow–derived MSCs and then followed for 24 weeks. The cumulated survival rate of the MSC group was 73.2% (95% confidence interval 61.6%‐84.8%) versus 55.6% (95% confidence interval 42.3%‐68.9%) for the SMT group (P = 0.03). There were no infusion‐related side effects, but fever was more frequent in MSC compared to SMT patients during weeks 5‐24 of follow‐up. No carcinoma occurred in any trial patient in either group. Compared with the control group, allogeneic bone marrow–derived MSC treatment markedly improved clinical laboratory measurements, including serum total bilirubin and Model for End‐Stage Liver Disease scores. The incidence of severe infection in the MSC group was much lower than that in the SMT group (16.1% versus 33.3%, P = 0.04). Mortality from multiple organ failure and severe infection was higher in the SMT group than in the MSC group (37.0% versus 17.9%, P = 0.02). Conclusion: Peripheral infusion of allogeneic bone marrow–derived MSCs is safe and convenient for patients with HBV‐related ACLF and significantly increases the 24‐week survival rate by improving liver function and decreasing the incidence of severe infections. (Hepatology 2017).

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Date de mise en ligne : Samedi 27 mai 2017
Guofeng Chen, Cheng Wang, Jing Chen, Dong Ji, Yudong Wang, Vanessa Wu, Johan Karlberg, George Lau
Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: A systematic review and meta‐analysis
There is an increased awareness of hepatitis B (HBV) reactivation in chronic hepatitis C (CHC) patients coinfected with HBV treated with pan‐oral direct‐acting antiviral agents (DAAs). We performed a systematic review and meta‐analysis to compare the rate of HBV reactivation in CHC patients coinfected with overt HBV (hepatitis B surface antigen [HBsAg] positive) and occult HBV (HBsAg negative with positive HBV DNA) infection separately, treated with interferon (IFN)‐based therapy to those with pan‐oral DAAs. The primary outcome was HBV reactivation, and the secondary outcomes included hepatitis due to HBV reactivation, sustained virologic response (SVR) for CHC, loss of HBV DNA and HBsAg seroclearance. Although the pooled incidence rate of HBV reactivation, among CHC patients with overt HBV (n = 779), was similar among those treated with IFN‐based therapy (14.5%, P < 0.001) and DAAs (12.2%, P = 0.03; P = 0.91 for heterogeneity between subgroups), it was reported to occur much earlier in those treated with DAAs (4‐12 weeks during treatment) than in those treated with IFN‐based therapies (most at the end of treatment and some during follow‐up). Also, studies with DAA‐based therapies were more likely to report incidence of hepatitis due to HBV reactivation (12.2% in DAAs vs. 0% in IFN; P = 0.009 for heterogeneity between subgroups). HBV reactivation and hepatitis due to HBV reactivation also occurred, though less frequently in CHC patients with occult HBV infection. CHC SVR was not affected by HBV reactivation (P = 0.27). Conclusion: HBV reactivation occurs earlier and is clinically more significant in CHC patients coinfected with overt and occult HBV who are treated with pan‐oral DAAs compared with IFN‐based therapy. It is therefore important to have all patients screened for evidence of overt or occult HBV infection and managed during pan‐oral DAAs therapy. (Hepatology 2017).

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Date de mise en ligne : Samedi 27 mai 2017
Chibuzo Iloabuchi, Amanda Stover, Pragya Rai, Yifan Zhang, Khalid M. Kamal
Letter to the Editor, Re: Cadier et al. (2017)
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Date de mise en ligne : Samedi 27 mai 2017
Kyle S. McCommis, Jerry R. Colca, Brian N. Finck
Reply
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Date de mise en ligne : Samedi 27 mai 2017
Terry Cheuk‐Fung Yip, Vincent Wai‐Sun Wong
How to identify patients with advanced liver disease in the community?
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Date de mise en ligne : Samedi 27 mai 2017
Pramod Kumar, Sunil Taneja, Virendra Singh
Does the dose and type of nonselective beta‐blocker really matter?
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Date de mise en ligne : Samedi 27 mai 2017
Pasquale Piccolo, Patrizia Annunziata, Leandro R. Soria, Sergio Attanasio, Anna Barbato, Raffaele Castello, Annamaria Carissimo, Luca Quagliata, Luigi M. Terracciano, Nicola Brunetti‐Pierri
Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin
α1‐Antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of AAT (ATZ) is a prototype of conformational disorder due to protein misfolding with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing human ATZ have altered expression of a network of hepatocyte transcriptional factors, including hepatocyte nuclear factor‐4α, that is early down‐regulated and induces a transcriptional repression of ATZ expression. Reduced hepatocyte nuclear factor‐4α was associated with activation of β‐catenin, which regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Down‐regulation of hepatocyte nuclear factor‐4α expression and defective zonation in livers have not been recognized so far as features of the liver disease caused by ATZ and are likely involved in metabolic disturbances and in the increased risk of hepatocellular carcinoma in patients with AAT deficiency. Conclusion: The findings of this study are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effects on metabolic liver functions. (Hepatology 2017)

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Date de mise en ligne : Samedi 27 mai 2017
Alain Braillon
Screening for hepatocellular carcinoma: A drug safety issue
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Date de mise en ligne : Samedi 27 mai 2017
Lucy Golden‐Mason, Hugo R. Rosen
Galectin‐9: Diverse roles in hepatic immune homeostasis and inflammation
Glycan‐binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin‐9 (Gal‐9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal‐9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal‐9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal‐9 is involved indirectly in the expansion of protective natural killer T‐cell populations. In ischemic liver injury, hepatocyte‐derived Gal‐9 is both diagnostic and cytoprotective. In drug‐induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal‐9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune‐mediated diseases and to develop new therapeutic interventions using glycan‐binding proteins. (Hepatology 2017).

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Date de mise en ligne : Samedi 27 mai 2017
Aijaz Ahmed, Stevan A. Gonzalez, George Cholankeril, Ryan B. Perumpail, Justin McGinnis, Sammy Saab, Rachel Beckerman, Zobair M. Younossi
Treatment of patients waitlisted for liver transplant with all‐oral direct‐acting antivirals is a cost‐effective treatment strategy in the United States
All‐oral direct acting antivirals (DAAs) have been shown to have high safety and efficacy in treating patients with hepatitis C virus (HCV) awaiting liver transplant (LT). However, there is limited empirical evidence comparing the health and economic outcomes associated with treating patients pre‐LT versus post‐LT. The objective of this study was to analyze the cost‐effectiveness of pre‐LT versus post‐LT treatment with an all‐oral DAA regimen among HCV patients with hepatocellular carcinoma (HCC) or decompensated cirrhosis (DCC). We constructed decision‐analytic Markov models of the natural disease progression of HCV in HCC patients and DCC patients waitlisted for LT. The model followed hypothetical cohorts of 1,000 patients with a mean age of 50 over a 30‐year time horizon from a third‐party US payer perspective and estimated their health and cost outcomes based on pre‐LT versus post‐LT treatment with an all‐oral DAA regimen. Transition probabilities and utilities were based on the literature and hepatologist consensus. Sustained virological response rates were sourced from ASTRAL‐4, SOLAR‐1, and SOLAR‐2. Costs were sourced from RedBook, Medicare fee schedules, and published literature. In the HCC analysis, the pre‐LT treatment strategy resulted in 11.48 per‐patient quality‐adjusted life years and $365,948 per patient lifetime costs versus 10.39 and $283,696, respectively, in the post‐LT arm. In the DCC analysis, the pre‐LT treatment strategy resulted in 9.27 per‐patient quality‐adjusted life years and $304,800 per patient lifetime costs versus 8.7 and $283,789, respectively, in the post‐LT arm. As such, the pre‐LT treatment strategy was found to be the most cost‐effective in both populations with an incremental cost‐effectiveness ratio of $74,255 (HCC) and $36,583 (DCC). Sensitivity and scenario analyses showed that results were most sensitive to the utility of patients post‐LT, treatment sustained virological response rates, LT costs, and baseline Model for End‐Stage Liver Disease score (DCC analysis only). Conclusion: The timing of initiation of antiviral treatment for HCV patients with HCC or DCC relative to LT is an important area of clinical and policy research; our results indicate that pre‐LT treatment with a highly effective, all‐oral DAA regimen provides the best health outcomes and is the most cost‐effective strategy for the treatment of HCV patients with HCC or DCC waitlisted for LT. (Hepatology 2017).

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Date de mise en ligne : Samedi 27 mai 2017
Francesca Campagna, Sara Montagnese, Lorenzo Ridola, Marco Senzolo, Sami Schiff, Michele De Rui, Chiara Pasquale, Silvia Nardelli, Ilaria Pentassuglio, Carlo Merkel, Paolo Angeli, Oliviero Riggio, Piero Amodio
The animal naming test: An easy tool for the assessment of hepatic encephalopathy
Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (minimal HE [MHE]/grade 1 HE) is important. We examined if the animal naming test (ANT1) (maximum number of animals listed in 1 minute) is useful in this context. In total, 208 healthy controls, 40 controls with inflammatory bowel disease, and 327 consecutive patients with cirrhosis underwent the ANT1. Patients were tested for MHE by the psychometric HE score, and 146 were assessed by electroencephalography; 202 patients were followed up regarding the occurrence of overt HE and death. In the healthy controls, ANT1 was influenced by limited education (<8 years) and advanced age (>80 years, P < 0.001). Using an age and education adjusting procedure, the simplified ANT1 (S‐ANT1) was obtained. An S‐ANT1 of <10 animals was abnormal. Of the patients, 169 were considered unimpaired, 32 as having HE ≥grade 2, and 126 as having MHE/grade 1 HE. This group had lower S‐ANT1 than unimpaired patients (12 ± 0.4 versus 16 ± 0.7, P < 0.001) and higher S‐ANT1 than those with HE ≥grade 2 (4 ± 0.9). In grade 1 HE the S‐ANT1 was lower than in MHE. Following receiver operating characteristic analysis (Youden's index), 15 animals produced the best discrimination between unimpaired and MHE/grade 1 HE patients. Thus, a three‐level score (0 for S‐ANT1 ≥15, 1 for 10 ≤ S‐ANT1 < 15, 2 for S‐ANT1 <10) was obtained. This score was correlated both to the psychometric HE score (P < 0.0001) and to electroencephalography (P = 0.007). By sample random split validation, both S‐ANT1 and its three‐level score showed prognostic value regarding the 1‐year risk of overt HE and death. No inflammatory bowel disease control had S‐ANT <15. Conclusion: The S‐ANT1 is an easily obtainable measure useful for the assessment of HE. (Hepatology 2017).

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Date de mise en ligne : Samedi 27 mai 2017
Guadalupe Garcia‐Tsao, Juan G. Abraldes, Annalisa Berzigotti, Jaime Bosch
Reply:
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Date de mise en ligne : Vendredi 26 mai 2017
Fernando Bril, Kenneth Cusi
Liver fat accumulation as a barometer of insulin responsiveness again points to adipose tissue as the culprit
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Date de mise en ligne : Vendredi 26 mai 2017
Pierre Nahon, Olivier Seror, Isabelle Durand‐Zaleski
Reply
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Date de mise en ligne : Vendredi 26 mai 2017
Anna D. Kosinska, Leila Pishraft‐Sabet, Weimin Wu, Zhong Fang, Marzena Lenart, Jieliang Chen, Kirsten K. Dietze, Cong Wang, Thekla Kemper, Yong Lin, Shiou‐Hwei Yeh, Jia Liu, Ulf Dittmer, Zhenghong Yuan, Michael Roggendorf, Mengji Lu
Low hepatitis B virus–specific T‐cell response in males correlates with high regulatory T‐cell numbers in murine models
Hepatitis B virus (HBV) infection shows significant gender‐related differences in pathogenesis, disease progression, and development of hepatocellular carcinoma. The gender‐associated differences in HBV replication and viral protein levels may be associated with distinct HBV‐specific immune responses in the host. In the present study, we examined the impact of gender on HBV‐specific immune responses in two different mouse models representing transient and persistent hepadnaviral infection; hydrodynamic injection with the HBV genome mimicked acute HBV infection, whereas the efficacy of therapeutic vaccination was studied in the woodchuck hepatitis virus transgenic mouse model. Consistent with previous reports, significantly higher HBV DNA and protein levels were detected in male compared to female mice. Although hydrodynamic injection with the HBV genome resulted in similar numbers of intrahepatic HBV‐specific cluster of differentiation 8–positive (CD8+) T cells, their functionality was significantly reduced in males and correlated with higher numbers of intrahepatic regulatory T cells (Tregs). Similar effects were observed in woodchuck hepatitis virus transgenic mice immunized with a DNA prime‐recombinant adenovirus boost vaccination protocol. Male mice showed functionally suppressed woodchuck hepatitis virus–specific CD8+ T‐cell responses in the liver and significantly higher numbers of intrahepatic Tregs compared to females. Blockade of Treg responses in male mice led to augmented effector functions of specific CD8+ T cells and subsequently improved virus control in both models of transient and persistent hepadnaviral infection. Conclusion: The functionality of virus‐specific CD8+ T cells in male mice was suppressed by intrahepatic Tregs and inversely correlated with levels of hepadnaviral DNA and viral protein; the induction of intrahepatic Tregs by viral replication and/or protein levels may explain the gender‐related differences in the outcomes of HBV infection and limit the success of immunotherapeutic strategies in male patients. (Hepatology 2017).

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Date de mise en ligne : Vendredi 26 mai 2017
Thierry Gustot, Javier Fernandez, Elisabet Garcia, Marco Pavesi, Vicente Arroyo
Reply
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Date de mise en ligne : Vendredi 26 mai 2017
Gitte Dam, Hendrik Vilstrup, Hugh Watson, Peter Jepsen
Reply
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Date de mise en ligne : Vendredi 26 mai 2017
Yingyun Yang, Ye Zhou, Jin Hou, Chunmei Bai, Zhenyang Li, Jia Fan, Irene O.L. Ng, Weiping Zhou, Huichuan Sun, Qiongzhu Dong, Joyce M.F. Lee, Chung‐Mau Lo, Kwan Man, Yun Yang, Nan Li, Guoshan Ding, Yizhi Yu, Xuetao Cao
Hepatic IFIT3 predicts interferon‐α therapeutic response in patients of hepatocellular carcinoma
Adjuvant interferon‐α (IFN‐α) therapy is used to control certain types of cancer in clinics. For hepatocellular carcinoma (HCC), IFN‐α therapy is effective in only a subgroup of patients; therefore, identifying biomarkers to predict the response to IFN‐α therapy is of high significance and clinical utility. As the induced IFN‐stimulated gene expression following IFN‐α treatment plays pivotal roles in IFN‐α effects, we screened IFN‐stimulated gene expression in HCC tissues and found that several IFN‐stimulated genes were significantly decreased in HCC. Interestingly, expression of IFN‐induced protein with tetratricopeptide repeats (IFIT) family members, including IFIT1, IFIT2, IFIT3, and IFIT5, was decreased in HCC tissues. We further analyzed the expression of IFIT family members in HCC and their roles in patients' responses to IFN‐α therapy in two independent randomized controlled IFN‐α therapy clinical trials of HCC patients. We found that higher expression of IFIT3, but not other IFITs, in HCC tissues predicts better response to IFN‐α therapy, suggesting that IFIT3 may be a useful predictor of the response to IFN‐α therapy in HCC patients. Mechanistically, IFIT3 enhanced the antitumor effects of IFN‐α by promoting IFN‐α effector responses both in vitro and in vivo. IFIT3 could bind signal transducer and activator of transcription 1 (STAT1) and STAT2 to enhance STAT1–STAT2 heterodimerization and nuclear translocation upon IFN‐α treatment, thus promoting IFN‐α effector signaling. Conclusion: Higher IFIT3 expression in HCC tissues predicts better response to IFN‐α therapy in HCC patients; IFIT3 promotes IFN‐α effector responses and therapeutic effects by strengthening IFN‐α effector signaling in HCC. (Hepatology 2017)

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Date de mise en ligne : Vendredi 26 mai 2017
Isabelle Durand‐Zaleski, Julie Bulsei, Olivier Seror, Pierre Nahon
Reply:
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Date de mise en ligne : Vendredi 26 mai 2017
Matthew A. Goldsworthy, Ian A. Rowe
Patient understanding of hepatocellular carcinoma surveillance
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Date de mise en ligne : Vendredi 26 mai 2017
Ângelo Zambam de Mattos, Suelen Aparecida da Silva Miozzo, Cristiane Valle Tovo, Angelo Alves de Mattos
Risks of proton pump inhibitors for patients with cirrhosis: The controversy remains
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Date de mise en ligne : Lundi 22 mai 2017
Samer Tohme, Hamza O. Yazdani, Yao Liu, Patricia Loughran, Dirk J. van der Windt, Hai Huang, Richard L. Simmons, Sruti Shiva, Sheng Tai, Allan Tsung
Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction
The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PGC‐1α) and up‐regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC‐1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC‐1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine‐induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll‐like receptor‐9. This binding leads to activation of p38 and subsequent phosphorylation of PGC‐1α, with resultant up‐regulation of mitochondrial biogenesis. Conclusion: Taken together, our findings suggest that during hypoxia HMGB1 up‐regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017).

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Date de mise en ligne : Lundi 22 mai 2017
Yong He, Dechun Feng, Man Li, Yanhang Gao, Teresa Ramirez, Haixia Cao, Seung‐Jin Kim, Yang Yang, Yan Cai, Cynthia Ju, Hua Wang, Jun Li, Bin Gao
Hepatic mitochondrial DNA/Toll‐like receptor 9/MicroRNA‐223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice
Acetaminophen (APAP) overdose is a leading cause of acute liver failure worldwide, in which mitochondrial DNA (mtDNA) released by damaged hepatocytes activates neutrophils through binding of Toll‐like receptor 9 (TLR9), further aggravating liver injury. Here, we demonstrated that mtDNA/TLR9 also activates a negative feedback pathway through induction of microRNA‐223 (miR‐223) to limit neutrophil overactivation and liver injury. After injection of APAP in mice, levels of miR‐223, the most abundant miRNAs in neutrophils, were highly elevated in neutrophils. Disruption of the miR‐223 gene exacerbated APAP‐induced hepatic neutrophil infiltration, oxidative stress, and injury and enhanced TLR9 ligand‐mediated activation of proinflammatory mediators in neutrophils. An additional deletion of the intercellular adhesion molecule 1 (ICAM‐1) gene ameliorated APAP‐induced neutrophil infiltration and liver injury in miR‐223 knockout mice. In vitro experiments revealed that miR‐223‐deficient neutrophils were more susceptible to TLR9 agonist‐mediated induction of proinflammatory mediators and nuclear factor kappa B (NF‐κB) signaling, whereas overexpression of miR‐223 attenuated these effects in neutrophils. Moreover, inhibition of TLR9 signaling by either treatment with a TLR9 inhibitor or by disruption of TLR9 gene partially, but significantly, suppressed miR‐223 expression in neutrophils post‐APAP injection. In contrast, activation of TLR9 up‐regulated miR‐223 expression in neutrophils in vivo and in vitro. Mechanistically, activation of TLR9 up‐regulated miR‐223 by enhancing NF‐κB binding on miR‐223 promoter, whereas miR‐223 attenuated TLR9/NF‐κB‐mediated inflammation by targeting IκB kinase α expression. Collectively, up‐regulation of miR‐223 plays a key role in terminating the acute neutrophilic response and is a therapeutic target for treatment of APAP‐induced liver failure. (Hepatology 2017).

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Date de mise en ligne : Lundi 22 mai 2017
Pin Liu, Mengmeng Ge, Junjie Hu, Xiaolei Li, Li Che, Kun Sun, Lili Cheng, Yuedong Huang, Maria G. Pilo, Antonio Cigliano, Giovanni M. Pes, Rosa M. Pascale, Stefania Brozzetti, Gianpaolo Vidili, Alberto Porcu, Antonio Cossu, Giuseppe Palmieri, Maria C. Sini, Silvia Ribback, Frank Dombrowski, Junyan Tao, Diego F. Calvisi, Ligong Chen, Xin Chen
A functional mammalian target of rapamycin complex 1 signaling is indispensable for c‐Myc‐driven hepatocarcinogenesis
Amplification and/or activation of the c‐Myc proto‐oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c‐Myc has been proven experimentally by the finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c‐Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c‐Myc‐dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits c‐Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E‐binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c‐Myc‐driven tumorigenesis. Intriguingly, microarray expression analysis revealed up‐regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c‐Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c‐Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c‐Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion: Our current study indicates that an intact mTORC1 axis is required for c‐Myc‐driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c‐Myc signaling. (Hepatology 2017).

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Date de mise en ligne : Lundi 22 mai 2017
Dana J. T. Bruden, Brian J. McMahon, Lisa Townshend‐Bulson, Prabhu Gounder, Jim Gove, Julia Plotnik, Chriss Homan, Annette Hewitt, Youssef Barbour, Philip R. Spradling, Brenna C. Simons, Susan McArdle, Michael Bruce
Risk of end stage liver disease, hepatocellular carcinoma, and liver‐related death by fibrosis stage in the hepatitis C Alaska Cohort
Long‐term prospective studies of the outcomes associated with hepatitis C virus (HCV) infection are rare and critical for assessing the potential impact of HCV treatment. Using liver biopsy as a starting point, we analyzed the development of end‐stage liver disease (ESLD), hepatocellular carcinoma (HCC), and liver‐related death (LRD) according to fibrosis stage among a cohort of American Indian/Alaska Native persons in Alaska. Persons were classified as having no/mild (Ishak = 0,1), moderate (Ishak = 2), or severe (Ishak = 3,4) fibrosis or cirrhosis (Ishak = 5,6). We examined time until development of ESLD, HCC, and LRD and report survival probabilities at 3, 5, 7, and 10 years. Of 407 persons, 39% (n = 150) had no/mild fibrosis, 32% (n = 131) had moderate fibrosis, 22% (n = 88) had severe fibrosis, and 9% (n = 38) had cirrhosis. The average time of follow‐up was 7.3 years. Within 5 years of biopsy, 1.7% (95% confidence interval [CI]: 0.4‐6.8) of persons with no/mild fibrosis developed ESLD compared with 7.9% (95% CI, 4.0‐15.2), 16.4% (95% CI, 9.6‐27.2), and 49.0% (95% CI, 33.0‐67.7) with moderate, severe fibrosis, and cirrhosis, respectively (P < 0.01). The 5‐year outcome of HCC was 1.0% (95% CI, 0.1‐7.0), 1.0% (95% CI, 0.1‐6.6), 1.1% (95% CI, 0.2‐7.7), and 13.4% (95% CI, 4.4‐36.7) among persons with no/mild fibrosis, moderate fibrosis, severe fibrosis, and cirrhosis, respectively (P < 0.01). Five years after biopsy, 0.0% (95% CI, 0.0‐14.8) of persons with no/mild fibrosis had suffered an LRD compared with 1.0% (95% CI, 0.2‐7.5) of persons with moderate fibrosis, 4.7% (95% CI, 1.5‐14.1) with severe fibrosis, and 16.3% (95% CI, 7.0‐35.1) with cirrhosis (P < 0.01). Conclusion: For prevention of HCC, LRD, and ESLD in the short term, HCV therapy should target individuals who have more than mild fibrosis. (Hepatology 2017).

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Date de mise en ligne : Lundi 22 mai 2017
Michael A. Nalesnik, Chandrashekhar R. Gandhi, Thomas E. Starzl
Augmenter of liver regeneration: A fundamental life protein
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Date de mise en ligne : Jeudi 18 mai 2017
Marco Cassano, Sandra Offner, Evarist Planet, Alessandra Piersigilli, Suk Min Jang, Hugues Henry, Markus B. Geuking, Catherine Mooser, Kathy D. McCoy, Andrew J. Macpherson, Didier Trono
Polyphenic trait promotes liver cancer in a model of epigenetic instability in mice
Hepatocellular carcinoma (HCC) represents the fifth‐most common form of cancer worldwide and carries a high mortality rate attributed to lack of effective treatment. Males are 8 times more likely to develop HCC than females, an effect largely driven by sex hormones, albeit through still poorly understood mechanisms. We previously identified TRIM28 (tripartite protein 28), a scaffold protein capable of recruiting a number of chromatin modifiers, as a crucial mediator of sexual dimorphism in the liver. Trim28hep–/– mice display sex‐specific transcriptional deregulation of a wide range of bile and steroid metabolism genes and development of liver adenomas in males. We now demonstrate that obesity and aging precipitate alterations of TRIM28‐dependent transcriptional dynamics, leading to a metabolic infection state responsible for highly penetrant male‐restricted hepatic carcinogenesis. Molecular analyses implicate aberrant androgen receptor stimulation, biliary acid disturbances, and altered responses to gut microbiota in the pathogenesis of Trim28hep–/–‐associated HCC. Correspondingly, androgen deprivation markedly attenuates the frequency and severity of tumors, and raising animals under axenic conditions completely abrogates their abnormal phenotype, even upon high‐fat diet challenge. Conclusion: This work underpins how discrete polyphenic traits in epigenetically metastable conditions can contribute to a cancer‐prone state and more broadly provides new evidence linking hormonal imbalances, metabolic disturbances, gut microbiota, and cancer. (Hepatology 2017).

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Date de mise en ligne : Jeudi 18 mai 2017
Pamela S. Belperio, Troy A. Shahoumian, Larry A. Mole, Lisa I. Backus
Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals
Reactivation of hepatitis B virus (HBV) has been reported in hepatitis C virus–infected individuals receiving direct‐acting antiviral (DAA) therapy. The overall risk among patients with current or prior HBV infection in the context of DAA treatment is unknown. The aim of this evaluation was to identify and characterize HBV reactivation among veterans treated with oral DAA therapy. This retrospective evaluation included 62,290 hepatitis C virus–infected veterans completing oral DAA treatment. Baseline HBV infection status for each veteran was identified from HBV laboratory data performed prior to DAA initiation. To assess for HBV reactivation and hepatitis we identified all hepatitis B surface antigen (HBsAg), HBV DNA, and alanine aminotransferase results obtained while on DAA treatment or 7 days after. HBV reactivation was defined as a >1000 IU/mL increase in HBV DNA or HBsAg detection in a person who was previously negative. Prior to DAA treatment 85.5% (53,784/62,920) had HBsAg testing and 0.70% (377/53,784) were positive; 84.6% (53,237/62,920) had a hepatitis B surface antibody test, of which 42.2% (22,479/53,237) were positive. In all, 9 of 62,290 patients treated with DAAs had evidence of HBV reactivation occurring while on DAA treatment. Eight occurred in patients known to be HBsAg‐positive, and 1 occurred in a patient known to be isolated hepatitis B core antibody–positive. Seventeen other patients had small increases in HBV DNA levels that did not qualify as HBV reactivation. Only 3 of the 9 patients identified with HBV reactivation in this cohort exhibited peak alanine aminotransferase elevations >2 times the upper limit of normal. Conclusion: HBV reactivation of varying severity, even in the setting of isolated hepatitis B core antibody, with or without accompanying hepatitis can occur—though the occurrence of accompanying severe hepatitis was rare. (Hepatology 2017).

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Date de mise en ligne : Jeudi 18 mai 2017
Wei Wang, Ming‐Jiang Xu, Yan Cai, Zhou Zhou, Haixia Cao, Partha Mukhopadhyay, Pal Pacher, Shusen Zheng, Frank J. Gonzalez, Bin Gao
Inflammation is independent of steatosis in a murine model of steatohepatitis
Obesity and alcohol consumption synergistically promote steatohepatitis, and neutrophil infiltration is believed to be associated with steatosis. However, the underlying mechanisms remain obscure. Peroxisome proliferator–activated receptor gamma (PPARγ) plays a complex role in lipid metabolism and inflammation; therefore, the purpose of this study was to dissect its role in regulating steatosis and neutrophil infiltration in a clinically relevant mouse steatohepatitis model of 3‐month high‐fat diet (HFD) feeding plus a binge of ethanol (HFD‐plus‐binge ethanol). Hepatocyte‐specific Pparg disruption reduced liver steatosis but surprisingly increased hepatic neutrophil infiltration after HFD‐plus‐binge ethanol. Knockout or knockdown of the PPARγ target gene, fat‐specific protein 27, reduced steatosis without affecting neutrophil infiltration in this model. Moreover, hepatocyte‐specific deletion of the Pparg gene, but not the fat‐specific protein 27 gene, markedly up‐regulated hepatic levels of the gene for chemokine (C‐X‐C motif) ligand 1 (Cxcl1, a chemokine for neutrophil infiltration) in HFD‐plus‐binge ethanol‐fed mice. In vitro, deletion of the Pparg gene also highly augmented palmitic acid or tumor necrosis factor alpha induction of Cxcl1 in mouse hepatocytes. In contrast, activation of PPARγ with a PPARγ agonist attenuated Cxcl1 expression in hepatocytes. Palmitic acid also up‐regulated interleukin‐8 (a key chemokine for human neutrophil recruitment) expression in human hepatocytes, which was attenuated and enhanced by cotreatment with a PPARγ agonist and antagonist, respectively. Finally, acute ethanol binge markedly attenuated HFD‐induced hepatic PPARγ activation, which contributed to the up‐regulation of hepatic Cxcl1 expression post–HFD‐plus‐binge ethanol. Conclusion: Hepatic PPARγ plays an opposing role in controlling steatosis and neutrophil infiltration, leading to dissociation between steatosis and inflammation; acute ethanol gavage attenuates hepatic PPARγ activation and subsequently up‐regulates hepatic CXCL1/interleukin‐8 expression, thereby exacerbating hepatic neutrophil infiltration. (Hepatology 2017).

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

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Date de mise en ligne : Jeudi 18 mai 2017
Robert P. Perrillo
Hepatitis B virus reactivation during direct‐acting antiviral treatment of chronic hepatitis C: A hidden danger of an otherwise major success story
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Date de mise en ligne : Mardi 16 mai 2017
Aynur Unalp‐Arida, Constance E. Ruhl
Liver fibrosis scores predict liver disease mortality in the United States population
Fatty liver disease is common in the United States and worldwide due to changing lifestyles and can progress to fibrosis and cirrhosis contributing to premature death. We examined whether liver fibrosis scores were associated with increased overall and disease‐specific mortality in a United States population–based prospective survey with up to 23 years of linked‐mortality data. Data were analyzed from 14,841 viral hepatitis–negative adult participants in the third National Health and Nutrition Examination Survey, 1988‐1994. Liver fibrosis was predicted using the aspartate aminotransferase–to‐platelet ratio index (APRI), fibrosis‐4 (FIB‐4) score, nonalcoholic fatty liver disease fibrosis score (NFS), and Forns score. Participants were passively followed for mortality, identified by death certificate underlying or contributing causes, by linkage to National Death Index records through 2011. Hazard ratios (HR) for mortality were calculated using Cox proportional hazards regression to adjust for mortality risk factors. During follow‐up, cumulative mortality was 28.0% from all causes and 0.82% with liver disease, including primary liver cancer. Elevated liver disease mortality was found with an intermediate to high APRI (HR, 9.44; 95% confidence interval [CI], 5.02‐17.73), intermediate (HR, 3.15; 95% CI, 1.33‐7.44) or high (HR, 25.14; 95% CI, 8.38‐75.40) FIB‐4 score, high NFS (HR, 6.52; 95% CI, 2.30‐18.50), and intermediate (HR, 3.58; 95% CI, 1.78‐7.18) or high (HR, 63.13; 95% CI, 22.16‐179.78) Forns score. Overall mortality was also greater with higher fibrosis scores. Conclusion: In the United States population, higher liver fibrosis scores were associated with increased liver disease and overall mortality. Liver health management with common clinical measures of fibrosis risk stratification merits further investigation. (Hepatology 2017).

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

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Date de mise en ligne : Mardi 09 mai 2017
Giulia Varrasso, Amalia Schiavetti, Silvia Lanciotti, Maria Sapio, Eva Ferrara, Alessandra De Grazia, Anna Clerico
Propranolol as first‐line treatment for life‐threatening diffuse infantile hepatic hemangioma: A case report
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Date de mise en ligne : Mardi 09 mai 2017
André Viveiros, Marion Reiterer, Benedikt Schaefer, Armin Finkenstedt, Stefan Schneeberger, Hubert Schwaighofer, Patrizia Moser, Rudolf Sprenger, Bernhard Glodny, Wolfgang Vogel, Andreas R. Janecke, Heinz Zoller
CCBE1 mutation causing sclerosing cholangitis: Expanding the spectrum of lymphedema‐cholestasis syndrome
A 52‐year old patient presented with lymphedema, protein loosing enteropathy, and sclerosing cholangitis and was diagnosed with lymphedema cholestasis syndrome (LCS). Cholangioscopy revealed dilated lymphatic vessels obstructing the bile duct and compound heterozygosity for collagen and calcium‐binding epidermal growth factor domain‐containing protein 1 (CCBE1) mutations was identified defining a novel type of LCS. (Hepatology 2017).

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Date de mise en ligne : Mardi 09 mai 2017
Sebastian Mueller, Pierre Nahon, Vanessa Rausch, Tessa Peccerella, Ines Silva, Eray Yagmur, Beate K. Straub, Carolin Lackner, Helmut K. Seitz, Pierre Rufat, Angela Sutton, Heike Bantel, Thomas Longerich
Caspase‐cleaved keratin‐18 fragments increase during alcohol withdrawal and predict liver‐related death in patients with alcoholic liver disease
Noninvasive assessment of disease activity in patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) is still unsettled, but essential for the evaluation of disease progression. We here studied the association of total (M65) and caspase‐cleaved (M30) serum keratin‐18 fragments (n = 204) with histological parameters (n = 106) in heavy drinkers primarily admitted for alcohol withdrawal before and after alcohol detoxification. An age‐, sex‐, and fibrosis‐stage matched NAFLD cohort (n = 30) was used for comparison. The prognostic value of M30 and M65 levels were assessed in an additional prospectively followed‐up cohort of 230 patients with alcoholic cirrhosis (AC) using competing risk analyses. Among the histological parameters, both M30/65 correlated significantly and better than any other serum marker with apoptosis and liver damage, such as ballooning (r = 0.65; P < 0.001), followed by lobular inflammation (0.48; P < 0.001), steatosis (0.46; P < 0.001), but less with fibrosis (0.24; P < 0.001). Area under the receiver operating characteristics curves to detect ballooning, steatosis, or steatohepatitis (SH) were slightly better for M30 (P < 0.005). Optimal M30 cut‐off values for mild and severe ballooning were 330 and 420 U/L, and 290 and 330 U/L for SH grades 1 and 2. No significant differences of M30/65 were found between the matched NAFLD and ALD cohort. In contrast to aspartate‐amino‐transferase and M65, M30 levels increased significantly from 391 to 518 U/L during alcohol detoxification. Moreover, levels of M30 and M65 predicted non–hepatocellular carcinoma liver‐related mortality in patients with AC during a mean observation interval of 67.2 months. Conclusion: Our data suggest M30 as highly specific marker of liver apoptosis both in ALD and NAFLD. In addition, hepatocellular apoptosis, as determined by M30 levels, occurs during alcohol withdrawal, and survival data point toward a novel underestimated role of apoptosis in patients with ALD. (Hepatology 2017).

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Date de mise en ligne : Mardi 09 mai 2017
Sander Lefere, Anne Hoorens, Sarah Raevens, Roberto Troisi, Xavier Verhelst, Hans Van Vlierberghe, Anja Geerts
Refractory subacute steatohepatitis after biliopancreatic diversion
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Date de mise en ligne : Lundi 08 mai 2017
Fu‐Ming Chang, Yen‐Po Wang, Hui‐Chu Lang, Chia‐Fen Tsai, Ming‐Chih Hou, Fa‐Yauh Lee, Ching‐Liang Lu
Statins decrease the risk of decompensation in hepatitis B virus– and hepatitis C virus–related cirrhosis: A population‐based study
Statin use decreases the risk of decompensation and mortality in patients with cirrhosis due to hepatitis C virus (HCV). Whether this beneficial effect can be extended to cirrhosis in the general population or cirrhosis due to other causes, such as hepatitis B virus (HBV) infection or alcohol, remains unknown. Statin use also decreases the risk of hepatocellular carcinoma (HCC) in patients with chronic HBV and HCV infection. It is unclear whether the effect can be observed in patients with pre‐existing cirrhosis. The goal of this study was to determine the effect of statin use on rates of decompensation, mortality, and HCC in HBV‐, HCV‐, and alcohol‐related cirrhosis. Patients with cirrhosis were identified from a representative cohort of Taiwan National Health Insurance beneficiaries from 2000 to 2013. Statin users, defined as having a cumulative defined daily dose (cDDD) ≥28, were selected and served as the case cohort. Statin nonusers (<28 cDDD) were matched through propensity scores. The association between statin use and risk of decompensation, mortality, and HCC were estimated. A total of 1350 patients with cirrhosis were enrolled. Among patients with cirrhosis, statin use decreased the risk of decompensation, mortality, and HCC in a dose‐dependent manner (P for trend <0.0001, <0.0001, and 0.009, respectively). Regression analysis revealed a lower risk of decompensation among statin users with cirrhosis due to chronic HBV (adjusted hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.25‐0.62) or HCV infection (HR, 0.51; 95% CI, 0.29‐0.93). The lowered risk of decompensation was of borderline significance among statin users with alcohol‐related cirrhosis (HR, 0.69; 95% CI, 0.45‐1.07). Conclusion: Statin use decreases the decompensation rate in both HBV‐ and HCV‐related cirrhosis. Of borderline significance is a decreased decompensation rate in alcohol‐related cirrhosis. (Hepatology 2017).

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

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

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

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Date de mise en ligne : Vendredi 19 mai 2017
Masthead
Masthead
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Date de mise en ligne : Vendredi 19 mai 2017
Table of contents
Table of contents
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Date de mise en ligne : Vendredi 19 mai 2017
Jean‐François Dufour
Hepatology Highlights
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Date de mise en ligne : Vendredi 28 avril 2017
Irwin M. Arias
Coming of age and building of bridges … reflections on the past, present, and, hesitatingly, future
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Date de mise en ligne : Mercredi 03 mai 2017
Duminda Suraweera, Sammy Saab
Hepatitis C treatment threshold in patients with decompensated liver disease
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Date de mise en ligne : Mercredi 03 mai 2017
Amy E.L. Stone, Michael J. Gale
Beyond sensing: Retinoic acid inducible gene‐I (RIG‐I) continues to expand its antiviral effector functions
1795

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Date de mise en ligne : Vendredi 28 avril 2017
Brian E. Hsu, Peter M. Siegel
Expanding the armamentarium for neutrophil‐mediated angiogenesis
1798

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Date de mise en ligne : Mercredi 03 mai 2017
Søren Møller, Jens D. Hove
Assessment of systolic function in the evaluation of patients with cirrhosis
1802

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Date de mise en ligne : Mercredi 03 mai 2017
Eric Lawitz, Fred Poordad, Jennifer Wells, Robert H. Hyland, Yin Yang, Hadas Dvory‐Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Carmen Landaverde, Julio Gutierrez
Sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin in direct‐acting antiviral–experienced patients with genotype 1 hepatitis C virus
The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1–infected patients who fail direct‐acting antiviral (DAA)‐based regimens remains unknown. In this phase 2, open‐label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA‐based regimen were randomized to receive treatment with a fixed‐dose combination tablet of sofosbuvir‐velpatasvir‐voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86‐100) receiving sofosbuvir‐velpatasvir‐voxilaprevir alone and 24 of 25 (96%; 95% CI, 80‐100) receiving the same treatment with RBV. None of the patients discontinued sofosbuvir‐velpatasvir‐voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with sofosbuvir‐velpatasvir‐voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir‐velpatasvir‐voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. Conclusion: A fixed‐dose combination of sofosbuvir‐velpatasvir‐voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803‐1809).

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Date de mise en ligne : Vendredi 28 avril 2017
Carlos Fernández Carrillo, Sabela Lens, Elba Llop, Juan Manuel Pascasio, Javier Crespo, Juan Arenas, Inmaculada Fernández, Carme Baliellas, José Antonio Carrión, Manuel de la Mata, Maria Buti, Lluís Castells, Agustín Albillos, Manuel Romero, Juan Turnes, Clara Pons, José María Moreno‐Planas, José Javier Moreno‐Palomares, Conrado Fernández‐Rodriguez, Javier García‐Samaniego, Martín Prieto, Miguel Fernández Bermejo, Javier Salmerón, Ester Badia, Magdalena Salcedo, José Ignacio Herrero, Rafael Granados, Michel Blé, Zoe Mariño, José Luis Calleja
Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of model for end‐stage liver disease: Analysis of data from the Hepa‐C registry
Direct‐acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa‐C registry investigated the effectiveness and safety of interferon‐free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child‐Turcotte‐Pugh [CTP] class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End‐Stage Liver Disease (MELD) score alone (cut‐off 18) was the best predictor of survival. Conclusion: Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810‐1822).

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Date de mise en ligne : Mercredi 03 mai 2017
Lei Xu, Wenshi Wang, Yunlong Li, Xinying Zhou, Yuebang Yin, Yijin Wang, Robert A. de Man, Luc J.W. van der Laan, Fen Huang, Nassim Kamar, Maikel P. Peppelenbosch, Qiuwei Pan
RIG‐I is a key antiviral interferon‐stimulated gene against hepatitis E virus regardless of interferon production
Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN‐stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of an individual ISG. The mechanism of action of the key anti‐HEV ISG was further studied. We identified retinoic acid–inducible gene I (RIG‐I), melanoma differentiation–associated protein 5, and IFN regulatory factor 1 (IRF1) as the key anti‐HEV ISGs. We found that basal expression of RIG‐I restricts HEV infection. Pharmacological activation of the RIG‐I pathway by its natural ligand 5′‐triphosphate RNA potently inhibits HEV replication. Overexpression of RIG‐I activates the transcription of a wide range of ISGs. RIG‐I also mediates but does not overlap with IFN‐α‐initiated ISG transcription. Although it is classically recognized that RIG‐I exerts antiviral activity through the induction of IFN production by IRF3 and IRF7, we reveal an IFN‐independent antiviral mechanism of RIG‐I in combating HEV infection. We found that activation of RIG‐I stimulates an antiviral response independent of IRF3 and IRF7 and regardless of IFN production. However, it is partially through activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascade of IFN signaling. RIG‐I activated two distinct categories of ISGs, one JAK‐STAT‐dependent and the other JAK‐STAT‐independent, which coordinately contribute to the anti‐HEV activity. Conclusion: We identified RIG‐I as an important anti‐HEV ISG that can be pharmacologically activated; activation of RIG‐I stimulates the cellular innate immunity against HEV regardless of IFN production but partially through the JAK‐STAT cascade of IFN signaling. (Hepatology 2017;65:1823‐1839).

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Date de mise en ligne : Vendredi 28 avril 2017
Khaled Thabet, Henry Lik Yuen Chan, Salvatore Petta, Alessandra Mangia, Thomas Berg, Andre Boonstra, Willem P. Brouwer, Maria Lorena Abate, Vincent Wai‐Sun Wong, Maiiada Nazmy, Janett Fischer, Christopher Liddle, Jacob George, Mohammed Eslam
The membrane‐bound O‐acyltransferase domain‐containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B
Chronic hepatitis B (CHB) is characterized by hepatic inflammation that promotes progression to cirrhosis and predisposes to the development of hepatocellular carcinoma (HCC). Subtle interindividual genetic variation as well as viral and environmental factors interact to determine disease progression between individuals. Recently, the rs641738 membrane‐bound O‐acyltransferase domain‐containing 7 (MBOAT7) polymorphism was demonstrated to influence histological liver damage in alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis C, but no data are available for CHB. We evaluated rs641738 influence on disease severity in a cohort of 1,101 patients with CHB. Forty‐two patients underwent gene expression analysis to assess the functional consequences of rs641738 on hepatic MBOAT7 expression. The minor allele (T) of rs641738 was associated with greater inflammation (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06‐1.95; P = 0.001) and fibrosis (OR = 1.31; 95% CI, 1.19‐1.92; P = 0.01). Risk allele frequency in whites (0.43) was greater than in Chinese (0.24), translating to a larger size effect in the former. The rs641738 (T) allele was associated with lower hepatic MBOAT7 expression (P = 0.008), and the latter was associated with serum liver enzymes and inflammation. Neither patatin‐like phospholipase domain‐containing protein 3 rs738409 nor transmembrane 6 superfamily member 2 rs58542926 polymorphisms influenced disease severity. Conclusion: In patients with CHB, MBOAT7 rs641738 influences hepatic inflammation and fibrosis stage. (Hepatology 2017;65:1840‐1850).

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Date de mise en ligne : Vendredi 28 avril 2017
Catarina Oliveira, Carole Fournier, Véronique Descamps, Virginie Morel, Corey A. Scipione, Rocco Romagnuolo, Marlys L. Koschinsky, Agnès Boullier, Paulo Marcelo, Jean‐Marc Domon, Etienne Brochot, Gilles Duverlie, Catherine Francois, Sandrine Castelain, Francois Helle
Apolipoprotein(a) inhibits hepatitis C virus entry through interaction with infectious particles
The development of different cell culture models has greatly contributed to increased understanding of the hepatitis C virus (HCV) life cycle. However, it is still challenging to grow HCV clinical isolates in cell culture. If overcome, this would open new perspectives to study HCV biology, including drug‐resistant variants emerging with new antiviral therapies. In this study we hypothesized that this hurdle could be due to the presence of inhibitory factors in patient serum. Combining polyethylene glycol precipitation, iodixanol gradient, and size‐exclusion chromatography, we obtained from HCV‐seronegative sera a purified fraction enriched in inhibitory factors. Mass spectrometric analysis identified apolipoprotein(a) (apo[a]) as a potential inhibitor of HCV entry. Apo(a) consists of 10 kringle IV domains (KIVs), one kringle V domain, and an inactive protease domain. The 10 KIVs are present in a single copy with the exception of KIV type 2 (KIV2), which is encoded in a variable number of tandemly repeated copies, giving rise to numerous apo(a) size isoforms. In addition, apo(a) covalently links to the apolipoprotein B component of a low‐density lipoprotein through a disulfide bridge to form lipoprotein(a). Using a recombinant virus derived from the JFH1 strain, we confirmed that plasma‐derived and recombinant lipoprotein(a) as well as purified recombinant apo(a) variants were able to specifically inhibit HCV by interacting with infectious particles. Our results also suggest that small isoforms are less inhibitory than the large ones. Finally, we observed that the lipoprotein moiety of HCV lipoviroparticles was essential for inhibition, whereas functional lysine‐binding sites in KIV7, KIV8, and KIV10 were not required. Conclusions: Our results identify apo(a) as an additional component of the lipid metabolism modulating HCV infection. (Hepatology 2017;65:1851‐1864)

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Date de mise en ligne : Lundi 10 avril 2017
Nunzia Pastore, Sergio Attanasio, Barbara Granese, Raffaele Castello, Jeffrey Teckman, Andrew A. Wilson, Andrea Ballabio, Nicola Brunetti‐Pierri
Activation of the c‐Jun N‐terminal kinase pathway aggravates proteotoxicity of hepatic mutant Z alpha1‐antitrypsin
Alpha1‐antitrypsin deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the serine protease inhibitor 1A (SERPINA1) gene leading to a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Alpha1‐antitrypsin defciency‐related liver disease is therefore caused by a gain‐of‐function mechanism due to accumulation of the mutant Z alpha1‐antitrypsin (ATZ) and is a key example of an disease mechanism induced by protein toxicity. Intracellular retention of ATZ triggers a complex injury cascade including apoptosis and other mechanisms, although several aspects of the disease pathogenesis are still unclear. We show that ATZ induces activation of c‐Jun N‐terminal kinase (JNK) and c‐Jun and that genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c‐Jun–mediated SERPINA1 gene expression. JNK activation was confirmed in livers of patients homozygous for the Z allele, with severe liver disease requiring hepatic transplantation. Treatment of patient‐derived induced pluripotent stem cell‐hepatic cells with a JNK inhibitor reduced accumulation of ATZ. Conclusion: These data reveal that JNK is a key pathway in the disease pathogenesis and add new therapeutic entry points for liver disease caused by ATZ. (Hepatology 2017;65:1865‐1874).

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Date de mise en ligne : Mardi 18 avril 2017
Francesca Virginia Bruschi, Thierry Claudel, Matteo Tardelli, Alessandra Caligiuri, Thomas M. Stulnig, Fabio Marra, Michael Trauner
The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells
The genetic polymorphism I148M of patatin‐like phospholipase domain–containing 3 (PNPLA3) is robustly associated with hepatic steatosis and its progression to steatohepatitis, fibrosis, and cancer. Hepatic stellate cells (HSCs) are key players in the development of liver fibrosis, but the role of PNPLA3 and its variant I148M in this process is poorly understood. Here we analyzed the expression of PNPLA3 during human HSC activation and thereby explored how a PNPLA3 variant impacts hepatic fibrogenesis. We show that expression of PNPLA3 gene and protein increases during the early phases of activation and remains elevated in fully activated HSCs (P < 0.01). Knockdown of PNPLA3 significantly decreases the profibrogenic protein alpha‐smooth muscle actin (P < 0.05). Primary human I148M HSCs displayed significantly higher expression and release of proinflammatory cytokines, such as chemokine (C‐C motif) ligand 5 (P < 0.01) and granulocyte‐macrophage colony‐stimulating factor (P < 0.001), thus contributing to migration of immune cells (P < 0.05). Primary I148M HSCs showed reduced retinol (P < 0.001) but higher lipid droplet content (P < 0.001). In line with this, LX‐2 cells stably overexpressing I148M showed augmented proliferation and migration, lower retinol, and abolished retinoid X receptor/retinoid A receptor transcriptional activities but more lipid droplets. Knockdown of I148M PNPLA3 (P < 0.001) also reduces chemokine (C‐C motif) ligand 5 and collagen1α1 expression (P < 0.05). Notably, I148M cells display reduced peroxisome proliferator–activated receptor gamma transcriptional activity, and this effect was attributed to increased c‐Jun N‐terminal kinase, thereby inhibiting peroxisome proliferator–activated receptor gamma through serine 84 phosphorylation and promoting activator protein 1 transcription. Conversely, the c‐Jun N‐terminal kinase inhibitor SP600125 and the peroxisome proliferator–activated receptor gamma agonist rosiglitazone decreased activator protein 1 promoter activity. Conclusions: These data indicate that PNPLA3 is required for HSC activation and that its genetic variant I148M potentiates the profibrogenic features of HSCs, providing a molecular mechanism for the higher risk of progression and severity of liver diseases conferred to patients carrying the I148M variant. (Hepatology 2017;65:1875‐1890).

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Date de mise en ligne : Vendredi 28 avril 2017
Yan Wang, Robert Vincent, Jinlian Yang, Amon Asgharpour, Xieer Liang, Michael O. Idowu, Melissa J. Contos, Kalyani Daitya, Mohammed S. Siddiqui, Faridoddin Mirshahi, Arun J. Sanyal
Dual‐photon microscopy‐based quantitation of fibrosis‐related parameters (q‐FP) to model disease progression in steatohepatitis
There is a need for further refinement of current histological systems for assessment of hepatic fibrosis in nonalcoholic fatty liver disease (NAFLD). This study evaluated hepatic fibrosis in NAFLD using dual‐photon microscopy‐based quantitation of fibrosis‐related parameters (q‐FPs). Fifty test cohort subjects and 42 validation cohort subjects with NAFLD and the full spectrum of fibrosis were studied. q‐FPs were measured in specific predefined regions of interest (general, vessel, perisinusoid, and vascular septa). Seventy q‐FPs had inter‐ and intraobserver concordance ≥0.8 and were related to the NASH Clinical Research Network fibrosis staging. Of these, 16 q‐FPs with the strongest correlations (P < 0.001 for all) were entered in a principal component analysis model (odds ratio [OR] 7.8, P < 0.001), which separated any stage of fibrosis versus no fibrosis, and cirrhosis versus earlier stages with the areas under the receiver operating characteristic curves of 0.88 and 0.93 (P ≤ 0.01 for both), respectively. In an independent multivariable analysis, four q‐FPs—the number of collagen strands (OR 8.5, P = 0.004), strand length (OR 12.0, P = 0.02), strand eccentricity (OR 8.3, P = 0.004), and strand solidity (OR 8.0, P = 0.003)—were independently associated with fibrosis stages and were used to model fibrosis along a continuous linear scale using desirability functions; this linear scale of fibrosis measurement was also related to fibrosis stage (P < 0.0001). The robustness of both the multivariable model and the linear scale of measurement was confirmed in the validation cohort. Conclusion: The q‐FP model provides an accurate reproducible method to evaluate fibrosis in NAFLD along a quantitative and continuous scale. (Hepatology 2017;65:1891‐1903).

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Date de mise en ligne : Vendredi 28 avril 2017
Zhiwen Fan, Luyang Li, Min Li, Xinjian Zhang, Chenzhi Hao, Liming Yu, Sheng Zeng, Huihui Xu, Mingming Fang, Aiguo Shen, Thomas Jenuwein, Yong Xu
The histone methyltransferase Suv39h2 contributes to nonalcoholic steatohepatitis in mice
Uncontrolled inflammatory response highlights the central theme of nonalcoholic steatohepatitis (NASH), a growing global pandemic. Hepatocytes and macrophages represent two major sources of hepatic inflammation during NASH pathogenesis, contributing to excessive synthesis of proinflammatory mediators. The epigenetic mechanism that accounts for the activation of hepatocytes and macrophages in this process remains obscure. Here, we report that compared to wild‐type littermates, mice with a deficiency in the histone H3K9 methyltransferase suppressor of variegation 39 homolog 2 (Suv39h2, knockout) exhibited a less severe form of NASH induced by feeding with a high‐fat, high‐carbohydrate diet. Pro‐NASH stimuli increased Suv39h2 expression in cell culture, in mice, and in human livers. In hepatocytes, Suv39h2 bound to the Sirt1 gene promoter and repressed Sirt1 transcription. Suv39h2 deficiency normalized Sirt1 expression, allowing nuclear factor kappa B/p65 to become hypoacetylated and thus dampening nuclear factor kappa B–dependent transcription of proinflammatory mediators. In macrophages, Suv39h2‐mediated repression of peroxisome proliferator–activated receptor gamma transcription favored a proinflammatory M1 phenotype over an anti‐inflammatory M2 phenotype, thereby elevating hepatic inflammation. Conclusion: Suv39h2 plays a pivotal role in the regulation of inflammatory response in hepatocytes and macrophages, contributing to NASH pathogenesis. (Hepatology 2017;65:1904‐1919).

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Date de mise en ligne : Mardi 02 mai 2017
Alex N. Gordon‐Weeks, Su Y. Lim, Arseniy E. Yuzhalin, Keaton Jones, Bostjan Markelc, K. Jin Kim, Jon N. Buzzelli, Emmanouil Fokas, Yunhong Cao, Sean Smart, Ruth Muschel
Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2–dependent angiogenesis in mice
Hepatic metastases are amenable to ablation; however, many patients are not suitable candidates for such therapy and recurrence is common. The tumor microenvironment is known to be essential for metastatic growth, yet identification of plausible targets for cancer therapy in the microenvironment has proven elusive. We found that human colorectal cancer liver metastases and murine gastrointestinal experimental liver metastases are infiltrated by neutrophils. Plasticity in neutrophils has recently been shown to lead to both protumor and antitumor effects. Here, neutrophils promoted the growth of hepatic metastases, given that depletion of neutrophils in already established, experimental, murine liver metastases led to diminished metastatic growth. Decreased growth was associated with reductions in vascular density and branching suggestive of vessel normalization. Metastasis‐associated neutrophils expressed substantially more fibroblast growth factor 2 (FGF2) than naïve neutrophils, indicating neutrophil polarization by the tumor microenvironment. Administration of FGF2 neutralizing antibody to mice bearing experimental liver metastases phenocopied neutrophil depletion by reducing liver metastatic colony growth, vascular density, and branching. Conclusion: Here, we show, using FGF2 as an example, that identification of factors responsible for the protumoral effects of infiltrating myeloid cells can be used to target established liver metastases. Such therapies could be utilized to limit disease progression and potentiate the effects of standard ablative therapies. (Hepatology 2017;65:1920‐1935).

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Date de mise en ligne : Mardi 18 avril 2017
Na Li, Zhang‐Sen Zhou, Yang Shen, Jie Xu, Hong‐Hua Miao, Ying Xiong, Feng Xu, Bo‐Liang Li, Jie Luo, Bao‐Liang Song
Inhibition of the sterol regulatory element‐binding protein pathway suppresses hepatocellular carcinoma by repressing inflammation in mice
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element‐binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78‐kDa cell‐surface glycoprotein or SREBP cleavage‐activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine‐induced HCC progression by down‐regulating tumor‐promoting cytokines, including interleukin (IL)‐6, tumor necrosis factor alpha, and IL‐1β. Conclusion: Inhibition of de novo lipid biosynthesis by suppressing the SREBP pathway prevents HCC. This study identifies a previously underappreciated role of the SREBP pathway in HCC and suggests a novel metabolic strategy to control liver cancer. (Hepatology 2017;65:1936‐1947).

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Date de mise en ligne : Vendredi 28 avril 2017
Xihua Yue, Jing Ai, Yang Xu, Yi Chen, Min Huang, Xinying Yang, Bo Hu, Haotian Zhang, Changxi He, Xinrong Yang, Weiguo Tang, Xia Peng, Liwei Dong, Hongyang Wang, Jia Fan, Jian Ding, Meiyu Geng
Polymeric immunoglobulin receptor promotes tumor growth in hepatocellular carcinoma
Deregulation of the immune system is believed to contribute to cancer malignancy, which has led to recent therapeutic breakthroughs facilitating antitumor immunity. In a malignant setting, immunoglobulin receptors, which are fundamental components of the human immune system, fulfill paradoxical roles in cancer pathogenesis. This study describes a previously unrecognized pro‐oncogenic function of polymeric immunoglobulin receptor (pIgR) in the promotion of cell transformation and proliferation. Mechanistically, pIgR overexpression is associated with YES proto‐oncogene 1, Src family tyrosine kinase (Yes) activation, which is required for pIgR‐induced oncogenic growth. Specifically, pIgR activates the Yes‐DNAX‐activating protein of 12 kDa‐spleen tyrosine kinase‐Rac1/CDC42‐MEK (extracellular signal‐regulated kinase kinase)/ERK (extracellular signal‐regulated kinase) cascade in an immunoreceptor tyrosine‐based activating motif (ITAM)‐dependent manner to promote cell transformation and tumor growth, although pIgR itself does not contain an ITAM sequence. Additionally, the combination of pIgR and phosphorylated Yes (p‐Yes) levels serves as a prognostic biomarker for hepatitis B surface antigen–positive and early‐stage hepatocellular carcinoma (HCC) patients. Moreover, pharmacological targeting of MEK/ERK or Yes represents a therapeutic option for the subgroup of patients with pIgR/p‐Yes–positive HCC based on our results with both cancer cell‐line–based xenografts and primary patient‐derived xenografts. Conclusion: Our findings reveal the molecular mechanism by which pIgR promotes cancer malignancy, suggest the clinical potential of targeting this pathway in HCC, and provide new insight into the oncogenic role of immunoglobulin receptors. (Hepatology 2017;65:1948‐1962).

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Date de mise en ligne : Lundi 10 avril 2017
Yutaka Shimizu, Nieves Peltzer, Alexandra Sevko, Elodie Lafont, Aida Sarr, Helena Draberova, Henning Walczak
The Linear ubiquitin chain assembly complex acts as a liver tumor suppressor and inhibits hepatocyte apoptosis and hepatitis
Linear ubiquitination is a key posttranslational modification that regulates immune signaling and cell death pathways, notably tumor necrosis factor receptor 1 (TNFR1) signaling. The only known enzyme complex capable of forming linear ubiquitin chains under native conditions to date is the linear ubiquitin chain assembly complex, of which the catalytic core component is heme‐oxidized iron regulatory protein 2 ubiquitin ligase‐1–interacting protein (HOIP). To understand the underlying mechanisms of maintenance of liver homeostasis and the role of linear ubiquitination specifically in liver parenchymal cells, we investigated the physiological role of HOIP in the liver parenchyma. To do so, we created mice harboring liver parenchymal cell–specific deletion of HOIP (HoipΔhep mice) by crossing Hoip‐floxed mice with albumin–Cre mice. HOIP deficiency in liver parenchymal cells triggered tumorigenesis at 18 months of age preceded by spontaneous hepatocyte apoptosis and liver inflammation within the first month of life. In line with the emergence of inflammation, HoipΔhep mice displayed enhanced liver regeneration and DNA damage. In addition, consistent with increased apoptosis, HOIP‐deficient hepatocytes showed enhanced caspase activation and endogenous formation of a death‐inducing signaling complex which activated caspase‐8. Unexpectedly, exacerbated caspase activation and apoptosis were not dependent on TNFR1, whereas ensuing liver inflammation and tumorigenesis were promoted by TNFR1 signaling. Conclusion: The linear ubiquitin chain assembly complex serves as a previously undescribed tumor suppressor in the liver, restraining TNFR1‐independent apoptosis in hepatocytes which, in its absence, is causative of TNFR1‐mediated inflammation, resulting in hepatocarcinogenesis. (Hepatology 2017;65:1963‐1978).

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Date de mise en ligne : Vendredi 28 avril 2017
Min Woo Lee, Steven S. Raman, Nazanin H. Asvadi, Surachate Siripongsakun, Robert M. Hicks, Jeffrey Chen, Akeanong Worakitsitisatorn, Justin McWilliams, Myron J. Tong, Richard S. Finn, Vatche G. Agopian, Ronald W. Busuttil, David S.K. Lu
Radiofrequency ablation of hepatocellular carcinoma as bridge therapy to liver transplantation: A 10‐year intention‐to‐treat analysis
In a long‐term (10‐year) study of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) as bridging therapy in patients listed for orthotopic liver transplantation (LT), we evaluated the impact of RFA on waiting list dropout rate, post‐LT tumor recurrence, and long‐term intention‐to‐treat, disease‐specific survival (DSS). From March 2004 to October 2014, RFA was performed as the initial stand‐alone bridge therapy to LT for 121 patients (men/women ratio, 83:38; mean age, 60.0 years) with 156 de novo HCCs (mean size, 2.4 cm). Follow‐up period from initial RFA ranged from 1.3 to 128.0 months (median, 42.9 months). We assessed the overall and tumor‐specific waiting list dropout rates, post‐LT tumor recurrence, and 10‐year post‐LT and intention‐to‐treat survival rates. Dropout from the waiting list due to tumor progression occurred in 7.4% of patients. HCC recurrence after LT occurred in 5.6% of patients. The post‐LT overall survival (OS) rate at 5 and 10 years was 75.8% and 42.2%, respectively, and the recurrence‐free survival (RFS) rate was 71.1% and 39.6%, respectively. Intention‐to‐treat OS, RFS, and DSS rates for the entire study population at 5 and 10 years were 63.5% and 41.2%, 60.8% and 37.7%, and 89.5% and 89.5%, respectively. Conclusion: RFA as a first‐line stand‐alone bridge therapy to LT achieves excellent long‐term overall and tumor‐specific survivals, with a low dropout rate from tumor progression despite long wait list times and a sustained low tumor recurrence rate upon post‐LT follow‐up of up to 10 years. (Hepatology 2017;65:1979‐1990)

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Date de mise en ligne : Vendredi 28 avril 2017
Laura Hargrove, Lindsey Kennedy, Jennifer Demieville, Hannah Jones, Fanyin Meng, Sharon DeMorrow, Walker Karstens, Taronish Madeka, John Greene, Heather Francis
Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice
Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC‐deficient (KitW‐sh) mice. Wild‐type (WT) and KitW‐sh mice were subjected to sham or BDL for up to 7 days and KitW‐sh mice were injected with cultured mast cells or 1× phosphate‐buffered saline (PBS) before collecting serum, liver, and cholangiocytes. Liver damage was assessed by hematoxylin and eosin and alanine aminotransferase levels. IBDM was detected by cytokeratin‐19 expression and proliferation by Ki‐67 immunohistochemistry (IHC). Fibrosis was detected by IHC, hydroxyproline content, and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and transforming growth factor‐beta 1 (TGF‐β1) expression/secretion were evaluated. Histidine decarboxylase (HDC) and histamine receptor (HR) expression were detected by qPCR and HA secretion by enzymatic immunoassay. To evaluate vascular cells, von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)‐C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and alpha‐smooth muscle actin levels were measured. BDL‐induced liver damage was reduced in BDL KitW‐sh mice, whereas injection of MCs did not mimic BDL‐induced damage. In BDL KitW‐sh mice, IBDM, proliferation, HSC activation/fibrosis, and TGF‐β1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW‐sh mice. vWF and VEGF‐C expression decreased in BDL KitW‐sh mice. In KitW‐sh mice injected with MCs, IBDM, proliferation, fibrosis, and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW‐sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW‐sh mice. Conclusion: MCs promote hyperplasia, fibrosis, and vascular cell activation. Knockout of MCs decreases BDL‐induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. (Hepatology 2017;65:1991‐2004).

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Date de mise en ligne : Vendredi 28 avril 2017
Yongqing Wang, Hiroaki Aoki, Jing Yang, Kesong Peng, Runping Liu, Xiaojiaoyang Li, Xiaoyan Qiang, Lixin Sun, Emily C. Gurley, Guanhua Lai, Luyong Zhang, Guang Liang, Masayuki Nagahashi, Kazuaki Takabe, William M. Pandak, Phillip B. Hylemon, Huiping Zhou
The role of sphingosine 1‐phosphate receptor 2 in bile‐acid–induced cholangiocyte proliferation and cholestasis‐induced liver injury in mice
Bile duct obstruction is a potent stimulus for cholangiocyte proliferation, especially for large cholangiocytes. Our previous studies reported that conjugated bile acids (CBAs) activate the protein kinase B (AKT) and extracellular signal‐regulated kinase 1 and 2 (ERK1/2) signaling pathways through sphingosine 1‐phosphate receptor (S1PR) 2 in hepatocytes and cholangiocarcinoma cells. It also has been reported that taurocholate (TCA) promotes large cholangiocyte proliferation and protects cholangiocytes from bile duct ligation (BDL)‐induced apoptosis. However, the role of S1PR2 in bile‐acid–mediated cholangiocyte proliferation and cholestatic liver injury has not been elucidated. Here, we report that S1PR2 is the predominant S1PR expressed in cholangiocytes. Both TCA‐ and sphingosine‐1‐phosphate (S1P)‐induced activation of ERK1/2 and AKT were inhibited by JTE‐013, a specific antagonist of S1PR2, in cholangiocytes. In addition, TCA‐ and S1P‐induced cell proliferation and migration were inhibited by JTE‐013 and a specific short hairpin RNA of S1PR2, as well as chemical inhibitors of ERK1/2 and AKT in mouse cholangiocytes. In BDL mice, expression of S1PR2 was up‐regulated in whole liver and cholangiocytes. S1PR2 deficiency significantly reduced BDL‐induced cholangiocyte proliferation and cholestatic injury, as indicated by significant reductions in inflammation and liver fibrosis in S1PR2 knockout mice. Treatment of BDL mice with JTE‐013 significantly reduced total bile acid levels in serum and cholestatic liver injury. Conclusion: This study suggests that CBA‐induced activation of S1PR2‐mediated signaling pathways plays a critical role in obstructive cholestasis and may represent a novel therapeutic target for cholestatic liver diseases. (Hepatology 2017;65:2005‐2018).

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Date de mise en ligne : Vendredi 28 avril 2017
Raquel Yotti, Cristina Ripoll, Yolanda Benito, Maria Vega Catalina, Jaime Elízaga, Diego Rincón, Francisco Fernández‐Avilés, Javier Bermejo, Rafael Bañares
Left ventricular systolic function is associated with sympathetic nervous activity and markers of inflammation in cirrhosis
An accurate evaluation of cardiac function in patients with cirrhosis remains a challenge. We used robust echocardiographic indices to characterize left ventricular (LV) systolic function and its relationship to activation of the sympathetic nervous system and inflammation in 59 patients with cirrhosis and 59 age‐matched controls. Additionally, in 11 patients we withdrew beta‐blockers and diuretics and used phenylephrine and albumin infusion to evaluate the response to acute afterload and preload changes (interventional substudy). Measures of systolic LV function such as the ejection intraventricular pressure difference (EIVPD) and the systolic strain rate were higher in patients with cirrhosis than in controls (median [1st‐3rd quartile], 4.0 [3.1‐5.1] versus 2.9 [2.4‐3.6] mm Hg and –1.3 [–1.6 to –1.1] versus –1.2 [–1.6 to –1.1)] s–1, respectively; P < 0.05 for both). EIVPD was related to the severity of liver disease (Model for End‐Stage Liver Disease, rho = 0.45, P < 0.001), the degree of sympathetic nervous system activation (noradrenaline, rho = 0.26, P = 0.05; heart rate variability, rho = –0.43, P = 0.003), and treatment with beta‐blockers (P = 0.001). In the interventional substudy, EIVPD was higher in patients with ascites (6.5 [5.4‐8.5] versus 4.0 [3.9‐5.1] mm Hg, P = 0.045). The decrease in EIVPD induced by phenylephrine was inversely related to baseline systolic function (P < 0.05) and associated with markers of systemic vasodilatation (nitric oxide, rho = –0.66, P = 0.06; diastolic blood pressure, rho = 0.68, P = 0.04) and inflammation (interleukin‐1beta, rho = –0.80, P = 0.009). Conclusion: LV systolic function is enhanced in cirrhosis due to augmented adrenergic tone and modulated by treatment with beta‐blockers; acute afterload stress induces a deeper impairment of systolic function in patients with more advanced degrees of vasodilatation and inflammation; these changes in LV function related to cirrhosis can be assessed using robust echocardiographic methods. (Hepatology 2017;65:2019‐2030).

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Date de mise en ligne : Mardi 02 mai 2017
Marina Vilaseca, Héctor García‐Calderó, Erica Lafoz, Oihane García‐Irigoyen, Matías A. Avila, Joan Carles Reverter, Jaume Bosch, Virginia Hernández‐Gea, Jordi Gracia‐Sancho, Joan Carles García‐Pagán
The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells
In cirrhosis, increased intrahepatic vascular resistance (IHVR) is the primary factor for portal hypertension (PH) development. Hepatic stellate cells (HSCs) play a major role increasing IHVR because, when activated, they are contractile and promote fibrogenesis. Protease‐activated receptors (PARs) can activate HSCs through thrombin and factor Xa, which are known PAR agonists, and cause microthrombosis in liver microcirculation. This study investigates the effects of the oral anticoagulant, rivaroxaban (RVXB), a direct antifactor Xa, on HSC phenotype, liver fibrosis (LF), liver microthrombosis, and PH in cirrhotic rats. Hepatic and systemic hemodynamic, nitric oxide (NO) bioavailability, LF, HSC activation, and microthrombosis were evaluated in CCl4 and thioacetamide‐cirrhotic rats treated with RVXB (20 mg/kg/day) or its vehicle for 2 weeks. RVXB significantly decreased portal pressure (PP) in both models of cirrhosis without changes in portal blood flow, suggesting a reduction in IHVR. RVXB reduced oxidative stress, improved NO bioavailability, and ameliorated endothelial dysfunction. Rivaroxaban deactivated HSC, with decreased alpha‐smooth muscle actin and mRNA expression of other HSC activation markers. Despite this marked improvement in HSC phenotype, no significant changes in LF were identified. RVXB markedly reduced fibrin deposition, suggesting reduced intrahepatic microthrombosis. Conclusion: RVXB decreases PP in two rat models of cirrhosis. This effect is mostly associated with decreased IHVR, enhanced NO bioavailability, HSC deactivation, and reduced intrahepatic microthrombosis. Our findings suggest that RVXB deserves further evaluation as a potential treatment for cirrhotic PH. (Hepatology 2017;65:2031‐2044).

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Date de mise en ligne : Vendredi 28 avril 2017
Avinash Kumar, Gangarao Davuluri, Rafaella Nascimento e Silva, Marielle P.K.J. Engelen, Gabrie A.M. Ten Have, Richard Prayson, Nicolaas E.P. Deutz, Srinivasan Dasarathy
Ammonia lowering reverses sarcopenia of cirrhosis by restoring skeletal muscle proteostasis
Sarcopenia or skeletal muscle loss is a frequent, potentially reversible complication in cirrhosis that adversely affects clinical outcomes. Hyperammonemia is a consistent abnormality in cirrhosis that results in impaired skeletal muscle protein synthesis and breakdown (proteostasis). Despite the availability of effective ammonia‐lowering therapies, whether lowering ammonia restores proteostasis and increases muscle mass is unknown. Myotube diameter, protein synthesis, and molecular responses in C2C12 murine myotubes to withdrawal of ammonium acetate following 24‐hour exposure to 10 mM ammonium acetate were complemented by in vivo studies in the hyperammonemic portacaval anastomosis rat and sham‐operated, pair‐fed Sprague‐Dawley rats treated with ammonia‐lowering therapy by l‐ornithine l‐aspartate and rifaximin orally for 4 weeks. We observed reduced myotube diameter, impaired protein synthesis, and increased autophagy flux in response to hyperammonemia, which were partially reversed following 24‐hour and 48‐hour withdrawal of ammonium acetate. Consistently, 4 weeks of ammonia‐lowering therapy resulted in significant lowering of blood and skeletal muscle ammonia, increase in lean body mass, improved grip strength, higher skeletal muscle mass and diameter, and an increase in type 2 fibers in treated compared to untreated portacaval anastomosis rats. The increased skeletal muscle myostatin expression, reduced mammalian target of rapamycin complex 1 function, and hyperammonemic stress response including autophagy markers normally found in portacaval anastomosis rats were reversed by treatment with ammonia‐lowering therapy. Despite significant improvement, molecular and functional readouts were not completely reversed by ammonia‐lowering measures. Conclusion: Ammonia‐lowering therapy results in improvement in skeletal muscle phenotype and function and molecular perturbations of hyperammonemia; these preclinical studies complement previous studies on ammonia‐induced skeletal muscle loss and lay the foundation for prolonged ammonia‐lowering therapy to reverse sarcopenia of cirrhosis. (Hepatology 2017;65:2045‐2058).

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Date de mise en ligne : Jeudi 04 mai 2017
Lei Wang, Wen Zhang, Chang‐Hui Ge, Rong‐Hua Yin, Yang Xiao, Yi‐Qun Zhan, Miao Yu, Chang‐Yan Li, Zhi‐Qiang Ge, Xiao‐Ming Yang
Toll‐like receptor 5 signaling restrains T‐cell/natural killer T‐cell activation and protects against concanavalin A–induced hepatic injury
Toll‐like receptor‐5 (TLR5) signaling regulates the immune privileged status of the liver and is involved in hepatic immune disorders. However, the role of TLR5 has not yet been investigated in experimental models of concanavalin A (Con A)–mediated liver injury. Here, we show that TLR5 is highly up‐regulated in the hepatic mononuclear cells of mice during Con A–induced hepatitis. Increased mortality and liver histopathology of TLR5‐deficient mice correlated with excessive production of proinflammatory cytokines, suggesting that TLR5 knockout mice were more susceptible to Con A–induced hepatitis. We also report that administration of CBLB502, an exogenous TLR5 agonist, substantially alleviated Con A–mediated hepatitis in wild‐type mice as shown by increased survival rates, reduced aminotransferase and proinflammatory cytokine production, impaired lymphocyte infiltration, and ameliorated hepatocyte necrosis and/or apoptosis. Mechanistic studies revealed that CBLB502 acts as a negative regulator in limiting T‐cell/natural killer T‐cell activity and cytokine production in the Con A–hepatitis model. Bone marrow transplantation experiments showed that TLR5 in bone marrow–derived cells contributed to the hepatoprotective efficacy of CBLB502 against Con A–induced liver injury. Moreover, interleukin‐6 elevation induced by CBLB502 is an important protective factor against Con A–induced liver injury. In addition, we demonstrate that CBLB502 suppresses α‐galactosylceramide‐induced natural killer T cell–dependent inflammatory liver injury. Conclusion: The TLR5 signaling pathway plays an important role in T cell–mediated hepatic injury and may be exploited for therapeutic treatment of inflammatory liver diseases. (Hepatology 2017;65:2059‐2073).

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Date de mise en ligne : Vendredi 28 avril 2017
Caroline Steinmetz, Anubha Kashyap, Nataliya Zhivkova, Henry Alizor, Isabell Ernst, Daniela Gottfried‐Brand, Henning Janssen, Andreas Teufel, Henning Schulze‐Bergkamen, Johannes Lotz, Jürgen Kuball, Matthias Theobald, Michael Heise, Hauke Lang, Peter R. Galle, Dennis Strand, Susanne Strand
Activation of silent mating type information regulation 2 homolog 1 by human chorionic gonadotropin exerts a therapeutic effect on hepatic injury and inflammation
Incidence and prevalence of inflammatory liver diseases has increased over the last years, but therapeutic options are limited. Pregnancy induces a state of immune tolerance, which can result in spontaneous improvement of clinical symptoms of certain autoimmune diseases including autoimmune hepatitis (AIH). We investigated the immune‐suppressive mechanisms of the human pregnancy hormone, chorionic gonadotropin (hCG), in the liver. hCG signaling activates silent mating type information regulation 2 homolog 1 (SIRT1), which deacetylates forkhead box o3 (FOXO3a), leading to repression of proapoptotic gene expression, because the immunosuppressive consequence attributed to the absence of caspase‐3 activity of hepatocellular interleukin 16 (IL‐16) is no longer processed and released. Thus, serum levels of IL‐16, a key chemotactic factor for CD4+ lymphocytes, were reduced and migration to injured hepatocytes prevented. Furthermore, elevated IL‐16 levels are found in the sera from patients with AIH, hepatitis B virus, hepatitis C virus, and nonalcoholic steatohepatitis. Conclusion: Here, we report that hCG regulates the SIRT1/FOXO3a axis in hepatocytes, resulting in immune suppression by attenuating caspase‐3–dependent IL‐16 processing and release, which concomitantly prevents autoaggressive T‐cell infiltration of the liver. Considering the low toxicity profile of hCG in humans, interrupting the inflammatory cycle by hCG opens new perspectives for therapeutic intervention of inflammatory liver diseases. (Hepatology 2017;65:2074‐2089).

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Date de mise en ligne : Vendredi 28 avril 2017
Veeral H. Ajmera, Norah A. Terrault, Stephen A. Harrison
Is moderate alcohol use in nonalcoholic fatty liver disease good or bad? A critical review
Moderate alcohol consumption in patients with nonalcoholic fatty liver disease (NAFLD) is common, yet the effects on cardiovascular and liver health are unclear. Moderate alcohol use is associated with improved insulin sensitivity and decreased cardiovascular mortality in the general population, but whether similar benefits would be observed in persons with NAFLD remains largely unstudied. There is significant overlap in the pathogenesis of alcoholic liver disease (ALD) and NAFLD, although studies of ALD have focused on pathological alcohol intake and few mechanistic studies of moderate alcohol use in NAFLD exist. We undertook a critical review of the effect of moderate alcohol use on cardiovascular and liver disease in patients with NAFLD. A total of seven observational studies met the criteria for inclusion (one for cardiovascular endpoints and six for liver endpoints). Insufficient studies have assessed the association of moderate alcohol use with cardiovascular outcomes. There was a positive association between moderate alcohol use and decreased NASH and fibrosis; however, heavy episodic drinking may accelerate fibrosis progression and moderate alcohol use may increase the risk of hepatocellular carcinoma in patients with advanced fibrosis. Significant methodological limitations were present, including incomplete adjustment for confounding factors and failure to measure lifetime use or the pattern of alcohol intake. Thus, a strong recommendation of benefit of moderate alcohol use in NAFLD cannot be made. There remains a need for additional high‐quality longitudinal studies that evaluate both cardiovascular and liver outcomes among NAFLD patients with moderate or lesser degrees of alcohol use. (Hepatology 2017;65:2090‐2099).

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Date de mise en ligne : Vendredi 28 avril 2017
Iliana Doycheva, Kymberly D. Watt, Naim Alkhouri
Nonalcoholic fatty liver disease in adolescents and young adults: The next frontier in the epidemic
Nonalcoholic fatty liver disease (NAFLD) is a significant health burden in adolescents and young adults (AYAs) which has substantially risen in prevalence over the last decades. The occurrence of NAFLD parallels high rates of obesity and metabolic syndrome in this age group, with unhealthy lifestyle also playing an independent role. Genetic factors, sex, and ethnicity should be considered in a risk stratification model. NAFLD and nonalcoholic steatohepatitis (NASH) in AYAs often go unrecognized and, if untreated, can progress eventually to cirrhosis requiring liver transplantation (LT) before the age of 40. Recently, NASH has increased as an indication for LT in this age group. Important knowledge gaps include the feasibility of noninvasive diagnostic tests and imaging modalities as well as uncertainty about unique histological features and their predictive value. Future clinical trials focused on AYAs are needed to determine effectiveness of therapies. Tools for increasing awareness and prevention of NAFLD in AYAs are greatly needed. (Hepatology 2017;65:2100‐2109).

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Date de mise en ligne : Jeudi 04 mai 2017
Ruud M. Buijs, Natali Guerrero Vargas
Synchrony between suprachiasmatic nucleus‐driven signals and the light/dark cycle is essential for liver homeostasis
2112

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Date de mise en ligne : Lundi 24 avril 2017
Alberto Rubio‐Tapia, Isabel A. Hujoel, Thomas C. Smyrk, John J. Poterucha
Emerging secondary syphilis presenting as syphilitic hepatitis
2115

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Date de mise en ligne : Mardi 18 avril 2017
Silvia Martini, Mauro Salizzoni, Ezio David, Francesco Tandoi, Paolo Fonio, Luisa Delsedime, Silvia Strona, Dominic Dell Olio, Giorgio Maria Saracco, Renato Romagnoli
Favorable short‐term outcome of hepatitis C virus–positive liver graft with bridging fibrosis: A plea for very early viral eradication
2118

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Date de mise en ligne : Mercredi 19 avril 2017
Agustin Castiella, José M. Alústiza, Eva Zapata, Leire Zubiaurre, Pedro Otazua, José I. Emparanza
Dysmetabolic iron overload syndrome: The need for an accurate liver iron concentration determination by magnetic resonance imaging
2119

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Date de mise en ligne : Mardi 18 avril 2017
Fabrice Lainé, Edouard Bardou‐Jacquet, Anita Paisant, Yves Gandon, Yves Deugnier
Reply
2120

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Date de mise en ligne : Vendredi 28 avril 2017
Felix Gundling, Maximilian Tiller, Wolfgang Schepp
Comment on “esophageal balloon tamponade vs. esophageal stent in controlling acute refractory variceal bleeding: A multicenter RCT”
2121

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Date de mise en ligne : Lundi 24 avril 2017
Àngels Escorsell, Oana Pavel, Andrés Cárdenas, Rosa Morillas, Elba Llop, Càndid Villanueva, Juan Càrlos Garcia‐Pagan, Jaime Bosch
Reply
2122

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Date de mise en ligne : Lundi 24 avril 2017
Amedeo Lonardo, Fabio Nascimbeni, Stefano Ballestri
NAFLD, Hepatotropic Viruses, and Cardiometabolic Risk
2123

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Date de mise en ligne : Vendredi 28 avril 2017
Eun‐Jeong Joo, Yoosoo Chang, Seungho Ryu
Reply
2124

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Date de mise en ligne : Mardi 18 avril 2017
Thomas R. O'Brien, Shyam Kottilil, Jordan J. Feld, Timothy R. Morgan, Ruth M. Pfeiffer
Race or genetic makeup for hepatitis C virus treatment decisions?
2125

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Date de mise en ligne : Lundi 24 avril 2017
Feng Su, George N. Ioannou
Reply
2126

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Date de mise en ligne : Lundi 24 avril 2017
Thomas Karlas, Sebastian Beer, Jonas Babel, Harald Busse, Alexander Schaudinn, Nicolas Linder, Johannes Wiegand, David Petroff
Do we need controlled attenuation parameter adjustment for fibrosis estimation in nonalcoholic fatty liver disease patients?
2128

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Date de mise en ligne : Vendredi 28 avril 2017
Salvatore Petta, Vincent Way‐Sun Wong, Victor de Ledinghen
Reply
2128

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Date de mise en ligne : Lundi 24 avril 2017
Jacob Meacham Smith, Josiah D. Rich
Addressing opioid use disorder in modeling hepatitis C transmission among persons who inject drugs
2129

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Date de mise en ligne : Mardi 18 avril 2017
Anthony Cousien, Viet Chi Tran, Sylvie Deuffic‐Burban, Marie Jauffret‐Roustide, Jean‐Stéphane Dhersin, Yazdan Yazdanpanah
Reply
2130

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Date de mise en ligne : Lundi 24 avril 2017
Edoardo G. Giannini, Vincenzo Savarino
Noninvasive assessment of varices needing treatment in patients with advanced chronic liver disease: No one should be left behind
2131

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Date de mise en ligne : Vendredi 28 avril 2017
Juan G. Abraldes, Annalisa Berzigotti,
Reply
2132

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Date de mise en ligne : Mardi 18 avril 2017
Lionel Arrivé, Sanaâ Mouhadi
MR lymphography of hepatic lymphatic system
2133

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Date de mise en ligne : Vendredi 28 avril 2017
Yasuko Iwakiri
Reply
2134

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Date de mise en ligne : Vendredi 28 avril 2017
Correction
Correction
2135

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Date de mise en ligne : Vendredi 28 avril 2017
Correction
Correction
2136

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Date de mise en ligne : Mercredi 03 mai 2017
Correction
Correction
2136

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Date de mise en ligne : Lundi 24 avril 2017
Xavier Forns
Juan Rodés, M.D., Ph.D. (1938–2017): Excellence and leadership
2138

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Date de mise en ligne : Vendredi 19 mai 2017
Notices
Notices
n/a

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

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