Mise à jour le : 07-02-2012
Les derniers abstracts de la revue Journal of Hepatology : |
Date de mise en ligne : Mercredi 01 février 2012
Editorial Board
Editorial Board
http://www.journal-of-hepatology.eu/article/PIIS0168827811007434/abstract?rss=yes
Date de mise en ligne : Mercredi 01 février 2012
EASL Monothematic Tallin, Estonia
EASL Monothematic Tallin, Estonia
http://www.journal-of-hepatology.eu/article/PIIS0168827811007446/abstract?rss=yes
Date de mise en ligne : Mercredi 01 février 2012
ILC Barcelona 2012
ILC Barcelona 2012
http://www.journal-of-hepatology.eu/article/PIIS0168827811007458/abstract?rss=yes
Date de mise en ligne : Mercredi 01 février 2012
Clinical School of Hepatology Bologna
Clinical School of Hepatology Bologna
http://www.journal-of-hepatology.eu/article/PIIS016882781100746X/abstract?rss=yes
Date de mise en ligne : Mercredi 01 février 2012
Short-Term Fellowship
Short-Term Fellowship
http://www.journal-of-hepatology.eu/article/PIIS0168827811007471/abstract?rss=yes
Date de mise en ligne : Mercredi 01 février 2012
Contents
Contents
http://www.journal-of-hepatology.eu/article/PIIS0168827811007495/abstract?rss=yes
Date de mise en ligne : Mardi 18 octobre 2011
Daniel Shouval
Focus
Advanced hepatic fibrosis is associated with a worse prognosis in patients with chronic hepatitis C virus (HCV) infection. Cumulative clinical experience also suggests that response rates to anti-viral therapy with pegylated interferons α2a or α2b and ribavirin are inversely proportional to the degree of fibrosis. The mechanism involved in the overall hyporesponsiveness to anti-viral treatment in patients with advanced fibrosis is not completely understood. At present, it is not clear whether advanced fibrosis per se is a key factor in the reduced responsiveness to anti-viral therapy or whether the different configuration of the pegylated interferon molecules and their impact on various genes expression play a role in this phenomenon. Among the various factors which have been implicated in failure of anti-viral therapy in such patients (i.e. high BMI, older age, ethnic background, genotype, viral load, incomplete adherence to treatment protocols, and cytopenia) it was postulated that the distorted hepatic architecture in advanced fibrosis prevents an optimal access of anti-viral drugs to the HCV infected hepatocytes, but proof for this hypothesis is still lacking. In this context, it was suggested that variations in pharmacodynamics, volume of distribution and pharmacokinetics between pegylated interferon α2a and α2b may explain, at least in part, the reported differences in obtaining an SVR by between the two agents .
Date de mise en ligne : Jeudi 29 septembre 2011
Ted Bader
Yes! Statins can be given to liver patients
Statins are given to 10–20% of adults in developed countries. Statins increase alanine aminotransferase (ALT) concentrations in 10% of patients without liver disease, and this increase can exceed more than three times the upper limit of normal in 1% of such patients. In contrast, we will note that this ALT escalation does not appear to occur when statins are initiated in patients with fatty liver or hepatitis C.
Date de mise en ligne : Mercredi 27 juillet 2011
Mario U. Mondelli
NKG2D and its ligands: Key to immunotherapy of liver cancer?
Hepatocellular carcinoma (HCC) is a common cancer accounting for a significant proportion of all cancers worldwide. Although most cases of HCC occur in countries where hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are endemic, the tumour is ubiquitous and one of the most challenging complications of advanced liver disease. HCC develops deviously and there are currently no reliable biomarkers for early diagnosis. Indeed, because alpha-foetoprotein (AFP) has poor sensitivity and specificity, and other serological markers such as des-gamma-carboxyprothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) perform only slightly better , abdominal ultrasound is presently considered the tool of choice for surveillance of patients at risk. Treatment of HCC has considerably improved over the last few decades from mere surgical resection in a minority of patients with good hepatic function and small tumours to orthotopic liver transplantation in selected patients satisfying the stringent Milan criteria , to locoregional ablation procedures, transarterial chemoembolization, and more recently antiangiogenetic drugs that increase survival in patients with advanced HCC for whom no therapy was hitherto available. Targeted treatment options are expected to expand exponentially as specific molecular signatures are being identified for HCC subgroups defined by microarray analysis . Despite the wealth of information on molecular biology, tumour growth rate, surveillance, diagnosis and management, there is currently only a scarcity of seminal studies addressing the immunopathogenesis of HCC, which may have important implications in the design of immunotherapeutic strategies. With respect to adaptive immunity it has been suggested that antigens such as AFP, the melanoma-associated antigen (MAGE), glypican 3 and NY-ESO, which are highly expressed in HCC (reviewed in ), are potential targets for T-cell responses. Moreover, several studies suggested that the presence of tumour-infiltrating cytotoxic T-cells is indicative of better survival. Interestingly, treatment of neoplastic nodules with radiofrequency thermal ablation (RFTA) can enhance the release and exposure of tumour antigens, which might help to overcome immune tolerance towards cancer cells . Innate immune responses have only been marginally explored in the setting of HCC. Natural killer (NK) cells are an essential component of innate immunity being instrumental in anti-tumour immune responses . A recent study provided important evidence in favour of their role in HCC, with increased frequencies of NK cells expressing higher levels of activating and reduced levels of inhibitory NK receptors, together with increased functional activity, e.g. interferon-γ production and cytotoxicity, in patients treated with RFTA . Interestingly, recurrence-free survival correlated with sustained functional NK cell activation, suggesting a role for these cells in the control of liver cancer.
Date de mise en ligne : Jeudi 29 septembre 2011
Wajahat Z. Mehal
HIF-1α is a major and complex player in alcohol induced liver diseases
Hepatic steatosis is one of the earliest and most consistent changes which occur with excessive consumption of alcohol. The development of steatosis is known to sensitize the liver to other insults, and is an important step towards the development of the full spectrum of alcohol-induced liver pathologies . The combination of high energy consumption by hepatocytes, and the venous inflow into the liver place hepatocytes at risk of hypoxia. Alcohol consumption was shown to increase hepatic oxygen consumption, with a smaller increase in hepatic oxygen delivery, resulting in central venous hypoxia . These findings bring together the fields of alcoholic liver disease and tissue adaptation to hypoxia. Adaptation to low oxygen tension is known to be regulated by transcriptional induction of genes important in myriad biological processes including metabolism, angiogenesis, cell cycle regulation, and cell death. The hypoxia inducible factor (HIF) family of heterodimeric transcription factors is important in regulating these processes . Functional HIF is composed of an alpha unit (HIF-1α, HIF-1β, or HIF-3α), and a HIF-1β subunit. Under normal conditions, the alpha units are rapidly degraded in the cytosol, but under hypoxic conditions they escape degradation, dimerise with the β unit, translocate to the nucleus, and regulate numerous gene transcription programs .
Date de mise en ligne : Lundi 23 mai 2011
Alexander J. Thompson, Paul J. Clark, Abanish Singh, Dongliang Ge, Jacques Fellay, Mingfu Zhu, Qianqian Zhu, Thomas J. Urban, Keyur Patel, Hans L. Tillmann, Susanna Naggie, Nezam H. Afdhal, Ira M. Jacobson, Rafael Esteban, Fred Poordad, Eric J. Lawitz, Jonathan McCone, Mitchell L. Shiffman, Greg W. Galler, John W. King, Paul Y. Kwo, Kevin V. Shianna, Stephanie Noviello, Lisa D. Pedicone, Clifford A. Brass, Janice K. Albrecht, Mark S. Sulkowski, David B. Goldstein, John G. McHutchison, Andrew J. Muir
Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients
Background & Aims: Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.Methods: 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×109/L and an absolute neutrophil count (ANC) ⩾1500/mm3. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294).Results: 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10−10). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10−12, p=10−7) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p=10−17) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.Conclusions: Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.
Date de mise en ligne : Mercredi 13 juillet 2011
Jennifer R. Kramer, Fasiha Kanwal, Peter Richardson, Minghua Mei, Hashem B. El-Serag
Gaps in the achievement of effectiveness of HCV treatment in national VA practice
Background & Aims: Antiviral treatment for hepatitis C virus (HCV) has high efficacy rates for achieving sustained viral response (SVR) in randomized controlled trials (RCTs) (40–80%); however, it can be lower in community-based practice settings. We wanted to determine the effectiveness of HCV treatment in Veterans Administration (VA) hospitals nationwide.Methods: Using the nationwide VA HCV Clinical Case Registry (CCR), we examined a cohort of veterans who had HCV viremia between 2000 and 2005 and identified patients who received pegylated-interferon (PEG-INF) and ribavirin. The duration of treatment and proportion of patients completing treatment was calculated. The effectiveness of treatment was measured as the proportion of patients who achieved SVR (negative viremia at least 12weeks after the end of treatment) in the entire cohort, and among patients who initiated and completed treatment.Results: We identified 99,166 patients with HCV viremia. Of those, 11.6% received PEG-INF with ribavirin and 6.4% completed treatment. Contraindications were present in 57.2% of the patients that did not receive treatment. SVR was documented in 39.9% and 58.3% of patients who completed treatment; 23.6% and 50.6% of patients who initiated treatment; and 3.9% and 11.2% of the entire HCV cohort for genotype 1 or 4 and 2 or 3, respectively. Overall, only 3.5% of the entire HCV viremic cohort had a documented SVR.Conclusions: Treatment effectiveness for HCV is low. In addition to fixed factors, such as race and virus genotype, the drop in effectiveness is due to low rates of antiviral treatment initiation and treatment completion.
Date de mise en ligne : Vendredi 02 septembre 2011
Hong Zhao, Wenyu Lin, Kattareeya Kumthip, Du Cheng, Dahlene N. Fusco, Oliver Hofmann, Nikolaus Jilg, Andrew W. Tai, Kaku Goto, Leiliang Zhang, Winston Hide, Jae Young Jang, Lee F. Peng, Raymond T. Chung
A functional genomic screen reveals novel host genes that mediate interferon-alpha’s effects against hepatitis C virus
Background & Aims: The precise mechanisms by which IFN exerts its antiviral effect against HCV have not yet been elucidated. We sought to identify host genes that mediate the antiviral effect of IFN-α by conducting a whole-genome siRNA library screen.Methods: High throughput screening was performed using an HCV genotype 1b replicon, pRep-Feo. Those pools with replicate robust Z scores ⩾2.0 entered secondary validation in full-length OR6 replicon cells. Huh7.5.1 cells infected with JFH1 were then used to validate the rescue efficacy of selected genes for HCV replication under IFN-α treatment.Results: We identified and confirmed 93 human genes involved in the IFN-α anti-HCV effect using a whole-genome siRNA library. Gene ontology analysis revealed that mRNA processing (23 genes, p=2.756e−22), translation initiation (nine genes, p=2.42e−6), and IFN signaling (five genes, p=1.00e−3) were the most enriched functional groups. Nine genes were components of U4/U6.U5 tri-snRNP. We confirmed that silencing squamous cell carcinoma antigen recognized by T cells (SART1), a specific factor of tri-snRNP, abrogates IFN-α’s suppressive effects against HCV in both replicon cells and JFH1 infectious cells. We further found that SART1 was not IFN-α inducible, and its anti-HCV effector in the JFH1 infectious model was through regulation of interferon stimulated genes (ISGs) with or without IFN-α.Conclusions: We identified 93 genes that mediate the anti-HCV effect of IFN-α through genome-wide siRNA screening; 23 and nine genes were involved in mRNA processing and translation initiation, respectively. These findings reveal an unexpected role for mRNA processing in generation of the antiviral state, and suggest a new avenue for therapeutic development in HCV.
Date de mise en ligne : Mercredi 13 juillet 2011
Caroline Le Lan, Anne Guillygomarc’h, Hélène Danielou, Gérard Le Dréau, Fabrice Lainé, Claude Védeilhié, Yves Deugnier, Pierre Brissot, Dominique Guyader, Romain Moirand
A multi-disciplinary approach to treating hepatitis C with interferon and ribavirin in alcohol-dependent patients with ongoing abuse
Background & Aims: Guidelines recommend 6months of alcohol abstinence before treating hepatitis C (HCV). Abstinence is difficult for alcohol-dependent patients to achieve. This study evaluated HCV treatment in alcoholic patients with ongoing consumption or less than 6months of abstinence.Methods: A multidisciplinary management model was built by a liver unit and two centers involved in the care of addict patients. Patients were included in a prospective observational study of treatment with pegylated interferon and ribavirin if they presented alcohol dependence with ongoing intoxication or abstinence of less than 6months. Pre-therapeutic evaluation and follow-up were multidisciplinary, and addiction care was personalized to patient condition and willingness. Alcohol abstinence or reduction was encouraged but not mandatory. The primary end point was sustained virological response (SVR). Results were compared to a control group of patients matched for genotype, viral load, fibrosis stage, sex, and age.Results: A total of 73 patients treated between 2002 and 2008 were included in the study. Intent to treat analysis showed an SVR in 48% (35/73) of patients versus 49% (36/73) of controls. Low viral load and length of abstinence during treatment were independently associated with SVR. During treatment, 20 (27%) patients were abstinent, 23 (32%) had controlled consumption, and 24 (33%) had excessive consumption. At the end of the follow-up, 22 (30%) patients were durably abstinent.Conclusions: A multidisciplinary approach allowed HCV treatment in alcohol-dependent patients with a satisfactory SVR rate and positive effects on addiction behavior.
Date de mise en ligne : Mercredi 13 juillet 2011
Gian Maria Prati, Alessio Aghemo, Maria Grazia Rumi, Roberta D’Ambrosio, Stella De Nicola, Maria Francesca Donato, Elisabetta Degasperi, Massimo Colombo
Hyporesponsiveness to PegIFNα2B plus ribavirin in patients with hepatitis C-related advanced fibrosis
Background & Aims: The success of pegylated-interferon (PegIFN)/ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNα-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis.Methods: A sub-analysis of the MIST study: 431 consecutive naïve patients randomly assigned, based on HCV genotype, to receive either (A) PegIFNα2a 180μg/wk plus daily Rbv 800–1200mg or (B) PegIFNα2b 1.5μg/kg/week plus daily Rbv 800–1200mg, were stratified according to Ishak staging (S) into mild (S0–S2) or moderate (S3, S4) fibrosis and cirrhosis (S5, S6).Results: In A the sustained virological response (SVR) rates were not significantly influenced by fibrosis stage (71% in S0–S2, 66% in S3, S4, 53% in S5, S6, p=0.12), compared to B where the SVR rates differed according to fibrosis stage (65%, 46%, and 38%, p=0.004, respectively). This was even more so in HCV-1/4 patients treated with PegIFNα2b where the SVR rates were twice as many in S0–S2 vs. S⩾3 (44% vs. 22%, p=0.02), while in A the SVR rates were similar between the two fibrosis subgroups (S0–S2: 47% vs. S⩾3: 48%, p=0.8). By logistic regression analysis genotype 1/4 and lack of rapid virological response were independent predictors of treatment failure in both treatment groups, while S⩾3 fibrosis was associated to PegIFNα2b treatment failure, only (OR 2.83, 95% CI 1.4–5.68, p=0.004).Conclusions: Liver fibrosis was an independent moderator of treatment outcome in patients receiving PegIFNα2b, not in those receiving PegIFNα2a.
Date de mise en ligne : Lundi 11 juillet 2011
Virendra Singh, Sahdeb P. Dhungana, Baljinder Singh, Rajesh Vijayverghia, Chander K. Nain, Navneet Sharma, Ashish Bhalla, Pramod K. Gupta
Midodrine in patients with cirrhosis and refractory or recurrent ascites: A randomized pilot study
Background & Aims: Splanchnic arterial vasodilatation plays an important role in cirrhotic ascites. The aim of this study was to evaluate the effects of long term administration of midodrine on systemic hemodynamics, renal function, and control of ascites in patients with cirrhosis and refractory or recurrent ascites.Methods: Forty cirrhotic patients with refractory or recurrent ascites were prospectively studied after long term administration of midodrine plus standard medical therapy (n=20) or standard medical therapy alone (n=20) in a randomized controlled trial at a tertiary centre.Results: A significant increase in urinary volume, urinary sodium excretion, mean arterial pressure, and decrease in plasma renin activity (p<0.05) was noted after 1month of midodrine administration. There was also a significant decrease in cardiac output and an increase in systemic vascular resistance after midodrine therapy at 3months (p<0.05). There was no change in glomerular filtration rate and model for end-stage liver disease (MELD) score. Midodrine plus standard medical therapy was significantly superior to standard medical therapy alone in the control of ascites (p=0.013) at 3months. The mortality rate in the standard medical therapy group was significantly higher than the midodrine group (p<0.046). There was no significant difference in the frequency of various complications at the end of follow-up.Conclusions: The results of this randomized pilot study suggest that midodrine plus standard medical therapy improves the systemic hemodynamics without any renal or hepatic dysfunction in these patients and is superior to standard medical therapy alone for the control of ascites.
Date de mise en ligne : Vendredi 02 septembre 2011
Mairene Coto-Llerena, Gonzalo Crespo, Patricia González, George Koutsoudakis, Rosa Miquel, Miquel Navasa, Xavier Forns, SofÃa Pérez-del-Pulgar
Determination of IL28B polymorphisms in liver biopsies obtained after liver transplantation
Background & Aims: Recipient and donor IL28B polymorphisms seem to play an important role in the response to hepatitis C treatment after liver transplantation (LT). Since donor peripheral blood mononuclear cells (PBMC) are not always available, the aim of our study was to assess whether follow-up biopsies obtained after LT could be used to determine donor IL28B genotype.Methods: Genotyping of IL28B rs12979860 was performed by TaqMan real-time PCR and direct sequencing in 56 HCV-infected LT recipients and their donors. Liver biopsies were obtained at the moment of LT (reperfusion) and at any time when clinically indicated (follow-up). Direct sequencing always confirmed the real-time PCR results.Results: Genotyping of donor IL28B rs12979860 polymorphisms showed a 100% match both in PBMC and reperfusion biopsies. The frequency of IL28B rs12979860 polymorphisms differed significantly between donors and follow-up biopsies (p=0.024). We found an enrichment of the IL28B rs12979860 CT genotype (72%) in follow-up biopsies compared to donor samples (46%). Recipient alleles were clearly detected in 14 heterozygous follow-up samples: 10 CT/CC, 1 CT/TT, and 3 TT/CC (recipient/donor), thus reflecting a mixture of both donor and recipient genotypes.Conclusions: Our results support that follow-up liver biopsies from LT recipients are not suitable for determining donor IL28B rs12979860 genotype by TaqMan real-time PCR or direct sequencing and that PBMC or reperfusion biopsies should be used instead. Thus, it is very important to obtain adequate samples in order to accurately determine the relative contributions of both donor and recipient.
Date de mise en ligne : Mercredi 13 juillet 2011
Bibo Ke, Xiu-Da Shen, Haofeng Ji, Naoko Kamo, Feng Gao, Maria Cecilia S. Freitas, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski
HO-1–STAT3 axis in mouse liver ischemia/reperfusion injury: Regulation of TLR4 innate responses through PI3K/PTEN signaling
Background & Aims: Signal transducer and activator of transcription 3 (STAT3), a key mediator of anti-inflammatory cytokine signaling, is essential for heme oxygenase-1 (HO-1)-induced cytoprotection. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog delete on chromosome 10 (PTEN) pathways regulate diverse innate immune responses. This study was designed to investigate the role of STAT3 in the regulation of PI3K/PTEN cascade after HO-1 induction in a mouse model of innate immune-dominated liver ischemia/reperfusion injury (IRI).Methods: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90min, followed by 6h of reperfusion.Results: Mice subjected to Ad-HO-1 transfer were resistant to liver IRI, and this cytoprotective effect correlated with increased intrahepatic PI3K/Akt and diminished PTEN expression. In contrast, mice undergoing adjunctive Ad-HO-1 treatment and STAT3 knockdown (siRNA) remained susceptible to IR-mediated local inflammatory response and hepatocellular damage. Consistent with decreased cell apoptosis and inhibited TLR4 expression after PI3K/Akt activation, treatment with specific PI3k inhibitor increased local inflammation and recreated liver IRI despite Ad-HO-1 gene transfer. Parallel in vitro studies with bone marrow derived-macrophages have confirmed that HO-1–STAT3 axis-induced PI3K/Akt negatively regulated PTEN expression in TLR4-dependent fashion.Conclusions: These findings underscore the role of HO-1 induced STAT3 in modulating PI3K/PTEN in liver IRI cascade. Activating PI3K/Akt provides negative feedback mechanism for TLR4-driven inflammation. Identifying molecular pathways of STAT3 modulation in the innate immune system provides the rationale for novel therapeutic approaches for the management of liver inflammation and IRI in transplant patients.
Date de mise en ligne : Mercredi 13 juillet 2011
Maite G. Fernández-Barrena, Maria J. Monte, Maria U. Latasa, Iker Uriarte, Eva Vicente, Haisul C.Y. Chang, Carlos M. Rodriguez-Ortigosa, Ronald Oude Elferink, Carmen Berasain, Jose J.G. Marin, Jesus Prieto, Matias A. Ãvila
Lack of Abcc3 expression impairs bile-acid induced liver growth and delays hepatic regeneration after partial hepatectomy in mice
Background & Aims: Bile acids (BA) are increasingly recognized as important modulators of liver regeneration. Increased enterohepatic BA flux has been proposed to generate specific signals that activate hepatocyte proliferation after partial hepatectomy (PH). We have investigated the role of the BA membrane transporter Mrp3 (Abcc3), which is expressed in the liver and gut, in the hepatic growth response elicited by BA and in liver regeneration after PH.Methods: Liver growth and regeneration, and the expression of growth-related genes, were studied in Mrp3+/+ and Mrp3−/− mice fed a cholic acid (CA) supplemented diet and after 2/3 PH. Activation of the BA receptor FXR was measured in mice after in vivo transduction of the liver with a FXR-Luciferase reporter plasmid. BA levels were measured in portal serum and liver tissue by high performance liquid chromatography-tandem mass spectrometry.Results: Liver growth elicited by CA feeding was significantly reduced in Mrp3−/− mice. These animals showed reduced FXR activation in the liver after CA administration and decreased portal serum levels of BA. Liver regeneration after PH was significantly delayed in Mrp3-deficient mice. Proliferation-related gene expression and peak DNA synthesis in Mrp3−/− mice occurred later than in wild types, coinciding with a retarded elevation in intra-hepatic BA levels.Conclusions: Lack of Abcc3 expression markedly impairs liver growth in response to BA and after PH. Our data suggest that Mrp3 plays a non-redundant role in the regulation of BA flux during liver regeneration.
Date de mise en ligne : Vendredi 02 septembre 2011
Einar Björnsson, Elin I. Jacobsen, Evangelos Kalaitzakis
Hepatotoxicity associated with statins: Reports of idiosyncratic liver injury post-marketing
Background & Aims: Limited data exist on drug-induced liver injury (DILI) associated with statins.Methods: Reports on adverse reactions suspected to be due to statins received by the Swedish Adverse Drug Reactions Advisory Committe 1988–2010 were analyzed. Only cases with >5×upper limit of normal (ULN) in aminotransferases and/or alkaline phosphatase >2×ULN were included.Results: The most common types of ADRs suspected were DILI in 124/217 (57%) cases. A total of 73/124 (59%) cases had at least possible relationship, median age 64years (57–73), 55% males, whereas 25/124 cases (20%) were excluded due to mild elevations of liver tests and 26 due to unlikely relationship and/or lack of data. A statin-related DILI episode was reported in 1.2/100,000 users. Atorvastatin was implicated in 30/73 (41%) cases, simvastatin in 28 (38%), fluvastatin (15%), and others. Two patients died of acute liver failure, one underwent liver transplantation and 25 (34%) had jaundice. Three patients were rechallenged with the same statin producing similar patterns of liver injury. The median duration of therapy was 90days (30–120), 120 (39–248) for atorvastatin, and 75 (30–150) for simvastatin (NS). Cholestatic/mixed injury was more common with atorvastatin, 17/30 (56%) than with simvastatin, 7/28 (24%) (p=0.018).Conclusions: Idiosyncratic liver injury associated with statins is rare but can be severe. After recovery, a similar pattern of liver injury can be reproduced on re-exposure. Most patients experience liver injury 3–4months after start of therapy. Atorvastatin is mostly associated with cholestatic liver injury whereas hepatocellular injury is more common with simvastatin.
Date de mise en ligne : Mercredi 13 juillet 2011
Hiroteru Kamimura, Satoshi Yamagiwa, Atsunori Tsuchiya, Masaaki Takamura, Yasunobu Matsuda, Shogo Ohkoshi, Makoto Inoue, Toshifumi Wakai, Yoshio Shirai, Minoru Nomoto, Yutaka Aoyagi
Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence
Background & Aims: The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated.Methods: We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines.Results: In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines.Conclusions: ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.
Date de mise en ligne : Vendredi 02 septembre 2011
Shupeng Liu, Weixing Guo, Jie Shi, Nan Li, Xiya Yu, Jie Xue, Xiaohui Fu, Kaijian Chu, Chongde Lu, Jiangsha Zhao, Dong Xie, Mengchao Wu, Shuqun Cheng, Shanrong Liu
MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma
Background & Aims: Portal vein tumor thrombus (PVTT) has previously been demonstrated to correlate with poor prognosis of hepatocellular carcinoma. Approximately 50–80% of HCC is accompanied by portal or hepatic vein invasion. The underlying mechanisms of PVTT development remain unclear. This study aimed to elucidate the role of miR-135a in PVTT tumorigenesis.Methods: In the present study, we investigated the expression of microRNAs and mRNAs in PVTT tissues using advanced microRNA and cDNA microarray techniques. MicroRNA (miR)-135a was noted to be highly over-expressed in PVTT and the cell line CSQT-2 and was selected for further study. We characterized the function of miR-135a in vitro and in vivo. We also analyzed the clinical relevance of miR-135a in relation to the prognosis and survival of HCC patients with PVTT.Results: Our analyses found that the miRNA and mRNA expression profiles of PVTT were distinct from the parenchyma tumor. Overexpression of miR-135a favors invasive and metastatic behavior in vitro. Furthermore, in a CSQT-2 orthotopic transplantation nude mouse model, blockade of miR-135a significantly reduced PVTT incidence. We also found that miR-135a was transcribed by forkhead box M1 (FOXM1), and metastasis suppressor 1 (MTSS1) was identified as the direct and functional target of miR-135a. Additionally, the cohort analysis revealed the relevance of miR-135a with respect to the prognosis and survival of HCC patients with PVTT.Conclusions: Our data suggest an important role for miR-135a in promoting PVTT tumorigenesis and indicate the potential application of miR-135a in PVTT therapy.
Date de mise en ligne : Mercredi 13 juillet 2011
Valentina Santi, Daniela Buccione, Antonio Di Micoli, Gianluca Fatti, Marta Frigerio, Fabio Farinati, Paolo Del Poggio, Gianludovico Rapaccini, Maria Anna Di Nolfo, Luisa Benvegnù, Marco Zoli, Franco Borzio, Edoardo Giovanni Giannini, Eugenio Caturelli, Maria Chiaramonte, Mauro Bernardi, Franco Trevisani
The changing scenario of hepatocellular carcinoma over the last two decades in Italy
Background & aims: This study investigates whether the aetiologic changes in liver disease and the improved management of hepatocellular carcinoma (HCC) have modified the clinical scenario of this tumour over the last 20years in Italy.Methods: Retrospective study based on the analysis of the ITA.LI.CA (Italian Liver Cancer) database including 3027 HCC patients managed in 11 centres. Patients were divided into 3 groups according to the period of HCC diagnosis: 1987–1996 (year of the “Milano criteria†publication), 1997–2001 (year of release of the EASL guidelines for HCC), and 2002–2008.Results: The significant changes were: (1) progressive patient ageing; (2) increasing prevalence of HCV infection until 2001, with a subsequent decrease, when the alcoholic aetiology increased; (3) liver function improvement, until 2001; (4) increasing “incidental†at the expense of “symptomatic†diagnoses, until 2001; (5) unchanged prevalence of tumours diagnosed during surveillance (around 50%), with an increasing use of the 6-month schedule; (6) favourable HCC “stage migrationâ€, until 2001; (7) increasing use of percutaneous ablation; (8) improving survival, until 2001.Conclusions: Over the last 20years, several aetiologic and clinical features regarding HCC have changed. The survival improvement observed until 2001 was due to an increasing number of tumours diagnosed in early stages and in a background of compensated cirrhosis, and a growing and better use of locoregional treatments. However, the prevalence of early cancers and survival did not increase further in the last years, a result inciting national policies aimed at implementing surveillance programmes for at risk patients.
Date de mise en ligne : Jeudi 21 juillet 2011
Ju Hyun Shim, Han Chu Lee, Hyung Jin Won, Yong Moon Shin, Kang Mo Kim, Young-Suk Lim, Dong Jin Suh
Maximum number of target lesions required to measure responses to transarterial chemoembolization using the enhancement criteria in patients with intrahepatic hepatocellular carcinoma
Background & Aims: The European Association for the Study of the Liver (EASL) criteria and, more recently, the modified Response Evaluation Criteria in Solid Tumors (mRECIST), have been widely adopted for evaluating responses to locoregional therapies for hepatocellular carcinoma (HCC). We wished to establish the optimum maximum number of target lesions that need to be measured in enhancement estimations.Methods: From a prospective registry in our institution we identified 160 consecutive patients who had at least two measurable HCCs of nodular type exceeding 10mm in diameter, and who initially underwent transarterial chemoembolization (TACE). Intra-patient and inter-method agreement on confirmed response status were evaluated based on a maximum of one, two, or three target lesions selected among the measurable lesions according to size, versus all baseline lesions.Results: Per patient analyses showed that the most consistent response distribution under both EASL and mRECIST was obtained using two or three targets versus all measurable lesions. These features were maintained even in analyses of subgroups stratified according to size, distribution, and number of tumors. The kappa values of comparisons between using a maximum of two or three targets versus using all the lesions were near 1.0, significantly higher than those obtained under both criteria using just the largest tumor. Similar conclusions were obtained when either two or three targets were measured.Conclusions: Our data indicate that evaluating the largest two lesions is generally the most useful procedure for measuring TACE responses under both EASL and mRECIST.
Date de mise en ligne : Mardi 12 juillet 2011
Jing-Houng Wang, Chih-Chi Wang, Chao-Hung Hung, Chao-Long Chen, Sheng-Nan Lu
Survival comparison between surgical resection and radiofrequency ablation for patients in BCLC very early/early stage hepatocellular carcinoma
Background & Aims: To compare the survival between surgical resection (SR) and radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) very early/early stage.Methods: Between 2002 and 2009, patients with newly diagnosed BCLC very early/early stage HCC who received SR or RFA were enrolled. Medical records were reviewed. The cumulative overall survival (OS) and disease-free survival (DFS) were compared.Results: A total of 605 patients, including 143 very early (SR: 52; RFA: 91) and 462 early stages (SR: 208; RFA: 254) were enrolled. For very early stage, the 3- and 5-year OS rates were 98% and 91.5% for SR, and 80.3% and 72% for RFA, respectively (p=0.073). The 3- and 5-year DFS rates were 62.1% and 40.7% for SR, and 39.8% and 29.3% for RFA, respectively (p=0.006). Either multiple adjustment by Cox model or match analysis based on propensity score showed no significant difference in OS between the two groups. For early stage, the 3- and 5-year OS rates were 87.8% and 77.2% for SR, and 73.5% and 57.4% for RFA, respectively (p=0.001). The 3- and 5-year DFS rates were 59.9% and 50.8% for SR, and 28.3% and 14.1% for RFA, respectively (p<0.001). After adjusting covariates, there was no significant difference in OS between the two groups. However, SR was superior to RFA in DFS.Conclusions: For HCC patients in BCLC very early/early stage, there was no significant difference in OS between SR and RFA. However, SR yielded better DFS than RFA.
Date de mise en ligne : Vendredi 02 septembre 2011
Zhen Li, Xiaoqian Huang, Huiqing Zhan, Zhiqiang Zeng, Caixia Li, Jan M. Spitsbergen, Svenja Meierjohann, Manfred Schartl, Zhiyuan Gong
Inducible and repressable oncogene-addicted hepatocellular carcinoma in Tet-on xmrk transgenic zebrafish
Background & Aims: Liver cancer, mainly hepatocellular carcinoma, is a major malignancy and currently there are no effective treatment protocols due to insufficient understanding of hepatocarcinogenesis. As a potentially high-throughput and cost-effective experimental model, the zebrafish is increasingly recognized for disease studies. Here, we aim at using the zebrafish to generate a convenient hepatocellular carcinoma model.Methods: Using the Tet-on system for liver-specific expression of fish oncogene xmrk, a hyperactive version of epidermal growth factor receptor homolog, we have generated transgenic zebrafish with inducible development of liver cancer.Results: Liver tumors were rapidly induced with 100% penetrance in both juvenile and adult xmrk transgenic fish. Histological examination indicated that they all showed features of hepatocellular carcinoma. The induced liver tumors regressed rapidly upon inducer withdrawal. During the tumor induction stage, we detected increased cell proliferation and activation of Xmrk downstream targets Erk and Stat5, which were important for liver tumorigenesis as proved by inhibition experiments. When tumors regressed, there were decreased phosphorylated Erk and Stat5 accompanied with an increase in apoptosis.Conclusions: Our zebrafish model demonstrates the potential of a hyperactivated epidermal growth factor receptor pathway in initiating heptocarcinogenesis. It provides clear evidence for the requirement of only a single oncogene for HCC initiation and maintenance and is thus a convenient model for further investigation of oncogene addiction and future anti-cancer drug screening.
Date de mise en ligne : Jeudi 08 septembre 2011
Pierre Nahon, Angela Sutton, Pierre Rufat, Nathalie Charnaux, Abdellah Mansouri, Richard Moreau, Nathalie Ganne-Carrié, Véronique Grando-Lemaire, Gisèle N’Kontchou, Jean-Claude Trinchet, Dominique Pessayre, Michel Beaugrand
A variant in myeloperoxidase promoter hastens the emergence of hepatocellular carcinoma in patients with HCV-related cirrhosis
Background & Aims: Genetic dimorphisms modulate the activities of several pro- or antioxidant enzymes, including myeloperoxidase (MPO), catalase (CAT), manganese superoxide dismutase (SOD2), and glutathione peroxidase 1 (GPx1). We assessed the role of the G(−463)A-MPO, T(−262)C-CAT, Ala16Val-SOD2, and Pro198Leu-GPx1 variants in modulating HCC development in patients with HCV-induced cirrhosis.Methods: Two hundred and five patients with HCV-induced, biopsy-proven cirrhosis but without detectable HCC at inclusion were prospectively followed-up for HCC development. The influence of various genotypes on HCC occurrence was assessed with the Kaplan–Meier method.Results: During follow-up (103.2±3.4months), 84 patients (41%) developed HCC, and 66 died. Whereas the Ala16Val-SOD2 or Pro198Leu-GPx1 dimorphisms did not modulate the risk, HCC occurrence was increased in patients with either the homozygous GG-MPO genotype (HR=2.8 [1.7–4.4]; first quartile time to HCC occurrence: 45 vs. 96months; LogRank <0.0001) or the homozygous CC-CAT genotype (HR=1.74 [1.06–2.82]; first quartile time to HCC occurrence: 55 vs. 96months; LogRank=0.02). Compared to patients with neither of these two at risk factors, patients with only the CC-CAT genotype had a HR of 2.05 [0.9–4.6] (p=0.08) and patients with only the GG-MPO genotype had a HR of 3.8 [1.5–9.1] (p=0.002), while patients with both risk factors had an HR of 4.8 [2.2–10.4] (p<0.0001). However, only the GG-MPO genotype was independently associated with the HCC risk in multivariate Cox analysis.Conclusions: The high activity-associated GG-MPO genotype increases the rate of HCC occurrence in patients with HCV-induced cirrhosis.
Date de mise en ligne : Mercredi 20 juillet 2011
Ming Song, Dale A. Schuschke, Zhanxiang Zhou, Theresa Chen, William M. Pierce, Renwei Wang, W. Thomas Johnson, Craig J. McClain
High fructose feeding induces copper deficiency in Sprague–Dawley rats: A novel mechanism for obesity related fatty liver
Background & Aims: Dietary copper deficiency is associated with a variety of manifestations of the metabolic syndrome, including hyperlipidemia and fatty liver. Fructose feeding has been reported to exacerbate complications of copper deficiency. In this study, we investigated whether copper deficiency plays a role in fructose-induced fatty liver and explored the potential underlying mechanism(s).Methods: Male weanling Sprague–Dawley rats were fed either an adequate copper or a marginally copper deficient diet for 4weeks. Deionized water or deionized water containing 30% fructose (w/v) was also given ad lib. Copper and iron status, hepatic injury and steatosis, and duodenum copper transporter-1 (Ctr-1) were assessed.Results: Fructose feeding further impaired copper status and led to iron overload. Liver injury and fat accumulation were significantly induced in marginal copper deficient rats exposed to fructose as evidenced by robustly increased plasma aspartate aminotransferase (AST) and hepatic triglyceride. Hepatic carnitine palmitoyl-CoA transferase I (CPT I) expression was significantly inhibited, whereas hepatic fatty acid synthase (FAS) was markedly up-regulated in marginal copper deficient rats fed with fructose. Hepatic antioxidant defense system was suppressed and lipid peroxidation was increased by marginal copper deficiency and fructose feeding. Moreover, duodenum Ctr-1 expression was significantly increased by marginal copper deficiency, whereas this increase was abrogated by fructose feeding.Conclusions: Our data suggest that high fructose-induced nonalcoholic fatty liver disease (NAFLD) may be due, in part, to inadequate dietary copper. Impaired duodenum Ctr-1 expression seen in fructose feeding may lead to decreased copper absorption, and subsequent copper deficiency.
Date de mise en ligne : Mercredi 07 septembre 2011
Yasumasa Nishiyama, Nobuhito Goda, Mai Kanai, Daisuke Niwa, Kota Osanai, Yu Yamamoto, Nanami Senoo-Matsuda, Randall S. Johnson, Soichiro Miura, Yasuaki Kabe, Makoto Suematsu
HIF-1α induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice
Background & Aims: Chronic alcohol intake stimulates hepatic oxygen consumption and subsequently causes liver hypoxia, leading to activation of hypoxia inducible factor-1 (HIF-1). Although HIF-1 plays a crucial role in the metabolic switch from aerobic to anaerobic metabolism in response to hypoxia, its roles in the regulation of lipid metabolism in alcoholic fatty liver remain unknown.Methods: Wild-type and hepatocyte-specific HIF-1α-null mice were subjected to a 6% ethanol-containing liquid diet for 4weeks, and functional effects of loss of the HIF-1α gene on lipid metabolism were examined in the liver.Results: Hepatocyte-specific HIF-1α-null mice developed severe hypertriglyceridemia with enhanced accumulation of lipids in the liver of mice exposed to a 6% ethanol-containing liquid diet for 4weeks. Sterol regulatory element-binding protein 1c (SREBP-1c) and its downstream target acetyl-CoA carboxylase were greatly activated as the hepatic steatosis progressed, and these alterations were inversely correlated with the expression of the HIF-1-regulated gene DEC1. Overexpression of DEC1 in the mutant liver abrogated the detrimental effects of loss of HIF-1α gene on ethanol-induced fatty liver with reduced SREBP-1c expression. Conversely, co-administration of the HIF hydroxylase inhibitor dimethyloxalylglycine for the last 2weeks improved markedly the ethanol-induced fatty liver in mice.Conclusions: The current results provide direct evidence for protective roles of HIF-1 induction in the development of ethanol-induced fatty liver via activation of the HIF-1-regulated transcriptional repressor DEC1.
Date de mise en ligne : Mercredi 13 juillet 2011
Ahmad Al-Serri, Quentin M. Anstee, Luca Valenti, Valerio Nobili, Julian B.S. Leathart, Paola Dongiovanni, Julia Patch, Anna Fracanzani, Silvia Fargion, Christopher P. Day, Ann K. Daly
The SOD2 C47T polymorphism influences NAFLD fibrosis severity: Evidence from case-control and intra-familial allele association studies
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity.Methods: The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients.Results: In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09–2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10−16).Conclusions: Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH.
Date de mise en ligne : Mardi 30 août 2011
Patrice Cacoub, Marc Bourlière, Jann Lübbe, Nicolas Dupin, Peter Buggisch, Geoffrey Dusheiko, Christophe Hézode, Odile Picard, Ramon Pujol, Siegfried Segaert, Bing Thio, Jean-Claude Roujeau
Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals
Summary: Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued.
Date de mise en ligne : Mercredi 03 août 2011
Bruno Sangro, Mercedes Iñarrairaegui, Jose I. Bilbao
Radioembolization for hepatocellular carcinoma
Summary: Radioembolization is a form of brachytherapy in which intra-arterially injected 90Y-loaded microspheres serve as sources for internal radiation purposes. It produces average disease control rates above 80% and is usually very well tolerated. Main complications do not result from the microembolic effect, even in patients with portal vein occlusion, but rather from an excessive irradiation of non-target tissues including the liver. All the evidence that support the use of radioembolization in HCC is based on retrospective series or non-controlled prospective studies. However, reliable data can be obtained from the literature, particularly since the recent publication of large series accounting for nearly 700 patients. When compared to the standard of care for the intermediate and advanced stages (transarterial embolization and sorafenib), radioembolization consistently provides similar survival rates. Two indications seem particularly appealing in the boundaries of these stages for first-line radioembolization. First, the treatment of patients straddling between the intermediate and advanced stages (intermediate patients with bulky or bilobar disease that are considered poor candidates for TACE, and advanced patients with solitary tumors invading a segmental or lobar branch of the portal vein). Second, the treatment of patients that are slightly above the criteria for resection, ablation or transplantation, for which downstaging could open the door for a radical approach. Radioembolization can also be used to treat patients progressing to TACE or sorafenib. With a number of clinical trials underway, the available evidence shows that it adds a significant value to the therapeutic weaponry against HCC of tertiary care centers dealing with this major cancer problem.
Date de mise en ligne : Vendredi 22 juillet 2011
Diethard Monbaliu, Jacques Pirenne, David Talbot
Liver transplantation using Donation after Cardiac Death donors
Summary: The success of solid organ transplantation has brought about burgeoning waiting lists with insufficient donation rates and substantial waiting list mortality. All countries have strived to expand donor numbers beyond the standard Donation after Brain Death (DBD). This has lead to the utilization of Donation after Cardiac Death (DCD) donors, also frequently referred to as Non-Heart Beating Donors (NHBD). Organs from these donors inevitably sustain warm ischaemic damage which varies in its extent and affects early graft function as well as graft survival. As a consequence, ‘non-vital’ organs such as renal transplants have increased rapidly from DCD donors but more ‘vital’ organ transplants such as the liver have lagged behind. However, an increasing proportion of liver transplants are now derived from DCD donors.This article covers this expansion, current results, pitfalls, and steps taken to minimize complications and to improve outcome, and future developments that are likely to occur.
Date de mise en ligne : Jeudi 29 septembre 2011
Jairo A. Garcia, Lewis R. Roberts
Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma
COMMENTARY ON: Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Park JW, Finn RS, Kim JS, Karwal M, Li RK, Ismail F, Thomas M, Harris R, Baudelet C, Walters I, Raoul JL. Clin Cancer Res 2011 Apr 1;17(7):1973–1983.
Date de mise en ligne : Mercredi 27 juillet 2011
Markus Peck-Radosavljevic
Back to basics: Staging and prognosis in HCC for medical oncologist
COMMENTARY ON: Advanced hepatocellular carcinoma: which staging systems best predict prognosis? Huitzil-Melendez FD, Capanu M, O’Reilly EM, Duffy A, Gansukh B, Saltz LL, Abou-Alfa GK. J Clin Oncol 2010 Jun 10;28(17):2889–95.
Date de mise en ligne : Mercredi 27 juillet 2011
Olivier Gires
EpCAM in hepatocytes and their progenitors
COMMENTARY ON: Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Yoon SM, Gerasimidou D, Kuwahara R, Hytiroglou P, Yoo JE, Park YN, Theise ND. Hepatology 2011 Mar;53(3):964–973.
Date de mise en ligne : Mercredi 27 juillet 2011
Maura Dandri, Jörg Petersen
Chimeric mouse model of hepatitis B virus infection
Chronic infection with hepatitis B virus (HBV) continues to be a major health problem affecting about 400 million people worldwide. The narrow species tropism of HBV has hindered progresses in HBV research and development of more efficient treatments. Due to strong restraints encountered using chimpanzees and animal models based on HBV-related viruses, recent developments focused on using the natural target of HBV infection: the human hepatocyte. However, in vitro susceptibility of human hepatocytes to HBV is limited and cultured cells may respond differently to the infection and other stimuli than hepatocytes in the liver. Attempts to create mice harboring human chimeric livers led to the establishment of two major models: the urokinase-type plasminogen activator (uPA) transgenic mice and the knockout fumarylacetoacetate hydrolase (Fah) mice . Common features of these systems are: (i) a transgene-induced hepatocyte damage creating space and regenerative stimulus for the transplanted cells to repopulate the host livers, and (ii) the absence of adaptive immune responses permitting xenogenic transplantation. Both models are amenable of infection with HBV . Here we present recent advances and applications of the uPA model, the most used and best characterized chimeric model currently available for HBV infection studies and preclinical drug evaluation.
Date de mise en ligne : Mercredi 27 juillet 2011
Stuart J. Forbes, Philip N. Newsome
New horizons for stem cell therapy in liver disease
Summary: There is an increasing range of potential applications of stem cells in liver diseases, with many clinical studies already undertaken. We identify four of the main areas which we propose stem cell therapy could be a realistic aim for in the future: (1) to improve regeneration and reduce scarring in liver cirrhosis by modulating the liver’s own regenerative processes, (2) to down-regulate immune mediated liver damage, (3) supplying hepatocyte-like cells (HLCs) derived from stem cells for use in extracorporeal bio-artificial liver machines, and (4) to use stem cell derived HLCs for cell transplantation to supplement or replace hepatocyte function.
Date de mise en ligne : Mercredi 27 juillet 2011
B. Schlosser, A. Stein, R. Neuhaus, S. Pahl, B. Ramez, D.H. Krüger, T. Berg, J. Hofmann
Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient
Abstract: Acute hepatitis E virus (HEV) infection is a self-limiting symptomatic or asymptomatic disease. However, as recently observed, it can manifest itself as chronic hepatitis in patients receiving solid organ transplants as well as in patients with HIV infection or severe hematologic disorders.Here, we describe the clinical course of a 73-year-old male patient in whom HEV transmission occurred after receiving a HEV-infected liver from a donor with occult HEV infection, whereby the patient had tested negative for HEV RNA and anti-HEV antibodies shortly before explantation.Anti-HEV IgG, IgM, and HEV RNA were detected in the first tested serum sample of the liver recipient obtained 150days after liver transplantation and remained positive (earlier samples after OLT were not available). Liver cirrhosis developed within 15months and the patient died of septic shock. Based on phylogenetic analyses of the donor and recipient’s HEV strains, we were able to prove that the occult HEV infection was transmitted via the graft.
Date de mise en ligne : Mercredi 29 juin 2011
Jeffrey J. Weiss, Marlene C. Alcorn, Judith G. Rabkin, Douglas T. Dieterich
The critical role of medication adherence in the success of boceprevir and telaprevir in clinical practice
The excitement about the new standard of care for the treatment of chronic hepatitis C virus (HCV) infection is warranted given the dramatically increased rates of sustained virologic response achieved with the addition of boceprevir or telaprevir to pegylated interferon and ribavirin in clinical trials. However, the success of these two new direct antiviral agents (DAAs) in the real world will depend on the ability of patients to adhere to them. Higher rates of psychiatric and substance use disorders and cognitive impairment in persons with chronic HCV, as compared to the general population, place them at risk for medication nonadherence. A similar development in the complexity of therapeutics occurred in the treatment of HIV infection in the late 1990s with the introduction of HIV protease inhibitors which led to an intensive focus on treatment adherence.
Date de mise en ligne : Vendredi 22 juillet 2011
Kristy Appelhans, Vasilios Frankos
Herbal medicine hepatotoxicity revisited
In the April 2011 issue of the Journal of Hepatology, an editorial discussed hepatotoxicity associated with the use of herbal preparations . The focus of the article is primarily on the need to develop specific biomarkers for compounds or ingredients suspected to be associated with hepatotoxicity in order to establish clinical specificity when determining if a relationship exists between an adverse event and the consumption of these agents. We agree that identification methods are crucial to product safety and the industry continues to develop and validate identification methods for many commercialized ingredients. This issue is also currently being addressed by the US Food and Drug Administration (FDA) and various other regulatory agencies worldwide. In the US, beginning in 2008, the FDA has enforced the formal requirement for dietary supplement manufacturers to comply with dietary supplement-specific Current Good Manufacturing Practices (cGMP) . The regulations outline the requirements that support product quality and safety including ingredient testing, manufacturing equipment and facilities, manufacturing process controls, product testing, product complaint handling, and documentation. It is important to appreciate how this higher level of scrutiny for dietary supplements allows for better assurance against potential safety issues, including issues related to contamination, adulteration, distribution, and safety monitoring. It would be equally prudent to acknowledge that since 2008, these manufacturing controls could mitigate ingredient contamination concerns that were suggested as the proposed mechanisms involved with cases of liver injury associated with these products. This article gives several examples of specific ingredients alleged to have been associated with cases of liver injury including references to Herbalife which is a brand, not a single product or ingredient. The reference to Herbalife is also somewhat immaterial in the context of the article’s discussion. Herbalife has formally responded to this publication to rebut articles cited by these authors . The articles were published in 2007 and present case reports with dates of onset that range from 1998 to 2004. These case reports involved a variety of food and supplement products that are not representative of currently marketed Herbalife products. Additionally, no toxic substance has been identified as responsible for the liver reactions that were alleged to have been associated with Herbalife products and none of the suspect compounds listed by these authors are found in any of Herbalife’s products. Although Herbalife uses green tea extracts in its current products, all green tea extracts are water-based extracts (equivalent to a hot tea infusion) that have never been implicated in causing liver toxicity. Furthermore, since January 2005, Herbalife has met and cooperated with 25 regulatory agencies, including the Swiss BAG, to address liver-related case reports and articles in the literature. None of the 25 agencies has taken any regulatory action affecting Herbalife products. Most recently, on December 22, 2010, Evira, the food safety authority in Finland, closed its multi-year inquiry involving Herbalife case reports, with the agency stating that all requirements were satisfied, and indicating Herbalife “acted properly†and in “a thorough manner†to “demonstrate its commitments to food safetyâ€.
Date de mise en ligne : Lundi 18 juillet 2011
Dominique Larrey, Stéphanie Faure
Reply to: “Herbal medicine hepatotoxicity revisitedâ€
The author’s letter states that the mention of some instances of herbal medicines is immaterial in the context of the article’s discussion. We do not agree with this view for the following reasons.
Date de mise en ligne : Vendredi 15 juillet 2011
Mark J.W. McPhail, Novraj S. Dhanjal, Vijay P. Grover, Simon D. Taylor-Robinson
Ammonia and cerebral water. Importance of structural analysis of the brain in hepatic encephalopathy
We read with interest the article by Mardini and colleagues , who induced hyperammonaemia experimentally in patients with cirrhosis. They show an increase in apparent diffusion coefficient (ADC) reported on diffusion tensor MR imaging (DTI) of the brain and a decrease in frontal white matter (FWM) myo-inositol (mI) demonstrated on concurrent 1H MR spectroscopy (MRS). These imaging abnormalities were reported in the absence of a change in cognitive status of the patients longitudinally across the study. The authors conclude that this is further evidence of compensated, low grade cerebral oedema in minimal hepatic encephalopathy (MHE), but we would caution against this firm conclusion in MHE patients, because the accumulated published data are uncertain, owing to a lack of direct structural analysis of brain volumes to date.
Date de mise en ligne : Vendredi 22 juillet 2011
Fiona Elizabeth Smith, Hanan Mardini, Christopher O. Record, Andrew M. Blamire
Reply to: “Ammonia and cerebral water. Importance of structural analysis of the brain in hepatic encephalopathyâ€
We thank McPhail et al. for their comments regarding our paper in which we reported that induced hyperammonaemia in patients with hepatic encephalopathy (HE) leads to a transient increase in brain water apparent diffusion coefficient (ADC) reported from diffusion tensor imaging (DTI), accompanied by a decrease in frontal white matter myo-inositol (mI) measured by proton magnetic resonance spectroscopy (MRS). McPhail et al. suggest that assessment of regional brain volume changes using voxel-based morphometry (VBM) would provide additional evidence available from our existing MR data as to the pathophysiological significance of brain water and low grade cerebral oedema in HE. In response to these comments, we have revisited the structural scans acquired during our study and performed a post hoc volumetric analysis of the brain in our patient group by three different methods.
Date de mise en ligne : Vendredi 02 septembre 2011
Teoman Dogru, Halil Genc, Sait Bagci
C reactive protein levels in non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. It represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, non-progressive clinical course, to nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Accurate evaluation of liver fibrosis in patients with NAFLD is important to identify patients who may develop complications. Over time, several biological markers have been studied for evaluating the extent of steatosis, the presence of necroinflammation, and the development of fibrosis to avoid performing liver biopsy, an invasive procedure that still represents the gold standard of diagnosis. The most important parameter to be identified through non-invasive methods is inflammation, as it plays a central role in NAFLD progression. Several biomarkers of inflammation were extensively studied in relation to fatty liver disease. The C reactive protein (CRP) is an acute-phase reactant produced by the liver and has an increased serum concentration in a variety of inflammatory conditions. The assessment of circulating levels of high sensitive CRP (hsCRP) proved to be useful in differentiating between simple steatosis and NASH. Moreover, it seems that high concentrations of hsCRP are associated with extensive liver fibrosis in NASH .
Date de mise en ligne : Mercredi 31 août 2011
Tine Jess, Esther Zimmermann, Rodolphe Anty, Joan Tordjman, An Verrijken, Philippe Gual, Albert Tran, Antonio Iannelli, Jean Gugenheim, Pierre Bedosa, Sven Francque, Yannick Le Marchand-Brustel, Karine Clement, Luc Van Gaal, Thorkild I.A. Sørensen
Reply to: “C-reactive protein levels in non-alcoholic fatty liver diseaseâ€
We thank Dr. Dogru et al. for their comments on our paper on C-reactive protein (CRP) levels in relation to various features of non-alcoholic fatty liver disease (NAFLD) among obese patients . In our study of 627 obese adults with liver histology and measures of body mass index (BMI, kg/m2), and high sensitivity (hs)-CRP, we confirmed a strong association between BMI and hs-CRP, with a 20% increase in hs-CRP level per 10% increase in BMI. Also, we observed a positive association between hs-CRP and liver steatosis, but no BMI independent association between hs-CRP and non-alcoholic steato-hepatitis (NASH), hence questioning whether CRP can be used as a marker of severity of NAFLD .