Vous êtes ici : Accueil > Espace Médecin > La revue de Presse > Hepatology

Mise à jour le : 19-01-2017

| | |




Les derniers abstracts de la revue Hepatology :


    Date de mise en ligne : Mercredi 18 janvier 2017
    Robert Driver, Ian A Rowe
    What is the benefit of early follow‐up after hospitalization for patients with cirrhosis?
    n/a


    Date de mise en ligne : Mercredi 18 janvier 2017
    CĂ ndid Villanueva, Isabel Graupera, Carles Aracil, Edilmar Alvarado, Josep Miñana, Ángela Puente, Virginia Hernandez‐Gea, Alba Ardevol, Oana Pavel, Alan Colomo, Mar ConcepciĂłn, MarĂ­a Poca, Xavier Torras, Josep M a Reñe, Carlos Guarner
    A Randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis
    Monitoring the hemodynamic response of portal pressure to drug therapy accurately stratifies the risk of variceal rebleeding. We assessed whether guiding therapy with HVPG‐monitoring may improve survival in the prevention of variceal rebleeding. Cirrhotic patients with controlled variceal bleeding were randomized to a HVPG‐guided‐therapy group (N= 84) or to a control group (N= 86). In both groups, HVPG and acute ÎČ‐blocker response were evaluated at baseline and HVPG measurements were repeated at 2‐4‐weeks to determine chronic response. In the HVPG‐guided group, acute responders were treated with nadolol and acute non‐responders with nadolol+nitrates. Chronic non‐responders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between‐group baseline characteristics were similar. During long‐term follow‐up (median of 24 months) mortality was lower in the HVPG‐guided‐therapy group than in the control group (29% vs 43%; HR= 0.59, 95%CI= 0.35‐0.99). Rebleeding occurred in 19% vs 31% of patients, respectively (HR= 0.53, 95%CI= 0.29‐0.98), and further decompensation of cirrhosis occurred in 52% vs 72% (HR= 0.68, 95%CI= 0.46‐0.99). The survival probability was higher with HVPG‐guided‐therapy than in controls, both in acute (HR= 0.59, 95%CI= 0.32‐1.08) and chronic non‐responders (HR= 0.48, 95%CI= 0.23‐0.99). HVPG‐guided patients had a greater reduction of HVPG and a lower final value than controls (P< 0.05). Conclusion: HVPG‐monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent variceal rebleeding using ÎČ‐blockers and ligation. HVPG‐guided‐therapy achieved a greater reduction in portal pressure, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 18 janvier 2017
    Zongwen Shuai, Jinjun Wang, Madhu Badamagunta, Jinjung Choi, Guoxiang Yang, Weici Zhang, Thomas P. Kenny, Kathryn Guggenheim, Mark J. Kurth, Aftab A. Ansari, John Voss, Ross L Coppel, Pietro Invernizzi, Patrick S.C. Leung, M. Eric Gershwin
    The Fingerprint of Antimitochondrial Antibodies and the Etiology of Primary Biliary Cholangitis
    The identification of environmental factors that lead to loss of tolerance has been coined the Holy Grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC‐E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein we successfully applied intein technology to construct a PDC‐E2 protein fragment containing amino acid residues 177‐314 of PDC‐E2 by joining a recombinant peptide spanning residues 177 to 252 (PDC‐228) with a 62 residue synthetic peptide from 253 to 314 (PP), which encompasses PDC‐E2 ILD. We named this intein‐constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA‐PPL) and xenobiotic 2‐octynoic acid conjugated PPL (2OA‐PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA modified PDC‐E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC‐E2 peptide. Interestingly, this unique AMA subfraction is of the IgM isotype and more dominant in early stage PBC, suggesting that exposure to 2OA‐PPL‐like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition we analyzed PPL, LA‐PPL and 2OA‐PPL using electron paramagnetic resonance spectroscopy, with confirmations by ELISA, immunoblotting and affinity antibody analysis. We demonstrate that the conformation of PDC‐E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid. In conclusion a molecular understanding of the conformation of xenobiotic modified PDC‐E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 18 janvier 2017
    Veeral H. Ajmera, Norah A. Terrault, Stephen A. Harrison
    Is Moderate Alcohol Use in Non‐Alcoholic 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 are seen in persons with NAFLD is largely unstudied. There is significant overlap in the pathogenesis of alcoholic liver disease (ALD) and NAFLD although studies of ALD have focused on pathologic 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 7 observational studies met criteria for inclusion (one for cardiovascular endpoints and 6 for liver endpoints). There were insufficient studies to assess the association 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 in patients with advanced fibrosis moderate alcohol use may increase the risk of hepatocellular carcinoma. Significant methodologic limitations were present including incomplete adjustment for confounders 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mercredi 18 janvier 2017
    Feng Su, George N. Ioannou
    Reply to: Race or Genetic Makeup for HCV Treatment Decisions?
    n/a


    Date de mise en ligne : Mercredi 18 janvier 2017
    Thomas R. O'Brien, Shyam Kottilil, Jordan J. Feld, Timothy R. Morgan, Ruth M. Pfeiffer
    Race or Genetic Makeup for HCV Treatment Decisions?
    n/a


    Date de mise en ligne : Mardi 17 janvier 2017
    Elizabeth C. Verna
    The Dynamic Landscape of Liver Transplant in the Era of Effective HCV Therapy
    n/a


    Date de mise en ligne : Mardi 17 janvier 2017
    Cynthia Levy
    PBC: Treatment options finally expand
    n/a


    Date de mise en ligne : Lundi 16 janvier 2017
    Jin‐Kyu Park, Mingjie Shao, Moon Young Kim, Soon Koo Baik, Mee Yon Cho, Teruo Utsumi, Ayano Satoh, Xinsho Ouyang, Chuhan Chung, Yasuko Iwakiri
    An endoplasmic reticulum protein, Nogo‐B, facilitates alcoholic liver disease through regulation of Kupffer cell polarization
    Background Nogo‐B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Since ER stress is known to induce M2 macrophage polarization, we examined whether Nogo‐B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). Methods M1 and M2 phenotypes were assessed in relation to Nogo‐B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild‐type (WT) and Nogo‐B knockout (KO) mice fed control or Lieber‐DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo‐B KO mice were assessed for M1 and M2 activation. Results A significant positive correlation was observed between Nogo‐B positive Kupffer cells and disease severity in ALD patients (n=30, r=0.66, p=0.048). Further, Nogo‐B positive Kupffer cells correlated with M1 activation (iNOS) (r=0.50, p=0.05) and negatively with markers of M2 status (CD163) (r=‐0.48, p=0.07) in these patients. WT mice exhibited significantly increased liver injury (p<0.05) and higher hepatic triglyceride levels (p<0.01), compared to Nogo‐B KO mice in response to chronic ethanol feeding. Nogo‐B in Kupffer cells promoted M1 polarization, whereas absence of Nogo‐B increased ER stress and M2 polarization in Kupffer cells. Conclusion Nogo‐B is permissive for M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo‐B in Kupffer cells may represent a new therapeutic target for ALD. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 16 janvier 2017
    Payal Arora, Amartya Basu, M. Lee Schmidt, Geoffrey J. Clark, Howard Donninger, Daniel B. Nichols, Diego F. Calvisi, Neerja Kaushik‐Basu
    NS5B Promotes Degradation of the NORE1A Tumor Suppressor to Facilitate Hepatitis C Virus Replication
    Hepatitis C infection is a common risk factor for the development of liver cancer. The molecular mechanisms underlying this effect are only partially understood. Here we show that the HCV protein NS5B directly binds to the tumor suppressor NORE1A (RASSF5) and promotes its proteosomal degradation. In addition, we show that NORE1A co‐localizes to sites of HCV viral replication and suppresses the process. Thus, NORE1A has anti‐viral activity which is specifically antagonized by NS5B. Moreover, the suppression of NORE1A protein levels correlated almost perfectly with elevation of Ras activity in primary human samples. Therefore, NORE1A inactivation by NS5B may be essential for maximal HCV replication and may make a major contribution to HCV induced liver cancer by shifting Ras signaling away from pro‐senescent/apoptotic signaling pathways. Conclusion: HCV uses NS5B to specifically suppress NORE1A facilitating viral replication and elevated Ras signaling. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 16 janvier 2017
    Lei Hei, Jin Zhong
    LGP2 plays an essential role in HCV infection‐induced interferon responses
    Retinoic acid‐inducible gene I (RIG‐I)‐like receptors (RLRs) are cytosolic pattern recognition receptors (PRR) that detect non‐self RNA and activate downstream interferon (IFN) signaling. One of the RLRs, Laboratory of genetics and physiology 2 (LGP2) was originally thought to be a negative feedback regulator in RIG‐I signaling pathway, but growing evidence indicates LGP2 is one co‐factor of Melanoma Differentiation‐Associated protein 5 (MDA5) in MDA5‐mediated IFN signaling activation. Our previous work showed that MDA5 was the major PRR to sense HCV infection in hepatocytes, but the role of LGP2 in HCV infection‐induced IFN signaling has not been elucidated. In this study, we reported that LGP2 was a positive regulator of HCV infection‐induced IFN signaling. Knockout of LGP2 in hepatocytes significantly diminished the IFN production in response to HCV infection but not to HCV 3'UTR RNA transfection. Mechanistic studies showed that LGP2 exerted its function at a step upstream of MDA5 in the IFN signaling. HCV infection promoted the molecular interaction between LGP2 and MDA5, which in turn enhanced MDA5‐HCV RNA association. Finally we demonstrated that the ATPase activity of LGP2 was critical for assisting MDA5‐HCV RNA interaction and activating IFN signaling during HCV infection. Conclusion: Our work demonstrated that LGP2 plays an essential role in activating IFN signaling against HCV infection by promoting MDA5 recognition of HCV PAMP. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 13 janvier 2017
    Eun‐Jeong Joo, Yoosoo Chang, Seungho Ryu
    Response to NAFLD, hepatotropic viruses and cardio‐metabolic risk
    n/a


    Date de mise en ligne : Vendredi 13 janvier 2017
    Amedeo Lonardo, Fabio Nascimbeni, Stefano Ballestri
    NAFLD, hepatotropic viruses and cardio‐metabolic risk
    n/a


    Date de mise en ligne : Vendredi 13 janvier 2017
    Michael A. Nalesnik, Chandrashekhar R. Gandhi, Thomas E. Starzl
    Augmenter of Liver Regeneration: A Fundamental Life Protein
    n/a


    Date de mise en ligne : Mercredi 11 janvier 2017
    Felix Gundling, Maximilian Tiller, Wolfgang Schepp
    Correspondence: Esophageal balloon tamponade vs esophageal stent in controlling acute refractory variceal bleeding: A multicenter RCT
    n/a


    Date de mise en ligne : Mardi 10 janvier 2017
    Naim Alkhouri, Ariel E. Feldstein
    Treating Nonalcoholic Steatohepatitis (NASH) in Children: Not a Cinch Task
    BACKGROUND & AIMS: No treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD. METHODS: We performed a double‐masked trial of 169 children with NAFLD Activity Scores ≄ 4 at 10 centers. From June 2012 to January 2014, the patients were randomly assigned to receive CBDR or placebo twice daily (300 mg for ≀65 kg, 375 mg for >65‐80 kg, 450 mg for >80 kg) for 52 weeks. The primary outcome from the intention to treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in NAFLD Activity Score ≄ 2 points without worsening fibrosis; patients without biopsies from week 52 (17 in the CBDR group and 6 in the placebo group) were considered non‐responders. We calculated relative risks (RR) of improvement using stratified Cochran‐Mantel‐Haenszel analysis. RESULTS: There was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% CI, 0.8‐2.1; P=.34). However, children receiving CBDR had significant changes in pre‐specified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction of 53±88 U/L vs a reduction of 8±77 U/L in the placebo group; P=.02) and aspartate aminotransferase (reduction of 31±52 vs a reduction of 4±36 U/L in the placebo group; P=.008), and a larger proportion had reduced lobular inflammation (in 36% of patients in the CBDR group vs placebo 21% of patients in the placebo group; RR, 1.8; 95% CI, 1.1‐2.9; P=.03). In a post‐hoc analyses, of children ≀65 kg, those taking CBDR had a 4‐fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3‐12.3; P=.005). CONCLUSIONS: In a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR did, however, have significant reductions in serum levels of aminotransferase levels and lobular inflammation. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 2017
    Mario Strazzabosco, John I. Allen, Elizabeth O. Teisberg
    Value based care in hepatology
    The migration from legacy fee‐for‐service reimbursement to payments linked to high value health care is accelerating in the United States because of new legislation and re‐design of payments from the Centers for Medicare and Medicaid Services (CMS). Since patients with chronic diseases account for substantial use of health care resources, payers and health systems are focusing on maximizing the value of care for these patients. Since chronic liver diseases impose a major health burden worldwide affecting the health and lives of many individuals and families as well as substantial costs for individuals and payers, hepatologists must understand how they can improve their practices . Hepatologists practice a high‐intensity cognitive sub‐specialty, using complex and costly procedures and medications. High value patient care requires multi‐disciplinary coordination, labor‐intensive support for critically ill patients and effective chronic disease management. Under current fee for service reimbursement, patient values, medical success and financial success all can be misaligned. Many current attempts to link health outcomes to reimbursement are based on compliance with process measures with less emphasis on outcomes that matter most to patients, thus slowing transformation to higher‐value team‐based care. Outcome measures that reflect the entire cycle of care are needed to assist both clinicians and administrators in improving quality and value of care. A comprehensive set of outcome measures for liver diseases is not currently available. Numerous researchers now are attempting to fill this gap by devising and testing outcome indicators and patients reported outcomes (PROMs) for the major liver conditions. These indicators will provide tools to implement a value‐based approach for patients with chronic liver diseases to compare results and value of care between referral centers, to perform health technology assessment and to guide decision‐making processes for health authorities. This review sets the groundwork for implementing a value‐based, patient‐centered approach to chronic liver diseases within a health system. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 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 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 on hepatic fibrogenesis. We show that PNPLA3 gene and protein expression increase during the early phases of activation and remain elevated in fully activated HSCs (p<0.01). Knockdown of PNPLA3 significantly decreases the pro‐fibrogenic protein α‐SMA (p<0.05). Primary human I148M HSCs displayed significantly higher expression and release of pro‐inflammatory cytokines, such as CCL5 (p<0.01) and GM‐CSF (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 droplets (LDs) content (p<0.001). In line, LX‐2 stably overexpressing I148M showed augmented proliferation, migration, lower retinol and abolished RXR/RAR transcriptional activities, but higher LDs. Knockdown of I148M PNPLA3 (p<0.001) also reduces CCL5 and Collagen1α1 expression(p<0.05). Notably, I148M cells display reduced PPARÎł transcriptional activity and this effect was attributed to increased JNK, thereby inhibiting PPARÎł via serine 84 phosphorylation and promoting AP‐1 transcription. Conversely, JNK inhibitor SP600125 and PPARÎł agonist rosiglitazone decreased AP‐1 promoter activity. Conclusions: These data indicate that PNPLA3 is required for HSC activation and its genetic variant I148M potentiates the pro‐fibrogenic 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 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
    n/a


    Date de mise en ligne : Mardi 10 janvier 2017
    Nunzia Pastore, Sergio Attanasio, Barbara Granese, Jeffrey Teckman, Andrew A. Wilson, Andrea Ballabio, and Nicola Brunetti‐Pierri
    Activation of JNK 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 SERPINA1 gene resulting in a single amino acid substitution that results in an unfolded protein that is prone to polymerization. Therefore, the liver disease is caused by a gain of function mechanism due to accumulation of the mutant Z alpha1‐antitrypsin (ATZ) and is a key example of an important 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 JNK and c‐JUN and genetic ablation of JNK1 or JNK2 decreased ATZ levels in vivo by reducing c‐JUN mediated SERPINA1 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 (iPSCs)‐hepatic cells with a JNK inhibitor reduced accumulation of ATZ. In 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 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 activation, which is required for pIgR‐induced oncogenic growth. Specifically, pIgR activates the Yes‐Dap12‐Syk‐Rac1/CDC42‐MEK/ERK 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 (HBsAg)‐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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 2017
    Jung Eun Jang, Han‐Sol Park, Hyun Ju Yoo, In‐Jeoung Baek, Ji Eun Yoon, Myoung Seok Ko, Ah‐Ram Kim, Hyoun Sik Kim, Hye‐Sun Park, Seung Eun Lee, Seung‐Whan Kim, Su Jung Kim, Jaechan Leem, Yu Mi Kang, Min Kyo Jung, Chan‐Gi Pack, Chong Jai Kim, Chang Ohk Sung, In‐Kyu Lee, Joong‐Yeol Park, JosĂ© C. FernĂĄndez‐Checa, Eun Hee Koh, Ki‐Up Lee
    Protective role of endogenous plasmalogens against hepatic steatosis and steatohepatitis
    Free cholesterol (FC) accumulation in the liver is an important pathogenic mechanism of nonalcoholic steatohepatitis (NASH). Plasmalogens, key structural components of the cell membrane, act as endogenous antioxidants and are primarily synthesized in the liver. However, the role of hepatic plasmalogens in metabolic liver disease is unclear. In this study, we found that hepatic levels of docosahexaenoic acid (DHA)‐containing plasmalogens, expression of glyceronephosphate O‐acyltransferase (Gnpat, the rate‐limiting enzyme in plasmalogen biosynthesis), and expression of Pparα were lower in mice with NASH caused by accumulation of free cholesterol (FC) in the liver. Cyclodextrin‐induced depletion of FC transactivated Δ‐6 desaturase by increasing Srebp2 expression in cultured hepatocytes. DHA, the major product of Δ‐6 desaturase activation, activated GNPAT, thereby explaining the association between high hepatic FC and decreased Gnpat expression. Gnpat siRNA treatment significantly decreased Pparα expression in cultured hepatocytes. In addition to GNPAT, DHA activated PPARα and increased expression of Pparα and its target genes, suggesting that DHA in the DHA‐containing plasmalogens contributed to activation of PPARα. Accordingly, administration of the plasmalogen precursor alkyl glycerol (AG) prevented hepatic steatosis and NASH through a PPARα‐dependent increase in fatty acid oxidation. Gnpat+/‐ mice were more susceptible to hepatic lipid accumulation and less responsive to the preventive effect of fluvastatin on NASH development, suggesting that endogenous plasmalogens prevent hepatic steatosis and NASH. Conclusions: Increased hepatic FC in animals with NASH decreased plasmalogens, thereby sensitizing animals to hepatocyte injury and NASH. Our findings uncover a novel link between hepatic FC and plasmalogen homeostasis via GNPAT regulation. Further study of AG or other agents that increase hepatic plasmalogen levels may identify novel therapeutic strategies against NASH. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 2017
    Einar S. Björnsson, Jon Gunnlaugur Jonasson
    Idiosyncratic drug‐induced liver injury associated with bile duct loss and vanishing bile duct syndrome: Rare but has severe consequences
    n/a


    Date de mise en ligne : Mardi 10 janvier 2017
    Sander Lefere, Anne Hoorens, Sarah Raevens, Roberto Troisi, Xavier Verhelst, Hans Van Vlierberghe, Anja Geerts
    Refractory subacute steatohepatitis after biliopancreatic diversion
    Steatohepatitis development after the biliopancreatic diversion (BPD) procedure for morbid obesity has rarely been reported. We present a case of fatal recurrent steatohepatitis post‐PBD despite repeated liver transplantations. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 2017
    Biljana Atanasovska, Sander S. Rensen, Marijke R. van der Sijde, Glenn Marsman, Vinod Kumar, Iris Jonkers, Sebo Withoff, Ronit Shiri‐Sverdlov, Jan Willem M. Greve, Klaas Nico Faber, Han Moshage, Cisca Wijmenga, Bart van de Sluis, Marten H. Hofker, Jingyuan Fu
    A liver‐specific long non‐coding RNA with a role in cell viability is elevated in human non‐alcoholic steatohepatitis
    Hepatocyte apoptosis in non‐alcoholic steatohepatitis (NASH) can lead to fibrosis and cirrhosis, which permanently damage the liver. Understanding the regulation of hepatocyte apoptosis is therefore important to identify therapeutic targets that may prevent the progression of NASH to fibrosis. Recently, increasing evidence has shown that lncRNAs are involved in various biological processes and that their dysregulation underlies a number of complex human diseases. By performing gene expression profiling of 4,383 lncRNAs in 82 liver samples from individuals with NASH (n=48), simple steatosis but no NASH (n=11) and healthy controls (n=23), we discovered a liver‐specific lncRNA (RP11‐484N16.1) on chromosome 18 that showed significantly elevated expression in the liver tissue of NASH patients. This lncRNA, which we named lnc18q22.2 based on its chromosomal location, correlated with NASH grade (r=0.51, P=8.11x10−7), lobular inflammation (r=0.49, P=2.35x10−6) and non‐alcoholic fatty liver disease activity score (r=0.48, P=4.69x10−6). The association of lnc18q22.2 to liver steatosis and steatohepatitis was replicated in 44 independent liver biopsies (r=0.47, P=0.0013). We provided a genetic structure of lnc18q22.2 showing an extended exon 2 in liver. Knockdown of lnc18q22.2 in four different hepatocyte cell lines resulted in severe phenotypes ranging from reduced cell growth to lethality. This observation was consistent with pathway analyses of genes co‐expressed with lnc18q22.2 in human liver or affected by lnc18q22.2 knockdown. Conclusion: we identified a lncRNA that can play an important regulatory role in liver function and provide new insights into the regulation of hepatocyte viability in NASH. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 10 janvier 2017
    Ling Lin, Ying Ding, Yi Wang, Zhenxin Wang, Xuefei Yin, Guoquan Yan, Lei Zhang, Pengyuan Yang, Huali Shen
    Functional lipidomics: palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism
    Lipids are essential cellular components and energy sources of living organisms, altered lipid composition is increasingly recognized as a signature of cancer. We performed the lipidomic analysis in a series of hepatocellular carcinoma (HCC) cells and identified over 1700 intact lipids originating from 3 major lipid categories. Comparative lipidomic screening revealed 93 significantly changed lipids and decreased palmitic acyl (C16:0)‐containing glycerophospholipids (GPs) were positively associated with metastatic abilities of HCC cells. Furthermore, both in vitro and in vivo experiments designated that C16:0 incubation specifically reduced malignant cell proliferation, impaired cell invasiveness, and suppressed tumor growth in mouse xenograft models. Biochemical experiments demonstrated that C16:0 treatment decreased cell membrane fluidity and limited glucose metabolism. Phosphoproteomics approach further revealed such C16:0 incubation attenuated phosphorylation levels of mTOR and Stat3 pathway proteins. MRM analysis showed 8 declined C16:0‐containing lipids out of total 10 changed lipids when compared cancer tissues with adjacent nontumor tissues in a cohort of clinical HCC specimens (P<0.05). Conclusion: These data collectively herald the biomedical potential of using altered lipid metabolism as a diagnostic marker for cancerous cells and open an opportunity for treating aggressive HCCs by targeting the altered C16:0 metabolism. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Lundi 09 janvier 2017
    Agustin Castiella, JosĂ© M. AlĂșstiza, Eva Zapata, Leire Zubiaurre, Pedro Otazua, JosĂ© I. Emparanza
    Dysmetabolic iron overload syndrome. The need for an accurate liver iron concentration determination by MRI
    n/a


    Date de mise en ligne : Lundi 09 janvier 2017
    LainĂ© Fabrice, Edouard Bardou‐Jacquet, Paisant Anita, Yves Gandon, Yves Deugnier
    Dysmetabolic iron overload syndrome: A mild but unquestionable iron overload is identified by MRI
    n/a


    Date de mise en ligne : Lundi 09 janvier 2017
    Anna Hadjihambi, Francesco De Chiara, Patrick S Hosford, Abeba Habtetion, Anastassios Karagiannis, Nathan Davies, Alexander V Gourine, Rajiv Jalan
    Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease
    The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte‐neuron lactate shuttle hypothesis suggests that neuronal activity is fuelled (at least in part) by lactate provided by neighbouring astrocytes. We hypothesised that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced‐hyperammonemia [HA]) and also evaluated the effect of ammonia‐lowering treatment (ornithine phenylacetate, OP). Plasma ammonia concentration in BDL rats was indeed significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia‐induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. Conclusion. The results of the present study demonstrate that HE is associated with CNS hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel‐mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 05 janvier 2017
    Prakash Baligar, Veena Kochat, Shailendra K. Arindkar, Zaffar Equbal, Snehashish Mukherjee, Swati Patel, Perumal Nagarajan, Sujata Mohanty, Jeffrey H. Teckman, Asok Mukhopadhyay
    Bone marrow stem cell therapy partially ameliorates pathological consequences in livers of mice expressing mutant human α1‐antitrypsin
    Alpha1‐antitrypsin deficiency (AATD) is a genetic disease, caused by mutation of the AAT gene. Accumulation of mutated AAT protein aggregates in hepatocytes leads to endoplasmic reticulum (ER) stress resulting in impairment of liver functions and in some cases hepatocellular carcinoma, whereas decline of AAT levels in sera is responsible for pulmonary emphysema. In critical cases of liver ailments, the only option for treatment is liver transplantation, whereas AAT replacement therapy is followed in case of emphysema. As hepatocytes are the primary affected cells in AATD, we investigated whether transplantation of bone marrow‐derived stem cells in transgenic mice expressing human AATZ (the Z variant of AAT) confers any competitive advantages compared to host cells for pathological improvement, if any. Mouse bone marrow (BM) progenitors and human mesenchymal stem cells (MSCs) appear to contribute in replacement of 40% and 13% host hepatocytes, respectively. Transplantation of cells resulted in decline of globule‐containing hepatocytes, improvement in proliferation of globule‐devoid hepatocytes from the host‐derived hepatocytes and potentially donor‐derived cells, as compared to AATZ globule containing hepatocytes. Further analyses revealed that transplantation partially improves liver pathology in terms of inflammatory response, fibrosis and apoptotic death of hepatocytes. Cell therapy was also found to improve liver glycogen storage and sera glucose level in the PiZ mice. These overall improvements in liver pathology were not restricted to the transplantation of mouse BM cells. Preliminary results also showed that in the case of human BM‐derived MSCs the globule‐containing hepatocytes declined and donor‐derived cells expressed human AAT protein. Conclusion: These results suggest that bone marrow stem cell transplantation may be a promising therapy in the future for AATD related liver disease. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 05 janvier 2017
    Luca Maroni, Simon D. Hohenester, Stan F.J. van de Graaf, Dagmar Tolenaars, Krijn van Lienden, Joanne Verheij, Marco Marzioni, Tom H. Karlsen, Ronald P.J. Oude Elferink, Ulrich Beuers
    Knockout of the Primary Sclerosing Cholangitis‐Risk Gene Fut2 Causes Liver Disease in Mice
    The etiopathogenesis of primary sclerosing cholangitis (PSC) is unknown. Genetic variants of fucosyltransferase 2 (FUT2) have been identified in genome‐wide association studies as risk factor for PSC. We investigated the role of Fut2 in murine liver pathophysiology by studying Fut2‐/‐ mice. Fut2‐/‐ mice were viable and fertile, had lower body weight than wild type (wt) littermates and grey fur, as described earlier. Half of the Fut2‐/‐ mice showed serum bile salt levels 40 times higher than wt (Fut2‐/‐high), whereas the remainder were normocholanemic (Fut2‐/‐low). Fut2‐/‐ mice showed normal serum liver tests, bile flow, biliary bile salt secretion, fecal bile salt loss, and expression of major hepatocellular bile salt transporters and Cyp7a1, the key regulator of bile salt synthesis, indicating that elevated serum bile salts in Fut2‐/‐high mice were not explained by cholestasis. Fut2‐/‐high mice, but not Fut2‐/‐low mice were sensitive to hydrophobic bile salt feeding (0.3% glycochenodeoxycholate); they rapidly lost weight, showed elevation of serum liver tests (ALP, AST, ALT) and areas of liver parenchymal necrosis. Histomorphological evaluation revealed presence of paraportal shunting vessels, increased numbers of portal vascular structures, wall thickening of some portal arteries and occurrence of periductal fibrosis in Fut2‐/‐high mice more than Fut2‐/‐low mice and not wt mice. Unconjugated bilirubin and ammonia were or tended to be elevated in Fut2‐/‐high mice only. Portosystemic shunting was demonstrated by portal angiography which disclosed virtually complete portosystemic shunting in Fut2‐/‐high mice, discrete portosystemic shunting in Fut2‐/‐low mice and no shunting in wt littermates. Conclusion: Liver pathology in Fut2‐/‐ mice is dominated by consequences of portosystemic shunting resulting in microcirculatory disturbances, mild (secondary) periductal fibrosis and sensitivity towards human bile salt toxicity. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Jeudi 05 janvier 2017
    Giulia Varrasso, Amalia Schiavetti, Silvia Lanciotti, Maria Sapio, Eva Ferrara, Alessandra De Grazia, and Anna Clerico
    Propranolol as First Line Treatment for Life‐threatening Diffuse Infantile Hepatic Hemangioma: A Case Report
    n/a


    Date de mise en ligne : Jeudi 29 décembre 2016
    Dennis L. Shung, Guadalupe Garcia‐Tsao
    Liver Capsule: Portal Hypertension and Varices: Pathogenesis, Stages and Management
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Manuela Sabelli, Giuliana Montosi, Cinzia Garuti, Angela Caleffi, Stefania Oliveto, Stefano Biffo, Antonello Pietrangelo
    Human macrophage ferroportin biology and the basis for the Ferroportin Disease
    Ferroportin (FPN1) is the sole iron‐exporter in mammals but its cell–specific function and regulation are still elusive. This study aims at studying FPN1 expression in human macrophages, the cells that mostly contribute on a daily basis to plasma iron turnover and are central in the pathogenesis of the disease due to lack‐of‐function FPN1 mutations, the Ferroportin Disease (FD). We characterized FPN1 protein expression and traffic by confocal microscopy, western blot, gel‐filtration and immunoprecipitation studies in macrophages from blood donors and patients with either FPN1 p.A77D, p.G80S and p.Val162del lack‐of‐function or p.A69T gain‐of‐function mutations. We found that in normal macrophages FPN1 cycles in the early endocytic compartment, does not multimerize, and is promptly degraded by hepcidin, its physiologic inhibitor, within 3‐6 hours. In FD macrophages, endogenous FPN1 showed a similar localization, except for higher accumulation in lysosomes. However, in contrast with previous studies using overexpressed mutant protein in cell lines, FPN1 could still reach the cell surface and be normally internalized and degraded upon exposure to hepcidin. However, when FD macrophages were exposed to large amount of heme iron, differently from donor and p.A69T macrophages, FPN1 could no longer reach the cell surface leading to intracellular iron retention. Conclusion. FPN1 cycles as a monomer within the endocytic/plasma membrane compartment and responds to its physiologic inhibitor, hepcidin, in both donor and FD cells. However, in FD, FPN1 fails to reach the cell surface when cells undergo high iron turnover. Our findings provide a basis for the FD characterized by a preserved iron transfer in the enterocytes (i.e. cells with low iron turnover) and iron retention in cells exposed to high iron flux, such as liver and spleen macrophages. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Yameng Sun, Jialing Zhou, Lin Wang, Xiaoning Wu, Yongpeng Chen, Hongxin Piao, Lungen Lu, Wei Jiang, Youqing Xu, Bo Feng, Yuemin Nan, Wen Xie, Guofeng Chen, Huanwei Zheng, Hai Li, Huiguo Ding, Hui Liu, Fudong Lv, Chen Shao, Tailing Wang, Xiaojuan Ou, Bingqiong Wang, Shuyan Chen, Aileen Wee, Neil D. Theise, Hong You, Jidong Jia
    New Classification of Liver Biopsy Assessment for Fibrosis in Chronic Hepatitis B Patients Before and After Treatment
    Liver fibrosis is the net result of dynamic changes between fibrogenesis and fibrolysis. Evidence has shown that antiviral therapy can reverse liver fibrosis or even early cirrhosis. However, the current evaluation systems mainly focus on the severity, but not the dynamic changes of fibrosis. Here, we propose a new classification to evaluate the dynamic changes in the quality of fibrosis, namely: predominantly progressive (thick/broad/loose/pale septa with inflammation), predominately regressive (delicate/thin/dense/splitting septa), and indeterminate which displayed an overall balance between progressive and regressive scarring. Then we used this classification to evaluate 71 paired liver biopsies of chronic hepatitis B patients before and after entecavirbased therapy for 78 weeks. Progressive, indeterminate and regressive were seen in 58%, 29% and 13% of patients before treatment, versus in 11%, 11% and 78% after treatment. Out of the 55 patients who showed predominantly regressive changes on post‐treatment liver biopsy, 29 cases (53%) had fibrosis improvement of at least one Ishak stage, and more interestingly, 25 cases (45%) had significant improvement in terms of Laennec substage, collagen percentage area and liver stiffness despite remaining in the same Ishak stage. Conclusions: This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of anti‐viral therapy. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Elizabeth A. O'Hare, Rongze Yang, Laura Yerges‐Armstrong, Urmilla Sreenivasan, Rebecca McFarland, Carmen C. Leitch, Meredith H. Wilson, Shilpa Narina, Alexis Gorden, Kathy Ryan, Alan R. Shuldiner, Steve A. Farber, G. Craig Wood, Christopher D. Still, Glenn S. Gerhard, Janet D. Robishaw, Carole Sztalryd, Norann A. Zaghloul
    TM6SF2 rs58542926 impacts lipid processing in liver and small intestine
    The transmembrane 6 superfamily member 2 (TM6SF2) loss‐of‐function variant, rs58542926, is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis, but is paradoxically associated with lower levels of hepatic‐derived triglyceride‐rich lipoproteins (TRLs). TM6SF2 is expressed predominately in liver and small intestine, sites for triglyceride rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System (GHS) in PA and from 3,556 study participants enrolled in the Amish Complex Disease Research Program (ACDRP). Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high fat challenge, carriers in the ACDRP cohort exhibited significantly lower postprandial serum triglycerides suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco‐2 enterocytes. In both systems TM6SF2‐deficiency resulted in defects in small intestine metabolism in response to dietary lipids including significantly increased lipid accumulation, decreased lipid clearance and increased endoplasmic reticulum stress. Conclusions: These data strongly support a role of TM6SF2 in regulation of postprandial lipemia potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically‐ and intestinally‐derived TRLs. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Jan Görtzen, Jonel Trebicka
    Rho‐Kinase inhibition is beneficial in fibrosis
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Yan‐Dan Ren, Zhen‐Shi Ye, Liu‐Zhu Yang, Li‐Xin Jin, Wen‐Jun Wei, Yong‐Yue Deng, Xiao‐Xiao Chen, Chuan‐Xing Xiao, Xiao‐Fang Yu, Hong‐Zhi Xu, Li‐Zhu Xu, Yun‐Na Tang, Fei Zhou, Xue‐Lian Wang, Mei‐Ya Chen, Li‐Gang Chen, Mei‐Zhu Hong, Jian‐Lin Ren, Jin‐Shui Pan
    Fecal Microbiota Transplantation Induces HBeAg Clearance in Patients with Positive HBeAg after Long‐Term Antiviral Therapy
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Kyle S. McCommis, Wesley T. Hodges, Elizabeth M. Brunt, ILKe Nalbantoglu, William G. McDonald, Christopher Holley, Hideji Fujiwara, Jean E. Schaffer, Jerry R. Colca, Brian N. Finck
    Targeting the Mitochondrial Pyruvate Carrier Attenuates Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis
    Diseases of the liver related to metabolic syndrome have emerged as the most common and undertreated hepatic ailments. The cause of nonalcoholic fatty liver disease (NAFLD) is the aberrant accumulation of lipid in hepatocytes, though the mechanisms whereby this leads to hepatocyte dysfunction, death, and hepatic fibrosis are still unclear. Insulin‐sensitizing thiazolidinediones have shown efficacy in treating nonalcoholic steatohepatitis (NASH), but their widespread use is constrained by dose‐limiting side effects thought to be due to activation of the peroxisome proliferator‐activated receptor γ (PPARγ). We sought to determine whether a next‐generation thiazolidinedione with markedly diminished ability to activate PPARγ (MSDC‐0602) would retain its efficacy for treating NASH in a rodent model. We also determined whether some or all of these beneficial effects would be mediated via an inhibitory interaction with the mitochondrial pyruvate carrier 2 (MPC2), which was recently identified as a mitochondrial binding site for thiazolidinediones, including MSDC‐0602. We found that MSDC‐0602 prevented and reversed liver fibrosis and suppressed expression of markers of stellate cell activation in livers of mice fed a diet rich in trans‐fatty acids, fructose, and cholesterol. Moreover, mice with liver‐specific deletion of MPC2 were protected from development of NASH on this diet. Finally, MSDC‐0602 directly reduced hepatic stellate cell activation in vitro, and MSDC‐0602 treatment or hepatocyte MPC2 deletion also limited stellate cell activation indirectly by affecting secretion of exosomes from hepatocytes. Conclusion: Collectively, these data demonstrate the effectiveness of MSDC‐0602 for attenuating NASH in a rodent model and suggest that targeting hepatic MPC2 may be an effective strategy for pharmacologic development. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Wai‐Kay Seto, Thomas Sau‐Yan Chan, Yu‐Yan Hwang, Danny Ka‐Ho Wong, James Fung, Kevin Sze‐Hang Liu, Harinder Gill, Yuk‐Fai Lam, Eric H.Y. Lau, Ka‐Shing Cheung, Albert K.W. Lie, Ching‐Lung Lai, Yok‐Lam Kwong, Man‐Fung Yuen
    Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study
    Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)‐negative, antibody to hepatitis B core antigen (anti‐HBc) positive patients after allogeneic hematopoietic stem cell transplantation (HSCT) have not been prospectively studied. HBsAg‐negative, anti‐HBc positive patients with undetectable HBV DNA undergoing allogeneic HSCT were prospectively monitored every 4 weeks. The primary endpoint was HBV reactivation, defined as detectable HBV DNA (≄10 IU/mL). Secondary endpoints included overall survival, HBsAg‐positivity, and changes in liver biochemistry and antibody to HBsAg levels. Among 297 allogeneic HSCT recipients, 85 (28.7%) were HBsAg‐negative, anti‐HBc positive, of which 62 patients were recruited and monitored for a median of 48 (4‐104) weeks. The 2‐year cumulative HBV DNA detectability rate was 40.8%, occurring at a median of 44 (8‐100) weeks. Multivariate analysis showed age ≄50 years (p=0.004, HR 8.2) and chronic graft‐versus‐host disease (GVHD) (p=0.010, HR 5.3) were significantly associated with HBV reactivation. Other clinical parameters, including baseline anti‐HBs status, serial changes in anti‐HBs levels and donor serology were not associated with HBV reactivation. Patients <50 years and without chronic GVHD, compared with the remaining patient cohort, had a significantly lower 2‐year cumulative HBV reactivation rate (5.6% versus 65.0%, p=0.004). Entecavir successfully suppressed HBV DNA to undetectable levels, with none of the case developing biochemical hepatitis. In conclusion, HBsAg‐negative, anti‐HBc positive patients had a high rate of HBV reactivation after allogeneic HSCT. Determinants of HBV reactivation include age ≄50 years and chronic GVHD. Treatment strategies based on these parameters may prevent HBV reactivation and subsequent complications. (ClinicalTrials.gov identifier NCT01481649) This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Puneeta Tandon, Maitreyi Raman, Marina Mourtzakis, Manuela Merli
    A Practical Approach to Nutritional Screening and Assessment in Cirrhosis
    Malnutrition is one of the most common complications of cirrhosis, associated with an increased risk of morbidity and mortality. As a potentially modifiable condition, it is of particular relevance to identify malnourished patients so that nutritional therapy can be instituted. Nutrition screening and assessment are currently performed infrequently in patients with cirrhosis. The reasons for this are multifactorial including the absence of a validated “rapid” screening tool, multiple definitions of what constitutes malnutrition, and challenges with interpreting body composition and laboratory results in the setting of volume overload and liver dysfunction. This article will summarize the clinically relevant evidence and present key issues, tools, and clinical options that are applicable to patients with cirrhosis. The definition, etiology and clinically relevant outcomes associated with malnutrition are reviewed. Rapid nutritional screening is differentiated from more detailed nutritional assessment. Nutritional assessment in special populations including women, the obese, and the role of inflammation are discussed. Multicenter studies using a common nutritional screening/assessment strategy are the next steps to fast‐track adoption and implementation of nutrition‐related evaluations into routine clinical practice. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Tammy T. Chang
    Reply: Rho‐Kinase inhibition is beneficial in fibrosis
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Kasper S. Wang, Greg Tiao, Lee M. Bass, Paula M. Hertel, Douglas Mogul, Nanda Kerkar, Matthew Clifton, Colleen Azen, Laura Bull, Philip Rosenthal, Dylan Stewart, Riccardo Superina, Ronen Arnon, Molly Bozic, Mary L. Brandt, Patrick A. Dillon, Annie Fecteau, Kishore Iyer, Binita Kamath, Saul Karpen, Frederick Karrer, Kathleen M. Loomes, Cara Mack, Peter Mattei, Alexander Miethke, Kyle Soltys, Yumirle P. Turmelle, Karen West, Jessica Zagory, Cat Goodhue, Benjamin L. Shneider,
    Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis
    To evaluate the efficacy of non‐transplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 Alagille syndrome (ALGS), 16 Familial Intrahepatic Cholestasis‐1 (FIC1), 18 Bile Salt Export Pump (BSEP) disease, & 4 others with low γ‐glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBD), 11 ileal exclusions (IE) and 7 gallbladder‐to‐colon diversion (GBC). Serum total bilirubin decreased after PEBD in FIC1 (8.1±4.0 vs. 2.9±4.1 mg/dL, preop vs. 12‐24 months postop respectively, p=0.02) but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695±465 vs. 457±319 mg/dL; preop vs. 12‐24 months postop respectively; p=0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182±70 vs. 260±73 IU/L, preop vs. 24 mos. p=0.03) but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS: 100% vs. 9% severe, FIC1: 64% vs. 10%; BSEP: 50% vs. 20%, preop vs. >24 mos. postop respectively, p<0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%, p=0.03. Overall, there were 15 major complications after surgery. 12 patients (3 ALGS, 3 FIC1, 6 BSEP) subsequently underwent liver transplantation. Conclusion: This is the first multi‐center analysis of non‐transplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally although not uniformly result in improvement of pruritus and cholestasis. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    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 SREBP pathway suppresses hepatocellular carcinoma through repressing inflammation
    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 gp78 or SCAP 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 (DEN)‐induced HCC progression through down‐regulating tumor promoting cytokines including IL‐6, TNF‐α and IL‐1ÎČ. 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. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Dieter HĂ€ussinger, Verena Keitel
    Dual role of the bile acid receptor TGR5 for hepatic lipid metabolism in feast and famine
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Tali Lanton, Anat Shriki, Yael Nechemia‐Arbely, Rinat Abramovitch, Orr Levkovitch, Revital Adar, Nofar Rosenberg, Mor Paldor, Daniel Goldenberg, Amir Sonnenblick, Amnon Peled, Stefan Rose‐John, Eithan Galun, Jonathan H. Axelrod
    IL6‐Dependent Genomic Instability Heralds Accelerated Carcinogenesis Following Liver Regeneration on a Background of Chronic Hepatitis
    Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For these patients surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long‐term survival of these patients. We have previously shown that partial hepatectomy (PH) in Mdr2 knockout (Mdr2‐/‐) mice, a model of chronic inflammation‐associated liver cancer, significantly accelerates hepatocarcinogenesis. Here, we explore the post‐surgical mechanisms that drive accelerated hepatocarcinogenesis in Mdr2‐/‐ mice by perioperative pharmacological inhibition of interleukin‐6 (IL6), which is a crucial liver regeneration priming cytokine. We demonstrate that inhibition of IL6 signaling dramatically impedes tumorigenesis following PH without compromising survival or liver mass recovery. IL6 blockade significantly inhibited hepatocyte cell cycle progression while promoting a hypertrophic regenerative response, without increasing apoptosis. Mdr2‐/‐ mice contain hepatocytes with a notable persistent DNA damage response (γH2AX, 53BP1) due to chronic inflammation. We now show that liver regeneration in this microenvironment leads to a striking increase in hepatocytes bearing micronuclei – a marker of genomic instability, which is suppressed by IL6 blockade. Conclusion: Our findings indicate that genomic instability derived during the IL6‐mediated liver regenerative response within a milieu of chronic inflammation links PH to accelerated hepatocarcinogenesis. This suggests a new therapeutic approach through the usage of an anti‐IL6 treatment to extend the tumor‐free survival of patients undergoing surgical resection. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Yi‐Ling Qiu, Jing‐Yu Gong, Jia‐Yan Feng, Ren‐Xue Wang, Jun Han, Teng Liu, Yi Lu, Li‐Ting Li, Mei‐Hong Zhang, Jonathan A. Sheps, Neng‐Li Wang, Yan‐Yan Yan, Jia‐Qi Li, Lian Chen, Christoph H. Borchers, Bence Sipos, A. S. Knisely, Victor Ling, Qing‐He Xing, Jian‐She Wang
    Defects in MYO5B are associated with a spectrum of previously undiagnosed low γ‐glutamyltransferase cholestasis
    Hereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase activity (GGT) is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin 5B (MYO5B) cause microvillus inclusion disease (MVID, MIM251850) with recurrent watery diarrhea. Cholestasis reported as an atypical presentation in MVID has been considered a side effect of parenteral alimentation. Here, however, we report ten patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who neither had recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; three are sporadic. Cholestasis in two patients was progressive, in three recurrent, in two transient and in three uncategorized due to insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of BSEP at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11/38 vs. 0/13). Conclusion: MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile‐acid excretion, resulting in a spectrum of cholestasis without diarrhea. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Dan Li, Xuefeng Liu, Jian Zhou, Jie Hu, Dongdong Zhang, Jing Liu, Yanyan Qiao, Qimin Zhan
    LncRNA HULC modulates the phosphorylation of YB‐1 through serving as a scaffold of ERK and YB‐1 to enhance hepatocarcinogenesis
    Dysregulated expressions of lncRNAs have been reported in many types of cancers, indicating that they may play critical roles in tumorigenesis. HULC (Highly Up‐regulated in Liver Cancer) was firstly characterized in hepatocelluar carcinoma (HCC). However, the detailed mechanisms of HULC remain unclear. Here, we demonstrated a novel mechanism by which lncRNA plays oncogenic roles through modulating the phosphorylation status of its interaction protein. First, we validated that the remarkably increased expression levels of HULC in HCC tissues compared to their adjacent non‐cancerous tissues. Furthermore, the upregulation of HULC was correlated with grading and overall survival. Meanwhile, HULC could promote cell proliferation, migration and invasion in vitro and also inhibit cisplatin‐induced apoptosis. Moreover, we have shown for the first time that HULC specifically binds to YB‐1 protein both in vitro and in vivo. YB‐1 is a major component of translationally inactive messenger ribonucleoprotein particles (mRNPs) which keeps mRNAs in a silent state. Our study further demonstrated that HULC could promote the phosphorylation of YB‐1 protein, which leads to the release of YB‐1 from its bound mRNAs. As a consequence, the translations of silenced oncogenic mRNAs would be activated, including Cyclin D1, Cyclin E1, MMP3 and etc. In addition, we have found that HULC promotes the phosphorylation of YB‐1 protein mainly through ERK kinase. Conclusion: We demonstrate that lncRNA HULC promotes the phosphorylation of YB‐1 via ERK pathway, and in turn regulates the interaction of YB‐1 with certain oncogenic mRNAs, and consequently accelerates the translation of these mRNAs in the process of tumorigenesis. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Kris V. Kowdley, Vinay Sundaram, Christie Y. Jeon, Kamran Qureshi, Nyan L. Latt, Amandeep Sahota, Stephen Lott, Michael P. Curry, Naoki Tsai, Nathorn Chaiyakunapruk, Yoori Lee, Jorg Petersen, Peter Buggisch
    Eight weeks of Ledipasvir/Sofosbuvir is effective for selected patients with genotype 1 Hepatitis C virus infection
    Eight weeks duration of ledipasvir/sofosbuvir (LDV/SOF) can be considered in genotype 1 hepatitis C virus (HCV) infected patients who are treatment naive, non‐cirrhotic and have pre‐treatment viral load < 6 million IU/ml. The effectiveness of this regimen, however, has not been fully confirmed by real‐world experience. Using data from real‐world cohorts, we aimed to determine the effectiveness of 8 weeks of LDV/SOF treatment, examine variables associated with relapse after treatment with this regimen, and compare the effectiveness of 8 weeks and 12 weeks of LDV/SOF treatment. To evaluate the effectiveness of 8 weeks of therapy and characteristics associated with relapse, we utilized individual patient data from IFI Institut fĂŒr InterdisziplinĂ€re Medizin (IFI), Burmans pharmacy, and Kaiser Permanente Southern California. All patients had fibrosis staging assessed with biopsy, transient elastography or serum biomarkers. We also performed a systematic review and meta‐analysis of 6 additional real world cohorts, to compare effectiveness of 8 weeks to 12 weeks duration. In our pooled data analysis, 634 patients were treated for 8 weeks with LDV/SOF, of which all patients had outcomes of cure or relapse, without loss to follow‐up. Per protocol sustained virologic response (SVR)12 rates were 98.1% (622/634) in the full cohort and 97.9% (571/583) among treatment eligible patients. Exact logistic regression revealed no specific patient characteristics associated with relapse. Our meta‐analysis of 6 additional real world cohorts, comprised of 5,637 patients, demonstrated similar risk for relapse between 8 weeks and 12 weeks of LDV/SOF (RR=0.99, 95% CI 0.98‐1.00). Conclusions: An 8‐week duration of treatment with LDV/SOF is highly effective in properly selected patients. Greater utilization of this regimen is recommended. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 27 décembre 2016
    Guojun Hou, Lei Chen, Gang Liu, Liang Li, Yuan Yang, He‐Xin Yan, Hui‐Lu Zhang, Jing Tang, Ying Cheng Yang, Ximeng Lin, Xin Chen, Gui juan Luo, Yanjing Zhu, Shanhua Tang, Jin Zhang, Hui Liu, Qingyang Gu, Ling‐Hao Zhao, Yixue Li, Lei Liu, Weiping Zhou, Hongyang Wang
    Aldehyde Dehydrogenase‐2 (ALDH2) Opposes HCC Progression By Regulating AMPK Signaling
    Potential biomarkers that can be used to determine prognosis and perform targeted therapies are urgently needed to treat patients with hepatocellular carcinoma (HCC). To meet this need, we performed a screen to identify functional genes associated with hepatocellular carcinogenesis and its progression at the transcriptome and proteome levels. We identified Aldehyde Dedydrogenase‐2 (ALDH2) as a gene of interest for further study. ALDH2 levels were significantly lower at the mRNA and protein level in tumor tissues than in normal tissues, and they were even lower in tissues that exhibited increased migratory capacity. A study of clinical associations showed that ALDH2 is correlated with survival and multiple migration‐associated clinicopathological traits including the presence of metastasis and portal vein tumor thrombus. The result of overexpressing or knocking down ALDH2 showed that this gene inhibited migration and invasion both in vivo and in vitro. We also found that ALDH2 altered the redox status of cells by regulating acetaldehyde levels and that it further activated the AMP‐activated protein kinase (AMPK) signaling pathway. CONCLUSIONS: Decreased levels of ALDH2 may indicate a poor prognosis in HCC patients, and forcing the expression of ALDH2 in HCC cells inhibited their aggressive behavior in vitro and in mice largely by modulating the activity of the ALDH2‐acetaldehyde‐redox‐AMPK axis. Therefore, identifying ALDH2 expression levels in HCC might be a useful strategy for classifying HCC patients and for developing potential therapeutic strategies that specifically target metastatic HCC. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Vendredi 23 décembre 2016
    Erfan Ayubi, Saeid Safiri, Mohadeseh Sani, Amin Doosti‐Irani, Ali Sanjari Moghaddam
    Effect of Metabolic syndrome on cardiovascular, hepatic events and death in CHB patients: Methodological issues
    n/a


    Date de mise en ligne : Vendredi 23 décembre 2016
    Jenny Yeuk‐Ki Cheng, Yee‐Kit Tse, Grace Lai‐Hung Wong
    Reply to Letter to the Editor by Erfan A et al.
    n/a


    Date de mise en ligne : Vendredi 23 décembre 2016
    Giovanni Brandi, Stefania De Lorenzo, Andrea Palloni, Guido Biasco, Francesco Tovoli
    Aspirin for cholangiocarcinoma prevention: new targets to shift the dogma from ascertained risk to possible prevention (Reply to: Risk Factors for Cholangiocarcinoma: Aspirin‐use and the Risk of Cholangiocarcinoma)
    n/a


    Date de mise en ligne : Vendredi 23 décembre 2016
    Umberto Cillo, Alessandro Vitale, Marina Polacco, Elisa Fasolo
    Liver transplantation for hepatocellular carcinoma through the lens of transplant benefit
    n/a


    Date de mise en ligne : Vendredi 23 décembre 2016
    Gordon D. McLaren, James C. Barton, Grant A. Ramm, Mary J. Emond, V. Nathan Subramaniam, Pradyumna D. Phatak, Paul C. Adams, Lawrie W. Powell, Lyle C. Gurrin, Gregory J. Anderson, Christine E. McLaren
    Reply to HEP 16‐0784.R1 and HEP 16‐0898
    n/a


    Date de mise en ligne : Mardi 20 décembre 2016
    Michael Trauner, Claudia Daniela Fuchs, Emina Halilbasic, Gustav Paumgartner
    New therapeutic concepts in bile acid transport and signaling for management of cholestasis
    The identification of the key regulators of bile acid synthesis and transport within the enterohepatic circulation has unravelled potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile acid receptors FXR and TGR5, the bile acid‐induced gut hormones FGF19 and GLP‐1, and the bile acid transport systems ASBT and NTCP within the enterohepatic circulation. Moreover, bile acid derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, the mechanisms of action and the clinical development of novel pharmacological strategies targeting bile acid transport and signaling in cholestatic liver diseases. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 20 décembre 2016
    Annalisa Berzigotti, AgustĂ­n Albillos, Candid Villanueva, Joan GenescĂĄ, Alba Ardevol, Salvador AugustĂ­n, Jose Luis Calleja, Rafael Bañares, Juan Carlos GarcĂ­a‐PagĂĄn, Francisco Mesonero, Jaime Bosch,
    Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: The sportdiet study
    Obesity increases the risk of clinical decompensation in cirrhosis, possibly by increasing portal pressure. Whether weight reduction can be safely achieved through lifestyle changes (diet and exercise) in overweight/obese patients with cirrhosis, and if weight loss reducesportal pressure in this setting is unknown. This prospective, multicentric, uncontrolled pilot study enrolled patients with compensated cirrhosis, portal hypertension (hepatic venous pressure gradient, HVPG≄ 6mmHg) and body mass index (BMI)≄26 Kg/m2 in an intensive 16‐week lifestyle intervention program (personalized hypocaloric normoproteic diet and 60 min/wk of supervised physical activity). We measured HVPG, body weight and composition, adipokines, health‐related quality‐of‐life and safety data prior and after the intervention. Changes in HVPG and body weight were pre‐defined as clinically relevant if ≄10% and ≄5%, respectively. Safety and body weight were re‐assessed after 6 months. 60 patients were included and 50 completed the study (56±8 y/o; 62% male; NASH etiology 24%; BMI 33.3±3.2Kg/m2; Child A 92%; HVPG ≄10 mmHg 72%). Lifestyle intervention significantly decreased body weight (average ‐5.0±4.0 Kg; p<0.0001), by ≄ 5% in 52% and ≄10% in 16%. HVPG also significantly decreased (from 13.9±5.6 mmHg to 12.3±5.2 mmHg, p<0.0001), by ≄10% in 42% and ≄20% in 24%. A ≄10% body weight loss was associated with a greater decrease in HVPG (‐23.7±19.9% vs. ‐8.2±16.6%,p=0.024). No episodes of clinical decompensation occurred. Weight loss achieved at 16‐wks was maintained at 6‐month; Child and MELD scores did not change. Conclusions. 16‐weeks of diet and moderate exercise were safe and reduced body weight and portal pressure in overweight/obese patients with cirrhosis and portal hypertension. This article is protected by copyright. All rights reserved.


    Date de mise en ligne : Mardi 20 décembre 2016
    Zongxin Ling, Xia Liu, Yiwen Cheng, Li Shao, Haiyin Jiang, Lanjuan Li
    Blood microbiota as a potential non‐invasive diagnostic biomarker for liver fibrosis in severely obese patients: Choose carefully
    n/a


    Date de mise en ligne : Mardi 20 décembre 2016
    Benjamin Lelouvier, Florence Servant, Michael Courtney, RĂ©my Burcelin, Jacques Amar
    Reply to HEP 16‐2001
    n/a


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


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


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


    Date de mise en ligne : Mardi 17 janvier 2017
    Senko Tsukuda, Koichi Watashi, Taichi Hojima, Masanori Isogawa, Masashi Iwamoto, Katsumi Omagari, Ryosuke Suzuki, Hideki Aizaki, Soichi Kojima, Masaya Sugiyama, Akiko Saito, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau, Takaji Wakita
    A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins
    Introduction of direct‐acting antivirals against hepatitis C virus (HCV) has provided a revolutionary improvement in the treatment outcome. In contrast to HCV, however, the strategy for developing new antiviral agents against hepatitis B virus (HBV), especially viral‐targeting compounds, is limited because HBV requires only four viral genes for its efficient replication/infection. Here, we identify an oligomeric flavonoid, proanthocyanidin (PAC) and its analogs, which inhibit HBV entry into host cells by targeting the HBV large surface protein (LHBs). Through cell‐based chemical screening, PAC was identified to inhibit HBV infection with little cytotoxic effect. PAC prevented the attachment of the preS1 region in the LHBs to its cellular receptor, sodium taurocholate cotransporting polypeptide (NTCP). PAC was shown to target HBV particles and impair their infectivity, whereas it did not affect the NTCP‐mediated bile acid transport activity. Chemical biological techniques demonstrated that PAC directly interacted with the region essential for receptor binding in the preS1 region in the LHBs protein. Importantly, PAC had a pan‐genotypic anti‐HBV activity and was also effective against a clinically relevant nucleoside analog‐resistant HBV isolate. We further showed that PAC augmented the ability of a nucleoside analog, tenofovir, to interrupt HBV spread over time in primary human hepatocytes by cotreatment. Moreover, derivative analysis could identify small molecules that demonstrated more‐potent anti‐HBV activity over PAC. Conclusion: PAC and its analogs represent a new class of anti‐HBV agents that directly target the preS1 region of the HBV large surface protein. These agents could contribute to the development of a potent, well‐tolerated, and broadly active inhibitor of HBV infection. (Hepatology 2016).


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


    Date de mise en ligne : Mercredi 11 janvier 2017
    Elisabeth M. G. de Vries, Manon de Krijger, Martti FĂ€rkkilĂ€, Johanna Arola, Peter Schirmacher, Daniel Gotthardt, Benjamin Goeppert, Palak J. Trivedi, Gideon M. Hirschfield, Henriette Ytting, Ben Vainer, Henk R. van Buuren, Katharina Biermann, Maren H. Harms, Olivier Chazouilleres, Dominique Wendum, Astrid D. Kemgang, Roger W. Chapman, Lai Mun Wang, Kate D. Williamson, Annette S. H. Gouw, Valerie Paradis, Christine Sempoux, Ulrich Beuers, Stefan G. HĂŒbscher, Joanne Verheij, Cyriel Y. Ponsioen
    Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study
    Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC‐related death and liver transplantation), 2 (liver transplantation), and 3 (liver‐related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow‐up was 142 months. During follow‐up, 31 patients died (20 PSC‐related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver‐related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49‐6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17‐3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10‐2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10‐1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19‐5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09‐3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22‐3.77). Interobserver agreement was moderate for Nakanuma stage (Îș = 0.56) and substantial for Nakanuma component fibrosis (Îș = 0.67), Ishak stage (Îș = 0.64), and Ludwig stage (Îș = 0.62). Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system—incorporating features of chronic biliary disease—again showed the strongest predictive value. (Hepatology 2016).


    Date de mise en ligne : Mardi 10 janvier 2017
    Sujit K. Mohanty, Bryan Donnelly, Inna Lobeck, Ashley Walther, Phylicia Dupree, Abigail Coots, Jaroslaw Meller, Monica McNeal, Karol Sestak, Greg Tiao
    The SRL peptide of rhesus rotavirus VP4 protein governs cholangiocyte infection and the murine model of biliary atresia
    Biliary atresia (BA) is a neonatal obstructive cholangiopathy that progresses to end‐stage liver disease, often requiring transplantation. The murine model of BA, employing rhesus rotavirus (RRV), parallels human disease and has been used to elucidate mechanistic aspects of a virus induced biliary cholangiopathy. We previously reported that the RRV VP4 gene plays an integral role in activating the immune system and induction of BA. Using rotavirus binding and blocking assays, this study elucidated how RRV VP4 protein governs cholangiocyte susceptibility to infection both in vitro and in vivo in the murine model of BA. We identified the amino acid sequence on VP4 and its cholangiocyte binding protein, finding that the sequence is specific to those rotavirus strains that cause obstructive cholangiopathy. Pretreatment of murine and human cholangiocytes with this VP4‐derived peptide (TRTRVSRLY) significantly reduced the ability of RRV to bind and infect cells. However, the peptide did not block cholangiocyte binding of TUCH and Ro1845, strains that do not induce murine BA. The SRL sequence within TRTRVSRLY is required for cholangiocyte binding and viral replication. The cholangiocyte membrane protein bound by SRL was found to be Hsc70. Inhibition of Hsc70 by small interfering RNAs reduced RRV's ability to infect cholangiocytes. This virus‐cholangiocyte interaction is also seen in vivo in the murine model of BA, where inoculation of mice with TRTRVSRLY peptide significantly reduced symptoms and mortality in RRV‐injected mice. Conclusion: The tripeptide SRL on RRV VP4 binds to the cholangiocyte membrane protein Hsc70, defining a novel binding site governing VP4 attachment. Investigations are underway to determine the cellular response to this interaction to understand how it contributes to the pathogenesis of BA. (Hepatology 2016)


    Date de mise en ligne : Mardi 10 janvier 2017
    Correction
    Correction
    n/a


    Date de mise en ligne : Vendredi 06 janvier 2017
    Gro Askgaard, David A. Leon, Mette S. KjĂŠr, Thomas Deleuran, Thomas A. Gerds, Janne S. Tolstrup
    Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study
    Alcoholic liver cirrhosis is usually preceded by many years of heavy drinking, in which cessation in drinking could prevent the disease. Alcohol problems are not consistently managed in hospital patients. We followed all Danish patients with an initial hospital contact with alcohol problems (intoxication, harmful use, or dependence) during 1998‐2002 for alcoholic liver cirrhosis development (n = 36,044). In this registry‐based cohort, we identified predictors of the absolute risk for alcoholic liver cirrhosis. Incidence rate ratios (IRRs) were estimated as the incidence rate of alcoholic liver cirrhosis in these patients relative to the general population. Age and alcohol diagnosis were significant predictors of alcoholic liver cirrhosis risk in men and women, whereas civil status, education, and type of hospital care were not. In men, the 15‐year absolute risk was 0.7% (95% confidence interval [CI], 0.4, 0.8) for 20‐29 years, 5.5% (95% CI, 4.9, 6.2) for 30‐39 years, 9.8% (95% CI, 9.0, 11) for 40‐49 years, 8.9% (95% CI, 8.1, 9.8) for 50‐59 years, 6.2% (95% CI, 5.1, 7.2) for 60‐69 years, and 2.5% (95% CI, 1.7, 3.3) for 70‐84 years. According to alcohol diagnosis in men, the 15‐year absolute risk was 2.6% (95% CI, 2.3, 2.9) for intoxication, 7.7% (95% CI, 6.4, 7.9) for harmful use, and 8.8% (95% CI, 8.2, 9.4) for dependence. The IRR for alcoholic liver cirrhosis in the cohort relative to the general population was 11 (95% CI, 10, 12) in men and 18 (95% CI, 15, 21) in women. Conclusion: Hospital patients with alcohol problems had a much greater risk for alcoholic liver cirrhosis compared to the general population. The risk was particularly increased for patients 40‐59 years and for patients diagnosed with harmful use or dependence. (Hepatology 2016).


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


    Date de mise en ligne : Vendredi 06 janvier 2017
    Estella M. Alonso, Simon P. Horslen, Edward M. Behrens, Edward Doo
    Pediatric acute liver failure of undetermined cause: A research workshop
    Pediatric acute liver failure (PALF) is a potentially devastating condition that occurs in previously healthy children of all ages and frequently leads to a rapid clinical deterioration. An identified cause for liver injury is lacking in approximately 30% of cases. Children with undetermined diagnosis have lower spontaneous survival and higher rates of transplantation and death than other diagnostic groups. A single‐day workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together clinicians and basic scientists to integrate aligned research findings and develop a foundation for new mechanistic studies and future treatment trials. The clinical phenotype of indeterminate PALF shares important similarities to the hyperinflammatory state characteristic of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). A failure of cytotoxic T cells to limit or contract inflammatory responses may propagate injury and lead to a local and systemic milieu that does not support normal hepatic regeneration. Evidence was presented that bone marrow (BM)‐derived Sinusoidal endothelial cell PROgenitor Cells (sprocs) play a vital role in hepatic regeneration. Overwhelming systemic inflammatory responses may suppress mobilization of BM sprocs and dampen hepatic recovery. Conclusion: Experience gained through treatment trials of HLH and MAS in childhood may inform study design for therapy of PALF. Successful approaches to limiting neuroinflammation through reduction of systemic inflammation and standardized neuroprotection protocols that limit glial injury could significantly improve intact survival. Finally, given that PALF is a rare disease, investigative efforts must include broad multicenter collaboration and careful stewardship of biorepository specimens. (Hepatology 2016).


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


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


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


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


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


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


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


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


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


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


    Date de mise en ligne : Vendredi 30 décembre 2016
    Imanol Zubiete‐Franco, Pablo FernĂĄndez‐Tussy, LucĂ­a Barbier‐Torres, Jorge Simon, David FernĂĄndez‐Ramos, Fernando Lopitz‐Otsoa, Virginia GutiĂ©rrez‐de Juan, Sergio LĂłpez de Davalillo, Antonio MartĂ­n Duce, Paula Iruzubieta, Daniel Taibo, Javier Crespo, Juan Caballeria, Erica Villa, Igor Aurrekoetxea, Patricia Aspichueta, Marta Varela‐Rey, Shelly C Lu, JosĂ© M. Mato, Naiara Beraza, Teresa C. Delgado, MarĂ­a L MartĂ­nez‐Chantar
    Deregulated neddylation in liver fibrosis
    Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin‐like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation– and CCl4‐induced fibrosis. Importantly, neddylation inhibition, by using the pharmacological inhibitor, MLN4924, reduced liver injury, apoptosis, inflammation, and fibrosis by targeting different hepatic cell types. On one hand, increased neddylation was associated with augmented caspase 3 activity in bile‐acid–induced apoptosis in mouse hepatocytes whereas neddylation inhibition ameliorated apoptosis through reduction of expression of the Cxcl1 and Ccl2 chemokines. On the other hand, chemokine receptors and cytokines, usually induced in activated macrophages, were reduced after neddylation inhibition in mouse Kupffer cells. Under these circumstances, decreased hepatocyte cell death and inflammation after neddylation inhibition could partly account for reduction of hepatic stellate cell (HSC) activation. We provide evidence that augmented neddylation characterizes activated HSCs, suggesting that neddylation inhibition could be important for resolving LF by directly targeting these fibrogenic cells. Indeed, neddylation inhibition in activated HSCs induces apoptosis in a process partly mediated by accumulation of c‐Jun, whose cullin‐mediated degradation is impaired under these circumstances. Conclusion: Neddylation inhibition reduces fibrosis, suggesting neddylation as a potential and attractive therapeutic target in liver fibrosis. (Hepatology 2016).


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


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


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


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


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


    Date de mise en ligne : Jeudi 29 décembre 2016
    Palittiya Sintusek, Anil Dhawan
    Lipid and copper metabolism in humans with wilson disease: Enigmatic relationship
    n/a


    Date de mise en ligne : Jeudi 29 décembre 2016
    Correction
    Correction
    n/a


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


    Date de mise en ligne : Jeudi 29 décembre 2016
    Melanie Tran, Li Wang
    Preserving LXR by inhibiting T39: A step closer to treating atherosclerosis and steatohepatitis?
    n/a


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


    Date de mise en ligne : Samedi 24 décembre 2016
    Maximilian Hatting, Frank Tacke
    From NAFLD to HCC: Is IL‐17 the crucial link?
    n/a


    Date de mise en ligne : Samedi 24 décembre 2016
    Jari E. Kaikkonen, Peter WĂŒrtz, Emmi Suomela, Miia Lehtovirta, Antti J. Kangas, Antti Jula, Vera MikkilĂ€, Jorma S.A. Viikari, Markus Juonala, Tapani Rönnemaa, Nina Hutri‐KĂ€hönen, Mika KĂ€hönen, Terho LehtimĂ€ki, Pasi Soininen, Mika Ala‐Korpela, Olli T. Raitakari
    Metabolic profiling of fatty liver in young and middle‐aged adults: Cross‐sectional and prospective analyses of the Young Finns Study
    Nonalcoholic fatty liver is associated with obesity‐related metabolic disturbances, but little is known about the metabolic perturbations preceding fatty liver disease. We performed comprehensive metabolic profiling to assess how circulating metabolites, such as lipoprotein lipids, fatty acids, amino acids, and glycolysis‐related metabolites, reflect the presence of and future risk for fatty liver in young adults. Sixty‐eight lipids and metabolites were quantified by nuclear magnetic resonance metabolomics in the population‐based Young Finns Study from serum collected in 2001 (n = 1,575), 2007 (n = 1,509), and 2011 (n = 2,002). Fatty liver was diagnosed by ultrasound in 2011 when participants were aged 34‐49 years (19% prevalence). Cross‐sectional associations as well as 4‐year and 10‐year risks for fatty liver were assessed by logistic regression. Metabolites across multiple pathways were strongly associated with the presence of fatty liver (P < 0.0007 for 60 measures in age‐adjusted and sex‐adjusted cross‐sectional analyses). The strongest direct associations were observed for extremely large very‐low‐density lipoprotein triglycerides (odds ratio [OR] = 4.86 per 1 standard deviation, 95% confidence interval 3.48‐6.78), other very‐low‐density lipoprotein measures, and branched‐chain amino acids (e.g., leucine OR = 2.94, 2.51‐3.44). Strong inverse associations were observed for high‐density lipoprotein measures, e.g., high‐density lipoprotein size (OR = 0.36, 0.30‐0.42) and several fatty acids including omega‐6 (OR = 0.37, 0.32‐0.42). The metabolic associations were attenuated but remained significant after adjusting for waist, physical activity, alcohol consumption, and smoking (P < 0.0007). Similar aberrations in the metabolic profile were observed already 10 years before fatty liver diagnosis. Conclusion: Circulating lipids, fatty acids, and amino acids reflect fatty liver independently of routine metabolic risk factors; these metabolic aberrations appear to precede the development of fatty liver in young adults. (Hepatology 2017).


    Date de mise en ligne : Samedi 24 décembre 2016
    Jian Chen, Vivek Shukla, Patrizia Farci, Jaclyn Andricovich, Wilma Jogunoori, Lawrence N. Kwong, Lior H. Katz, Kirti Shetty, Asif Rashid, Xiaoping Su, Jon White, Lei Li, Alan Yaoqi Wang, Boris Blechacz, Gottumukkala S. Raju, Marta Davila, Bao‐Ngoc Nguyen, John R. Stroehlein, Junjie Chen, Sang Soo Kim, Heather Levin, Keigo Machida, Hidekazu Tsukamoto, Peter Michaely, Alexandros Tzatsos, Bibhuti Mishra, Richard Amdur, Lopa Mishra
    Loss of the transforming growth factor‐ÎČ effector ÎČ2‐Spectrin promotes genomic instability
    Exposure to genotoxins such as ethanol‐derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ÎČ/mothers against decapentaplegic homolog 3 adaptor ÎČ2‐Spectrin (ÎČ2SP, gene Sptbn1) in maintaining genomic stability following alcohol‐induced DNA damage. ÎČ2SP supports DNA repair through ÎČ2SP‐dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ÎČ2SP leads to decreased Fancd2 levels and sensitizes ÎČ2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1‐deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double‐strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ÎČ stimulation is regulated by the ÎČ2SP/mothers against decapentaplegic homolog 3 complex. Conclusion: Dysfunctional transforming growth factor ÎČ/ÎČ2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2016)


    Date de mise en ligne : Samedi 24 décembre 2016
    Jean‐Louis Delaunay, Alix Bruneau, Brice Hoffmann, Anne‐Marie Durand‐Schneider, VĂ©ronique Barbu, Emmanuel Jacquemin, MichĂšle Maurice, Chantal Housset, Isabelle Callebaut, Tounsia AĂŻt‐Slimane
    Functional defect of variants in the adenosine triphosphate–binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX‐770)
    ABCB4 (MDR3) is an adenosine triphosphate (ATP)‐binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding. Five disease‐causing variations in these motifs have been identified in ABCB4 (G535D, G536R, S1076C, S1176L, and G1178S), three of which are homologous to the gating mutations of cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7; i.e., G551D, S1251N, and G1349D), that were previously shown to be function defective and corrected by ivacaftor (VX‐770; Kalydeco), a clinically approved CFTR potentiator. Three‐dimensional structural modeling predicted that all five ABCB4 variants would disrupt critical interactions in the binding of ATP and thereby impair ATP‐induced nucleotide‐binding domain dimerization and ABCB4 function. This prediction was confirmed by expression in cell models, which showed that the ABCB4 mutants were normally processed and targeted to the plasma membrane, whereas their PC secretion activity was dramatically decreased. As also hypothesized on the basis of molecular modeling, PC secretion activity of the mutants was rescued by the CFTR potentiator, ivacaftor (VX‐770). Conclusion: Disease‐causing variations in the ATP‐binding sites of ABCB4 cause defects in PC secretion, which can be rescued by ivacaftor. These results provide the first experimental evidence that ivacaftor is a potential therapy for selected patients who harbor mutations in the ATP‐binding sites of ABCB4. (Hepatology 2016)


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


    Date de mise en ligne : Samedi 24 décembre 2016
    Stephen Caldwell, Ton Lisman
    The cirrhotic platelet: Shedding light on an enigma
    n/a


    Date de mise en ligne : Samedi 24 décembre 2016
    James Hamilton, Svetlana Lutsenko
    Reply
    n/a


    Date de mise en ligne : Samedi 24 décembre 2016
    Li Zhang, Zhihong Yang, Jocelyn Trottier, Olivier Barbier, Li Wang
    Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay
    Bile acids (BAs) play critical physiological functions in cholesterol homeostasis, and deregulation of BA metabolism causes cholestatic liver injury. The long noncoding RNA maternally expressed gene 3 (MEG3) was recently shown as a potential tumor suppressor; however, its basic hepatic function remains elusive. Using RNA pull‐down with biotin‐labeled sense or anti‐sense MEG 3RNA followed by mass spectrometry, we identified RNA‐binding protein polypyrimidine tract‐binding protein 1 (PTBP1) as a MEG3 interacting protein and validated their interaction by RNA immunoprecipitation (RIP). Bioinformatics analysis revealed putative binding sites for PTBP1 within the coding region (CDS) of small heterodimer partner (SHP), a key repressor of BA biosynthesis. Forced expression of MEG3 in hepatocellular carcinoma cells guided and facilitated PTBP1 binding to the Shp CDS, resulting in Shp mRNA decay. Transient overexpression of MEG3 RNA in vivo in mouse liver caused rapid Shp mRNA degradation and cholestatic liver injury, which was accompanied by the disruption of BA homeostasis, elevation of liver enzymes, as well as dysregulation of BA synthetic enzymes and metabolic genes. Interestingly, RNA sequencing coupled with quantitative PCR (qPCR) revealed a drastic induction of MEG3 RNA in Shp−/− liver. SHP inhibited MEG3 gene transcription by repressing cAMP response element‐binding protein (CREB) transactivation of the MEG3 promoter. In addition, the expression of MEG3 and PTBP1 was activated in human fibrotic and cirrhotic livers. Conclusion: MEG3 causes cholestasis by serving as a guide RNA scaffold to recruit PTBP1 to destabilize Shp mRNA. SHP in turn represses CREB‐mediated activation of MEG3 expression in a feedback‐regulatory fashion. (Hepatology 2016).


    Date de mise en ligne : Samedi 24 décembre 2016
    Sarmistha Mukherjee, Karthikeyani Chellappa, Andrea Moffitt, Joan Ndungu, Ryan W. Dellinger, James G. Davis, Beamon Agarwal, Joseph A. Baur
    Nicotinamide adenine dinucleotide biosynthesis promotes liver regeneration
    The regenerative capacity of the liver is essential for recovery from surgical resection or injuries induced by trauma or toxins. During liver regeneration, the concentration of nicotinamide adenine dinucleotide (NAD) falls, at least in part due to metabolic competition for precursors. To test whether NAD availability restricts the rate of liver regeneration, we supplied nicotinamide riboside (NR), an NAD precursor, in the drinking water of mice subjected to partial hepatectomy. NR increased DNA synthesis, mitotic index, and mass restoration in the regenerating livers. Intriguingly, NR also ameliorated the steatosis that normally accompanies liver regeneration. To distinguish the role of hepatocyte NAD levels from any systemic effects of NR, we generated mice overexpressing nicotinamide phosphoribosyltransferase, a rate‐limiting enzyme for NAD synthesis, specifically in the liver. Nicotinamide phosphoribosyltransferase overexpressing mice were mildly hyperglycemic at baseline and, similar to mice treated with NR, exhibited enhanced liver regeneration and reduced steatosis following partial hepatectomy. Conversely, mice lacking nicotinamide phosphoribosyltransferase in hepatocytes exhibited impaired regenerative capacity that was completely rescued by administering NR. Conclusion: NAD availability is limiting during liver regeneration, and supplementation with precursors such as NR may be therapeutic in settings of acute liver injury. (Hepatology 2017).


    Date de mise en ligne : Samedi 24 décembre 2016
    Feng Su, Pamela K. Green, Kristin Berry, George N. Ioannou
    The association between race/ethnicity and the effectiveness of direct antiviral agents for hepatitis C virus infection
    Black race and Hispanic ethnicity were associated with lower rates of sustained virologic response (SVR) to interferon‐based treatments for chronic hepatitis C virus infection, whereas Asian race was associated with higher SVR rates compared to white patients. We aimed to describe the association between race/ethnicity and effectiveness of new direct‐acting antiviral regimens in the Veterans Affairs health care system nationally. We identified 21,095 hepatitis C virus–infected patients (11,029 [52%] white, 6,171 [29%] black, 1,187 [6%] Hispanic, 348 [2%] Asian/Pacific Islander/American Indian/Alaska Native, and 2,360 [11%] declined/missing race or ethnicity) who initiated antiviral treatment with regimens containing sofosbuvir, simeprevir + sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ombitasvir/ritonavir/dasabuvir during the 18‐month period from January 1, 2014, to June 30, 2015. Overall SVR rates were 89.8% (95% confidence interval [CI] 89.2‐90.4) in white, 89.8% (95% CI 89.0‐90.6) in black, 86.0% (95% CI 83.7‐88.0) in Hispanic, and 90.7% (95% CI 87.0‐93.5) in Asian/Pacific Islander/American Indian/Alaska Native patients. However, after adjustment for baseline characteristics, black (adjusted odds ratio = 0.77, P < 0.001) and Hispanic (adjusted odds ratio = 0.76, P = 0.007) patients were less likely to achieve SVR than white patients, a difference that was not explained by early treatment discontinuations. Among genotype 1–infected patients treated with ledipasvir/sofosbuvir monotherapy, black patients had significantly lower SVR than white patients when treated for 8 weeks but not when treated for 12 weeks. Conclusion: Direct‐acting antivirals produce high SVR rates in white, black, Hispanic, and Asian/Pacific Islander/American Indian/Alaska Native patients; but after adjusting for baseline characteristics, black race and Hispanic ethnicity remain independent predictors of treatment failure. Short 8‐week ledipasvir/sofosbuvir monotherapy regimens should perhaps be avoided in black patients with genotype 1 hepatitis C virus. (Hepatology 2016).


    Date de mise en ligne : Samedi 24 décembre 2016
    Jin‐zhao Ma, Fu Yang, Chuan‐chuan Zhou, Feng Liu, Ji‐hang Yuan, Fang Wang, Tian‐tian Wang, Qing‐guo Xu, Wei‐ping Zhou, Shu‐han Sun
    METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6‐methyladenosine‐dependent primary MicroRNA processing
    N6‐Methyladenosine (m6A) modification has been implicated in many biological processes. However, its role in cancer has not been well studied. Here, we demonstrate that m6A modifications are decreased in hepatocellular carcinoma, especially in metastatic hepatocellular carcinoma, and that methyltransferase‐like 14 (METTL14) is the main factor involved in aberrant m6A modification. Moreover, METTL14 down‐regulation acts as an adverse prognosis factor for recurrence‐free survival of hepatocellular carcinoma and is significantly associated with tumor metastasis in vitro and in vivo. We confirm that METTL14 interacts with the microprocessor protein DGCR8 and positively modulates the primary microRNA 126 process in an m6A‐dependent manner. Further experiments show that microRNA 126 inhibits the repressing effect of METTL14 in tumor metastasis. Conclusion: These studies reveal an important role of METTL14 in tumor metastasis and provide a fresh view on m6A modification in tumor progression. (Hepatology 2016).


    Date de mise en ligne : Samedi 24 décembre 2016
    Sergio A. Gradilone
    Extracellular vesicles as therapeutic carriers of microRNAs for cholangiocarcinoma
    n/a


    Date de mise en ligne : Samedi 24 décembre 2016
    Nina Kimer, Julie Steen Pedersen, Troels Malte Busk, Lise Lotte Gluud, Lise Hobolth, Aleksander Krag, SĂžren MĂžller, Flemming Bendtsen,
    Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double‐blind, placebo‐controlled trial
    Decompensated cirrhosis is characterized by disturbed systemic and splanchnic hemodynamics. Bacterial translocation from the gut is considered the key driver in this process. Intestinal decontamination with rifaximin may improve hemodynamics. This double‐blind, randomized, controlled trial (clinicaltrials.gov, NCT01769040) investigates the effects of rifaximin on hemodynamics, renal function, and vasoactive hormones. We randomized 54 stable outpatients with cirrhosis and ascites to rifaximin 550 mg twice a day (n = 36) or placebo twice a day (n = 18). Forty‐five patients were male, mean age 56 years (±8.4), average Child score 8.3 (±1.3), and Model for End‐Stage Liver Disease score 11.7 (±3.9). Measurements of hepatic venous pressure gradient, cardiac output, and systemic vascular resistance were made at baseline and after 4 weeks. The glomerular filtration rate and plasma renin, noradrenaline, lipopolysaccharide binding protein, troponin T, and brain natriuretic peptide levels were measured. Rifaximin had no effect on hepatic venous pressure gradient, mean 16.8 ± 3.8 mm Hg at baseline versus 16.6 ± 5.3 mm Hg at follow‐up, compared to the placebo, mean 16.4 ± 4 mm Hg at baseline versus 16.3 ± 4.4 mm Hg at follow‐up, P = 0.94. No effect was found on cardiac output, mean 6.9 ± 1.7 L/min at baseline versus 6.9 ± 2.3 L/min at follow‐up, compared to placebo, mean 6.6 ± 1.9 L/min at baseline compared to 6.5 ±2.1 L/min at follow‐up, P = 0.66. No effects on the glomerular filtration rate, P = 0.14, or vasoactive hormones were found. Subgroup analyses on patients with increased lipopolysaccharide binding protein and systemic vascular resistance below the mean (1,011 dynes × s/cm5) revealed no effect of rifaximin. Conclusion: Four weeks of treatment with rifaximin did not reduce the hepatic venous pressure gradient or improve systemic hemodynamics in patients with cirrhosis and ascites; rifaximin did not affect glomerular filtration rate or levels of vasoactive hormones. (Hepatology 2017).


    Date de mise en ligne : Lundi 19 décembre 2016
    Arthur J. McCullough
    Anthony S. Tavill, M.D., F.A.C.P., F.R.C.P., F.A.C.G. (1936‐2016)
    n/a


    Date de mise en ligne : Lundi 19 décembre 2016
    Dana Tedesco, Manoj Thapa, Sanjeev Gumber, Elizabeth J. Elrod, Khalidur Rahman, Chris C. Ibegbu, Joseph F. Magliocca, Andrew B. Adams, Frank Anania, Arash Grakoui
    CD4+Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T‐cell suppression during chronic liver disease
    Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to nonfunctional intrahepatic CD8+ T‐cell responses. In light of dampened CD8+ T‐cell responses, liver disease often manifests systemically as immunoglobulin (Ig)‐related syndromes due to aberrant B‐cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4+ T‐cell help. Elevated CD4+ forkhead box P3–positive (Foxp3+) T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8+ T‐cell responses, aberrant B‐cell activities were maintained due to expression of CD40 ligand on a subset of CD4+ Foxp3+ T cells. In vivo blockade of CD40 ligand attenuated B‐cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4+ Foxp3+, CD40 ligand–positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. Conclusion: Liver disease elicits alterations in the intrahepatic CD4+ T‐cell compartment that suppress T‐cell immunity while concomitantly promoting aberrant IgG mediated manifestations. (Hepatology 2017).


    Date de mise en ligne : Lundi 19 décembre 2016
    Sukanta Das, Jaswinder Singh Maras, Md. Shabir Hussain, Shvetank Sharma, Paul David, Sukriti Sukriti, Saggere Muralikrishna Shasthry, Rakhi Maiwall, Nirupama Trehanpati, Tej P. Singh, Shiv Kumar Sarin
    Hyperoxidized albumin modulates neutrophils to induce oxidative stress and inflammation in severe alcoholic hepatitis
    Albumin is a potent scavenger of reactive oxygen species (ROS). However, modifications in albumin structure may reduce its antioxidant properties and modulate its immune‐regulatory functions. We examined alterations in circulating albumin in severe alcoholic hepatitis (SAH) patients and their contribution to neutrophil activation, intracellular stress, and alteration in associated molecular pathways. Albumin modifications and plasma oxidative stress were assessed in SAH patients (n = 90), alcoholic cirrhosis patients (n = 60), and healthy controls (n = 30) using liquid chromatography/mass spectrometry and spectrophotometry. Activation and intracellular ROS were measured in healthy neutrophils after treatment with purified albumin from the study groups. Gene expression of SAH neutrophils was analyzed and compared to gene expression from healthy neutrophils after stimulation with purified albumin from SAH patient plasma. SAH‐albumin showed the highest albumin oxidative state (P < 0.05) and prominent alteration as human nonmercaptalbumin 2 (P < 0.05). Plasma oxidative stress (advanced oxidative protein product) was higher in SAH versus alcoholic cirrhosis patients and healthy controls (P < 0.05). Neutrophil gelatinase‐associated lipocalin, myeloperoxidase, and intracellular ROS levels were highest in SAH‐albumin‐treated neutrophils (P < 0.05). Genes associated with neutrophil activation, ROS production, intracellular antioxidation, and leukocyte migration plus genes for proinflammatory cytokines and various toll‐like receptors were overexpressed in SAH neutrophils compared to healthy neutrophils (P < 0.05). Expression of the above‐mentioned genes in SAH‐albumin‐stimulated healthy neutrophils was comparable with SAH patient neutrophils, except for genes associated with apoptosis, endoplasmic reticulum stress, and autophagy (P < 0.05). Conclusions: In patients with SAH, there is a significant increase in albumin oxidation, and albumin acts as a pro‐oxidant; this promotes oxidative stress and inflammation in SAH patients through activation of neutrophils. (Hepatology 2017).


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


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


    Date de mise en ligne : Lundi 19 décembre 2016
    Eric Lawitz, Fred Poordad, Julio A. Gutierrez, Jennifer T. Wells, Carmen E. Landaverde, Barbara Evans, Anita Howe, Hsueh‐Cheng Huang, Jerry Jing Li, Peggy Hwang, Frank J. Dutko, Michael Robertson, Janice Wahl, Eliav Barr, Barbara Haber
    Short‐duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: A randomized trial
    Direct‐acting antiviral agents (DAAs) represent the standard of care for patients with hepatitis C virus (HCV) infection. Combining DAAs with different mechanisms may allow for shorter treatment durations that are effective across multiple genotypes. The aim of the C‐SWIFT study was to identify the minimum effective treatment duration across multiple genotypes. C‐SWIFT was an open‐label, single‐center trial in treatment‐naïve patients with chronic HCV genotype (GT)1 or 3 infection. All patients received elbasvir (EBR) 50 mg/grazoprevir (GZR) 100 mg with sofosbuvir (SOF) 400 mg for 4‐12 weeks. Patients with GT1 infection who failed therapy were eligible for retreatment with EBR/GZR+SOF and ribavirin for 12 weeks. The primary efficacy endpoint was sustained virological response [SVR]12 (SVR of HCV RNA <15 IU/mL 12 weeks after the end of therapy). Rates of SVR12 were 32% (10 of 31) and 87% (26 of 30) in patients without cirrhosis with GT1 infection treated for 4 and 6 weeks and 80% (16 of 20) and 81% (17 of 21) in GT1‐infected patients with cirrhosis treated for 6 and 8 weeks. Among GT3‐infected patients without cirrhosis, SVR12 was 93% (14 of 15) and 100% (14 of 14) after 8 and 12 weeks. SVR12 in GT3‐infected patients with cirrhosis was 83% (10 of 12) after 12 weeks of treatment. Twenty‐three GT1‐infected patients who relapsed following initial treatment completed retreatment; all achieved SVR12. In the initial treatment phase, there was one serious adverse event of pneumonia, which led to treatment discontinuation, and during retreatment, 1 patient discontinued ribavirin because of pruritus. Conclusion: Data from this study support the use of 8‐week treatment regimens that maintain high efficacy, even for patients with HCV GT3 infection. Retreatment of patients who failed short‐duration therapy was achieved through extended treatment duration and addition of ribavirin. (Hepatology 2016).


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


    Date de mise en ligne : Mercredi 30 novembre 2016
    Anika Wranke, Beatriz Calle Serrano, Benjamin Heidrich, Janina Kirschner, Birgit Bremer, Patrick Lehmann, Svenja Hardtke, Katja Deterding, Kerstin Port, Max Westphal, Michael P. Manns, Markus Cornberg, Heiner Wedemeyer
    Antiviral treatment and liver‐related complications in hepatitis delta
    Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG‐IFNα) is effective in only 25%‐30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long‐term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti‐HDV‐positive patients who were followed for at least 6 months in a retrospective single‐center cohort (mean time of follow‐up, 5.2 years; range, 0.6‐18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty‐nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)‐based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver‐related death developed in 55 patients (40%). Patients who received IFNα‐based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi‐square and Kaplan‐Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long‐term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07‐0.9). Loss of HDV RNA during follow‐up was more frequent in IFNα‐treated patients and strongly linked with a lower likelihood to experience liver‐related complications. Conclusion: IFNα‐based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2016).


    Date de mise en ligne : Mercredi 30 novembre 2016
    Christopher Goldring, Daniel J. Antoine, Frank Bonner, Jonathan Crozier, Chris Denning, Robert J. Fontana, Neil A. Hanley, David C. Hay, Magnus Ingelman‐Sundberg, Satu Juhila, Neil Kitteringham, Beatriz Silva‐Lima, Alan Norris, Chris Pridgeon, James A. Ross, Rowena Sison Young, Danilo Tagle, Belen Tornesi, Bob van de Water, Richard J. Weaver, Fang Zhang, B. Kevin Park
    Stem cell–derived models to improve mechanistic understanding and prediction of human drug‐induced liver injury
    Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug‐induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug‐induced liver injury means that no current single‐cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug‐induced liver injury. Nevertheless, a single‐cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte‐like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell–derived hepatocyte‐like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment. (Hepatology 2016).


    Date de mise en ligne : Mardi 29 novembre 2016
    Maria Kalafateli, Fred Wickham, Maria Burniston, Evangelos Cholongitas, Eleni Theocharidou, Matteo Garcovich, James O'Beirne, Rachel Westbrook, Gioacchino Leandro, Andrew K. Burroughs, Emmanuel A. Tsochatzis
    Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate
    Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between “true” and calculated glomerular filtration rate (GFR). We compared the performance of the four‐variable and six‐variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with “true,” or measured, GFR (mGFR) and the impact of this difference on Model for End‐Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≄3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine–0·836) × (urea–0·229) × (international normalized ratio–0·113) × (age−0.129 [Corrected November 29, 2016: originally written as “age‐129.”]) × (sodium0·972) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. Conclusion: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017).


    Date de mise en ligne : Mardi 29 novembre 2016
    Hongli Hu, Wenwei Zhu, Jun Qin, Min Chen, Liyan Gong, Long Li, Xiangyuan Liu, Yongzhen Tao, Huiyong Yin, Hu Zhou, Lisha Zhou, Dan Ye, Qinghai Ye, Daming Gao
    Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis
    Phosphoglycerate kinase 1 (PGK1) is an important enzyme in the metabolic glycolysis pathway. In this study, we observed a significant overexpression of PGK1 in liver cancer tissues and a negative correlation between PGK1 expression and liver cancer patient survival. Furthermore, depletion of PGK1 dramatically reduced cancer cell proliferation and tumorigenesis, indicating an oncogenic role of PGK1 in liver cancer progression. Moreover, we identified acetylation at the K323 site of PGK1 as an important regulatory mechanism for promoting its enzymatic activity and cancer cell metabolism. And we further characterized P300/cyclic adenosine monophosphate response element binding protein–binding protein–associated factor (PCAF) and Sirtuin 7 as the enzymes regulating K323 acetylation from both directions in liver cancer cells. Conclusion: These findings demonstrate a novel regulation of PGK1 as well as its important role in liver cancer progression. (Hepatology 2016).


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


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


    Date de mise en ligne : Mardi 29 novembre 2016
    David B. Haslam
    Nonalcoholic steatohepatitis and the intestinal microbiota
    n/a


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


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


    Date de mise en ligne : Mardi 27 décembre 2016
    Masthead
    Masthead
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Table of contents
    Table of contents
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Jean‐François Dufour
    Hepatology Highlights
    3


    Date de mise en ligne : Jeudi 10 novembre 2016
    Kenneth Cusi
    Nonalcoholic steatohepatitis in nonobese patients: Not so different after all
    7


    Date de mise en ligne : Samedi 05 novembre 2016
    Ken Liu, Weiqi Xu, Vincent Wai‐Sun Wong
    Serum biomarkers for nonalcoholic fatty liver disease: Are we there yet?
    11


    Date de mise en ligne : Mardi 18 octobre 2016
    Pieter Borger, Pierre‐Alain Clavien
    Silencing sirtuins: A novel way to thwart reperfusion injury?
    14


    Date de mise en ligne : Mardi 29 novembre 2016
    James F. Trotter
    An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection
    17


    Date de mise en ligne : Samedi 05 novembre 2016
    Akira Nishio, Tomohide Tatsumi, Takatoshi Nawa, Takahiro Suda, Teppei Yoshioka, Yoshiki Onishi, Satoshi Aono, Minoru Shigekawa, Hayato Hikita, Ryotaro Sakamori, Daisuke Okuzaki, Takasuke Fukuhara, Yoshiharu Matsuura, Naoki Hiramatsu, Tetsuo Takehara
    CD14+ monocyte‐derived galectin‐9 induces natural killer cell cytotoxicity in chronic hepatitis C
    Natural killer (NK) cell activation is associated with both liver injury and persistent infection in chronic hepatitis C (CHC); however, the detailed mechanism of this activation has not yet been fully elucidated. Because galectin‐9 (Gal‐9) has been reported to be increased in the serum and liver tissue of CHC patients, we investigated the function of Gal‐9 in NK cell activation in CHC. First, we evaluated the function of Gal‐9 on NK cytotoxicity in vitro. Gal‐9 treatment resulted in increased cytotoxicity of naĂŻve NK cells, and the Gal‐9‐activated NK cells demonstrated cytotoxicity toward hepatoma cells and T cells. Additionally, coculturing peripheral blood mononuclear cells (PBMCs) with JFH‐1/Huh7.5.1 cells increased both Gal‐9 production and NK cell cytotoxicity. Next, we investigated the source of Gal‐9 and the mechanism of Gal‐9 production. Deletion of CD14+ monocytes from PBMCs resulted in reduced Gal‐9 production in the coculture with JFH‐1/Huh7.5.1 cells. Gal‐9 production was driven by coculturing of PBMCs with apoptotic hepatocytes. Blocking integrin αvÎČ3, a receptor for phosphatidylserine expressed on apoptotic cells, also resulted in decreased Gal‐9 production. Finally, we found that serum Gal‐9 levels were significantly higher in CHC patients than in healthy donors and patients who achieved sustained virologic response. Among CHC patients, serum Gal‐9 levels were significantly higher in patients with elevated alanine aminotransferase (ALT) than in those with normal ALT. Conclusion: These results demonstrate that CD14+ monocyte‐derived Gal‐9 increases NK cell cytotoxicity in HCV infection, which might be associated with liver injury and persistent infection. (Hepatology 2017;65:18‐31).


    Date de mise en ligne : Mardi 22 novembre 2016
    Adam C. Labonte, Sun‐Sang J. Sung, Lucas T. Jennelle, Aditya P. Dandekar, Young S. Hahn
    Expression of scavenger receptor‐AI promotes alternative activation of murine macrophages to limit hepatic inflammation and fibrosis
    The liver maintains an immunologically tolerant environment as a result of continuous exposure to food and bacterial constituents from the digestive tract. Hepatotropic pathogens can take advantage of this niche and establish lifelong chronic infections causing hepatic fibrosis and hepatocellular carcinoma. Macrophages (Mϕ) play a critical role in regulation of immune responses to hepatic infection and regeneration of tissue. However, the factors crucial for Mϕ in limiting hepatic inflammation or resolving liver damage have not been fully understood. In this report, we demonstrate that expression of C‐type lectin receptor scavenger receptor‐AI (SR‐AI) is crucial for promoting M2‐like Mϕ activation and polarization during hepatic inflammation. Liver Mϕ uniquely up‐regulated SR‐AI during hepatotropic viral infection and displayed increased expression of alternative Mϕ activation markers, such as YM‐1, arginase‐1, and interleukin‐10 by activation of mer receptor tyrosine kinase associated with inhibition of mammalian target of rapamycin. Expression of these molecules was reduced on Mϕ obtained from livers of infected mice deficient for the gene encoding SR‐AI (msr1). Furthermore, in vitro studies using an SR‐AI‐deficient Mϕ cell line revealed impeded M2 polarization and decreased phagocytic capacity. Direct stimulation with virus was sufficient to activate M2 gene expression in the wild‐type (WT) cell line, but not in the knockdown cell line. Importantly, tissue damage and fibrosis were exacerbated in SR‐AI–/– mice following hepatic infection and adoptive transfer of WT bone‐marrow–derived Mϕ conferred protection against fibrosis in these mice. Conclusion: SR‐AI expression on liver Mϕ promotes recovery from infection‐induced tissue damage by mediating a switch to a proresolving Mϕ polarization state. (Hepatology 2017;65:32‐43).


    Date de mise en ligne : Vendredi 25 novembre 2016
    Joanne E. Brady, Danielle K. Liffmann, Anthony Yartel, Natalie Kil, Alex D. Federman, Joseph Kannry, Cynthia Jordan, Omar I. Massoud, David R. Nerenz, Kimberly A. Brown, Bryce D. Smith, Claudia Vellozzi, David B. Rein
    Uptake of hepatitis C screening, characteristics of patients tested, and intervention costs in the BEST‐C study
    From December 2012 to March 2014, three randomized trials, each implementing a unique intervention in primary care settings (repeated mailing, an electronic health record best practice alert [BPA], and patient solicitation), evaluated hepatitis C virus (HCV) antibody testing, diagnosis, and costs for each of the interventions compared with standard‐of‐care testing. Multilevel multivariable models were used to estimate the adjusted risk ratio (aRR) for receiving an HCV antibody test, and costs were estimated using activity‐based costing. The goal of this study was to estimate the effects of interventions conducted as part of the Birth‐Cohort Evaluation to Advance Screening and Testing for Hepatitis C study on HCV testing and costs among persons of the 1945‐1965 birth cohort (BC). Intervention resulted in substantially higher HCV testing rates compared with standard‐of‐care testing (26.9% versus 1.4% for repeated mailing, 30.9% versus 3.6% for BPA, and 63.5% versus 2.0% for patient solicitation) and significantly higher aRR for testing after controlling for sex, birth year, race, insurance type, and median household income (19.2 [95% confidence interval (CI), 9.7–38.2] for repeated mailing, 13.2 [95% CI, 3.6–48.6] for BPA, and 32.9 [95% CI, 19.3–56.1] for patient solicitation). The BPA intervention had the lowest incremental cost per completed test ($24 with fixed startup costs, $3 without) and also the lowest incremental cost per new case identified after omitting fixed startup costs ($1691). Conclusion: HCV testing interventions resulted in an increase in BC testing compared with standard‐of‐care testing but also increased costs. The effect size and incremental costs of BPA intervention (excluding startup costs) support more widespread adoption compared with the other interventions. (Hepatology 2017;65:44‐53).


    Date de mise en ligne : Lundi 25 juillet 2016
    Jonathan Chung‐Fai Leung, Thomson Chi‐Wang Loong, Jeremy Lok Wei, Grace Lai‐Hung Wong, Anthony Wing‐Hung Chan, Paul Cheung‐Lung Choi, Sally She‐Ting Shu, Angel Mei‐Ling Chim, Henry Lik‐Yuen Chan, Vincent Wai‐Sun Wong
    Histological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients
    Although nonalcoholic fatty liver disease (NAFLD) is closely linked to obesity, around 10%‐20% of nonobese Americans and Asians still develop NAFLD. Data on this special group are limited. We therefore studied the severity and clinical outcomes of nonobese NAFLD patients. Consecutive NAFLD patients who underwent liver biopsy were prospectively recruited. We used the NASH Clinical Research Network system to score the histology. The Asian body mass index cutoff of 25 kg/m2 was used to define nonobese NAFLD. Among 307 recruited NAFLD patients, 72 (23.5%) were nonobese. Compared to obese patients, nonobese patients had lower NAFLD activity score (3.3 ± 1.3 vs. 3.8 ± 1.2; P = 0.019), mainly contributed by steatosis (1.7 ± 0.8 vs. 2.0 ± 0.8; P = 0.014) and presence of hepatocyte ballooning (60.9% vs. 73.4%; P = 0.045). Similarly, nonobese patients had lower fibrosis stage (1.3 ± 1.5 vs. 1.7 ± 1.4; P = 0.004), serum cytokeratin‐18 fragments (283 vs. 404 U/L; P < 0.001) and liver stiffness measurement by transient elastography (6.3 vs. 8.6 kilopascals; P < 0.001). By multivariate analysis in nonobese patients, only elevated serum triglyceride level was independently associated with higher NAFLD activity score (adjusted odds ratio [OR], 1.644; P = 0.021), whereas elevated creatinine level was the only factor associated with advanced fibrosis (adjusted OR, 1.044; P = 0.025). After a median follow‐up of 49 months, 6 patients died, 2 developed hepatocellular carcinoma, and 1 had liver failure, all of whom were in the obese group. Conclusion: Nonobese NAFLD patients tend to have less‐severe disease and may have a better prognosis than obese patients. Hypertriglyceridemia and higher creatinine are the key factors associated with advanced liver disease in nonobese patients. (Hepatology 2017;65:54‐64)


    Date de mise en ligne : Mercredi 12 octobre 2016
    Veeral Ajmera, Emily R. Perito, Nathan M. Bass, Norah A. Terrault, Katherine P. Yates, Ryan Gill, Rohit Loomba, Anna Mae Diehl, Bradley E. Aouizerat,
    Novel plasma biomarkers associated with liver disease severity in adults with nonalcoholic fatty liver disease
    Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), therapeutic options and noninvasive markers of disease activity and severity remain limited. We investigated the association between plasma biomarkers and liver histology in order to identify markers of disease activity and severity in patients with biopsy‐proven NAFLD. Thirty‐two plasma biomarkers chosen a priori as possible discriminators of NAFLD were measured in participants enrolled in the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network. Dichotomized histologic outcomes were evaluated using centrally read biopsies. Biomarkers with statistically significant associations with NAFLD histology were evaluated in multivariable models adjusted for clinical factors. Of 648 participants (74.4% white, 61.7% female, mean age 47.7 years), 58.0% had definite NASH, 55.5% had mild/no fibrosis (stage 0‐1), and 44.4% had significant fibrosis (stage 2‐4). Increased activated plasminogen activator inhibitor 1 had a strong association with definite NASH compared to not NASH or borderline NASH in multivariable analysis (odds ratio = 1.20, 95% confidence interval 1.08‐1.34, P < 0.001). Biomarkers associated with significant fibrosis (versus mild/no fibrosis) in multivariable analysis included higher levels of interleukin‐8, monocyte chemoattractant protein‐1, resistin, soluble interleukin‐1 receptor I, soluble interleukin‐2 receptor alpha, and tumor necrosis factor alpha and lower levels of insulin‐like growth factor 2. Conclusions: Specific plasma biomarkers are significantly associated with disease activity and severity of fibrosis in NAFLD and are potentially valuable tools for noninvasive stratification of patients with NAFLD and identification of targets for therapeutic intervention. (Hepatology 2017;65:65‐77).


    Date de mise en ligne : Mardi 15 novembre 2016
    Martin L. Decaris, Kelvin W. Li, Claire L. Emson, Michelle Gatmaitan, Shanshan Liu, Yenny Wang, Edna Nyangau, Marc Colangelo, Thomas E. Angel, Carine Beysen, Jeffrey Cui, Carolyn Hernandez, Len Lazaro, David A. Brenner, Scott M. Turner, Marc K. Hellerstein, Rohit Loomba
    Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood
    Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and noninvasively in blood. Twenty‐one patients with suspected NAFLD ingested heavy water (2H2O, 50‐mL aliquots) two to three times daily for 3‐5 weeks prior to a clinically indicated liver biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on 2H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0‐F4) and as having nonalcoholic fatty liver or nonalcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advancing disease stage (e.g., higher in NASH than nonalcoholic fatty liver, positive correlation with fibrosis score and liver stiffness) and correlated with hemoglobin A1C. In addition, plasma lumican FSR demonstrated a significant correlation with hepatic collagen FSR. Conclusion: Using a well‐characterized cohort of patients with biopsy‐proven NAFLD, this study demonstrates that hepatic scar in NASH is actively remodeled even in advanced fibrosis, a disease that is generally regarded as static and slowly progressive. Moreover, hepatic collagen FSR correlates with established risks for fibrotic disease progression in NASH, and plasma lumican FSR correlates with hepatic collagen FSR, suggesting applications as direct or surrogate markers, respectively, of hepatic fibrogenesis in humans. (Hepatology 2017;65:78‐88).


    Date de mise en ligne : Mardi 22 novembre 2016
    Juri Bergmann, Miryam MĂŒller, Niklas Baumann, Manuel Reichert, Carola Heneweer, Julia Bolik, Karsten LĂŒcke, Sabine Gruber, Antonella Carambia, Susanne Boretius, Ivo Leuschner, Thomas Becker, Björn Rabe, Johannes Herkel, F. Thomas Wunderlich, Hans‐Willi MittrĂŒcker, Stefan Rose‐John, Dirk Schmidt‐Arras
    IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice
    Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin‐6 (IL‐6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL‐6 classic and the IL‐6 trans‐signaling pathway. Whereas IL‐6 classic signaling is important for innate and acquired immunity, IL‐6 trans‐signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL‐6 trans‐signaling, but not IL‐6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA‐damage‐induced hepatocyte apoptosis through suppression of p53 and enhances ÎČ‐catenin activation and tumor proliferation. Second, IL‐6 trans‐signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL‐6 trans‐signaling are largely protected from tumor formation in a diethylnitrosamine/3,3â€Č,5,5â€Č‐tetrachloro‐1,4‐bis(pyridyloxy)benzene model of HCC. Conclusion: IL‐6 trans‐signaling, and not IL‐6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL‐6 trans‐signaling, rather than total inhibition of IL‐6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL‐6 classic signaling‐driven protective immune responses. (Hepatology 2017;65:89‐103).


    Date de mise en ligne : Mardi 29 novembre 2016
    Pavel Sumazin, Yidong Chen, Lisa R. Treviño, Stephen F. Sarabia, Oliver A. Hampton, Kayuri Patel, Toni‐Ann Mistretta, Barry Zorman, Patrick Thompson, Andras Heczey, Sarah Comerford, David A. Wheeler, Murali Chintagumpala, Rebecka Meyers, Dinesh Rakheja, Milton J. Finegold, Gail Tomlinson, D. Williams Parsons, Dolores LĂłpez‐Terrada
    Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups
    Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large‐scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk‐stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high‐risk tumors were characterized by up‐regulated nuclear factor, erythroid 2–like 2 activity; high lin‐28 homolog B, high mobility group AT‐hook 2, spalt‐like transcription factor 4, and alpha‐fetoprotein expression; and high coordinated expression of oncofetal proteins and stem‐cell markers, while low‐risk tumors had low lin‐28 homolog B and lethal‐7 expression and high hepatic nuclear factor 1 alpha activity. Conclusion: Analysis of immunohistochemical assays using antibodies targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis; our results pave the way for clinical collaborative studies to validate candidate biomarkers and test their potential to improve outcome for HB patients. (Hepatology 2017;65:104‐121).


    Date de mise en ligne : Vendredi 25 novembre 2016
    Neehar D. Parikh, Vincent D. Marshall, Amit G. Singal, Hari Nathan, Anna S. Lok, Rajesh Balkrishnan, Vahakn Shahinian
    Survival and cost‐effectiveness of sorafenib therapy in advanced hepatocellular carcinoma: An analysis of the SEER–Medicare database
    Sorafenib is the only chemotherapeutic approved for treatment of advanced hepatocellular carcinoma (HCC). However, its effectiveness in patients with Child‐Pugh class B cirrhosis and any moderating effects of health system characteristics are unclear. We examined the survival and cost‐effectiveness associated with sorafenib in elderly patients with advanced HCC. We performed an analysis of Medicare beneficiaries with HCC diagnoses from 2007 to 2009. We compared advanced stage patients with HCC (American Joint Committee on Cancer stage III/IV) who received sorafenib within 6 months of diagnosis (and were otherwise untreated) to advanced stage patients with HCC who received no therapy (control). We performed univariate and multivariate analyses to identify predictors of survival. Incremental cost‐effectiveness ratios (ICERs) were calculated for sorafenib‐treated and control patients. We included 228 sorafenib‐treated patients and 870 control patients. The median survival of the sorafenib‐treated patients was 150.5 days versus 62 days for control patients. On multivariate analysis, significant predictors of improved survival were treatment with sorafenib (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57‐0.77), being seen at a National Cancer Institute–designated cancer center (HR, 0.77; 95% CI, 0.62‐0.97), and being seen at a transplantation center (HR, 0.77; 95% CI, 0.65‐0.93). Predictors of worse survival included stage IV disease (HR, 1.40; 95% CI, 1.24‐1.58), decompensated cirrhosis (HR, 1.49; 95% CI, 1.30‐1.70), and treatment in an urban setting (HR, 1.45; 95% CI, 1.21‐1.73.) Although sorafenib use was associated with a survival benefit (HR, 0.61; 95% CI, 0.47‐0.79) among patients with decompensated cirrhosis, the median survival benefit was 31 days, and it was not cost‐effective (ICER, $224,914 per life year gained). Conclusion: Sorafenib is associated with improved survival in elderly patients with advanced HCC; however, it is not cost‐effective among those with hepatic decompensation. (Hepatology 2017;65:122‐133).


    Date de mise en ligne : Vendredi 25 novembre 2016
    Shizhong Ke, Shuzhen Chen, Zihui Dong, Christopher S. Hong, Qi Zhang, Liang Tang, Pinghua Yang, Jian Zhai, Hexin Yan, Feng Shen, Zhengping Zhuang, Wen Wen, Hongyang Wang
    Erythrocytosis in hepatocellular carcinoma portends poor prognosis by respiratory dysfunction secondary to mitochondrial DNA mutations
    Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma. Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. We demonstrate an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas. In the subset of hepatocellular carcinoma patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting in impairment of respiratory metabolism, which sequentially led to depletion of α‐ketoglutarate, stabilization of hypoxia inducible factor‐α, and expression of target genes such as EPO. Cell lines and patient‐derived xenograft models were used to demonstrate that EPO promoted cancer stem cell self‐renewal and expansion in an autocrine/paracrine manner through enhanced Janus kinase/signal transducer and activator of transcription signaling both in vitro and in vivo. Furthermore, to explore the therapeutic targeting of EPO‐induced tumor changes, we found that blocking EPO signaling with soluble EPO receptor extracellular domain Fc fusion protein could inhibit tumor growth both in vitro and in vivo. Conclusion: These findings suggest clinical and therapeutic implications for erythrocytosis in hepatocellular carcinoma. There is an underlying link between mitochondrial function and hypoxia inducible factor alpha signaling, revealing a mechanism of erythrocytosis in a subset of hepatocellular carcinoma patients who may benefit from treatment involving EPO signaling interference. (Hepatology 2017;65:134‐151).


    Date de mise en ligne : Jeudi 10 novembre 2016
    GĂ©raldine Dahlqvist, Farid Gaouar, Fabrice Carrat, Sofia Meurisse, Olivier ChazouillĂšres, Raoul Poupon, Catherine Johanet, Christophe Corpechot,
    Large‐scale characterization study of patients with antimitochondrial antibodies but nonestablished primary biliary cholangitis
    The prevalence, clinical characteristics, and outcomes of patients with antimitochondrial antibodies (AMAs), but no clinical evidence of primary biliary cholangitis (PBC), are largely unknown. A prospective study of AMA incidence was conducted through a nation‐wide network of 63 French immunology laboratories. Clinical data from 720 of 1,318 AMA‐positive patients identified in 1 year were collected. Patients were categorized as either newly diagnosed with PBC (n = 275), previously diagnosed with PBC (n = 216), or with nonestablished diagnosis of PBC (n = 229). The latter group was specifically evaluated. Follow‐up data were collected for up to 7 years after detection of AMAs. Prevalence of AMA‐positive patients without evidence of PBC was 16.1 per 100,000. These patients had the following characteristics: 78% female; median age 58 years; median AMA titer 1:160; extrahepatic autoimmune disorders 46%; normal serum alkaline phosphatases (ALP) 74%; ALP above 1.5 times the upper limit of normal 13%; and cirrhosis 6%. Compared to those newly diagnosed with PBC, the patients were slightly younger, had lower AMA titers, and lower sex‐ratio imbalance. Among the patients with normal ALP and no evidence of cirrhosis, the 5‐year incidence rate of PBC was 16%. Whereas no patients died from PBC, the 5‐year survival rate was 75%, as compared to 90% in a control, standardized population matched for age and sex (P < 0.05). Conclusion: Nearly half of the newly detected AMAs in clinical practice does not lead to a diagnosis of PBC. PBC is unrecognized in 13% of those cases. Only 1 in 6 patients with AMAs and normal ALP will develop PBC after 5 years. The mortality of AMA‐positive patients without PBC is increased irrespective of the risk of PBC development. (Hepatology 2017;65:152‐163).


    Date de mise en ligne : Mercredi 05 octobre 2016
    Emmanuel Gonzales, Sarah A. Taylor, Anne Davit‐Spraul, Alice ThĂ©baut, NadĂšge Thomassin, Catherine Guettier, Peter F. Whitington, Emmanuel Jacquemin
    MYO5B mutations cause cholestasis with normal serum gamma‐glutamyl transferase activity in children without microvillous inclusion disease
    Some patients with microvillus inclusion disease due to myosin 5B (MYO5B) mutations may develop cholestasis characterized by a progressive familial intrahepatic cholestasis‐like phenotype with normal serum gamma‐glutamyl transferase activity. So far MYO5B deficiency has not been reported in patients with such a cholestasis phenotype in the absence of intestinal disease. Using a new‐generation sequencing approach, we identified MYO5B mutations in five patients with progressive familial intrahepatic cholestasis‐like phenotype with normal serum gamma‐glutamyl transferase activity without intestinal disease. Conclusion: These data show that MYO5B deficiency may lead to isolated cholestasis and that MYO5B should be considered as an additional progressive familial intrahepatic cholestasis gene. (Hepatology 2017;65:164‐173).


    Date de mise en ligne : Jeudi 10 novembre 2016
    Celine S. Lages, Julia Simmons, Avery Maddox, Keaton Jones, Rebekah Karns, Rachel Sheridan, Shiva Kumar Shanmukhappa, Sujit Mohanty, Matthew Kofron, Pierre Russo, Yui‐Hsi Wang, Claire Chougnet, Alexander G. Miethke
    The dendritic cell–T helper 17–macrophage axis controls cholangiocyte injury and disease progression in murine and human biliary atresia
    Biliary atresia (BA) is a fibroinflammatory obstruction of the extrahepatic biliary tree in neonates. While intrahepatic bile duct proliferation is universal at diagnosis, bile duct paucity develops later. We hypothesized that polarized T helper lymphocyte responses orchestrate progression of intrahepatic biliary injury in this disease. Interleukin 17A (IL‐17A)‐green fluorescent protein, cluster of differentiation 11c (CD11c)/diphtheria toxin receptor, and IL‐17 receptor A−/− mice were used to examine T‐lymphocyte polarization, inflammatory leukocyte recruitment, and biliary injury in rhesus rotavirus–induced BA. Multiparameter flow cytometry and automated image analysis of immunostaining were applied to liver tissue samples from infants with BA. In the mouse model, activated CD4+ lymphocytes started to emerge in the liver on day 8 after viral challenge, while innate immune responses were waning. Plasma IL‐17A levels rose concomitantly with hepatic accumulation of T helper 17 lymphocytes and myeloid dendritic cells. Targeted depletion of CD11c+ dendritic cells diminished hepatic IL‐17A production and ameliorated intrahepatic bile duct injury. Recombinant IL‐17A induced expression of chemokine (C‐C motif) ligand 2 in neonatal cholangiocytes in vitro, and blockade of the corresponding chemokine (C‐C motif) receptor 2 reduced recruitment of inflammatory macrophages to the liver in vivo. Genetic disruption of IL‐17A signaling was associated with down‐regulation of hepatic Ccl2/Ccr2 messenger RNA expression, reduced infiltration of the liver with inflammatory Ly6Chi macrophages, and improved survival. In the liver of infants with BA, cholangiocytes were found to express IL‐17 receptor A, and the prevalence of IL‐17A+ cells was positively correlated with the degree of CD68+ macrophage infiltration at diagnosis. Hepatic CD4+ lymphocytes were chief producers of IL‐17A in patients with progressive disease undergoing liver transplantation. Conclusion: These findings identify the dendritic cell–T helper 17–macrophage axis as a target for the development of strategies to block progression of intrahepatic bile duct injury in patients with BA. (Hepatology 2017;65:174‐188).


    Date de mise en ligne : Mardi 29 novembre 2016
    Moreshwar S. Desai, Bhoomika Mathur, Zeena Eblimit, Hernan Vasquez, Heinrich Taegtmeyer, Saul J. Karpen, Daniel J. Penny, David D. Moore, Sayeepriyadarshini Anakk
    Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart
    Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator‐activated receptor‐γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator‐activated receptor‐γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid–mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice. Conclusions: Decreased proliferator‐activated receptor‐γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189‐201).


    Date de mise en ligne : Lundi 28 novembre 2016
    JosĂ© Alcaraz‐Quiles, Esther Titos, Mireia Casulleras, Marco Pavesi, Cristina LĂłpez‐Vicario, Bibiana Rius, Aritz Lopategi, Andrea Gottardi, Ivo Graziadei, Henning Gronbaek, Pere GinĂšs, Mauro Bernardi, Vicente Arroyo, Joan ClĂ ria
    Polymorphisms in the IL‐1 gene cluster influence systemic inflammation in patients at risk for acute‐on‐chronic liver failure
    Acute‐on‐chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short‐term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single‐nucleotide polymorphisms (SNPs) in inflammation‐related genes (interleukin [IL]‐1 beta [IL‐1ÎČ], rs1143623; IL‐1 receptor antagonist [IL‐1ra], rs4251961; IL‐10, rs1800871; suppressor of cytokine signaling‐3, rs4969170; nucleotide‐binding oligomerization domain‐containing protein 2, rs3135500; and chemerin chemokine‐like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL‐1 gene cluster (IL‐1ÎČ and IL‐1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL‐1ÎČ (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13‐0.89; P < 0.05) and IL‐1ra (OR, 0.58; 95% CI, 0.35‐0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL‐1ÎČ, IL‐1α, IL‐6, granulocyte‐colony stimulating factor, granulocyte‐macrophage colony‐stimulating factor, and C‐reactive protein at enrollment as well as after 7‐14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28‐day mortality rate. Conclusion: These data identify two common functional polymorphisms in the IL‐1 gene cluster, which are associated with the inflammatory process related to development of ACLF. (Hepatology 2017;65:202‐216).


    Date de mise en ligne : Mardi 29 novembre 2016
    Puneeta Tandon, K. Rajender Reddy, Jacqueline G. O'Leary, Guadalupe Garcia‐Tsao, Juan G. Abraldes, Florence Wong, Scott W. Biggins, Benedict Maliakkal, Michael B. Fallon, Ram M. Subramanian, Paul Thuluvath, Patrick S. Kamath, Leroy R. Thacker, Jasmohan S. Bajaj,
    A Karnofsky performance status–based score predicts death after hospital discharge in patients with cirrhosis
    Identification of patients with cirrhosis at risk for death within 3 months of discharge from the hospital is essential to individualize postdischarge plans. The objective of the study was to identify an easy‐to‐use prognostic model based on the Karnofsky Performance Status (KPS). The North American Consortium for the Study of End‐Stage Liver Disease consists of 16 tertiary‐care hepatology centers that prospectively enroll nonelectively admitted cirrhosis patients. Patients enrolled had KPS assessed 1 week postdischarge. KPS was categorized into low (score 10‐40), intermediate (50‐70), and high (80‐100). Of 954 middle‐aged patients (57 ± 10 years, 63% men) with a median Model for End‐Stage Liver Disease (MELD) score of 17 (interquartile range 13‐21), the mortality rates for the low, intermediate, and high performance status groups were 23% (36/159), 11% (55/489), and 5% (15/306), respectively. Low, intermediate, and high performance status was seen in 17%, 51%, and 32% of the cohort, respectively. Low performance status was associated with older age, dialysis, hepatic encephalopathy, longer length of stay, and higher white blood cell count or MELD score at discharge. A model was derived using the three independent predictors of 3‐month mortality: KPS, age, and MELD score. This score had better discrimination (area under the receiver operating characteristic curve = 0.74) than a model using MELD (area under the receiver operating characteristic curve = 0.62) or MELD and age (area under the receiver operating characteristic curve = 0.67) to predict 3‐month mortality. Conclusions: Cirrhosis patients at risk for 3‐month postdischarge mortality can be identified using a novel KPS‐based score; this score may be adopted in practice to guide postdischarge early interventions, including the integrated provision of active and palliative management strategies. (Hepatology 2017;65:217‐224).


    Date de mise en ligne : Vendredi 07 octobre 2016
    Jie Wang, Hyoung‐Won Koh, Lu Zhou, Ui‐Jin Bae, Hwa‐Suk Lee, In Hyuk Bang, Sun‐O Ka, Seon‐Hee Oh, Eun Ju Bae, Byung‐Hyun Park
    Sirtuin 2 aggravates postischemic liver injury by deacetylating mitogen‐activated protein kinase phosphatase‐1
    Sirtuin 2 (Sirt2) is known to negatively regulate anoxia‐reoxygenation injury in myoblasts. Because protein levels of Sirt2 are increased in ischemia‐reperfusion (I/R)‐injured liver tissues, we examined whether Sirt2 is protective or detrimental against hepatic I/R injury. We overexpressed Sirt2 in the liver of C57BL/6 mice using a Sirt2 adenovirus. Wild‐type and Sirt2 knockout mice were subjected to a partial (70%) hepatic ischemia for 45 minutes, followed by various periods of reperfusion. In another set of experiments, wild‐type mice were pretreated intraperitoneally with AGK2, a Sirt2 inhibitor. Isolated hepatocytes and Kupffer cells from wild‐type and Sirt2 knockout mice were subjected to hypoxia‐reoxygenation injury to determine the in vitro effects of Sirt2. Mice subjected to I/R injury showed typical patterns of hepatocellular damage. Prior injection with Sirt2 adenovirus aggravated liver injury, as demonstrated by increases in serum aminotransferases, prothrombin time, proinflammatory cytokines, hepatocellular necrosis and apoptosis, and neutrophil infiltration relative to control virus‐injected mice. Pretreatment with AGK2 resulted in significant improvements in serum aminotransferase levels and histopathologic findings. Similarly, experiments with Sirt2 knockout mice also revealed reduced hepatocellular injury. The molecular mechanism of Sirt2's involvement in this aggravation of hepatic I/R injury includes the deacetylation and inhibition of mitogen‐activated protein kinase phosphatase‐1 and consequent activation of mitogen‐activated protein kinases. Conclusion: Sirt2 is an aggravating factor during hepatic I/R injury. (Hepatology 2017;65:225‐236).


    Date de mise en ligne : Vendredi 25 novembre 2016
    Xuehua Piao, Soh Yamazaki, Sachiko Komazawa‐Sakon, Sanae Miyake, Osamu Nakabayashi, Takeyuki Kurosawa, Tetsuo Mikami, Minoru Tanaka, Nico Van Rooijen, Masaki Ohmuraya, Akira Oikawa, Yuko Kojima, Soichiro Kakuta, Yasuo Uchiyama, Masato Tanaka, Hiroyasu Nakano
    Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum
    Tissue‐resident macrophages and bone marrow (BM)‐derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte‐specific Cflar‐deficient (CflarHep‐low) mice. Cellular FLICE‐inhibitory protein expression was down‐regulated in Cflar‐deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor–induced apoptosis. CflarHep‐low mice developed acute hepatitis and recovered with clearance of apoptotic hepatocytes at 24 hours after injection of low doses of tumor necrosis factor α (TNFα), which could not induce hepatitis in wild‐type (WT) mice. Depletion of Kupffer cells (KCs) by clodronate liposomes did not impair clearance of dying hepatocytes or exacerbate hepatitis in CflarHep‐low mice. To elucidate the roles of BM‐derived monocytes and neutrophils in clearance of apoptotic hepatocytes, we examined the effect of depletion of these cells on TNFα‐induced hepatitis in CflarHep‐low mice. We reconstituted CflarHep‐low mice with BM cells from transgenic mice in which human diphtheria toxin receptor (DTR) was expressed under control of the lysozyme M (LysM) promoter. TNFα‐induced infiltration of myeloid cells, including monocytes and neutrophils, was completely ablated in LysM‐DTR BM‐reconstituted CflarHep‐low mice pretreated with diphtheria toxin, whereas KCs remained present in the livers. Under these experimental conditions, LysM‐DTR BM‐reconstituted CflarHep‐low mice rapidly developed severe hepatitis and succumbed within several hours of TNFα injection. We found that serum interleukin‐6 (IL‐6), TNFα, and histone H3 were aberrantly increased in LysM‐DTR BM‐reconstituted, but not in WT BM‐reconstituted, CflarHep‐low mice following TNFα injection. Conclusion: These findings indicate an unexpected role of myeloid cells in decreasing serum IL‐6, TNFα, and histone H3 levels via the suppression of TNFα‐induced hepatocyte apoptosis. (Hepatology 2017;65:237‐252).


    Date de mise en ligne : Mardi 29 novembre 2016
    Qian Sun, Patricia Loughran, Richard Shapiro, Indira H. Shrivastava, Daniel J. Antoine, Tunliang Li, Zhengzheng Yan, Jie Fan, Timothy R. Billiar, Melanie J. Scott
    Redox‐dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice
    Sterile liver inflammation, such as liver ischemia‐reperfusion, hemorrhagic shock after trauma, and drug‐induced liver injury, is initiated and regulated by endogenous mediators including DNA and reactive oxygen species. Here, we identify a mechanism for redox‐mediated regulation of absent in melanoma 2 (AIM2) inflammasome activation in hepatocytes after redox stress in mice, which occurs through interaction with cytosolic high mobility group box 1 (HMGB1). We show that in liver during hemorrhagic shock in mice and in hepatocytes after hypoxia with reoxygenation, cytosolic HMGB1 associates with AIM2 and is required for activation of caspase‐1 in response to cytosolic DNA. Activation of caspase‐1 through AIM2 leads to subsequent hepatoprotective responses such as autophagy. HMGB1 binds to AIM2 at a non‐DNA‐binding site on the hematopoietic interferon‐inducible nuclear antigen domain of AIM2 to facilitate inflammasome and caspase‐1 activation in hepatocytes. Furthermore, binding of HMGB1 to AIM2 is stronger with fully reduced all‐thiol HMGB1 than with partially oxidized disulfide‐HMGB1, and binding strength corresponds to caspase‐1 activation. These data suggest that HMGB1 redox status regulates AIM2 inflammasome activation. Conclusion: These findings suggest a novel and important mechanism for regulation of AIM2 inflammasome activation in hepatocytes during redox stress and may suggest broader implications for how this and other inflammasomes are activated and how their activation is regulated during cell stress, as well as the mechanisms of inflammasome regulation in nonimmune cell types. (Hepatology 2017;65:253‐268).


    Date de mise en ligne : Mercredi 05 octobre 2016
    Abraham Shaked, Bao‐Li Chang, Michael R. Barnes, Peter Sayre, Yun R. Li, Smita Asare, Michele DesMarais, Michael V. Holmes, Toumy Guettouche, Brendan J. Keating
    An ectopically expressed serum miRNA signature is prognostic, diagnostic, and biologically related to liver allograft rejection
    The ability to noninvasively diagnose acute cellular rejection (ACR) with high specificity and sensitivity would significantly advance personalized liver transplant recipient care and management of immunosuppression. We performed microRNA (miRNA) profiling in 318 serum samples from 69 liver transplant recipients enrolled in the Immune Tolerance Network immunosuppression withdrawal (ITN030ST) and Clinical Trials in Organ Transplantation (CTOT‐03) studies. We quantified serum miRNA at clinically indicated and/or protocol biopsy events (n = 130). The trajectory of ACR diagnostic miRNAs during immunosuppression withdrawal were also evaluated in sera taken at predetermined intervals during immunosuppression minimization before and at clinically indicated liver biopsy (n = 119). Levels of 31 miRNAs were significantly associated with ACR diagnosis with two miRNAs differentiating ACR from non‐ACR (area under the receiver operating characteristic curve = 90%, 95% confidence interval = 82%‐96%) and predicted ACR events up to 40 days before biopsy‐proven rejection. The most differentially expressed miRNAs were low or absent in the blood of healthy individuals but highly expressed in liver tissue, indicating an ectopic origin from the liver allograft. Pathway analyses of rejection‐associated miRNAs and their target messenger RNAs (mRNAs) showed induction of proinflammatory and cell death‐related pathways. Integration of differentially expressed serum miRNA with concordant liver biopsy mRNA demonstrates interaction between molecules with a known role in transplant rejection. Conclusion: Distinct miRNA levels profiled from sera at the time of clinical allograft dysfunction can be used to noninvasively diagnose ACR. Predictive trajectories of the same profile during supervised immunosuppression minimization diagnosed rejection up to 40 days prior to clinical expression. The rejection‐associated miRNAs in sera appear to be ectopically expressed liver and specific immune cell miRNAs that are biologically related, and the consequences of immune‐mediated damage to the allograft. (Hepatology 2017;65:269‐280).


    Date de mise en ligne : Samedi 12 novembre 2016
    Theodorus B.M. Hakvoort, Youji He, Wim Kulik, Jacqueline L.M. Vermeulen, Suzanne Duijst, Jan M. Ruijter, Jurgen H. Runge, Nicolaas E.P. Deutz, S. Eleonore Koehler, Wouter H. Lamers
    Pivotal role of glutamine synthetase in ammonia detoxification
    Glutamine synthetase (GS) catalyzes condensation of ammonia with glutamate to glutamine. Glutamine serves, with alanine, as a major nontoxic interorgan ammonia carrier. Elimination of hepatic GS expression in mice causes only mild hyperammonemia and hypoglutaminemia but a pronounced decrease in the whole‐body muscle‐to‐fat ratio with increased myostatin expression in muscle. Using GS‐knockout/liver and control mice and stepwise increments of enterally infused ammonia, we show that ∌35% of this ammonia is detoxified by hepatic GS and ∌35% by urea‐cycle enzymes, while ∌30% is not cleared by the liver, independent of portal ammonia concentrations ≀2 mmol/L. Using both genetic (GS‐knockout/liver and GS‐knockout/muscle) and pharmacological (methionine sulfoximine and dexamethasone) approaches to modulate GS activity, we further show that detoxification of stepwise increments of intravenously (jugular vein) infused ammonia is almost totally dependent on GS activity. Maximal ammonia‐detoxifying capacity through either the enteral or the intravenous route is ∌160 ÎŒmol/hour in control mice. Using stable isotopes, we show that disposal of glutamine‐bound ammonia to urea (through mitochondrial glutaminase and carbamoylphosphate synthetase) depends on the rate of glutamine synthesis and increases from ∌7% in methionine sulfoximine‐treated mice to ∌500% in dexamethasone‐treated mice (control mice, 100%), without difference in total urea synthesis. Conclusions: Hepatic GS contributes to both enteral and systemic ammonia detoxification. Glutamine synthesis in the periphery (including that in pericentral hepatocytes) and glutamine catabolism in (periportal) hepatocytes represents the high‐affinity ammonia‐detoxifying system of the body. The dependence of glutamine‐bound ammonia disposal to urea on the rate of glutamine synthesis suggests that enhancing peripheral glutamine synthesis is a promising strategy to treat hyperammonemia. Because total urea synthesis does not depend on glutamine synthesis, we hypothesize that glutamate dehydrogenase complements mitochondrial ammonia production. (Hepatology 2017;65:281‐293).


    Date de mise en ligne : Vendredi 25 novembre 2016
    Daniel A. Patten, Garrick K. Wilson, Dalan Bailey, Robert K. Shaw, Sirpa Jalkanen, Marko Salmi, Antal Rot, Chris J. Weston, David H. Adams, Shishir Shetty
    Human liver sinusoidal endothelial cells promote intracellular crawling of lymphocytes during recruitment: A new step in migration
    The recruitment of lymphocytes via the hepatic sinusoidal channels and positioning within liver tissue is a critical event in the development and persistence of chronic inflammatory liver diseases. The hepatic sinusoid is a unique vascular bed lined by hepatic sinusoidal endothelial cells (HSECs), a functionally and phenotypically distinct subpopulation of endothelial cells. Using flow‐based adhesion assays to study the migration of lymphocytes across primary human HSECs, we found that lymphocytes enter into HSECs, confirmed by electron microscopy demonstrating clear intracellular localization of lymphocytes in vitro and by studies in human liver tissues. Stimulation by interferon‐γ increased intracellular localization of lymphocytes within HSECs. Furthermore, using confocal imaging and time‐lapse recordings, we demonstrated “intracellular crawling” of lymphocytes entering into one endothelial cell from another. This required the expression of intracellular adhesion molecule‐1 and stabilin‐1 and was facilitated by the junctional complexes between HSECs. Conclusion: Lymphocyte migration is facilitated by the unique structure of HSECs. Intracellular crawling may contribute to optimal lymphocyte positioning in liver tissue during chronic hepatitis. (Hepatology 2017;65:294‐309).


    Date de mise en ligne : Jeudi 01 décembre 2016
    Guadalupe Garcia‐Tsao, Juan G. Abraldes, Annalisa Berzigotti, Jaime Bosch
    Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases
    335


    Date de mise en ligne : Mardi 25 octobre 2016
    Mark W. Russo, Ayman A. Koteish, Michael Fuchs, K. Gautham Reddy, Oren K. Fix
    Workforce in hepatology: Update and a critical need for more information
    The field of hepatology has experienced dramatic changes since the last workforce study in hepatology over 15 years ago. Hepatology practice has been dominated by hepatitis C but is now being overtaken by patients with nonalcoholic fatty liver disease. Expertise once attainable only through informal training, hepatology now has an accredited fellowship pathway and is recognized as a distinct discipline from gastroenterology with its own board certification. These changes that have occurred since the last workforce study in the prevalence and therapy of liver diseases and training may impact workforce needs. The time has come to conduct an updated analysis of the state of the hepatology workforce. The purpose of this article is to discuss the current issues facing training and workforce in hepatology and propose the next steps in conducting a workforce study. (Hepatology 2017;65:336‐340).


    Date de mise en ligne : Mardi 15 novembre 2016
    Hugo RamĂłn Rosen
    “Hep C, where art thou”: What are the remaining (fundable) questions in hepatitis C virus research?
    Hepatitis C virus (HCV) has dominated the field of hepatology for the past 25 years, and its cure in the majority of treated patients is one of the greatest achievements in all of medicine. However, the latter has led to the belief by some that HCV research should be shelved for other, more pressing areas. The mission for HCV eradication is far from accomplished. As a historical reference, we should consider that disease elimination has required vaccination with all previously controlled infections including smallpox and polio and that simple, effective treatment is not sufficient in most infections to lead to substantial control. Syphilis is the best example, for which a single dose of penicillin (which literally costs pennies and that we have had since 1945) is curative in early stages. Not only have we not eradicated syphilis, rates of infection have increased in many places within the United States in recent years. Most HCV‐infected subjects are unaware of their infection, remaining at risk for transmission to others and disease progression, including cirrhosis and hepatocellular carcinoma. In the era of highly effective direct‐acting antivirals (DAAs), many questions pertaining to HCV remain, but they are more complex and difficult to answer. Here, I provide my perspective on some of these salient issues: the residual risk for disease progression after sustained virologic response, the optimal approach to current DAA failures, the impact of targeting people who inject drugs with DAAs, vaccine prospects, and application of neutralizing HCV glycoprotein antibodies. (Hepatology 2017;65:341‐349).


    Date de mise en ligne : Jeudi 04 août 2016
    Juan P. Arab, Saul J. Karpen, Paul A. Dawson, Marco Arrese, Michael Trauner
    Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives
    Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium‐dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile‐acid‐related pathways to address this growing world‐wide disease. (Hepatology 2017;65:350‐362)


    Date de mise en ligne : Jeudi 17 novembre 2016
    Victor J. Navarro, Ikhlas Khan, Einar Björnsson, Leonard B. Seeff, Jose Serrano, Jay H. Hoofnagle
    Liver injury from herbal and dietary supplements
    Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS‐induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS‐induced liver injury were the focus of a 2‐day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS‐induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi‐ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self‐limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis‐like injury. Currently, however, the majority of cases of HDS‐associated liver injury are due to multi‐ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS‐induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363‐373).


    Date de mise en ligne : Mardi 27 décembre 2016
    Misako Sato‐Matsubara, Norifumi Kawada
    New player in tumor‐stromal interaction: Granulin as a novel therapeutic target for pancreatic ductal adenocarcinoma liver metastasis
    376


    Date de mise en ligne : Mardi 15 novembre 2016
    Barbara Rehermann
    Mature peritoneal macrophages take an avascular route into the injured liver and promote tissue repair
    379


    Date de mise en ligne : Samedi 05 novembre 2016
    Paul Kaminsky, Joshua Preiss, Eizaburo Sasatomi, David A. Gerber
    Biliary adenofibroma: A rare hepatic lesion with malignant features
    383


    Date de mise en ligne : Mercredi 24 août 2016
    Raffaela Rametta, Paola Dongiovanni, Silvia Fargion, Luca Valenti
    GNPAT p.D519G variant and iron metabolism during oral iron tolerance test
    385


    Date de mise en ligne : Mardi 23 août 2016
    Gin‐Ho Lo
    The use of esophageal stent in controlling acute refractory variceal bleeding
    386


    Date de mise en ligne : Vendredi 26 août 2016
    Angels Escorsell, Jaime Bosch
    Reply
    387


    Date de mise en ligne : Mercredi 24 août 2016
    RaĂșl A. Marinelli, Julieta Marrone
    Aquaporin gene therapy for cholestasis
    388


    Date de mise en ligne : Jeudi 06 octobre 2016
    Christophe Renou, Bruno Lesgourgues, Gilles Macaigne, Arnaud Pauwels, Yann Le Bricquir, Jean Henrion, Faiza Khemissa, Emma Clair, Thierry Paupard, Agnes Pelaquier, HĂ©lĂšne Agostini, Anne‐Marie Roque‐Afonso
    Hepatitis E in decompensated alcoholic cirrhosis
    389


    Date de mise en ligne : Jeudi 06 octobre 2016
    Robert J. Fontana, Ronald E. Engle, Robert H. Purcell, William M. Lee,
    Reply
    390


    Date de mise en ligne : Mardi 18 octobre 2016
    Inmaculada Medina‐Cáliz, Mercedes Robles‐Díaz, M. Isabel Lucena, Raul J. Andrade
    Drug‐induced liver and skin reactions: In need of a consensus definition
    391


    Date de mise en ligne : Mardi 18 octobre 2016
    Harshad Devarbhavi, Sujata Raj
    Reply
    392


    Date de mise en ligne : Mardi 15 novembre 2016
    Muhammad Ali Khan, George Cholankeril, Colin W. Howden
    Are proton pump inhibitors a threat for spontaneous bacterial peritonitis and hepatic encephalopathy in cirrhosis? Not so fast
    393


    Date de mise en ligne : Jeudi 10 novembre 2016
    Gitte Dam, Hendrik Vilstrup, Hugh Watson, Peter Jepsen
    Reply
    394


    Date de mise en ligne : Mardi 22 novembre 2016
    Christine Baechlein, Paul Becher
    No evidence for zoonotic hepatitis E virus infection through dairy milk in Germany
    395


    Date de mise en ligne : Vendredi 25 novembre 2016
    Fen Huang, Yunlong Li, Wenhai Yu, Chenchen Yang
    Reply
    396


    Date de mise en ligne : Jeudi 17 novembre 2016
    Correction
    Correction
    397


    Date de mise en ligne : Jeudi 17 novembre 2016
    Correction
    Correction
    397


    Date de mise en ligne : Mardi 27 décembre 2016
    Notices
    Notices
    n/a


    Date de mise en ligne : Mardi 27 décembre 2016
    Instructions to authors and Information for readers
    Instructions to authors and Information for readers
    n/a