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  • The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-16
    Hamish Innes, Stephen T. Barclay, Peter C. Hayes, Andrew Fraser, John F. Dillon, Adrian Stanley, Andy Bathgate, Scott A McDonald, David Goldberg, Heather Valerio, Ray Fox, Nick Kennedy, Pete Bramley, Sharon J. Hutchinson

    BACKGROUND Previous studies have reported a high frequency of hepatocellular carcinoma (HCC) occurrence in patients with advanced liver disease, after receipt of interferon(IFN)-free therapy for hepatitis C virus (HCV) infection. Our objective was to verify and account for this phenomenon using data from the Scottish HCV Clinical Database. METHODS We identified HCC-naïve individuals with liver cirrhosis receiving a course of antiviral therapy in Scotland from 1997-2016 resulting in a SVR. Patients were followed-up from their treatment start date to the earliest of: date of death, date of HCC occurrence, or Jan 2017. We used Cox regression to compare the risk of HCC occurrence according to treatment regimen after adjusting for relevant co-factors (including: demographic factors; baseline liver disease stage; comorbidities/health behaviours, virology, and previous treatment experience). HCC occurrence was ascertained through the both the HCV clinical database and medical chart review. For our main analysis, treatment regimen was defined as IFN-free versus IFN-containing. RESULTS 857 patients met the study criteria, of whom 31.7% received an IFN-free regimen. Individuals receiving IFN-free therapy were more likely to be: older; of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic; non-genotype 3; and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free receipt was associated with a significantly increased risk of HCC (HR: 2.48; P=0.021). However after multivariate adjustment for baseline factors, no significant risk attributable to IFN-free therapy persisted (aHR: 1.15, P=0.744). CONCLUSION These findings suggest that the higher incidence of HCC following SVR with IFN-free therapy relates to baseline risk factors/patient selection, and not the use of IFN-free therapy per se. LAY SUMMARY We examined the risk of liver cancer among 857 patients with cirrhosis in Scotland who received hepatitis C antiviral therapy and achieved a cure. We compared the risk of first-time liver cancer in patients treated with the newest interferon-free regimens, to patients treated with interferon. After accounting for the different characteristics of these two treatment groups, we found no evidence that interferon-free therapy is associated with a higher risk of liver cancer.

    更新日期:2017-11-17
  • The UK-DCD-Risk-Score: a new proposal to define futility in Donation after Circulatory Death liver transplantation
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-15
    Andrea Schlegel, Marit Kalisvaart, Irene Scalera, Richard W Laing, Hynek Mergental, Darius F Mirza, Thamara Perera, John Isaac, Philipp Dutkowski, Paolo Muiesan

    Objectives To design a new score on risk assessment in liver transplantation donated after circulatory death (DCD) based on donor and recipient parameters. Background Primary-non-function (PNF) and ischemic cholangiopathy (IC) are the most feared complications following DCD liver transplantation. Methods Using the United Kingdom (UK) national DCD database, a risk analysis was performed in adult recipients of DCD liver grafts in UK between 2000 and 2015 (n=1153). A new risk score was calculated (UK-DCD-Risk-Score) on the basis of regression analysis, and validated using the UNOS (United Network for Organ Sharing) database (n=1617) and our own DCD liver transplant database (n=315). Finally, the new score was compared with two other available prediction systems, the DCD risk scores from UCLA and Kings-College-Hospital, London. Results Seven strongest predictors of DCD graft survival were identified: functional donor warm ischemia, cold ischemia, recipient MELD, recipient age, donor age, previous OLT, and donor body-mass-index (BMI). A combination of these risk factors (UK-DCD-Risk-Model) stratified best recipients in terms of graft survival in the entire UK-DCD-database as well as in the UNOS and in our own DCD population. Importantly, the UK-DCD-Risk-Score significantly predicted graft loss due to PNF or IC in the futile group (>10 score points). The new prediction model demonstrated a better C statistic of 0,79, compared to the two other available systems (0,71 and 0,64; respectively). Conclusions The UK-DCD-Risk-Score is a reliable tool to detect high risk and futile combinations of donor and recipient factors in DCD liver transplantation. It is simple to use and offers a great potential to better decide which DCD graft should be rejected or may benefit from functional assessment and further optimization by machine perfusion. Lay Summary Here we provide a new prediction model for graft loss in donation after circulatory death (DCD) liver transplantation. Based on national data from United Kingdom (UK), the new UK-DCD-Risk Score involves the following 7 clinical relevant risk factors: donor age, donor BMI, functional donor warm ischemia, cold storage, recipient age, recipient lab MELD and retransplantation. Three risk classes were defined: low risk (0-5points), high risk (6-10 points) and futile (>10points). This new model stratified best in terms of graft survival, compared to other available models. Futile combinations (>10 points) achieved an only very limited one and five-year graft survival of 37% and less than 20% respectively. In contrast, low risk combinations (≤ 5points) showed an excellent graft survival. The new model, is easy to calculate at the time of liver acceptance and may help to decide, which risk combination will benefit from additional graft treatment or which DCD liver should be declined for a certain recipient.

    更新日期:2017-11-17
  • Association between non-alcoholic fatty liver disease and cancer incidence rate
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-14
    Gi-Ae Kim, Han Chu Lee, Jaewon Choe, Min-Ju Kim, Min Jung Lee, Hye-Sook Chang, In Young Bae, Hong-Kyu Kim, Jihyun An, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim

    Background & AimsLittle is known about the association between non-alcoholic fatty liver disease (NAFLD) and cancer development. This study investigated the cancer incidence rates in NAFLD and analysed the association between NAFLD and cancer development.MethodsThis historical cohort study included subjects who were followed up for >1 year after having a heath checkup at a tertiary hospital in Korea from September 1, 2004 to December 31, 2005. NAFLD was diagnosed by ultrasonographic detection of hepatic steatosis in the absence of other known liver disease, including alcoholic or viral hepatitis. Cox proportional hazards regression model was conducted to assess the association between NAFLD and cancer development.ResultsOf 25,947 subjects, 8,721 (33.6%) had NAFLD. During the total follow-up of 164,671 person-years (median 7.5 years), the cancer incidence rate of the NAFLD group was higher than that of the non-NAFLD group (782.9 vs. 592.8 per 100,000 person-years; hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.17–1.49; p <0.001). When demographic and metabolic factors were adjusted for, NAFLD showed a strong association with three cancers: hepatocellular carcinoma ([HCC]; HR 16.73; 95% CI 2.09–133.85; p = 0.008), colorectal cancer in males (HR 2.01; 95% CI 1.10–3.68; p = 0.02), and breast cancer in females (HR 1.92; 95% CI 1.15–3.20; p = 0.01). A high NAFLD fibrosis score (NFS) and a high fibrosis-4 (FIB-4) score were associated with the development of all cancers and HCC.ConclusionNAFLD was associated with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NFS and a high FIB-4 score showed a strong association with the development of all cancers and HCC.Lay summaryNon-alcoholic fatty liver disease (NAFLD) is associated with developing hepatocellular carcinoma (HCC). There have been limited data on the association between NAFLD and extrahepatic cancers. This study demonstrated that patients with NAFLD showed a higher association with the development of HCC, colorectal cancer in males, and breast cancer in females. A high NAFLD fibrosis score and a high fibrosis-4 score showed a strong association with the development of all cancers and HCC.

    更新日期:2017-11-15
  • Determinants of Fibrosis Progression and Regression in NASH
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-14
    Detlef Schuppan, Rambabu Surabattula, Xiao Yu Wang

    Cirrhosis has become the major liver related clinical endpoint in nonalcoholic steatohepatitis. However, progression to cirrhosis is less predictable in NASH compared to other chronic liver diseases. This is due to the complex and multifactorial etiology of NASH, which is determined by life style and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus modest changes in these cofactors can also induce fibrosis regression, at least in precirrhotic patients. Fibrogenesis in NASH correlates with but is indirectly coupled to classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force for progression, activated hepatic stellate cells and myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix themselves are major fibrogenic effectors and thus pharmacological targets to inhibit fibrosis progression and induce fibrosis reversal. With the advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH, an improved detection, stratification and follow up of patients with progressive NASH becomes feasible. These noninvasive tools will also promote the clinical development of antifibrotic drugs by permitting the design of lean proof of concept studies, and finally allowing a personalized antifibrotic therapy for patients with rapid fibrosis progression or advanced disease.(215 words)

    更新日期:2017-11-15
  • Macrophage scavenger receptor 1 contributes to pathogenesis of fulminant hepatitis via neutrophil mediated complement activation
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-14
    Yuan Tang, Huifang Li, Junru Li, Yunzhi Liu, Yanli Li, Jing Zhou, Jia Zhou, Xiao Lu, Wei Zhao, Jinlin Hou, Xiang-Yang Wang, Zhengliang Chen, Daming Zuo

    Background & AimsThe macrophage scavenger receptor 1 (Msr1, also called SRA) is a pattern recognition receptor primarily expressed on myeloid cells, playing an important role in the maintenance of immune homeostasis. Since MSR1 expression was up-regulated in the livers of patients with fulminant hepatitis (FH), we investigated the functional mechanism of Msr1 as related to FH pathogenesis.MethodsMsr1-deficient (Msr1–/–) mice and their wild-type (WT) littermates were infected with mouse hepatitis virus strain-A59 (MHV-A59) to induce FH, and the levels of tissue damage, serum alanine aminotransferase (ALT), inflammatory cytokines and complement C5a were measured and compared. Liver injury was studied after MHV infection with or without neutrophil depletion.ResultsOur results showed that Msr1–/– mice were resistant to MHV-induced hepatitis. Treatment with the C5aR antagonist (C5aRa) diminished the differences in inflammatory responses and liver injury between MHV-infected WT and Msr1–/– mice, suggesting that C5a-induced pro-inflammatory response plays a critical role in the Msr1-mediated regulation of FH pathogenesis. We demonstrated that Msr1 efficiently enhanced TAK1 phosphorylation in neutrophils upon MHV-A59 stimulation, thereby promoting the activation of ERK pathway and subsequent NETosis formation. Moreover, we provided evidence that blockage of Msr1 attenuated the liver damage caused by MHV-A59 infection.ConclusionsMsr1 promotes the pathogenesis of virus-induced FH by enhancing induction of neutrophil NETosis and following complement activation. Targeting Msr1 may be employed as a new immunotherapeutic strategy for FH.Lay summaryVirus-induced fulminant hepatitis (FH) is a disease with a high mortality worldwide. Enhanced level of macrophage scavenger receptor 1 (Msr1) in the liver of patients with FH and of murine experimental FH indicated Msr1 play a role in the pathogenesis of FH. Here, we demonstrate that mice deficient in Msr1 are resistant to FH induced by MHV-A59, and the Msr1 inhibitor fucoidan suppresses the progression of FH in mice. Our study suggests that use of drugs inhibiting MSR1 function could be beneficial to patients with FH.

    更新日期:2017-11-15
  • Lipotoxicity and the gut-liver axis in NASH pathogenesis
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-14
    Fabio Marra, Gianluca Svegliati-Baroni

    The pathogenesis of nanoalcoholic fatty liver disease is still incompletely understood, in particolar the mechanisms whereby a minority of patients develop a more severe phenotype characterized by hepatocellular damage, inflammation, and fibrosis. In this review we discuss two pivotal aspects of the pathogenesis of NASH. We first analyze the initial mechanisms responsible of hepatocellular damage and inflammation, which derive from the toxic effects of excess lipids. Accumulating data indicate that the total amount of triglycerides stored in hepatocytes is not the major determinant of lipotoxicity, and that specific lipid classes act as damaging agents on liver cells. In particular, the role of free fatty acids such as palmitic acid, cholesterol, lysophosphatidylcholine and ceramides has emerged by recent investigation. These lipotoxic agents affect the cell behavior via multiple mechanisms, including activation of signaling cascades such as JNK and death receptors, ER stress, modification of mitochondrial function, and oxidative stress. In the second part of the review, the cellular and molecular players involved in the cross-talk between the gut and the liver are considered. These include modifications of the microbiota, which provides signals through the intestine and through bacterial products, and hormones which are produced in the bowel and affect metabolism at different levels including the liver. Finally, the activation of nuclear receptor by bile acids is analyzed.

    更新日期:2017-11-15
  • Contrast enhanced ultrasound identifies hepatocellular carcinoma in cirrhosis: a large multicenter retrospective study
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-11
    Eleonora Terzi, Massimo Iavarone, Maurizio Pompili, Letizia Veronese, Giuseppe Cabibbo, Mirella Fraquelli, Laura Riccardi, Ludovico De Bonis, Angelo Sangiovanni, Simona Leoni, Maria Assunta Zocco, Sandro Rossi, Nicola Alessi, Stephanie R. Wilson, Fabio Piscaglia, Alessandro Granito, Veronica Salvatore, Francesco Tovoli, Matteo Angelo Manini, Gian Lodovico Rapaccini, Maria Elena Ainora, Valentina Ravetta, Giorgia Ghittoni, Agostino Ventra, Giuseppe Mogavero

    Background & Aims The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned for the risk of false positive diagnosis in case of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS LI-RADS) classifying lesions at risk for HCC investigated by CEUS. Aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. Methods A total of 1006 nodules in 848 patients with chronic liver disease at risk for HCC collected in 5 Italian centers were retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥ 1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 seconds after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (=506) or histology (n=500). Results Median size was 2 cm. Of 1006 nodules, HCC were 820 (81%), cholangiocarcinoma 40 (4%), regenerative nodules (±dysplastic) 116 (11%). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96=47%) and the LR-4 202 (HCC 173=87%). Conclusions The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non invasive diagnosis. LAY SUMMARY A retrospective study of approximately 1000 focal lesions at risk for HCC, demonstrates that the refined definition of the typical contrast enhanced ultrasound pattern of hepatocellular carcinoma (HCC) introduced by the Liver Imaging Reporting and Data System (LI RADS) practically abolishes the risk of misdiagnosis of other malignant entities (e.g. cholangiocellular carcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose hepatocellular carcinoma in cirrhosis.

    更新日期:2017-11-11
  • Potentially Inappropriate Liver Transplantation in the Era of the “Sickest-first” Policy - A Search for the Upper Limits
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-11
    Michael Linecker, Tanja Krones, Thomas Berg, Claus U. Niemann, Randolph H. Steadman, Philipp Dutkowski, Pierre-Alain Clavien, Ronald W. Busuttil, Robert D. Truog, Henrik Petrowsky

    Liver transplantation has emerged to a highly efficient treatment for a variaty of acute and chronic liver diseases. Organ shortage, however, is becoming an increasing problem worldwide, limiting the applicability of liver transplantation. In addition, potential recipients are becoming sicker, thereby increasing the risk of loosing the graft during transplantation or in the initial post-operative period after liver transplantation (3 months). This trend is challenging the MELD allocation model where sickest candidates are prioritized and no delisting criteria are given. The weighing of two conflicting bio-ethical concepts, the deontological demand for “equity”, trying to save every patient, regardless of the overall utility, and “efficiency”, rooted in utilitarianism, trying to save as many patients as possible and increase the overall quality of life of patients facing the same problem, has to be reconsidered. In this article we are aiming at overcoming the widespread and wide concept of futility in liver transplantation, provide a definition of potentially inappropriate liver transplantation and give decision guidance in which situations not to proceed with liver transplantion to decrease the mortality rate in the first 3 months after transplanation. “Absolute” and “relative” conditions, when early posttransplant mortality is highly probable, are proposed, usually not captured in risk scores predicting post-transplant survival. Withholding listed patients for the chance of liver transplantation, who are assessed as not being clearly futile but potentially inappropriate, is a far-reaching decision. Up to now, this decision has to be extensively discussed on a individual basis, applying explicit communication and conflict resolution processes, since the MELD score and most international allocation systems do not include explicit delisting criteria for supporting a fair delisting process. More work is needed to better identify liver transplant candidates where transplanation is potentially inappropriate and to integrate and discuss these delisting criteria in allocation systems, triggered by a societal debate on what we owe to all liver transplant candidates.

    更新日期:2017-11-11
  • Real-world effectiveness of 8 weeks treatment with ledipasvir/sofosbuvir in chronic hepatitis C
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-11
    Peter Buggisch, Johannes Vermehren, Stefan Mauss, Rainer Günther, Eckart Schott, Anita Pathil, Klaus Boeker, Tim Zimmermann, Gerlinde Teuber, Heike-Pfeiffer Vornkahl, Karl-Georg Simon, Claus Niederau, Heiner Wedemeyer, Stefan Zeuzem

    Background and aims Ledipasvir/Sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the summary of product characteristics (SmPC), 8 weeks treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of 8 week regimen of LDV/SOF under real-world conditions available. Aim of the present study was to characterise patients receiving 8 weeks LDV/SOF compared with 12 weeks treatment duration and to describe outcome of therapy in routine clinical practice. Methods The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Results Overall, 84.6% (2,034/2,404) of the Intention-to-Treat (ITT) population and 98.2% (2,029/2,066) of the Per Protocol (PP) population achieved SVR12. In the 8 week group, 85.1% (824/968) of ITT and 98.3% (821/835) of PP patients achieved SVR12, while in the 12 week group, 85.5% (1210/1415) of ITT, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). Conclusions Under real world conditions a high proportion of eligible patients received 8 week LDV/SOF treatment. Relapse occurred in particular in patients who did not meet the selection criteria according to the SmPC. Lay summary In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8 week) resulted in equivalent cure rates to 12 weeks treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy.

    更新日期:2017-11-11
  • Preclinical Models of Nonalcoholic Fatty Liver Disease
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-09
    Prasanna K. Santhekadur, Divya P. Kumar, Arun J. Sanyal

    Nonalcoholic fatty liver disease (NAFLD) can manifest as nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH). NASH is often associated with progressive fibrosis which can lead to cirrhosis and hepatocellular cancer (HCC). NASH is increasing as an etiology for end-stage liver disease as well as HCC. There are currently no approved therapies for NASH. A major barrier to development of therapeutics for NASH is the lack of preclinical models of disease that are appropriately validated to represent the biology and outcomes of human disease. There are many in vitro and animal models that have been developed. In vitro models do not fully capture the hepatic and extrahepatic mileu of human NASH and large animal models are expensive and logistically difficult to use. There is therefore considerable interest in the development and validation of mouse models for NAFLD including NASH. Several models based on varying genetic or dietary manipulations have been developed. The majority of models do not develop steatohepatitis as defined strictly by the presence of hepatocellular ballooning with or without Mallory-Denk bodies and accompanying inflammation in the presence of macrovesicular steatosis. Others lack validation against human disease. In this review, we describe the best practices in development of mouse models of NASH. We further review existing models and the literature supporting their use as a surrogate for human disease. Finally, data on models to evaluate protective genes are discussed. It is hoped these will provide guidance in the interpretation of data derived from mouse models and also in the development and validation of newer models.

    更新日期:2017-11-10
  • Pharmacotherapy for NASH: Current and Emerging
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-06
    Monica A. Konerman, Jacob C. Jones, Stephen A. Harrison

    Non-alcoholic fatty liver disease (NAFLD) has become one of the most prominent forms of chronic liver disease worldwide as a reflection of the global obesity epidemic. Those with the progressive variant of NAFLD, nonalcoholic steatohepatitis (NASH), are at significantly increased risk for multisystem morbidity and mortality. However, there are currently no approved pharmacologic therapies for NASH. Given the disease burden, there is an important unmet need for pharmacologic treatment options for this patient population. The underlying pathophysiologic mechanisms that contribute to the development and progression of NAFLD and NASH are complex and reflected by the myriad of therapies under investigation affecting different targets of engagement. In broad strokes, drug development has focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis. Although much progress has been made in enhancing our understanding of NAFLD pathogenesis, development of pharmacologic treatments has been hindered by challenges in clinical trial enrollment and complexities in clinical trial design. The compounds in phase 2a have thus far had promising results in terms of potential benefit in various aspects of histopathology. Agents in later stages of development have shown fairly modest results in terms of reduction of hepatic steatosis, necro-inflammation and fibrosis. If longer-term safety and efficacy are established among heterogeneous cohorts, these medications may help mitigate potential morbidity and mortality for this burgeoning patient population.

    更新日期:2017-11-10
  • Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence?
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-06
    Amedeo Lonardo, Fabio Nascimbeni, Alessandro Mantovani, Giovanni Targher

    Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD.

    更新日期:2017-11-10
  • Should we undertake surveillance for hcc in patients with nafld?
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-06
    Ramy Younes, Elisabetta Bugianesi

    The pandemic spread of obesity and its related complications is rapidly changing the epidemiology of many type of cancers, including Hepatocellular Carcinoma (HCC). Non Alcoholic Fatty Liver Disease (NAFLD) is becoming a main source of HCC, with a steadily rising trend compared to chronic hepatitis due to Virus B, C and alcohol. The much larger spread of the underlying liver disease in the general population and the chance of arising in non-cirrhotic liver are the most worrisome aspects of HCC in NAFLD. Effective screening programs are currently hampered by the limited knowledge of the pathways of carcinogenesis and the lack of tools able to stratify the risk in the NAFLD population. Hence poor surveillance has prevented an adequate treatment of NAFLD-related HCC so far. Systemic and hepatic molecular mechanisms involved in hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review describes the current clinical impact of HCC in NAFLD and discusses the most important unmet needs for its effective management.

    更新日期:2017-11-10
  • The nutritional geometry of liver disease including non-alcoholic fatty liver disease (NAFLD)
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-06
    Stephen J. Simpson, David Raubenheimer, Victoria C. Cogger, Laurence Macia, Samantha M. Solon-Biet, David G. Le Couteur, Jacob George

    Nutrition has a profound effect on chronic liver disease, especially non-alcoholic fatty liver disease (NAFLD). Most observational studies and clinical trials have focussed on the effects of total energy intake, or the intake of individual macronutrients and certain micronutrients, such as vitamin D, on liver disease. Although these studies have shown the importance of nutrition on hepatic outcomes, there is not yet any unifying framework for understanding the relationship between diet and liver disease. The Geometric Framework for Nutrition (GFN) is an innovative model for designing nutritional experiments or interpreting nutritional data that can determine the effects of nutrients and their interactions on animal behaviour and phenotypes. Recently the GFN has provided insights into the relationship between dietary energy and macronutrients on obesity and ageing in mammals including humans. Mouse studies using the GFN have disentangled the effects of macronutrients on fatty liver and the gut microbiome. The GFN is likely to play a significant role in disentangling the effects of nutrients on liver disease, especially NAFLD, in humans.

    更新日期:2017-11-10
  • Genetics and epigenetics of NAFLD and NASH: Clinical impact
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-06
    Mohammed Eslam, Luca Valenti, Stefano Romeo

    Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.

    更新日期:2017-11-10
  • Arid1a regulates response to anti-angiogenic therapy in advanced hepatocellular carcinoma
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-04
    Chaobo Hu, Weiping Li, Feng Tian, Kai Jiang, Xiaoting Liu, Jin Cen, Qiang He, Zhixin Qiu, Yvonne Kienast, Zhong Wang, Haibin Zhang, Yuan Ji, Junhao Hu, Lijian Hui

    Background & AimsArid1a, a component of the chromatin-remodelling complex, has emerged as a tumor suppressor gene. It is frequently mutated in hepatocellular carcinoma (HCC). However, it remains unknown how Arid1a suppresses HCC development and whether Arid1a deficiency could be exploited for therapy.MethodsThe expression of Arid1a in human and mouse HCCs was determined by immunohistochemical (IHC) staining. Gene expression was determined by qPCR, ELISA or Western blotting. Arid1a knockdown HCC cell lines were established by lentiviral-based shRNA. Tumor angiogenesis was quantified based on vessel density. The regulation of Ang2 expression by Arid1a was identified by chromatin immunoprecipitation (ChIP) assay. Tumor promoting function of Arid1a loss was studied with xenograft model in nude mice and diethylnitrosamine (DEN)-induced HCC in Arid1a conditional knockout mice. The therapeutic values of Ang2 antibody and sorafenib treatment were evaluated both in vitro and in vivo.ResultsWe demonstrate that Arid1a deficiency, occurring in advanced human HCCs, is associated with increased vessel density. Mechanistically, loss of Arid1a causes aberrant histone H3K27ac deposition at the angiopoietin-2 (Ang2) enhancer and promoter, which eventually leads to ectopic expression of Ang2 and promotes HCC development. Ang2 blockade in Arid1a-deficient HCCs significantly reduces vessel density and tumor progression. Importantly, sorafenib treatment, which suppresses H3K27 acetylation and Ang2 expression, profoundly halts the progression of Arid1a-deficient HCCs.ConclusionsArid1a-deficiency activates Ang2-dependent angiogenesis and promotes HCC progression. Loss of Arid1a in HCCs confers sensitivity to Ang2 blockade and sorafenib treatment.Lay summaryArid1a-deficiency promotes Ang2-dependent angiogenesis for HCC progression and leads to sensitization to Ang2 blockade and sorafenib treatment.

    更新日期:2017-11-10
  • The chaperone dynein LL1 mediates cytoplasmic transport of empty and mature hepatitis B virus capsids
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-04
    Quentin Osseman, Lara Gallucci, Shelly Au, Christian Cazenave, Elodie Berdance, Marie-Lise Blondot, Aurélia Cassany, Dominique Bégu, Jessica Ragues, Cindy Aknin, Irina Sominskaya, Andris Dishlers, Birgit Rabe, Fenja Anderson, Nelly Panté, Michael Kann

    Background & aimsHepatitis B virus (HBV) has a DNA genome but replicates within nucleus by transcription of an RNA pregenome, which is converted to DNA in cytoplasmic capsids. Capsids in this compartment are correlated with inflammation and epitopes of the capsid protein core (Cp) are the main target for T cell-mediated immune response. We investigated the mechanism of cytoplasmic capsid transport, which is important for infection but also for cytosolic capsid removal.MethodsWe used virion-derived capsids with a mature rcDNA (matC), empty capsids (empC), and RNA containing capsids (rnaC) as control. The investigations comprised pull-down assays for identification of cellular interaction partners, immune fluorescence microcopy for their colocalisation and electron microscopy after microinjection for determining the biological significance.ResultsmatC and empC underwent active transport through the cytoplasm towards the nucleus, while rnaC was not transported. We identified the dynein light chain LL1 as functional interaction partner linking capsids to the dynein motor complex and showed that there is no compensatory transport pathway. Using capsid and dynein LL1 mutants we characterized the required domains on capsid and LL1.ConclusionsThis is the first investigation on the detailed molecular mechanism of how matC pass the cytoplasm upon infection and how empC can be actively removed from the cytoplasm into the nucleus. Considering that hepatocytes with cytoplasmic capsids are better recognized by the T cells, we hypothesize that targeting capsid DynLL1-interaction not only blocks HBV infection but also stimulates elimination of infected cells.Lay summaryIn this study, we identified the molecular details of HBV translocation through the cytoplasm. Our evidence offers a new drug target which allows not only inhibition of infection but also stimulate immune clearance of HBV infected cells.

    更新日期:2017-11-10
  • The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for progressive fatty liver disease
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-04
    Marie Boyle, Steven Masson, Quentin M. Anstee

    Current medical practice artificially dichotomises a diagnosis of fatty liver disease into one of two common forms: alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Together, these account for the majority of chronic liver diseases worldwide. In recent years, there has been a dramatic increase in the prevalence of obesity and metabolic syndrome within the general population. These factors now coexist with alcohol consumption in a substantial proportion of the population. Each exposure sensitises the liver to the injurious effects of the other; an interaction that drives and potentially accelerates the genesis of liver disease. We review the epidemiological evidence and scientific literature that considers how alcohol consumption interacts with components of the metabolic syndrome to exert additive and synergistic effects on the development and progression of liver disease, before discussing how these interactions may be addressed in clinical practice.

    更新日期:2017-11-10
  • Access to Care in Rare Liver Diseases: New Challenges and New Opportunities
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-04
    David Jones, Ekkehard Sturm, Ansgar W. Lohse

    Patients with rare diseases are often disadvantaged, and this applies to rare liver disease in particular. Reasons for disadvantage include delayed or overlooked diagnosis, lack of local expertise and high quality care, poor scientific understanding of the disease process and limited therapeutic options. In adult liver disease in particular this can be compounded by prejudices towards patients with liver disease in general because of a perception (incorrect for all rare liver disease), that liver disease is lifestyle related and thus “self-inflicted”. In paediatric rare liver disease such as biliary atresia optimizing outcomes, including developmental, requires a particularly timely diagnosis. Irrespective of patient age, the scientific and medical community has to rise to the challenge of advancing our understanding of rare liver disease, searching for more effective and specific therapies, and providing an infrastructure to take the best care to all patients, infants, children, young and older adults. The European Reference Network for Rare Liver diseases is an important step in this direction.

    更新日期:2017-11-10
  • Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-01
    Julia Pollmann, Jana-Julia Götz, Daniel Rupp, Otto Strauss, Markus Granzin, Oliver Grünvogel, Pascal Mutz, Catharina Kramer, Felix Lasitschka, Volker Lohmann, Niklas K. Björkström, Robert Thimme, Ralf Bartenschlager, Adelheid Cerwenka
    更新日期:2017-11-01
  • Should Living Donor Liver Transplantation Be an Option When Deceased Donation Is Not?
    J. Hepatol. (IF 12.486) Pub Date : 2017-11-01
    Sarah R. Lieber, Thomas D. Schiano, Rosamond Rhodes

    When a liver transplantation candidate is declined for listing to receive a deceased organ, sometimes a loved one comes forward and offers to be a living donor. This raises the ethical question of whether a patient who is not eligible for deceased donor liver transplantation should be eligible for living donor liver transplantation. We compare living organ donation in kidney and liver transplantation and explore key ethical concepts of justice, fairness, and societal trust. Ultimately, because there is no alternative life-preserving therapy in end-stage liver disease, and because transplantation with a living donor organ does not involve removing a resource from the common pool of transplant organs, we argue that a “slightly less benefit” than what is required for deceased transplantation listing standard should be used to determine the acceptability of living donor liver transplantation.

    更新日期:2017-11-01
  • Clinical states of cirrhosis and competing risks
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-27
    Gennaro D'Amico, Alberto Morabito, Mario D'Amico, Linda Pasta, Giuseppe Malizia, Paola Rebora, Maria Grazia Valsecchi
    更新日期:2017-10-28
  • Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-26
    Gyuri Kim, Suk-Yong Jang, Chung Mo Nam, Eun Seok Kang
    更新日期:2017-10-27
  • Hedgehog Signaling in Liver Pathophysiology
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-26
    Mariana Verdelho Machado, Anna Mae Diehl

    Liver disease remains a leading cause of mortality worldwide despite recent successes in the viral hepatitis field because increases in alcohol consumption and obesity are fueling epidemics of chronic fatty liver disease for which there are currently no effective medical therapies. About 20% of individuals with chronic liver injury ultimately develop end-stage liver disease due to cirrhosis and hence, treatments to prevent and reverse cirrhosis in individuals with ongoing liver injury are desperately needed. Success requires improved understanding of mechanisms that control liver disease progression. The liver responds to diverse insults with a conserved wound healing response, suggesting that it might be generally beneficial to optimize pathways that are crucial for effective liver repair. The Hedgehog pathway has emerged as a potential target based on compelling preclinical and clinical data which demonstrate that it critically regulates the liver’s response to injury. This review will summarize evidence about the Hedgehog pathway’s role in liver disease and discuss how modulating pathway activity might be applied to improve liver disease outcomes.

    更新日期:2017-10-27
  • The contribution of alcohol-use disorder to decompensated cirrhosis among people with hepatitis C: an international study
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-26
    Maryam Alavi, Naveed Z. Janjua, Mei Chong, Jason Grebely, Esther J. Aspinall, Hamish Innes, Heather M. Valerio, Behzad Hajarizadeh, Peter C. Hayes, Mel Krajden, Janaki Amin, Matthew G. Law, Jacob George, David J. Goldberg, Sharon J. Hutchinson, Gregory J. Dore
    更新日期:2017-10-27
  • A Novel Orally Available Small Molecule That Inhibits Hepatitis B Virus Expression
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-25
    Henrik Mueller, Steffen Wildum, Souphalone Luangsay, Johanna Walther, Anais Lopez, Philipp Tropberger, Giorgio Ottaviani, Wenzhe Lu, Neil John Parrott, Jitao David Zhang, Roland Schmucki, Tomas Racek, Jean-Christophe Hoflack, Erich Kueng, Floriane Point, Xue Zhou, Guido Steiner, Marc Lütgehetmann, Gianna Rapp, Tassilo Volz, Maura Dandri, Song Yang, John A.T. Young, Hassan Javanbakht
    更新日期:2017-10-26
  • Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-13
    Jean-Charles Nault, Olivier Sutter, Pierre Nahon, Nathalie Ganne-Carrié, Olivier Séror

    Percutaneous treatment of hepatocellular carcinoma (HCC) encompasses a vast range of techniques, including monopolar radiofrequency ablation (RFA), multibipolar RFA, microwave ablation, cryoablation and irreversible electroporation. RFA is considered to be one of the main curative treatments for HCC of less than 5 cm developing on cirrhosis, together with surgical resection and liver transplantation. However, controversies exist concerning the respective roles of ablation and liver resection for HCC of less than 3 to 5 cm on cirrhosis. In line with the therapeutic algorithm of early HCC, percutaneous ablation could also be used as a bridge to liver transplantation or in a sequence of upfront percutaneous treatment, followed by transplantation if tumor relapses. Moreover, several innovations in ablation methods may help to efficiently treat early HCC initially considered as “non-ablatable”, and might, in some cases, extend ablation criteria beyond early HCC in order to treat the largest number of patients using a curative approach.

    更新日期:2017-10-14
  • Pediatric CLIF-SOFA score is the best predictor of 28-day mortality in children with decompensated chronic liver disease
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-10
    Rishi Bolia, Anshu Srivastava, Surender Kumar Yachha, Ujjal Poddar
    更新日期:2017-10-10
  • Advanced liver fibrosis but not steatosis is independently associated with albuminuria in Chinese patients with type 2 diabetes
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-06
    Ming-Wai Yeung, Grace Lai-Hung Wong, Kai Chow Choi, Andrea On-Yan Luk, Raymond Kwok, Sally She-Ting Shu, Anthony Wing-Hung Chan, Eric Siu Him Lau, Ronald Ching Wan Ma, Henry Lik-Yuen Chan, Juliana Chung-Ngor Chan, Vincent Wai-Sun Wong, Alice Pik-Shan Kong
    更新日期:2017-10-06
  • Impact of time to surgery in the outcome of patients with liver resection for BCLC 0-A stage hepatocellular carcinoma
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-06
    Chetana Lim, Prashant Bhangui, Chady Salloum, Concepción Gómez Gavara, Eylon Lahat, Alain Luciani, Philippe Compagnon, Julien Calderaro, Cyrille Feray, Daniel Azoulay
    更新日期:2017-10-06
  • Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-06
    Naoto Fujiwara, Scott L. Friedman, Nicolas Goossens, Yujin Hoshida

    Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after complete HCC tumor resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumors, which progress into incurable, advanced-stage disease in the majority of patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, practice guideline-recommended “one-size-fits-all” HCC screening for early tumor detection is utilized in less than 20% of the target population, and performance of screening modalities, i.e., ultrasound and alpha-fetoprotein is suboptimal. Furthermore, optimal screening strategies for emerging at-risk patient populations such as chronic hepatitis C after viral cure and non-cirrhotic non-alcoholic fatty liver disease remain controversial. New HCC biomarkers and imaging modalities may improve sensitivity and specificity of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed by tailored HCC screening for individual patients to maximize its cost-effectiveness and optimize allocation of limited medical resources. Several etiology-specific and generic HCC chemoprevention strategies are evolving. Epidemiological and experimental studies have identified candidate chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular targeted agents, although their clinical testing has been limited by the lengthy process of cancer development that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome the challenge by enabling personalized chemoprevention targeting high-risk patients to achieve precision HCC prevention and substantially improve the dismal prognosis of HCC.

    更新日期:2017-10-06
  • Durability of Hepatitis B Surface Antigen Seroclearance in Untreated and Nucleos(t)ide Analogue-Treated Patients
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-06
    Terry Cheuk-Fung Yip, Grace Lai-Hung Wong, Vincent Wai-Sun Wong, Yee-Kit Tse, Grace Chung-Yan Lui, Kelvin Long-Yan Lam, Henry Lik-Yuen Chan
    更新日期:2017-10-06
  • Retreatment with direct-acting antivirals of genotypes 1-3-4 hepatitis C patients who failed an anti-NS5A regimen in real world
    J. Hepatol. (IF 12.486) Pub Date : 2017-10-04
    Philippe Halfon, Caroline Scholtès, Jacques Izopet, Sylvie Larrat, Pascale Trimoulet, Fabien Zoulim, Laurent Alric, Sophie Métivier, Vincent Leroy, Denis Ouzan, Victor de Lédinghen, Sofiane Mohamed, Guillaume Pénaranda, Hacène Khiri, Marie-Ange Thélu, Anne Plauzolles, Laurent Chiche, Marc Bourlière, Florence Abravanel

    Introduction The aim was to study retreatment according to baseline nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) after the failure of first-line DAA-based treatment. Patients and Methods From January 2014 to March 2016, 2995 HCV-infected patients were treated with NS5A inhibitors in six French liver referral centers; 80 (2.7%) patients relapsed. This “real-world” study included 24 of those 80 patients who had failed to achieve sustained virological response (SVR) on previous NS5A-based therapy. These 24 patients were re-treated with different regimen combinations. Antiviral efficacy was evaluated using the primary endpoints of SVR at weeks 4 and 12 post-treatment (SVR4, SVR12). Results The presence of NS5A RASs/polymorphisms was found in 20 (80%) patients at baseline of retreatment. All patients achieved SVR with HCV RNA below the lower limit of quantification (<15 IU/mL) by the end of treatment. SVR4 and SVR12 were achieved in 23/24 patients (96%), and the remaining patient relapsed four weeks post-treatment. Conclusions Based on these results, retreatment of patients after the failure of a first-line NS5A regimen is effective (96% SVR). In the future, either dual or triple therapy regimens may have similar results with shorter treatment duration.

    更新日期:2017-10-04
  • Controversies in Clinical Trials for Alcoholic Hepatitis
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-28
    Sarah R. Lieber, John P. Rice, Michael R. Lucey, Ramon Bataller

    Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease, contributing to significant morbidity and mortality. Yet, the only available therapies that improve survival are corticosteroids and liver transplantation with no new drugs successfully developed for decades. This article describes briefly the current state of affairs in AH therapy and examines the practical and ethical challenges to conducting controlled trials in patients with severe AH. While prednisolone is considered to be standard of care in severe AH, this recommendation remains controversial given the marginal benefits and questionable longterm safety of steroids. Placebo controlled trials without steroids may be necessary and ethically justified in certain populations of AH who have not been adequately investigated. Ultimately, we suggest the field will advance with the development of a plausible animal model of true AH, a consensus on a composite clinical end-point that does not rely solely on mortality for use in future RCTs, and the adoption of the recommendations of the NIAAA Alcoholic Hepatitis Consortia regarding standard definitions and when to require a liver biopsy prior to study entry.

    更新日期:2017-09-29
  • Protective effect of coffee consumption on all-cause mortality of French HIV-HCV co-infected patients
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-21
    Maria Patrizia Carrieri, Camelia Protopopescu, Fabienne Marcellin, Silvia Rosellini, Linda Wittkop, Laure Esterle, David Zucman, François Raffi, Eric Rosenthal, Isabelle Poizot-Martin, Dominique Salmon-Ceron, François Dabis, Bruno Spire
    更新日期:2017-09-29
  • Tenofovir alafenamide as a Rescue Therapy in a Cirrhotic HBV Patient with a Hystory of Fanconi Syndrome and Multidrug Resistance: A Case Report
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-21
    Glenda Grossi, Alessandro Loglio, Floriana Facchetti, Marta Borghi, Roberta Soffredini, Enrico Galmozzi, Giovanna Lunghi, Anuj Gaggar, Pietro Lampertico

    Tenofovir disoproxil fumarate (TDF) is a recommended first-line therapy for both naïve and experienced chronic hepatitis B (CHB) patients although reduced estimated glomerular filtration rate (eGFR), hypophosphatemia, hyperphosphaturia and Fanconi syndrome have been reported in some patients. Entecavir (ETV) could be considered as a rescue therapy for TDF treated patients developing renal dysfunction, though patients with prior history of treatment with Lamivudine (LAM) can develop ETV resistance strains which can lead to potentially severe hepatitis flares. Tenofovir alafenamide (TAF), a new prodrug of tenofovir, has been recently developed with the aim to improve the renal and bone safety profile compared to TDF, while maintaining the same virological efficacy. The recently published 48-week phase III TAF registration studies confirmed the superior safety profile. Here we describe a case of a 75-year old woman with compensated HBV cirrhosis who developed ETV resistant strains and grade 3 chronic kidney disease after many years of LAM and Adefovir (ADV) treatment and a TDF-induced Fanconi syndrome. The administration of 25 mg/day of TAF, granted as part of a compassionate use program, rapidly suppressed viral replication to undetectable levels without worsening renal function or side effects.

    更新日期:2017-09-29
  • IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-21
    Meng Wang, Guannan Shen, Liangguo Xu, Xiaodong Liu, Jared M. Brown, Dechun Feng, Ruth Ann Ross, Bin Gao, Suthat Liangpunsakul, Cynthia Ju
    更新日期:2017-09-29
  • IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-21
    Hamza O Yazdani, Hui-Wei Chen, Samer Tohme, Sheng Tai, Dirk J. van der Windt, Patricia Loughran, Brian R. Rosborough, Vikas Sud, Donna Beer-Stolz, Heth R Turnquist, Allan Tsung, Hai Huang
    更新日期:2017-09-29
  • Relationship between serum HBV-RNA levels and intrahepatic viral as well as histologic activity markers in entecavir-treated patients
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-21
    Jing Wang, Yiqi Yu, Guojun Li, Chuan Shen, Zhefeng Meng, Jianming Zheng, Yanhong Jia, Shaolong Chen, Xiao Zhang, Mengqi Zhu, Jiangjiang Zheng, Zhangzhang Song, Jing Wu, Lingyun Shao, Peiyu Qian, Xiaona Mao, Xuanyi Wang, Yuxian Huang, Caiyan Zhao, Jiming Zhang, Chao Qiu, Wenhong Zhang
    更新日期:2017-09-29
  • Hypothermic oxygenated perfusion (HOPE) for fatty liver grafts in rats and humans
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-21
    P. Kron, A. Schlegel, L. Mancina, P.-A. Clavien, P. Dutkowski
    更新日期:2017-09-29
  • Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: A cohort study
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-20
    Dong Hyun Sinn, Danbee Kang, Hye Ryoun Jang, Seonhye Gu, Soo Jin Cho, Seung Woon Paik, Seungho Ryu, Yoosoo Chang, Mariana Lazo, Eliseo Guallar, Juhee Cho, Geum-Youn Gwak
    更新日期:2017-09-21
  • Peak hyperammonemia and atypical acute liver failure: the eruption of an urea cycle disorder during hyperemesis gravidarum
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-20
    Nicolas Weiss, Fanny Mochel, Marika Rudler, Sophie Demeret, Pascal Lebray, Filomena Conti, Damien Galanaud, Chris Ottolenghi, Jean-Paul Bonnefont, Marc Dommergues, Jacques Bernuau, Dominique Thabut

    Background Inborn urea cycle deficiencies are under-recognized metabolic causes of hyperammonaemia in adults. Methods A 28-year-old primigravida, 7-week pregnant woman affected by hyperemesis gravidarum developed acute liver injury and then acute liver failure (ALF) in less than 48 hours. Results Because the patient developed atypical features, especially mildly elevated serum transaminases contrasting with very high blood ammonia levels (281 μmol/l), concomitant with normal serum creatinine, an inborn error of metabolism was suspected. We performed emergency metabolic analyses, stopped all protein intake and started with IV high caloric intake, nitrogen scavenger drugs and hemodialysis. The neurological and hepatic status of the patient quickly improved together with the normalization of her ammonaemia levels. In the plasma, high glutamine but low arginine, citrulline and ornithine as well high urinary orotic acid were suggestive of an ornithine transcarbamylase (OTC) deficiency, which was later confirmed by molecular analyses. Fetal sex was female, as determined by fetal DNA analysis in maternal blood, and fetal development was unremarkable all along the pregnancy. Delivery was induced at 39 weeks with a close monitoring of ammonaemia levels and IV perfusion of carbohydrates and lipids during labor and immediate post-partum to avoid hypercatabolism. Delivery was uneventful and the patient delivered a healthy female baby. Conclusion Urea cycle deficiencies shall be contemplated in non-jaundiced ALF with severe hyperammonaemia and normal serum creatinine regardless of serum aminotransferase levels. The prompt recognition of this rare condition and the rapid initiation of adequate metabolic therapy are mandatory to prevent irreversible neurological sequelae and to avoid LT.

    更新日期:2017-09-20
  • Effectiveness of ravidasvir plus sofosbuvir in interferon-naïve and treated patients with chronic hepatitis c genotype-4
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-19
    Gamal Esmat, Tamer Elbaz, Maissa El Raziky, Asmaa Gomaa, Mahmoud Abouelkhair, Hadeel Gamal El Deen, Aliaa Sabry, Mohamed Ashour, Naglaa Allam, Mohamed Abdel-Hamid, Ola Nada, Sherine Helmy, Hanaa Abdel-Maguid, Richard Colonno, Nathaniel Brown, Eric Ruby, Pamela Vig, Imam Waked
    更新日期:2017-09-20
  • Targets for immunotherapy of liver cancer
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-18
    Tim F. Greten, Bruno Sangro

    Drug development in HCC has been characterized in the past by many failures. Despite good rationales and promising phase II data, many phase III trials failed. Immunotherapy represents an alternate treatment approach and has been successful in many different types of cancer. Being an inflammation induced cancer HCC represents a very interesting target for immune based approaches and indeed early results from clinical trials testing immune checkpoint inhibitors are not only promising but have already led to evaluation of such in a phase III setting. Here we summarize our current knowledge on the rationale, mechanism of action and clinical data for immune checkpoint blockade in HCC. In addition, we provide an overview about other novel immune based approaches currently under development for the treatment of HCC such as adoptive cell based and antibody-based approaches.

    更新日期:2017-09-19
  • Targeting the gut-liver axis in liver disease
    J. Hepatol. (IF 12.486) Pub Date : 2017-05-16
    Reiner Wiest, Agustin Albillos, Michael Trauner, Jasmohan S. Bajaj, Rajiv Jalan

    The gut-liver axis is widely implicated in the pathogenesis of liver diseases, where it is increasingly the focus of clinical research. Recent studies trialling an array of therapeutic and preventative strategies have yielded promising results. Considering these strategies, the armamentarium for targeting the gut-liver axis will continue to expand. Further clinical trials, translated from our current knowledge of the gut-liver axis, promise an exciting future in liver treatment.

    更新日期:2017-09-15
  • Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-14
    Dominique Thabut, Arnaud Pauwels, Nicolas Carbonell, Andre Jean Remy, Pierre Nahon, Xavier Causse, Jean-Paul Cervoni, Jean-François Cadranel, Isabelle Archambeaud, Slim Bramli, Florent Ehrhard, Philippe Ah-Soune, Florian Rostain, Alexandre Pariente, Julien Vergniol, Jean-Pierre Dupuychaffray, Anne-Laure Pelletier, Florence Skinazi, Anne Guillygomarc'h, René-Louis Vitte, Jean Henrion, Stéphanie Combet, Marika Rudler, Christophe Bureau
    更新日期:2017-09-14
  • Dusp14 protects against hepatic ischemia-reperfusion injury via Tak1 suppression
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-06
    Xiaozhan Wang, Wenzhe Mao, Chun Fang, Song Tian, Xueyong Zhu, Ling Yang, Zan Huang, Hongliang Li
    更新日期:2017-09-06
  • Premature ovarian senescence and high miscarriage rate impair fertility in women with hepatitis C virus infection
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-05
    Aimilia Karampatou, Xue Han, Loreta A. Kondili, Gloria Taliani, Alessia Ciancio, Filomena Morisco, Rosina Maria Critelli, Enrica Baraldi, Veronica Bernabucci, Giulia Troshina, Maria Guarino, Simonetta Tagliavini, Federica D'Ambrosio, Laura Bristot, Laura Turco, Stefano Rosato, Stefano Vella, Tommaso Trenti, Isabella Neri, Antonio La Marca, Shivaji Manthena, Andrea S. Goldstein, Savino Bruno, Yanjun Bao, Yuri Sanchez Gonzalez, Erica Villa
    更新日期:2017-09-06
  • HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-05
    George N. Ioannou, Pamela K. Green, Kristin Berry
    更新日期:2017-09-06
  • Identification of Slug and Sox7 as transcriptional repressors binding to the Hepatitis B Virus Core Promoter
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-05
    Hui Ling Ko, Tze Hau Lam, Huijin Ng, Jiaying Toh, Liang Wei Wang, Ee Chee Ren
    更新日期:2017-09-06
  • Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention
    J. Hepatol. (IF 12.486) Pub Date : 2017-09-05
    Stanley M. Lemon, Jördis J. Ott, Pierre Van Damme, Daniel Shouval

    Hepatitis A virus (HAV) infection is an ancient disease and likely to have afflicted mankind since humans first began to live in groups large enough to sustain transmission of the causative agent, HAV. In reviewing what was known as 'catarrhal jaundice' in 1912, Cockayne noted descriptions of epidemic jaundice extending back to antiquity1. The infectious nature of the disease was proven several decades later in deliberate human transmission studies2. Such experiments led to a clear distinction between hepatitis A ('infectious hepatitis') and hepatitis B ('homologous serum jaundice') and recognition of the lack of cross immunity between these two forms of transmissible hepatitis as early as 19453. However, the responsible virus was not identified until almost 30 years later, when small, round viral particles were discovered by immune electron microscopy in the feces of an experimentally-infected human subject by Feinstone et al. in 19734. This review provides an up-to-date in in-depth overview of HAV and the acute inflammatory hepatic infection it causes in humans, including recently recognized aspects of its molecular virology, evolution, natural history, pathogenesis, epidemiology and prevention.

    更新日期:2017-09-06
  • Hepatitis E Virus-Induced Primary Cutaneous CD30(+) T cell Lymphoproliferative Disorder
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-30
    Vincent Mallet, Julie Bruneau, Julien Zuber, Cécile Alanio, Stéphanie Leclerc-Mercier, Anne-Marie Roque-Afonso, Anke R.M. Kraft, Lucile Couronné, Dominique Roulot, Heiner Wedemeyer, Matthew L. Albert, Patrick Hillon, Liliane Laroche, Stanislas Pol, Olivier Hermine
    更新日期:2017-09-06
  • Toronto HCC Risk Index: A validated scoring system to predict 10-year risk of HCC in patients with cirrhosis
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-24
    Suraj A Sharma, Matthew Kowgier, Bettina E Hansen, Willem Pieter Brouwer, Raoel Maan, David Wong, Hemant Shah, Korosh Khalili, Colina Yim, E. Jenny Heathcote, Harry L.A. Janssen, Morris Sherman, Gideon M. Hirschfield, Jordan J Feld
    更新日期:2017-09-06
  • Disease Outcomes in a Cohort of Women Infected by Hepatitis C-Contaminated anti-D Immunoglobulin During 1970s
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-24
    Patricia Garvey, Niamh Murphy, Paula Flanagan, Aline Brennan, Garry Courtney, Orla Crosbie, John Crowe, John Hegarty, John Lee, Margaret McIver, Carol McNulty, Frank Murray, Niamh Nolan, Cliona O'Farrelly, Stephen Stewart, Michele Tait, Suzanne Norris, Lelia Thornton
    更新日期:2017-09-06
  • Trunk events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-24
    Sara Torrecilla, Daniela Sia, Andrew N. Harrington, Zhongyang Zhang, Laia Cabellos, Helena Cornella, Agrin Moeini, Genis Camprecios, Wei-Qiang Leow, Maria Isabel Fiel, Ke Hao, Laia Bassaganyas, Milind Mahajan, Swan N. Thung, Augusto Villanueva, Sander Florman, Myron E. Schwartz, Josep M. Llovet
    更新日期:2017-09-06
  • Bivalent role of Intra-Platelet Serotonin in Liver Regeneration and Tumor Recurrence in Humans
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-24
    Robin Padickakudy, David Pereyra, Florian Offensperger, Philipp Jonas, Lukas Oehlberger, Christian Schwarz, Stefanie Haegele, Alice Assinger, Christine Brostjan, Thomas Gruenberger, Patrick Starlinger
    更新日期:2017-09-06
  • Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-24
    Juan Manuel Pascasio, Carmen Vinaixa, María Teresa Ferrer, Jordi Colmenero, Angel Rubin, Lluis Castells, María Luisa Manzano, Sara Lorente, Milagros Testillano, Xavier Xiol, Esther Molina, Luisa González-Diéguez, Elena Otón, Sonia Pascual, Begoña Santos, José Ignacio Herrero, Magdalena Salcedo, José Luis Montero, Gloria Sánchez-Antolín, Isidoro Narváez, Flor Nogueras, Álvaro Giráldez, Martín Prieto, Xavier Forns, María-Carlota Londoño
    更新日期:2017-09-06
  • Macrophage heme oxygenase-1-SIRT1-p53 Axis Regulates Sterile Inflammation in Liver Ischemia-Reperfusion Injury
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-23
    Kojiro Nakamura, Min Zhang, Shoichi Kageyama, Bibo Ke, Takehiro Fujii, Rebecca A. Sosa, Elaine F. Reed, Nakul Datta, Ali Zarrinpar, Ronald W. Busuttil, Jesus A. Araujo, Jerzy W. Kupiec-Weglinski
    更新日期:2017-09-06
  • Evaluation of HCC Response to Locoregional Therapy: Validation of MRI-Based Response Criteria versus Explant Pathology
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-18
    Sonja Gordic, Idoia Corcuera-Solano, Ashley Stueck, Cecilia Besa, Pamela Argiriadi, Preethi Guniganti, Michael King, Shingo Kihira, James Babb, Swan Thung, Bachir Taouli
    更新日期:2017-09-06
  • Monocytes inhibit hepatitis C virus-induced TRAIL expression on CD56bright NK cells
    J. Hepatol. (IF 12.486) Pub Date : 2017-08-11
    Dalila Mele, Stefania Mantovani, Barbara Oliviero, Giulia Grossi, Andrea Lombardi, Mario U. Mondelli, Stefania Varchetta
    更新日期:2017-09-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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