Journal of Hepatology

Editorial Board

2012-06-01

EASL Monothematic Conference: HIV and the Liver, London, December 2012

2012-06-01

EASL Short-Term Fellowship Application

2012-06-01

EASL iLiver app for iPhone & iPad

2012-06-01

EASL Monothematic Conference: Vascular Liver Diseases, Tallinn, June 2012

2012-06-01

EASL-AASLD Special Conference: Therapy of Hepatitis C, Clinical application & drug development, Prague, September 2012

2012-06-01

The International Liver Congress™ by EASL, Amsterdam 2013

2012-06-01

Focus: Long-term treatment with lamivudine in HBeAg negative patients with chronic hepatitis B: To switch or not to switch?

Daniel Shouval — 2012-03-09

The original observation reported in 1991 that lamivudine, the 2′,3′-dideoxy-3′-thiacytidine nucleoside analogue, inhibits hepatitis B virus (HBV) replication in vitro has revolutionized the treatment of chronic hepatitis B (CHB) . Subsequent clinical trials confirmed at that time the anti-viral potency of this agent in vivo. Lamivudine was repeatedly shown to suppress viral replication, improve hepatocellular injury as well as fibrosis progression and reduce the risk of evolving hepatocellular carcinoma. Consequently, between 1998 and 2005, lamivudine became the backbone for anti-viral therapy in HBeAg positive and negative, treatment naïve CHB patients and in CHB patients who failed interferon α therapy. Despite the initial excellent safety and tolerability record, it soon became clear that treatment with lamivudine is associated with a significant and progressively rising risk for developing a viral breakthrough with genotypic and phenotypic resistance, which may exceed >70% within 5years of treatment. However, some patients continue to benefit from long-term lamivudine therapy beyond 5years of intake without emerging resistance. The factor(s) associated with maintaining long-term anti-viral activity of lamivudine in these sub-cohorts are not entirely known. Information on follow-up of patients treated with lamivudine for more than 5years is scarce, although early and maximal suppression of viral load and adequate compliance seem to play a major role in successfully treated patients. Fortunately, newer and significantly more potent anti-viral nucleos(t)ide analogues, including entecavir, telbivudine, and tenofovir were developed and introduced into clinical practice. These agents and especially entecavir and tenofovir, which provide a much higher barrier to resistance, have further improved our ability to control persistent HBV infection and its complications. The high risk for emerging resistance to lamivudine in the first 5–6years of treatment is well recognized . Consequently the European (EASL) and American (AASLD) Associations for the Study of the Liver strongly recommend that treatment naïve CHB patients who are not candidates for interferon therapy as well as experienced patients not responding to interferon, should be treated with one of the newer, most potent anti-viral agents to reduce the risk of emerging resistance . Management of resistant patients to lamivudine through add on therapy i.e. with adefovir, entecavir or tenofovir or switching to monotherapy with entecavir or tenofovir has also received much attention in recent years . Yet, current guidelines do not provide clear recommendations whether stable patients who are on long-term lamivudine treatment without evidence for emerging resistance should be switched to a more potent anti-viral agent. There are quite a number of arguments to support such a switch. However, replacement of lamivudine by one of the newer anti-virals is associated with a more than 10× increase in cost/pill. In this context, it should be remembered that generic lamivudine remains sometimes the only affordable anti-viral agent, especially in low income countries in Asia and Africa where CHB is most prevalent. Following the rapid progress in development of more potent anti-viral agents against HBV and despite the lack of evidence, hepatologists frequently advise their stable patients treated successfully with lamivudine who still did not develop resistance, to switch to a more potent anti-viral agent. Convincing evidence to justify such a switch in anti-viral agents in this particular cohort of patients, which is of particular relevance in low-income regions, is still lacking. Thus, in view of the rather large number of patients in different continents who continue to receive lamivudine, it is important to collect more information through monitoring efficacy and safety of lamivudine in patients treated for more than 5years.

Gut microbiome and intestinal barrier failure – The “Achilles heel” in hepatology?

Daniel Benten, Reiner Wiest — 2012-03-09

Bacterial translocation (BT) includes the migration of viable microorganisms but also all microbial products (endotoxins such as lipopolysaccharide [LPS], lipoteichoic acid, bacterial DNA, peptidoglycans, and fragments, e.g. muramyldipeptide, etc.) across an even, anatomically intact intestinal barrier from the intestinal lumen to mesenteric lymph nodes (MLN) and other extraintestinal organs and sites . Although the term “BT” summarizes all these various bacterial products, the route, and site as well as the immunological response between them are most likely very different. BT in liver disease has been extensively studied in the past, mainly due to its long known role as an underlying mechanism in the development of spontaneous bacterial infections such as spontaneous bacterial peritonitis (SBP) in decompensated cirrhosis . Moreover, in advanced cirrhosis, pathological BT most likely impacts on the natural course of liver cirrhosis via triggering and/or aggravating hepatic failure, encephalopathy or hepatorenal syndrome. On this background, it has been proposed that intestinal decontamination could improve disease severity in cirrhotic patients . Concerning the mechanisms promoting BT in chronic liver disease, the majority of the studies have been performed in decompensated cirrhosis unraveling three main factors: intestinal bacterial overgrowth (IBO), increased intestinal permeability (IP), and impaired immunity. IBO has usually been evaluated at only one site, namely the upper small intestine, by applying culture techniques since it is defined as >105CFU/ml aspirate. However, it needs to be stressed that only a minority of the enteral flora can be cultured by conventional techniques and whether the small intestine is the site of most prevalent translocation has not been addressed so far. Nonetheless, in advanced liver cirrhosis IBO is a very frequent finding and has been linked to the development of BT, endotoxemia, and SBP . Indeed, bacteria causing SBP are not only normal commensal gut bacteria but most frequently exactly those overgrowing in the small intestine. So it has been said that BT is caused by “too much of the good guys at the wrong place” since, the upper intestine is not made to host this load of bacteria. Increases in IP in cirrhosis have been reported by various methods and factors involved including structural changes, oxidative stress, and alterations in enterocyte mitochondrial function . Moreover, the secretory barrier limiting adhesion of bacteria to the epithelium is diminished due to deficiencies in bile, IgA, and antimicrobial peptides .

TACE with or without systemic therapy?

Jean-François Dufour — 2012-03-06

Transarterial chemoembolisation (TACE) delivers a chemotherapeutic agent (usually doxorubicin) into the feeding vessels of a hepatocellular carcinoma (HCC) and blocks the subsequent perfusion of these vessels by the injection of a plugging material. Two randomized controlled trials, conducted 10years ago, reported a survival advantage for patients with a preserved liver function . Subsequent meta-analysis confirmed that TACE increased the survival of patients with HCC . TACE is a particularly attractive option for the management of patients with HCC because it is associated with few side effects and requires no more than a 24-h hospitalization. Until recently, TACE was a notoriously heterogeneous procedure with variable outcomes. The demonstration that the delivery of small beads loaded with doxorubicin was associated with fewer systemic side effects led to a standardization of the TACE procedure . TACE is offered to patients in stage B of the Barcelona classification, which represents the largest fraction of patients seeking treatment. Therefore, improvements of TACE therapy are a matter of urgency.

Control of iron metabolism – Lessons from neonatal hemochromatosis

Heinz Zoller, A.S. Knisely — 2012-03-06

When hepatologists begin their investigations at the scene of liver damage, iron is certainly on the list of “usual suspects” to be rounded up. Hemochromatosis, a well-known cause of chronic liver disease, is the most prevalent genetic disorder in adults . Serum iron parameters are therefore included in most guidelines on how to investigate patients with elevated transaminases or chronic liver disease .

A predictive model of treatment outcome in patients with chronic HCV infection using IL28B and PD-1 genotyping

2012-02-09

Background & Aims: The advent of new chronic hepatitis C virus (HCV) therapies requires characterization of patients in order to predict adequate treatment. A good candidate marker is Programmed Cell Death-1 (PD-1) which is involved in progression of HCV infection. The aim of this study was to analyse the effect of several single nucleotide polymorphisms of PD-1 gene and several previously associated factors (IL28B and KIR receptors) on treatment responses.Methods: 407 HCV chronic infected patients treated with PEG-IFN-α and ribavirin were recruited and classified according to their response to treatment. They were genotyped for PD-1 and IL28B polymorphisms, killer immunoglobulin-like receptors (KIR) and HLA genes. A multivariate logistic regression analysis and a Chi-squared Automatic Interaction Detector (CHAID) prediction model of response included these and other clinical parameters.Results: Our results showed that PD-1.3/A allele was significantly associated with sustained virological response (SVR) in a multivariate logistic regression analysis (p<0.01, OR=2.57). Additionally, IL28B C/C genotype was the most significant predictor of an SVR to treatment in all HCV genotypes (74.5%). In IL28B C/C patients, the presence of PD-1.3/A allele increased the probability of an SVR to 93.3%. Moreover, when this analysis was made only with patients infected by HCV-1, the predictive value of IL28B C/C genotype with PD-1.3/A allele was 90%.Conclusions: PD-1.3/A allele is associated with SVR to treatment and notably increases the predictive value of IL28B C/C genotype. Both markers in conjunction could be a useful tool, more relevant than HCV genotype in some cases, in clinical practice.

Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis

2012-02-13

Background & Aims: The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy.Methods: HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed.Results: Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines.Conclusions: IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

2012-02-13

Background & Aims: TMC435 is an investigational, once-daily, oral NS3/4A protease inhibitor currently in phase III development for the treatment of hepatitis C virus (HCV) infection. Phase I and II studies in patients infected with HCV genotype 1 have demonstrated that TMC435 is generally well tolerated, has a pharmacokinetic profile that supports once daily dosing, and demonstrates potent antiviral activity. This phase IIa study (TMC435-C202; NCT00812331) was conducted to investigate the antiviral activity, safety, tolerability, and pharmacokinetics of TMC435 in treatment-naїve patients infected with HCV genotypes 2–6.Methods: The study consisted of 7days of monotherapy with TMC435 (200mg once daily). Patients could begin treatment with pegylated interferon/ribavirin from day 8 with a follow-up period up to days 37–42.Results: Thirty-seven patients were enrolled in Germany, Belgium and Thailand. For the primary end point at day 8, the mean (± standard error) change in plasma HCV ribonucleic acid (log10IU/ml) from baseline was the greatest for genotypes 6 (−4.35±0.29) and 4 (−3.52±0.43), followed by genotypes 2 (−2.73±0.71) and 5 (−2.19±0.39). No antiviral activity was evident for genotype 3. Viral breakthrough occurred in six patients during the monotherapy phase and in six additional patients during PegIFN/RBV-only period. All adverse events were mild or moderate and there were no discontinuations during the TMC435 monotherapy period.Conclusions: The results of this phase IIa proof-of-concept trial provide evidence that TMC435 has a spectrum of activity against multiple HCV genotypes, except for genotype 3. In this study, TMC435 was generally safe and well tolerated.

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5years

2012-02-17

Background & Aims: In long-term responder patients, it is unclear whether lamivudine (LAM) monotherapy should be continued or switched to a high-genetic-barrier analogue. This study aims at assessing LAM efficacy over a 5-year period and the residual risk of drug resistance. The rate of HBsAg clearance and LAM long-term safety profile were also evaluated.Methods: One hundred and ninety-one patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5years were included. Biochemical and virological tests were assessed every 3months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients.Results: One hundred and ninety-one patients (148 males, median age 53years, 72 with compensated cirrhosis) responding to 60-month LAM monotherapy continued to receive LAM monotherapy beyond the initial 5years and were followed for an additional 36-month median period (range 1–108). Virological response was maintained in 128/191 patients (67%) and HBsAg clearance was observed in 15/128 (11.7%) after a 32-month median period (range 1–65). The 63 remaining patients (33%) showed virological breakthrough after a 15-month median treatment (range 1–78). RT region analysis was performed in 38/63 breakthrough patients and LAM resistant mutations were found in 37/38. No significant side effects were observed.Conclusions: In long-term responder patients, continuation of LAM monotherapy resulted in persistent viral suppression in most cases with undetectable HBV DNA by real-time PCR; moreover, 11.7% of these patients cleared HBsAg. Selection of LAM resistance, however, can still occur even after successful long-term therapy, thus emphasising the importance of a careful virological monitoring.

Lack of TGF-β production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection

2012-02-13

Background & Aims: Immunity and genetic factors govern the recovery from acute hepatitis C virus (HCV) infection. No predictive factors have been yet identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGF-β) predict the outcome of acute HCV coinfection, independently of the IL-28B gene polymorphism.Methods: Intracellular cytokine staining assays against HCV-core, E1, NS2, and NS4 overlapping peptides were used for the analysis of peripheral HCV-specific TGF-β-producing T cells. Patients were genotyped for IL-28B polymorphisms. Healthy donors’ samples were tested as controls. Twenty-four acute hepatitis C-HIV+ patients were followed-up for 15months defining two groups: (A) Recovered (n=16, 5 spontaneous recoveries, 11 sustained virologic response after treatment), (B) Chronic HCV (n=8, 4 spontaneous chronic course, 4 therapeutic failures).Results: During the acute pretreatment phase, core/NS2-specific TGF-β-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGF-β+ cells was characteristic of healthy donors and Group A, except for 2 cases, with frequencies significantly lower than in Group B (p=0.04 and 0.01), and was associated with recovery in 14/16 cases. Presence of anti-HCV TGF-β+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGF-β production was independent of the rs129679860 SNP (p=1.0) which was not associated with recovery (p=1.0).Conclusions: During acute hepatitis C, pre-therapeutic HCV-specific TGF-β-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.

Decreased infectivity of nucleoside analogs-resistant hepatitis B virus mutants

Gaëtan Billioud, Christian Pichoud, Romain Parent, Fabien Zoulim — 2012-02-06

Background & Aims: To understand the mechanisms of emergence and selection of HBV polymerase variants, which may also harbor mutations in the overlapping envelope protein, we analyzed the in vitro virus production and infectivity of the main viral mutants resistant to lamivudine and adefovir.Methods: HBV-resistant mutants (rtL180M+M204V, rtV173L+L180M+M204V, rtM204I, rtL180M+M204I, rtN236T, rtA181V, rtA181V+rtN236T, rtA181T+N236T, and rtA181T) were produced in HepG2 cells permanently expressing the respective viral genomes. Viral protein expression, secretion, and viral particle production were studied by ELISA, Western blot, and transmission electron microscopy. To study only the effect of surface gene mutants on virus infectivity, HepaRG cells were inoculated with HDV pseudo-particles coated with the mutant HBV envelopes. To evaluate infectivity and replication in a global fashion, HepaRG cells were inoculated with HBV mutants.Results: HBeAg was expressed and secreted in cell supernatants in all mutant-expressing cell lines. As expected, mutants harboring a sW196Stop mutation in the surface gene did not express small envelope proteins. All mutants expressing HBsAg were able to produce viral particles. HDV particles coated with mutant envelopes were less infectious than WT in HepaRG cells. Finally, we found that resistant mutants exhibit lower infectivity and replication ability than WT virus.Conclusions: Based on this study, we found that envelope substitutions modulate viral protein expression, HDV coating, and viral infectivity. These envelope modifications provide novel insights into the features of emerging HBV variants during antiviral therapies and suggest that such mutants are less prone to transmission than their WT counterpart.

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin

2012-02-06

Background & Aims: It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of treatment influences the probability of achieving a sustained virological response (SVR) in patients without a week 4 rapid virological response (RVR).Methods: Data were retrospectively analyzed from two studies in which treatment-naive patients received peginterferon alfa-2a (40KD) 180μg/week plus ribavirin 1000/1200mg/day for 48weeks. Five hundred and fifty-eight genotype 1 patients with evaluable HCV RNA at baseline and week 4 were grouped according to RVR status: RVR (HCV RNA<50IU/ml) or no RVR. Non-RVR patients were subdivided into discrete mutually exclusive categories according to week 4 HCV RNA; the proportion of patients with undetectable HCV RNA at week 12 was calculated per each category, and among them, the proportion with an SVR.Results: Overall, 88% of RVR patients and 43% of non-RVR patients achieved an SVR (p<0.0001). Among non-RVR patients, SVR rates were 77%, 61%, 43%, 27% and 13%, respectively (trend test p<0.0001) in those with unquantifiable HCV RNA or ⩾3 log10, ⩾2 log10, ⩾1 log10, or<1 log10 drop to week 4. In patients HCV RNA positive at week 4, SVR rates were 67% for those negative at week 12 vs. 17% (HCV RNA positive patients or who had missing values at week 12 [p<0.0001]).Conclusions: The probability of achieving SVR is graded in relation to the magnitude of reduction in HCV RNA at week 4 and 12. Patients with a⩾3 log10 drop in HCV RNA at week 4 have a high probability of achieving an SVR.

Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease

2012-02-13

Background & Aims: Intestinal dysbiosis and bacterial translocation are common in patients with advanced liver disease, and there is strong evidence that the translocation of bacteria and their products across the epithelial barrier drives experimental liver disease progression. The aims of our study were to investigate dynamics of bacterial translocation and changes in the enteric microbiome in early stages of liver disease.Methods: Cholestatic liver injury was induced by ligation of the common bile duct (BDL) and toxic liver injury by injection of carbon tetrachloride (CCl4) in mice.Results: Increased intestinal permeability and bacterial translocation occurred one day following liver injury in both disease models. This was accompanied by decreased intestinal expression of the tight junction protein occludin. Although BDL resulted in a rapid onset of intestinal bacterial overgrowth, bacterial overgrowth was observed in mice injected with CCl4 only in advanced stages of liver fibrosis. To further assess the qualitative changes in the intestinal microbiome, massively parallel pyrosequencing of 16S rRNA genes revealed minor microbial changes following BDL, while CCl4 administration resulted in a relative abundance of Firmicutes and Actinobacteria compared with oil-injected mice. Four different liver disease models (cholestasis, toxic, alcohol, obesity) show few similarities in their intestinal microbiome.Conclusions: Acute liver injury is associated with an early onset of increased intestinal permeability and bacterial translocation that precede changes in the microbiome. The enteric microbiome differs with respect to the etiology of liver disease.

Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: A randomized study

2012-02-07

Background & Aims: Various vasoconstrictors are useful in the management of hepatorenal syndrome (HRS). Terlipressin is the drug of choice; however, it is expensive. In this study, we evaluated safety and efficacy of terlipressin and noradrenaline in the treatment of HRS.Methods: Forty-six patients with HRS type 1 were managed with terlipressin (group A, N=23) or noradrenaline (Group B, N=23) with albumin in a randomized controlled trial at a tertiary center.Results: HRS reversal could be achieved in 9 (39.1%) patients in group A and 10 (43.4%) patients in group B (p=0.764). Univariate analysis showed baseline Child Turcotte Pugh score (CTP), model of end stage liver disease (MELD), urine output on day 1(D1), albumin, and mean arterial pressure (MAP) were associated with response. However, on multivariate analysis only CTP score was associated with response. Fourteen patients in group A and 12 in group B died at day 15 (p>0.05). Noradrenaline was less expensive than terlipressin (p<0.05). No major adverse effects were seen.Conclusions: The results of this randomized study suggest that noradrenaline is as safe and effective as terlipressin, but less expensive in the treatment of HRS and baseline CTP score is predictive of response.

C-Reactive protein predicts short-term mortality in patients with cirrhosis

2012-02-06

Background & Aims: We aimed at improving prediction of short-term mortality in cirrhotic inpatients by evaluating C-reactive protein (CRP) as a surrogate marker of systemic inflammatory response syndrome (SIRS).Methods: One-hundred and forty-eight consecutive cirrhotic patients with Child-Pugh score ⩾B8 and without hepatocellular carcinoma were prospectively included and followed for 182days. The primary end point was 6-month survival.Results: Main baseline characteristics were as follows: alcoholic liver disease in 88.5%; bacterial infection in 37%; hepatorenal syndrome in 7% of cases. CRP range was 1–240mg/L (median 26mg/L); 42 patients (28.4%) had SIRS as defined by ACCP/SCCM-criteria. CRP levels were higher in patients with SIRS (50 vs. 21mg/L; p<0.0001), infection (46 vs. 27mg/L; p<0.0001), and alcoholic hepatitis (44 vs. 32mg/L, p=0.049). Forty-two patients died within the first 6months of follow-up. Short-term mortality was associated with extrahepatic co-morbidities (p=0.002), high MELD score (p<0.001; AUROC=0.67), renal failure (p=0.008), elevated blood lactates (p<0.001), and high baseline CRP levels (p=0.003; AUROC=0.63; best cut-off value at 29mg/L). Among patients with baseline CRP ⩾29mg/L, 32 still had CRP ⩾29mg/L at day 15 (group A). Group A was associated with 6-month mortality in the overall population (p<0.001) and also through sentitivity analyses restricted to patients without infection or alcoholic hepatitis. Multivariate analysis (Cox) adjusted for age identified three predictors of mortality: high MELD score (HR=1.08; 95% CI: 1.03–1.12; p<0.001), extrahepatic co-morbidities (HR=2.51; 95% CI: 1.31–4.84; p=0.006), and CRP level (group A) (HR=2.73; 95% CI: 1.41–5.26; p=0.003). The performance of the three variables taken together for predicting death was 0.80 (AUROC).Conclusions: In Child-Pugh score ⩾B8 cirrhotic patients, persistent CRP levels ⩾29mg/L predicted short-term mortality independently of age, MELD, and co-morbidities, and better than infection or clinically-assessed SIRS.

The effect of steroid pretreatment of deceased organ donors on liver allograft function: A blinded randomized placebo-controlled trial

2012-02-13

Background & Aims: Brain death-associated inflammatory response contributes to increased risk of impaired early liver allograft function, which might be counterbalanced by steroid pretreatment of the organ donor. The aim of this randomized controlled trial was to elucidate whether steroid pretreatment of liver donors improves early liver allograft function, prevents rejection and prolongs survival.Methods: A placebo-controlled blinded randomized clinical trial was performed in three different centers in Austria and Hungary between 2006 and 2008. Ninety deceased organ donors received either 1000mg of methylprednisolone or placebo 6h before recovery of organs. The primary end point was the concentration slope of transaminases within the first week. The secondary end point included survival and biopsy-confirmed acute rejection (BCAR) within 3 years after transplantation.Results: Of the 90 randomized donors, 83 recipients were eligible for study. The trajectories of ALT and AST were not different between treatments (p=0.40 and p=0.13, respectively). Eight subjects died in the steroid and 13 in the placebo group within 3 years after engraftment (RR=0.63 95% CI [0.29,1.36], p=0.31). Eleven recipients experienced biopsy-confirmed rejection (BCAR) in the steroid and 11 in the placebo group (RR=1.02 95% CI [0.50,2.10], p=1.00). No effect modification could be identified in the predefined strata of donor age, sex, cold ischemic time, and cause of donor death.Conclusions: Steroid pretreatment of organ donors did not improve outcomes after liver transplantation.

Comparison of two non-contemporaneous HCV-liver transplant cohorts: Strategies to improve the efficacy of antiviral therapy

2012-02-06

Background & Aims: In a previous study, advanced fibrosis was associated with worsening efficacy of antiviral therapy in HCV-transplant patients. We aimed at assessing whether changes in treatment policy, that is starting therapy at lesser stages of fibrosis, have resulted in improved efficacy.Methods: Efficacy (rapid, early, end-of-treatment, and sustained viral response (SVR)) and tolerability (peginterferon (pIFN)/ribavirin (RBV) doses, premature discontinuation, dose reductions, anemia, growth factors, transfusions) were compared between two non-contemporaneous cohorts of post-LT naïve patients treated with pIFN-RBV: Group 1 (n=44), a historical cohort of patients treated during the period 2005–2007 and Group 2 (n=70), patients treated more recently (2007–2010), where treatment was started once there was evidence of fibrosis.Results: SVR increased from 25% to 54% (p=0.002) due to a reduction in relapse rate. Comparing both cohorts, a decrease in the number of cirrhotic patients together with an increase in platelet count was observed in recent years. Additional non-intentional changes included: (i) an increase of patients treated under cyclosporine immunosuppression, (ii) treatment-related factors with an increase in patients treated with initial full pIFN and RBV doses, who developed anemia and hence required dose modifications and erythropoietin. Baseline factors associated with SVR were younger donor age, lack of cirrhosis or severe necroinflammation and the use of RBV at full doses at initiation while on-treatment variables were adherence and viral kinetics.Conclusions: Treatment in the absence of cirrhosis is associated with higher SVR warranting strict disease progression monitoring. A more aggressive approach, particularly regarding RBV dosage, is also associated with improved efficacy. Further studies are required to assess whether switching to cyclosporine will result in improved SVR.

Non-invasive diagnosis of hepatocellular carcinoma ⩽2cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI

2012-02-06

Background & Aims: To prospectively assess the diagnostic accuracy of the incorporation of additional magnetic resonance imaging (MRI) parameters in those based on contrast enhancement pattern for the diagnosis of solitary nodules between 5 and 20mm, detected during surveillance in patients with cirrhosis.Methods: Between November 2003 and January 2010, we prospectively included 159 cirrhotic patients with a newly detected solitary nodule between 5 and 20mm in diameter by screening ultrasonography (US). Hepatic MRI and fine-needle biopsy were performed in all patients.Results: Final diagnoses were hepatocellular carcinoma (HCC) (n=103), other malignant lesions (intrahepatic cholangiocarcinoma/metastases) (n=4), and benign lesions (n=52). The specific enhancement pattern (arterial enhancement followed by washout) yielded a sensitivity and specificity of 58.3% and 96.4%, respectively. Peritumoral capsule was present in 43 HCC and in 2 non-HCC lesions. Intralesional fat was detected in 24 nodules; 5 nodules were non-HCC. Finally, the presence of both capsule and fat was observed in 10 cases, all of them HCC (100% specificity), but all of them also displayed the specific enhancement pattern, thus adding no sensitivity or specificity.Conclusions: Conclusive non-invasive diagnosis of HCC in cirrhosis should be based only on the contrast enhancement pattern, while other characteristics at MRI do not increase the diagnostic accuracy.

Role of the routine use of chest computed tomography and bone scan in staging workup of hepatocellular carcinoma

2012-02-07

Background & Aims: The value of chest computed tomography (CT) and bone scan (BS) during initial staging workup for hepatocellular carcinoma (HCC) patients has not been evaluated in a large patient group.Methods: A prospective cohort of 381 patients who were initially diagnosed as having HCC at our institution between 2008 and 2010 was enrolled. We evaluated whether chest CT and BS could affect Barcelona Clinic Liver Cancer (BCLC) and Union for International Cancer Control (UICC) (7th) staging, compared with liver dynamic CT (LDCT) and chest X-ray.Results: Abnormal findings on chest CT and BS were observed in 59.6% and 52.8% of 381 patients, respectively. Thirty and eight patients, respectively, had truly metastatic intrathoracic and bone lesions, with 19 (49.8%) and 7 (87.5%) exhibiting the same lesions on LDCT or chest X-ray. Of the 381 patients, 60 (15.7%), 134 (35.2%), 61 (16.0%), 119 (31.2%), and 7 (1.8%) had BCLC stages 0, A, B, C, and D, respectively; 176 (46.2%), 83 (21.8%), 41 (10.8%), 39 (10.2%), 0 (0%), 8 (2.1%), and 34 (8.9%) had UICC stages I, II, IIIA, IIIB, IIIC, IVA, and IVB, respectively before chest CT and BS. Only three of 381 patients showed a shift in BCLC stage [B→C (3/61, 4.9%)]. Chest CT and BS revealed additional metastases in only 1.1%, 14.0%, and 5.6% of patients with UICC stage T2, T3a, and T3b, respectively.Conclusions: Chest CT and BS do not provide additional information on metastasis in HCC patients with BCLC 0, A, C, or D stages, and UICC T1 or T4 stages on LDCT.

Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design

2012-02-06

Background & Aims: Transarterial chemoembolisation (TACE) improves survival of properly selected patients with hepatocellular carcinoma (HCC). Drug eluting beads (DEB) provide a calibrated and homogenous procedure while increasing efficacy. Outcome data applying this technology is lacking, and this is instrumental for clinical decision-making and for trial design.We evaluated the survival of HCC patients treated with DEB-TACE following a strict selection (preserved liver function, absence of symptoms, extrahepatic spread or vascular invasion).Methods: We registered baseline characteristics, the development of treatment-related adverse events, and the overall survival of all HCC patients treated by DEB-TACE from February 2004 to June 2010.Results: One hundred and four patients were treated with DEB-TACE. All but one were cirrhotic, 62.5% HCV+, 95% Child-Pugh A, 41 BCLC-A and 63 BCLC-B. Causes of DEB-TACE treatment in BCLC-A patients were: 35 unfeasible ablation, and six post-treatment recurrences. After a median follow-up of 24.5months, 38 patients had died, two patients had received transplantation and 24 had received sorafenib because of untreatable tumour progression. Median survival of the cohort was 48.6months (95% CI: 36.9–61.2), while it was 54.2months in BCLC stage A and 47.7months in stage B. Median survival after censoring follow-up at time of transplant/sorafenib was 47.7 (95%CI: 37.9–57.5) months.Conclusions: These data validate the safety of DEB-TACE and show that the survival expectancy applying current selection criteria and technique is better than that previously reported. A 50% survival at 4years should be considered when suggesting treatment for patients fitting into controversial scenarios such as expanded criteria for transplantation/resection for multifocal HCC.

Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma

2012-02-06

Background & Aims: Transarterial chemoembolization (TACE) is an important palliative treatment for unresectable hepatocellular carcinoma (HCC), but TACE-induced ischemic injury can upregulate angiogenic factors and is associated with poor prognosis. The aim of this study was to evaluate the safety and efficacy of concurrent conventional TACE and sorafenib in patients with unresectable HCC.Methods: The primary objectives of this prospective, single-arm, phase II study were to evaluate safety and time to progression (TTP). Sorafenib was given 3days after TACE and was administered for up to 24weeks. Repeated TACE was performed on demand. Tumor response was assessed every 8weeks.Results: Fifty patients were treated and followed from July 2009 to May 2011. All patients were in Barcelona Clinic Liver Cancer (BCLC) stage B (82%) or C (18%). The median time of follow-up was 14.9months and a median of 1 TACE session was given (range, 1–4). The median dose intensity of sorafenib was 68.7% (range, 37.3–100) of 800mg daily. The most common reasons for dose reduction were hand–foot syndrome and thrombocytopenia. Thirty patients completed the study and 17 patients discontinued sorafenib due to disease progression. The overall median TTP was 7.1months (95% confidence interval (CI), 4.8–7.5months): 7.3months in BCLC stage B; 5.0months in BCLC stage C. The 6-month progression-free survival rate was 52% (95% CI, 37.3–66.1).Conclusions: Concurrent treatment of unresectable HCC with conventional TACE and sorafenib demonstrates a manageable safety profile and a possibility of promising efficacy.

Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib

2012-02-07

Background & Aims: Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer.Methods: Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in three liver cancer cell lines and a murine xenograft model.Results: Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and HDAC5 mRNAs was significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts.Conclusions: Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination.

Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease

2012-02-07

Background & Aims: Gestational alloimmune liver disease is the main cause of the neonatal hemochromatosis phenotype, wherein severe neonatal liver disease is associated with iron overload and extrahepatic tissue siderosis. How fetal liver disease produces extrahepatic siderosis is not known. We hypothesized that fetal liver injury causes deficient hepcidin production and poor regulation of placental iron flux. Under the resulting conditions of iron overload, the tissue pattern of extrahepatic siderosis is determined by the normal expression of proteins involved in the import of non-transferrin-bound iron and the export of cellular iron.Methods: Liver and extrahepatic tissues from infants with gestational alloimmune liver disease were examined and compared to normal age-appropriate tissues.Results: Serum iron indices indicate iron overload and excess non-transferrin bound iron in gestational alloimmune liver disease. The diseased liver showed significantly reduced hepcidin, hemojuvulin, and transferrin gene expression compared to the normal fetal and neonatal liver. Those extrahepatic tissues that are typically involved in pathological siderosis in neonatal hemochromatosis, whether from normal or diseased newborns, consistently expressed solute carrier family 39 (zinc transporter), member 14 (ZIP14) for non-transferrin-bound iron uptake and expressed little ferroportin for iron export.Conclusions: Excess non-transferrin-bound iron in gestational alloimmune liver disease may result from fetal liver injury that causes reduced synthesis of key iron regulatory and transport proteins. Whereas, the pattern of extrahepatic siderosis appears to be determined by the normal capacity of various tissues to import non-transferrin-bound iron and not export cellular iron.

IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease

2012-02-06

Background & Aims: Genetic background may affect liver damage in patients with non-alcoholic fatty liver disease (NAFLD). The main outcomes of the study were to assess whether IL28B rs12979860 and rs8099917 polymorphisms, together with PNPLA3 rs738409 C>G polymorphism, are associated with lobular inflammation and fibrosis, in NAFLD patients.Methods: One hundred sixty consecutive NAFLD patients were assessed by liver biopsy (Kleiner score); anthropometric, and biochemical and metabolic features were included. IL28B rs12979860 C>T, IL28B rs8099917 G>C, and PNPLA3 rs738409 C>G single nucleotide polymorphisms were tested.Results: Seventy-four (46.2%) patients had IL28B rs12979860 CC polymorphism, compared with 72 (45%) and 14 (8.8%) with TC and TT variants, respectively. PNPLA3 rs738409 CC polymorphism was present in 47 (29.4%) patients, compared with 79 (49.4%) and 34 (21.3%) with CG and GG variants, respectively. Multivariate logistic regression analysis showed that age (OR 1.043, 95% CI 1.012–1.075, p=0.007), triglycerides (OR 1.005, 95% CI 1.000–1.010, p=0.04), hyperuricemia (OR 5.027, 95% CI 1.839–13.742, p=0.002), IL28B rs12979860 TT/TC (OR 0.219, 95% CI 0.101–0.472, p<0.001), and steatosis grade (OR 1.704, 95% CI 1.048–2.773, p=0.03) were independently linked to moderate-severe lobular inflammation. Finally, IL28B rs12979860 CC was associated with severe fibrosis (F3–F4) on univariate analysis, even if only older age (OR 1.064, 95% CI 1.026–1.104, p=0.001), high HOMA (OR 1.213, 95% CI 1.068–1.377, p=0.003), and lobular inflammation (OR 3.181, 95% CI 1.438–7.036, p=0.004), remained associated in multivariate logistic regression analysis.Conclusions: In NAFLD patients, IL28B rs12979860 CC genotype, together with PNPLA3 rs738409 GG, is associated with the severity of liver damage.

Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers

2012-02-06

Background & Aims: The diagnosis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is limited by the need for liver biopsy. We aimed at testing the accuracy of cytokeratin-18 fragment (CK-18), adipocyte fatty acid binding protein (AFABP) and fibroblast growth factor 21 (FGF21) for the diagnosis of NAFLD and NASH.Methods: 146 patients with biopsy-proven NAFLD and 74 age- and gender-matched healthy controls were included. Serum CK-18, AFABP and FGF21 levels were determined by enzyme-linked immunosorbent assay.Results: Serum CK-18, AFABP, and FGF21 increased in a stepwise fashion in control subjects (median 103U/L, 15.4ng/ml, and 104pg/ml), patients with non-NASH NAFLD (263U/L, 18.9ng/ml, and 249pg/ml) and NASH (418U/L, 19.4ng/ml, and 354pg/ml) (p<0.001, 0.060, and 0.016, respectively). The area under receiver-operating characteristics curve to diagnose NAFLD and NASH was 0.91 and 0.70 for CK-18, 0.66 and 0.59 for AFABP, and 0.84 and 0.62 for FGF21. At cut-offs of 203 and 670U/L, CK-18 had 71% negative predictive value (NPV) and 77% positive predictive value (PPV) to exclude and diagnose NASH. A 2-step approach measuring CK-18 followed by FGF21 further improved the NPV to 74% and PPV to 82%. In a validation cohort of 51 patients with paired liver biopsies, the NPV and PPV of the 2-step approach were 67% and 78%, respectively.Conclusions: CK-18 is the most accurate biomarker for NAFLD and NASH. A two-step approach using CK-18 and FGF21 further improves the accuracy in diagnosing NASH.

Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma

Florie Borel, Pavlina Konstantinova, Peter L.M. Jansen — 2012-02-06

Summary: MicroRNAs (miRNAs) are evolutionary conserved small non-coding RNAs that regulate gene expression by mediating post-transcriptional silencing of target genes. Since miRNAs are involved in fine-tuning of physiological responses, they have become of interest for diagnosis and therapy of a number of diseases. Moreover, the role of dysregulated miRNAs in maintaining the malignant phenotype has profound implications for cancer therapy. We will review the best defined cellular miRNAs and changes in their expression profile in hepatocellular carcinoma (HCC). Cellular miRNAs can also be released into the circulation, and these miRNAs are detected in most body fluids. Circulating miRNAs are associated with HCC and are possible biomarkers. Finally, by affecting several clinically relevant targets, artificially increasing or decreasing the expression level of a given miRNA offers fascinating therapeutic perspectives. We will therefore highlight recent developments in miRNA-based gene therapy with a focus on their therapeutic potential for HCC.

Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

György Baffy, Elizabeth M. Brunt, Stephen H. Caldwell — 2012-02-13

Summary: Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.

Adult hepatoblastoma: Learning from children

Anne-Laure Rougemont, Valérie A. McLin, Christian Toso, Barbara E. Wildhaber — 2012-02-13

Summary: Hepatoblastoma is the most common malignant liver tumour in infants and young children. Its occurrence in the adult population is debated and has been questioned. The aim of this paper is to review the histological and clinical features of adult hepatoblastoma as described in the adult literature, and to compare the findings with those of paediatric hepatoblastoma. The developmental and molecular aspects of hepatoblastoma are reviewed and their potential contribution to diagnosis of adult hepatoblastoma discussed.Case reports of adult hepatoblastoma identified by a PubMed search of the English, French, German, Italian, and Spanish literature through March 2011 were reviewed.Forty-five cases of hepatoblastoma were collected. Age at presentation was variable. Survival was uniformly poor, except for the rare patients who presented with the relatively differentiated, foetal type. The common denominator between adult and paediatric cases is the occurrence of embryonal or immature aspect of the tumours. Whether the adult cases of hepatoblastoma represent blastemal tumours, stem cell tumours, or unusual differentiation patterns in otherwise more frequent adult liver tumours remains to be established. Adult tumours labelled as hepatoblastoma are characterised by malignant appearing mesenchymal components. Surgical management is the cornerstone of therapy in children and also appears to confer an improved prognosis in adults.Whether adult hepatoblastoma exists, remains controversial. Indeed, several features described in adult cases are markedly different from hepatoblastoma as it is understood in children, and other differential diagnoses should also be entertained. Nonetheless, hepatoblastoma should be considered in adults presenting with primary liver tumours in the absence of pre-existing liver disease. Adult and paediatric patients with immature hepatoblastoma appear to have worse outcomes, and adults presenting with presumed hepatoblastoma have an overall poorer prognosis than children with hepatoblastoma. In all patients, surgery should be the treatment of choice, neoadjuvant chemotherapy is advisable.

Futility and rationing in liver retransplantation: When and how can we say no?

Scott W. Biggins — 2012-02-06

Donor livers are a scarce, life-saving resource. For patients whose lives depend upon liver transplantation, the policies defining priority for donor livers are of ultimate importance. Fair and just utilization of available livers requires that policy makers understand how to balance the needs and interests of each of the stakeholders. Although significant medical and surgical advances have been made in the last three decades, many patients who undergo liver transplantation will eventually have early complications or recurrent liver disease resulting in failure of their transplanted liver graft. When this occurs, repeat liver transplantation is often the only definitive treatment. Unfortunately, retransplantation has lower graft survival rates than primary transplant (). Numerous prognostic models have been developed to aid clinical decision-making as to whether or not pursuit of retransplantation can be justified based on the estimated survival after retransplantation. The fundamental principles of medical ethics i.e. autonomy, non-malfeasance, beneficence, justice, and utility can further inform the rational application of prognostic models to retransplantation. Yet, to do so, will require a blunt and frank dialogue, within our transplant community and society at large, about the concepts of futility and rationing.

At the cancer steering wheel: Defining key genomic drivers of liver cancer with next generation sequencing

Anuradha Budhu, Xin Wei Wang — 2012-01-27

COMMENTARY ON: Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA, Pawlik TM, Daniel HD, Kannangai R, Offerhaus GJ, Velculescu VE, Wang L, Zhou S, Vogelstein B, Hruban RH, Papadopoulos N, Cai J, Torbenson MS, Kinzler KW. Nat Genet. August 7 2011;43(9):828–9. doi:10.1038/ng.903. Copyright (2011). Abstract reprinted with permission from Macmillan Publishers Ltd.

Genetic testing for hepatocellular carcinoma: An ambitious goal still to achieve

Enrico Galmozzi, Massimo Colombo — 2012-01-27

COMMENTARY ON: A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL, Yamada S, Sninsky JJ, O’Brien TR, Dienstag JL, Tanabe KK, Chung RT; HALT-C Trial Group. Gastroenterology. July 2011;141(1):141–9. Copyright (2011). Abstract reprinted with permission from the American Gastroenterological Association.

Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution

Prakash Ramachandran, John P. Iredale — 2012-02-06

Hepatic fibrosis is the common end point to chronic injury of varied aetiology. There is now excellent evidence in both human studies and animal models that liver fibrosis is a bidirectional process with a significant reversible component. The hepatic stellate cell (HSC), following activation to a myofibroblast phenotype, is the principal cell producing extracellular matrix (ECM) during fibrogenesis and is the main source of TIMP-1, which inhibits the endogenous matrix-degrading activity of matrix metalloproteinases (MMPs), thus promoting scar deposition. Furthermore, apoptosis of activated HSCs is a critical feature of scar resolution. However, emerging evidence indicates that it is the hepatic macrophage that is the master regulator of this dynamic fibrogenesis–fibrosis resolution paradigm.

Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept

Georgios Germanidis, Prodromos Hytiroglou, Marina Zakalka, Loukas Settas — 2011-11-28

Abatacept is a biologic response modifier that is used in the treatment of refractory rheumatoid arthritis. This agent is not known to be associated with reactivation of hepatitis B virus (HBV) infection . We report a patient with occult HBV infection, who developed severe hepatitis B following treatment with abatacept.

Post-liver transplantation graft biopsies should not be used to assess the IL28B donor genotype in HCV recipients

Maria Francesca Donato, Enrico Galmozzi, Cristina Rigamonti, Alessio Aghemo — 2012-01-27

We read with interest the article by Coto-Llerena et al. showing that the determination of the donor interleukin 28B (IL28B) genotype on post-liver transplantation (LT) graft biopsies carries a high risk of misclassification, as it adds to the current debate on the clinical role of this test in LT patients. Indeed, following LT it is still somewhat unclear whether the donor, the recipient or the combination of the two IL28B genotypes is actually associated with the achievement of a sustained virological response (SVR) after interferon (IFN)-based treatment in HCV patients . Clearing this matter would have important clinical implications, especially since IL28B genotyping of the recipient can be easily performed by DNA extraction from the blood, while on the other hand, given that donor blood is not always routinely available for clinical use, donor DNA needs to be extracted from formalin-fixed paraffin embedded (FFPE) liver tissue specimens obtained before, during or after LT. Although this is feasible from a technical standpoint, no study has shown whether the IL28B genotype obtained matches that obtained from peripheral blood mononuclear cells (PBMC). For this matter, the authors analyzed the IL28B rs12979860 donor genotype, by TaqMan real-time PCR and direct sequencing, in 56 HCV-infected LT recipients and their donors, in PBMCs and/or liver biopsies obtained at the moment of LT (reperfusion) or at any time during post-transplant follow-up. Overall, IL28B rs12979860 genotyping was successful in up to 98% of samples. The authors report a 100% match in IL28B genotype between donor PBMC and reperfusion biopsies in 36 out of 56 patients studied, while, they found a high rate of discordant results between IL28B genotype in donor PBMC or reperfusion liver biopsies compared to post-transplant liver biopsy specimens. To externally validate these findings, we analyzed the IL28B genotype of 39 liver donors by comparing DNA extracted from donor PBMC and FFPE or snap frozen post-transplant follow-up liver biopsies. IL28B rs12979860 genotyping was performed by TaqMan real-time PCR, and confirmed by Tetra-primers Amplification Refractory Mutation System (T-ARMS) PCR . As shown in , we replicate Coto-Llerena’s findings, since overall in 39% of cases there was a mismatch between IL28B genotype obtained in PBMCs and post-LT liver biopsies. Moreover, similar mismatch rates were found when IL28B genotype was tested from DNA extracted from snap frozen or FFPE follow-up liver biopsies (36% vs. 45%, p=0.55). Our data therefore show that, independently from the source used to extract DNA, the use of follow-up biopsies should be discouraged as a routine test to determine donor IL28B genotype due to an extremely high mismatch rate.

Network-based discovery of gene signature for vascular invasion prediction in HCC

Wei Liu, Fuchu He, Ying Jiang — 2012-02-06

We read with great interest the paper by Minguez and colleagues . In this study, the authors successfully defined a 35-gene signature of vascular invasion (VI) by gene expression profiling of HCV-related hepatocellular carcinoma (HCC) samples, and validated this gene panel in an independent mixed cohort of patients with various etiologies, including HBV, HCV, and alcohol. It is already known that VI can predict recurrence and survival in HCC patients after tumor resection or liver transplantation . The signature may be of help during candidate selection for liver transplantation, and as a guide to therapeutic intervention.

Reply to: “Network-based discovery of gene signature for vascular invasion prediction in HCC”

Beatriz Mínguez, Daniela Sia, Josep María Llovet — 2012-02-07

Liu and colleagues raise some issues regarding our recently published study to which we would like to make the following comments. We acknowledge the limitations that a gene-expression-based biomarker could have, and that our signature is not unique. Certainly, previous attempts to find such a signature have been published in the past . We also know that, as in other gene expression studies, potential bias could occur. In fact, reported prognostic signatures are often not reproducible, in most of the cases due to suboptimal study design, small sample sizes, and also because many of them have been based on retrospectively collected tissue samples . Even after taking into account these sources of bias or inconsistencies, it so happens that only a small minority of the reported signatures truly retain prognostic significance. In fact, our recent outcome analysis including 22 gene signatures with prognostic significance in HCC (18 from the tumor, and four from the non-tumoral adjacent tissue) showed that only two signatures retained independent prognostic value .

Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: Why is it different?

Guohong Cai, Ya Liu, Wen Yin — 2012-01-09

HBV is a major cause of acute and chronic liver infection, and can lead to hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) , which is the fifth most common cancer and the third leading cause of cancer death worldwide. More than 80% of HCC patients are in developing countries, especially in Southeast Asia and sub-Saharan Africa. However, the incidence of HCC has been rising in Western countries in recent years . The current standard of care and therapy for patients with advanced HCC are not satisfactory. Surgical resection or liver transplantation remains the most effective treatment options for HCC, but few patients are fortunate to get the treatment, for all kinds of reasons. Therefore, the analysis of the molecular mechanisms of oncogenesis is badly needed to uncover novel targets for specific systemic therapy and to discover novel biomarkers for early diagnosis of HCC.

Reply to: “Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: Why is it different?”

Chun-Ming Wong, Irene Oi-Lin Ng — 2012-01-09

Yin et al. drew attention to the differences between the findings on miR-221, miR-21 and miR-122 deregulation in hepatocarcinogenesis reported in our recent study and others . Yin et al. further speculated that the inconsistence of the findings among these reports might be due to different risk factors for HCC and called for further investigations on this subject.

Is a liver biopsy necessary in alcoholic hepatitis?

Ewan H. Forrest, Dermot Gleeson — 2012-02-06

The paper by Mookerjee et al. allowed a fascinating insight into the prognostic relevance of the systemic inflammatory response (SIRS) in decompensated alcoholic liver disease (ALD), especially the presence of alcoholic steatohepatitis (ASH) . However, the paper makes some assertions which require further discussion.

Reply to: “Is a liver biopsy necessary in alcoholic hepatitis?”

Rajeshwar P. Mookerjee, Rajiv Jalan — 2012-02-29

We thank Drs. Forrest and Gleeson for their interest in our paper . Their letter makes two points; one clinical and the other logistical, which will be addressed in turn. Our study describes the value of early liver biopsy (between days 1 and 7 from admission) in patients presenting with acute decompensation of cirrhosis. As correctly identified by Forrest and Gleeson, only biopsies taken early in the admission are valuable in interpreting the cause of decompensation. However, we beg to differ with them on the relative importance placed on hyperbilirubinaemia as a key feature of ASH versus other causes of decompensated alcoholic liver disease. Indeed, in the paper they cite by Katoonizadeh et al. , patients with acute-on-chronic liver failure (ACLF) presenting with hyperbilirubinaemia had most commonly sepsis with high SIRS, confirmed by ductular bilirubinostasis, which was also an independent prognostic factor. In our series, mean bilirubin values of 227μmol/L in heavy drinkers with onset of jaundice less than 1month from the acute admission fits with other studies addressing diagnostic criteria in ASH . However, 50% of patients with high SIRS had no significant histological features of ASH using the grading system we describe and yet sepsis related mortality was higher in these patients with their biopsies showing significant cholestasis. Thus, high bilirubin cannot distinguish infection from the hepatic inflammation of ASH in decompensated cirrhosis and their respective management is completely different.

Erratum to: “EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma” [J Hepatol 2012;56:908–943]

2012-04-09

was incomplete for BCLC stage A, and it has been corrected as per below. Patients at BCLC stage A and single tumors can be evaluated for surgical resection.

EASL Clinical School of Hepatology Course 19: Liver Transplantation and Acute Liver Failure, London 2012

2012-06-01

Journal of Hepatology

Editorial Board

EASL Monothematic Conference: HIV and the Liver, London, December 2012

EASL Short-Term Fellowship Application

EASL iLiver app for iPhone & iPad

EASL Monothematic Conference: Vascular Liver Diseases, Tallinn, June 2012

EASL-AASLD Special Conference: Therapy of Hepatitis C, Clinical application & drug development, Prague, September 2012

Contents

The International Liver Congress™ by EASL, Amsterdam 2013

Focus: Long-term treatment with lamivudine in HBeAg negative patients with chronic hepatitis B: To switch or not to switch?

Gut microbiome and intestinal barrier failure – The “Achilles heel” in hepatology?

TACE with or without systemic therapy?

Control of iron metabolism – Lessons from neonatal hemochromatosis

A predictive model of treatment outcome in patients with chronic HCV infection using IL28B and PD-1 genotyping

Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis

Antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6: TMC435-C202, a phase IIa, open-label study

HBV DNA suppression and HBsAg clearance in HBeAg negative chronic hepatitis B patients on lamivudine therapy for over 5years

Lack of TGF-β production by hepatitis C virus-specific T cells during HCV acute phase is associated with HCV clearance in HIV coinfection

Decreased infectivity of nucleoside analogs-resistant hepatitis B virus mutants

Refined prediction of week 12 response and SVR based on week 4 response in HCV genotype 1 patients treated with peginterferon alfa-2a (40KD) and ribavirin

Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease

Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: A randomized study

C-Reactive protein predicts short-term mortality in patients with cirrhosis

The effect of steroid pretreatment of deceased organ donors on liver allograft function: A blinded randomized placebo-controlled trial

Comparison of two non-contemporaneous HCV-liver transplant cohorts: Strategies to improve the efficacy of antiviral therapy

Non-invasive diagnosis of hepatocellular carcinoma ⩽2cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI

Role of the routine use of chest computed tomography and bone scan in staging workup of hepatocellular carcinoma

Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design

Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma

Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib

Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease

IL28B and PNPLA3 polymorphisms affect histological liver damage in patients with non-alcoholic fatty liver disease

Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers

Diagnostic and therapeutic potential of miRNA signatures in patients with hepatocellular carcinoma

Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

Adult hepatoblastoma: Learning from children

Futility and rationing in liver retransplantation: When and how can we say no?

At the cancer steering wheel: Defining key genomic drivers of liver cancer with next generation sequencing

Genetic testing for hepatocellular carcinoma: An ambitious goal still to achieve

Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution

Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept

Post-liver transplantation graft biopsies should not be used to assess the IL28B donor genotype in HCV recipients

Network-based discovery of gene signature for vascular invasion prediction in HCC

Reply to: “Network-based discovery of gene signature for vascular invasion prediction in HCC”

Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: Why is it different?

Reply to: “Deregulation of microRNAs expression occurs in stages of multistep hepatocarcinogenesis: Why is it different?”

Is a liver biopsy necessary in alcoholic hepatitis?

Reply to: “Is a liver biopsy necessary in alcoholic hepatitis?”

Erratum to: “EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma” [J Hepatol 2012;56:908–943]

EASL Clinical School of Hepatology Course 19: Liver Transplantation and Acute Liver Failure, London 2012