Liver international: official journal of the International Association for the Study of the Liver (Liver Int )

Publisher: International Association for the Study of the Liver, Blackwell Publishing

Description

The general aim of Liver International is to promote all aspects of the science of hepatology from basic research to applied clinical studies. It is an international Journal providing a forum for the publication of high quality original research in hepatology. It provides an essential resource for all professionals concerned with normal and abnormal structure and function in the liver and its constituent cells and is intended for clinicians and basic scientists involved in the multi-disciplinary field of hepatology. It includes studies of pathobiology from experimental models and human material. Liver International welcomes articles from all fields of hepatology, which may be published as original articles, rapid communications, reviews, and letters to the Editor. Case reports will be accepted if the clinical problem is studied in detail and of sufficient interest in a wider context. Papers are normally evaluated by a peer review process involving at least two independent reviewers. Within the scope of the Journal, articles will be accepted on the basis of scientific quality, originality and up-to-date relevance.

  • Impact factor
    3.87
  • 5-year impact
    3.54
  • Cited half-life
    3.70
  • Immediacy index
    1.35
  • Eigenfactor
    0.02
  • Article influence
    1.04
  • Website
    Liver International website
  • Other titles
    Liver international (Online)
  • ISSN
    1478-3231
  • OCLC
    52034063
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Blackwell Publishing

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    • See Wiley-Blackwell entry for articles after February 2007
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    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley-Blackwell'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and aimsLiver stiffness (LS), spleen stiffness (SS) and serum markers have been proposed to noninvasively assess portal hypertension or esophageal varices (EV) in cirrhotic patients. We aimed to evaluate the performance of a stepwise algorithm that combines Lok-score with LS and SS for diagnosing high-risk EV (HREV) and to compare it with other already-validated noninvasive methods.Methods We performed a cross-sectional study including 136 consecutive compensated cirrhotic patients with various etiologies, divided into training (90) and validation (46) set. Endoscopy was performed within 6 months from inclusion for EV screening. Spleen diameter was assessed by ultrasonography. LS and SS were measured using Fibroscan. Lok-score, platelet count/spleen diameter ratio, LSM-spleen diameter to platelet ratio score and esophageal varices risk score (EVRS) were calculated and their diagnostic accuracy for HREV was assessed. The algorithm classified patients as having/not-having HREV. Its performance was tested and compared in both groups.ResultsIn the training set, all variables could select patients with HREV with moderate accuracy, the best being LSPS (AUROC=0.818; 0.93 sensitivity; 0.63 specificity). EVRS, however, was the only independent predictor of HREV (OR=1.521; p=0.032). The algorithm correctly classified 69 (76.66%) patients in the training set (p<0.0001) and 36 (78.26%) in the validation one. In the validation group, the algorithm performed slightly better than LSPS and EVRS, showing 100% sensitivity and negative predicted value.Conclusion The stepwise algorithm combining Lok-score, LS and SS could be used to select patients at low risk of having HREV and who may benefit from more distanced endoscopic evaluation.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: Background & AimsIn liver fibrosis, activated hepatic stellate cells (HSC) secrete excess extracellular matrix, thus, represent key targets for antifibrotic treatment strategies. Intermediate-conductance Ca2+-activated K+-channels (KCa3.1) are expressed in non-excitable tissues affecting proliferation, migration and vascular resistance rendering KCa3.1 potential targets in liver fibrosis. So far, no information about KCa3.1 expression and their role in HSC exists. Aim was to quantify the KCa3.1 expression in HSC depending on HSC activation and investigation of antifibrotic properties of the specific KCa3.1 inhibitor TRAM-34 in vitro and in vivo.MethodsKCa3.1 expression and functionality were studied in TGF-β1-activated HSC by quantitative real time PCR, western-blot and patch-clamp analysis, respectively. Effects of TRAM-34 on HSC proliferation, cell cycle and fibrosis-related gene expression were assessed by [3H]-thymidine incorporation, FACS-analysis and RT-PCR, respectively. In vivo, vascular resistance and KCa3.1 gene and protein expression were determined in bile duct ligated rats by in situ liver perfusion, Taqman PCR and immunohistochemistry, respectively.ResultsFibrotic tissues and TGF-β1-activated HSC exhibited higher KCa3.1-expressions than normal tissue and untreated cells. KCa3.1 inhibition with TRAM-34 reduced HSC proliferation by induction of cell cycle arrest and reduced TGF-β1-induced gene expression of collagen I, alpha-smooth muscle actin and TGF-β1 itself. Further, TRAM-34 blocked TGF-β1-induced activation of TGF-β signaling in HSC. In vivo, TRAM-34 reduced the thromboxane agonist-induced portal perfusion pressure.Conclusion Inhibition of KCa3.1 with TRAM-34 downregulates fibrosis-associated gene expression in vitro, and reduces portal perfusion pressure in vivo. Thus, KCa3.1 may represent novel targets for the treatment of liver fibrosis.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
  • Gary L. Norman, Chen‐Yen Yang, Heather P. Ostendorff, Zakera Shums, Mark J. Lim, Jinjun Wang, Amany Awad, Gideon M. Hirschfield, Piotr Milkiewicz, Donald B. Bloch, Kenneth J. Rothschild, Christopher L. Bowlus, Iannis E. Adamopoulos, Patrick S.C. Leung, Harry J. Janssen, Angela C. Cheung, Catalina Coltescu, M. Eric Gershwin
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    ABSTRACT: Background Using high-density human recombinant protein microarrays, we identified two potential biomarkers, kelch-like 12 (KLHL12) and hexokinase-1 (HK1), in primary biliary cirrhosis (PBC). The objective of this study was to determine the diagnostic value of anti-KLHL12/HK1 autoantibodies in PBC.AimsInitial discovery used sera from 22 patients with PBC and 62 non-PBC controls. KLHL12 and HK1 proteins were then analyzed for immunoglobulin reactivity by immunoblot and enzyme-linked immunosorbent assay (ELISA) in two independent cohorts of PBC and disease/healthy control patients.Methods Serum samples from 100 patients with PBC and 165 non-PBC disease controls were analyzed by immunoblot and samples from 366 patients with PBC, 174 disease controls, and 80 healthy donors were tested by ELISA.ResultsAnti-KLHL12 and anti-HK1 antibodies were each detected more frequently in PBC compared with non-PBC disease controls (p < 0.001). Not only are both markers highly specific for PBC (≥ 95%), but they also yielded higher sensitivity than anti-gp210 and anti-sp100 antibodies. Combining anti-HK1 and anti-KLHL12 with available markers (MIT3, gp210 and sp100) increased the diagnostic sensitivity for PBC. Most importantly, anti-KLHL12 and anti-HK1 antibodies were present in 10~35% of AMA-negative PBC patients and adding these two biomarkers to conventional PBC assays dramatically improved the serological sensitivity in AMA-negative PBC from 55% to 75% in immunoblot and 48.3% to 68.5% in ELISA.Conclusions The addition of tests for highly specific anti-KLHL12 and anti-HK1 antibodies to AMA and ANA serological assays significantly improves efficacy in the clinical detection and diagnosis of PBC, especially for AMA-negative subjects.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: Background and aimsIn the absence of overt infection, the systemic inflammatory response is increasingly recognised as a pathogenetic factor in the circulatory dysfunction of advanced cirrhosis. Our aim was to determine whether the neutrophil-to-lymphocyte ratio, a marker of systemic inflammation, is predictive of mortality in patients with end stage cirrhosis listed for liver transplantation.MethodsA single centre study of 570 patients listed for first elective single organ liver transplantation January 2007-June 2011.ResultsThe median listing neutrophil-to-lymphocyte ratio was 2.9 (IQR 1.9-4.7). Neutrophil-to-lymphocyte ratio demonstrated a positive correlation with listing serum bilirubin (p<0.001), negative correlation with serum sodium (p<0.001), and positive correlation with the MELD score (p<0.001). Neutrophil-to-lymphocyte ratio increased with increasing severity of ascites (p<0.001). A higher neutrophil count (p<0.001) and lower lymphocyte count (p=0.001) were predictors of wait-list death. In a multivariate competing risk Cox model, neutrophil-to-lymphocyte ratio remained independently associated with mortality (HR 1.10; 95% CI 1.05-1.15, p<0.001). The proportion of patients with a neutrophil-to-lymphocyte ratio <2, 2-4.9 and ≥5 who had died by 3-months of listing was 3%, 13.8% and 37.3%, respectively (p<0.001). After adjusting for MELD, increasing increments of neutrophil-to-lymphocyte ratio were predictive of death by 3-months (p=0.043).Conclusions The blood neutrophil-to-lymphocyte ratio, a simple and readily available marker of systemic inflammation, is an independent predictor of mortality in patients with liver failure listed for liver transplantation.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: Background The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL), M-, L- and H-ficolin and collectin-liver-1 (CL-L1), which are predominantly synthesised in the liver.AimWe aimed to study lectin levels in ALF patients and associations with clinical outcome.Methods: Serum samples from 75 patients enrolled by the U.S. ALF Study Group were collected on days 1 and 3. We included 75 healthy blood donors and 20 cirrhosis patients as controls. Analyses were performed using sandwich-type immunoassays (ELISA, TRIFMA).ResultsAt day 1, the MBL level in ALF patients was 40% lower compared with healthy controls ((median(interquartile range) 0.72 μg/ml(0.91) vs. 1.15(1.92)(p=0.02)), and increased significantly by day 3 (0.83 μg/ml(0.94)(p=0.01)). The M-ficolin level was 60% lower (0.54 μg/ml(0.50) vs. 1.48(1.01)(p<0.0001)). The CL-L1 level at day 1 was slightly higher compared with healthy controls (3.20 μg/ml(2.37) vs. 2.64(0.72)(p=0.11)); this was significant at day 3 (3.35(1.84)(p=0.006)). H- and L-ficolin levels were similar to healthy controls. Spontaneous ALF survivors had higher levels of MBL at day 1 (0.96 μg/ml(1.15) vs. 0.60(0.60)(p=0.02)) and lower levels of L-ficolin by day 3 compared with patients who died or were transplanted (1.61 μg/ml(1.19) vs. 2.17(2.19)(p=0.02)).Conclusion We observed significant dynamics in lectin levels in ALF patients, which may suggest they play a role in ALF pathogenesis. High MBL and low L-ficolin levels are associated with survival.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: Background&AimsLiver stiffness (LS) measurement using transient elastography and the FibroTest (FT) are alternatives to liver biopsy (LB) in assessing liver fibrosis. We investigated the prognostic role of the combined use of LS and FT in predicting liver-related events (LREs) in patients with chronic hepatitis B (CHB).Methods Consecutive patients with CHB who underwent LB, along with LS and FT on the same day from 2007 to 2010 were recruited. LRE was defined as hepatic decompensation, hepatocellular carcinoma (HCC), or liver-related death.ResultsA total of 151 patients (86 male) were analyzed. During follow-up (median 59.9 months), overall 18 (11.9%) patients experienced LREs. The areas under receiver-operating characteristic curves of LS, FT, LS+FT and LSxFT in predicting LRE were 0.701, 0.668, 0.702 and 0.741, respectively. After adjusting for age and histological fibrosis staging, significant variables in univariate analysis (both P<0.05), LS+FT and LSxFT were independent predictors of LREs with hazard ratios (HRs) of 1.080 and 1.126 (all P<0.05), respectively. When subjects were divided into three groups according to quartile stratification (low quartile, interquartile and high quartile) using LS+FT and LSxFT, cumulative LRE development rate significantly increased with a corresponding increase in value among three groups, respectively (log-rank test, all P<0.05).Conclusion The combined use of LS and FT significantly predicted forthcoming LRE development, but with only a slight additional benefit compared to LS or FT alone.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
  • Eduardo Linck Guimarães, Leslie Stradiot, Inge Mannaerts, Ben Schroyen, Leo A. Grunsven
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    ABSTRACT: Background Liver fibrosis is induced by the accumulation of extracellular matrix, deposited mainly by activated hepatic stellate cells (HSCs). One key characteristic of stellate cell activation is the directional migration to the site of injury during the wound-healing process. P311 is a protein that has been shown to play a role in migration and we aimed to study a possible role for this protein during stellate cell migration.Methods Mouse stellate cells were isolated and cultured in vitro in order to investigate P311 protein and gene expression during HSC activation by immunocytochemistry and RT-qPCR, respectively. Expression of P311 during in vivo activation was evaluated in CCl4 and bile duct ligation-induced liver fibrosis. Production of reactive oxygen species was determined using the fluorescent probe DCFH-DA. By siRNA-mediated knockdown of P311 we investigated a possible effect on proliferation by incorporation of EdU and on migration by Boyden chamber assays.ResultsP311 gene expression was increased during both in vitro and in vivo activation of HSCs. siRNA-mediated knockdown led to a decrease in reactive oxygen production and cell proliferation. Migration induced by different chemokines, such as PDGF-bb and MCP-1 was inhibited by knockdown of P311.ConclusionsP311 is central to reactive oxygen species-mediated HSC migration induced by different chemokines.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: Background & AimAccurate prognostication of acute-on-chronic liver failure (ACLF) is essential for therapeutic decisions. Our aim was to validate a novel scoring system for predicting mortality, the chronic liver failure-sequential organ failure assessment (CLIF-SOFA), in a population of Asian patients with ACLF.MethodsA total of 345 patients with acutely decompensated alcoholic cirrhosis were selected for study, comparing areas under the receiver operating characteristic (AUROC) curves of CLIF-SOFA and five existing scoring systems for end-stage liver disease (model for end-stage liver disease [MELD], MELD-Na, Refit-MELD, Refit-MELD-Na, and Child-Turcotte-Pugh).ResultsCLIF-SOFA displayed the highest AUROC of 0.943 significantly outperforming all five reference methods in predicting short-term mortality at Week 4 (all P<0.001) by competing risk analysis. In 262 patients given supportive care only, the power of CLIF-SOFA to predict short-term mortality was high (AUROC: 0.952 at Week 1; 0.959 at Week 4), again surpassing the other methods (all P<0.001). For the remaining 83 liver transplant recipients, CLIF-SOFA also excelled in predicting 12-week mortality (AUROC: 0.978); and high-grade ACLF by CLIF-SOFA was associated with prolonged postoperative mechanical support (ie, mechanical ventilation and renal replacement therapy) and ICU stays (all P<0.05).ConclusionsCLIF-SOFA enables more accurate prediction of short-term mortality in patients with acutely decompensated alcoholic cirrhosis than other available scoring systems and is useful in predicting both 12-week mortality and the need for mechanical support after liver transplantation.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: The availability of safe and well-tolerated oral antiviral therapies for hepatitis C virus (HCV) has transformed the management of liver transplant (LT) candidates and recipients. In this issue of Liver International, Donato and colleagues report the successful eradication of HCV infection in a patient with decompensated cirrhosis due to post-LT recurrent HCV who received a combination of sofosbuvir and ribavirin for 1 week prior to and 23 weeks after repeat LT(1). This is the first report of sofosbuvir and ribavirin use in the immediate post-LT period, providing preliminary data regarding the safety of an early post-LT approach.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: Background and Aims: A greater understanding of cholestatic disease is necessary to advance diagnostic tools and therapeutic options for conditions such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The purpose of this study was to determine and compare the serum metabolomes of patients with PBC (n=18) or PSC (n=21) and healthy controls (n=10) and to identify metabolites that may differentiate these two cholestatic diseases. Methods and Results: Using a mass spectrometry-based, non-targeted biochemical profiling approach we identified 420 serum metabolites, 101 that differed significantly (p≤0.05) between PBC and control groups, 115 that differed significantly between PSC and control groups, and 56 that differed significantly between PSC and PBC groups. Random forest classification analysis was able to distinguish patients with PBC or PSC with 95% accuracy with selected biochemicals reflective of protein and amino acid metabolism identified as the major contributors. Metabolites related to bile acid metabolism, lipid metabolism, inflammation, and oxidative stress/lipid peroxidation were also identified as differing significantly when comparing the disease groups and controls, with some of these pathways differentially affected in the PBC and PSC groups. Conclusion: In this study identified novel metabolic changes associated with cholestatic disease that were both consistent and different between PBC and PSC. Validation studies in larger patient cohorts are required to determine the utility of these biochemical markers for diagnosis and therapeutic monitoring of patients with PBC and PSC.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014;
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    ABSTRACT: We recently demonstrated that the combination of liver stiffness measurement with NAFLD fibrosis score (NFS), two complementary, easy-to-perform, and widely available tools, is able to accurately diagnose or exclude the presence of severe liver fibrosis, in addition to reducing the number of needed diagnostic liver biopsies by about 50% - 60% [1]. We thank Dr. Sertoglu and colleagues for their comments, which prompted us to further clarify the results of our analyses. First, they pointed out that data from Sicilian and northern Italian patients should be assessed for normal distribution before comparing these patients in terms of demographic, laboratory, metabolic, and histologic variables. In response, we examined the data, and found that only some variables, such as ALT levels, did not have normal distributionThis article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: Background Antibodies (Abs) to soluble liver antigen/liver pancreas (anti-SLA/LP) are considered markers of worse prognosis and outcome in patients with autoimmune hepatitis (AIH) although this assumption has recently been attributed to their frequent co-expression with Abs against Ro52 (anti-Ro52).AimsTo assess the clinical significance of anti-SLA/LP Abs alone or in combination with anti-Ro52 in AIH patients and determine the immunodominant Ro52 epitopes according to the anti-SLA/LP status.Methods23 anti-SLA/LP-positive and 106 anti-SLA/LP-negative AIH patients were included. Anti-SLA/LP were determined by ELISA using recombinant antigen, and confirmed by immunoblot using cytosolic rat liver fraction or HuH-7 extract. Anti-Ro52 Abs were determined by ELISA using recombinant antigen. Epitope mapping was assessed by ELISA using overlapping peptides covering the whole Ro52 protein in 26 AIH patients and 12 patients with Sjögren's syndrome.ResultsAnti-SLA/LP positivity was not associated with the clinical, laboratory or histological characteristics of AIH patients. Treatment response, corticosteroid withdrawal, relapse after stopping treatment and outcome, were not associated with the presence of anti-SLA/LP, anti-Ro52 or double reactivity. Moreover, Ro52 epitope mapping revealed new epitopes unique for AIH and independent from anti-SLA/LP positivity.Conclusions Neither anti-SLA/LP nor anti-Ro52 Abs or their combination could specify a distinct group of AIH patients in terms of clinical characteristics, treatment response and outcome. Further studies are needed in order to clarify whether the newly discovered immunodominant epitopes of Ro52 antigen which were associated specifically with AIH have any clinical or pathogenetic significance in AIH.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: Background Hepatitis B surface antigen (HBsAg) clearance is the main indicator of viral cure in patients infected with the hepatitis B virus (HBV).AimsWe sought to identify the parameters associated with HBsAg loss in a well-characterized real-life clinical cohort of chronically HBV-infected patients.Methods Patients with chronic HBV infection were prospectively included, classified according to the disease stage, and followed up to determine parameters associated with HBsAg clearance.ResultsIn total, 315 patients were followed up for a mean of almost 6 years. At study entry, 109 (34.6%) were inactive HBsAg carriers, 204 (64.8%) had chronic active hepatitis (CAH), and two (0.6%) were immune-tolerant carriers. During follow-up, 128 (62.7%) of the 204 patients with CAH received antiviral therapy. Sixty-nine had HBeAg-positive CAH: 55 (79.7%) were treated and 14 (20.3%) untreated. One hundred thirty-five had HBeAg-negative CAH: 73 (54.1%) were treated and 62 (45.9%) untreated. Inactive carriers showed an annual HBsAg clearance incidence rate of 23.4 cases per 1,000 persons-years, which was higher than that of CAH groups. The clearance incidence rates (in cases per 1,000 persons-years) of CAH groups were: treated HBeAg-positive (20.7), untreated HBeAg-positive (19.1), treated HBeAg-negative (10.1), and untreated HBeAg-negative (8.1). Older age (p=0.001) and inactive carrier status (p=0.019) were independent predictors of HBsAg clearance.Conclusions In a well-characterized real-life clinical cohort of chronically HBV-infected patients in various disease phases, older age and inactive HBsAg carrier status were the only predictors of HBsAg clearance, whereas anti-HBV therapy only marginally increased annual incidence of HBsAg loss.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: We have read with great interest the article by Petta et al. (1). In this study, the performance of combined noninvasive tools for identifying advanced fibrosis was assessed in two independent cohorts of Italian biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. In conclusion, the combination of liver stiffness measurement (LSM) with NAFLD fibrosis score (NFS) was found to be able to accurately diagnose or exclude the presence of severe liver fibrosis, also reducing of about 50–60% the number of needed diagnostic liver biopsies. However, we would like to share our thoughts and contributions with Petta and colleagues.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: Background and aimsCommon bile duct ligation (CBDL) rats is an accepted experimental model of hepatopulmonary syndrome (HPS), defined as liver disease and intrapulmonary vascular dilatation and hypoxemia. Pulmonary Akt and ERK activation, followed by angiogenesis in the later stages of CBDL, contribute to the pathogenesis of HPS. However, the mechanisms behind Akt and ERK activation remain undefined. Pulmonary injury induced by increased bilirubin, endotoxin and inflammatory mediators occurs in the early stages of CBDL. We assessed the effects of relieving pulmonary injury on Akt and ERK activation and on the development of HPS following CBDL.Methods Pulmonary injury, angiogenesis, arterial oxygenation, cell proliferation and, phospho-Akt and ERK1 were evaluated in CBDL animals with or without caspase-3 inhibition (Z-DEVD-FMK). Pulmonary injury was assessed by histology and quantifying apoptosis and AQP1 levels. Lung angiogenesis was assessed by quantifying AQP1 level, vWF-positive cells and microvessel count.ResultsPulmonary apoptosis and caspase-3 activation were markedly increased in the early stages of CBDL. Caspase-3 inhibition alleviated apoptosis, the reduction in AQP1, phospho-Akt and ERK1 levels, and pulmonary injury 1 week after CBDL. Caspase-3 inhibition also reduced AQP1, phospho-Akt and ERK1 levels, vWF-positive cells, cell proliferation, microvessel count, and microvascular dilatation, and improved arterial oxygenation 3 weeks following CBDL.Conclusions Caspase-3 inhibition alleviates pulmonary injury, thereby preventing angiogenesis as well as the development of HPS in CBDL rats. These effects are related to the regulation of the Akt and ERK1 pathways.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: Background Branched-chain amino acids (BCAA) reduce the incidence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the mechanisms that underlie these effects remain unknown. Previously, we reported that oxidative stress in male transgenic mice that expressed hepatitis C virus polyprotein (HCVTgM) caused hepatic iron accumulation by reducing hepcidin transcription, thereby leading to HCC development. Aims: This study investigated whether long-term treatment with BCAA reduced hepatic iron accumulation and oxidative stress in iron-overloaded HCVTgM and in patients with HCV-related advanced fibrosis.Methods Male HCVTgM were fed an excess-iron diet that comprised either casein or 3.0% BCAA, or a control diet, for 6 months.ResultsFor HCVTgM, BCAA supplementation increased the serum hepcidin-25 levels and antioxidant status [ratio of biological antioxidant potential (BAP) relative to derivatives of reactive oxygen metabolites (dROM)], decreased the hepatic iron contents, attenuated reactive oxygen species generation, and restored mitochondrial superoxide dismutase expression and mitochondrial complex I activity in the liver compared with mice fed the control diet. After 48 weeks of BCAA supplementation in patients with HCV-related advanced fibrosis, BAP/dROM and serum hepcidin-25 increased and serum ferritin decreased compared with the pretreatment levels.ConclusionsBCAA supplementation reduced oxidative stress by restoring mitochondrial function and improved iron metabolism by increasing hepcidin-25 in both iron-overloaded HCVTgM and patients with HCV-related advanced fibrosis. These activities of BCAA may partially account for their inhibitory effects on HCC development in liver cirrhosis patients.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: PurposeEpithelial-mesenchymal transition (EMT) process and extracellular signal-regulated kinase 1 (ERK1) signaling pathway play pivotal roles in hepatic stellate cell (HSC) activation, which is associated with the altered expression patterns of microRNAs (miRNAs). miR-155 is considered a typical multifunctional miRNA to regulate many biological processes. However, little attention has been given to the contributions of miR-155 to simultaneous regulation of EMT process and ERK1 pathway during HSC activation.Methods Differential expression of miR-155 was assessed in activated HSC, sera and liver tissues from cirrhotic patients. Whether miR-155 could directly interact with 3′-untranslated region (3′-UTR) of T cell factor 4 (TCF4) and angiotensin II receptor type 1 (AGTR1) respectively was detected by luciferase reporter assay. The effects of enhanced miR-155 on EMT process and ERK1 pathway, cell apoptosis in HSC activation were also evaluated.ResultsA significant decrease in miR-155 expression was observed in activated HSC, sera or liver tissues of cirrhotic patients. MiR-155 was found to simultaneously interact with 3’-UTR of TCF4 and AGTR1 mRNAs, which are known as important regulators associated with EMT and ERK1 pathway repectively. Inhibiting miR-155 expression could stimulate the EMT state and ERK1 pathway activity, thus contributing to HSC activation. Forced miR-155 expression markedly decreased the mesenchymal markers and phosphorylated ERK1 level, and enhanced E-cadherin expression, leading to the synchronous inhibitory effect on EMT and ERK1 pathway and inducing HSC apoptosis.Conclusions Our results implicate that miR-155 plays an important role in regulating the pathological network involving EMT process and ERK1 pathway during HSC activation.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: We have read with great interest the recently published article by Goh et al.1 In this study, authors aimed to evaluate association between the use of commonly used medications, particularly renin-angiotensin system (RAS) blocking agents, and severity of hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) patients with hypertension. In conclusion, hypertensive patients with NAFLD on baseline RAS blockers were found to be having less advanced hepatic fibrosis suggesting a beneficial effect of RAS blockers in NAFLD.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: Background/AimsGenome-wide association studies (GWAS) recently indicated that polymorphisms in the human leukocyte antigen (HLA)-DP genes were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV, but the effect of HLA-DP gene polymorphisms on the effect of antiviral therapy was unknown. We here investigated whether such polymorphisms were associated with decreases in HBsAg levels and seroclearance in patients who received long-term lamivudine (LAM) treatment.Methods Japanese patients (202) who were hepatitis B e antigen-positive at baseline, received LAM as first-line treatment, and consented to HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535) were categorized into 2 cohorts, viz., a cohort who achieved virological response without rescue therapy (cohort 1) and those who did so with rescue therapy (cohort 2).ResultsSerum HBsAg levels declined significantly between year 3 and 9 from baseline among cohort 1 patients possessing ≥ 2 A-alleles at rs3077 and rs9277535. The percentages of such patients in cohort 1 patients with decreases in HBsAg ≥ 0.5 log IU/mL were higher than those with <2 A-alleles (71.8% [28/39] vs. 38.9% [23/59]; P = 0.004). However, there was no significant difference in cumulative HBsAg seroclearance rates between patients with ≥ 2 and those with < 2 A-alleles in cohort 1. In cohort 2, HBsAg seroclearance rates were higher in patients with ≥ 2 A-alleles than in those with < 2 A-alleles (P = 0.003).Conclusion We found an association between HLA-DP polymorphisms and decreases in HBsAg levels and seroclearance among HBeAg-positive patients treated with LAM.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;
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    ABSTRACT: Background & AimsA critical role of the Toll-like receptor (TLR)-4 and its downstream mediators in the pathogenesis of small-for-size liver graft injury has been documented. Recently, the microRNA-146 (miR-146) was identified as a potent negative regulator of the TLR4 signaling pathway. In this study, the role of miR-146a and miR-146b in the attenuation of TLR-4 signaling and small-for-size liver graft injury was investigated.Methods The expression levels of miR-146a and miR-146b during small-for-size liver graft injury were studied in vivo. In addition, the effects of miR-146a and miR-146b on the expression of IRAK1 and TRAF6 in the rat macrophage cell line NR8383 and rat liver kupffer cells were studied in vitro. The in vivo effect of miR-146a and miR-146b on small-for-size liver graft injury was studied by the tail vein injection of miR-146a mimics and miR-146b mimics.ResultsThe levels of miR-146a and miR-146b decreased with a small-for-size liver graft. MiR-146a and miR-146b inhibited IRAK1 and TRAF6 expression by binding to the 3′UTR of IRAK1 or TRAF6, respectively, in the rat macrophage cell line NR8383. The administration of miR-146a mimics and miR-146b mimics prevented liver graft injury in small-for-size liver graft injury via the inactivation of IRAK1 and TRAF6 in vivo.ConclusionsmiR-146a and miR-146b prevent liver injury in small-for-size liver graft injury via the inactivation of IRAK1 and TRAF6.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 08/2014;

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