Journal of Hepatology - Articles in Press

Erratum to: “Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients responding to 24 weeks peginterferon/ribavirin” [J Hepatol 2012;56:34–44] - Uncorrected Proof

2012-02-21

of our recently published manuscript entitled “Interleukin-28B genetic variants in identification of hepatitis C virus genotype 1 patients responding to 24weeks peginterferon/ribavirin” was incorrectly typed. In contrast to Fig. 1, it should read RVR(−) cases rather than RVR(+) and should be amended as follows: RVR(+)→RVR(−); RVR(+)+LVL→RVR(−)+LVL; RVR(+)+HVL→RVR(−)+HVL.

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

2012-02-17

Abstract: Background & Aims: In long-term responder patients, it is unclear if 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: 191 patients with chronic HBeAg-negative hepatitis B successfully treated with LAM monotherapy for at least 5 years were included. Biochemical and virological tests were assessed every 3 months in all patients and HBsAg quantification was performed in 45/191. Reverse-transcriptase (RT) region was directly sequenced in virological breakthrough patients.Results: 191 patients (148 males, median age 53 years, 72 with compensated cirrhosis) responding to 60-month-LAM monotherapy continued receiving LAM monotherapy beyond the initial 5 years 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 emphasizing the importance of a careful virological monitoring.

Sorafenib Prolongs Survival, but what Happens to the Symptoms? - Accepted Manuscript

Bruno M. Strebel — 2012-02-15

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

2012-02-13

Abstract: 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 < 50 IU/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.Conclusion: IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant anti-viral/anti-proliferative 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.

The therapeutic effect of histone deacetylase inhibitor PCI-24781 on gallbladder carcinoma in BK5.erbB2 mice - Accepted Manuscript

2012-02-13

Abstract: Background & Aims: Gallbladder carcinoma (GBCa), a type of biliary tract cancer (BTC), has proven challenging to treat demonstrating the need for more effective therapeutic strategies. In our current study, we examined the therapeutic effects of the histone deacetylase (HDAC) inhibitor PCI-2478 against GBCa that developed in BK5.erbB2 mice.Methods: PCI-24781 [50 mg/kg/day] and control solution were delivered to BK5.erbB2 mice for four weeks. The therapeutic effect of PCI-24781 was evaluated via ultrasound biomicroscopy (USBM) throughout the experiment and histological analyses at the end of the experiment. To investigate potential mechanisms for the therapeutic effects of PCI-24781 on GBCa in BK5.erbB2 mice, PCI-24781-treated gallbladders were subjected to Western blot and RT-PCR analysis. The inhibitory effect of PCI-24781 on the growth of BTC cells was compared to the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and gemcitabine. To study the role of miRNAs in GBCa tumorigenesis, the expression profile of 368 miRNAs in GBCas from BK5.erbB2 (both treated and untreated) and wild-type mice was analyzed.Results: Treatment of BK5.erbB2 mice with PCI-24781 for one month prevented 79% of GBCa cases from progression and showed a clinical effect in 47% of cases. We also confirmed a potent inhibitory effect on tumor cell growth in human BTC cell lines treated with PCI-24781. This effect was associated with down-regulation of erbB2 mRNA and erbB2 protein/activity and up-regulation of acetylated histone and acetylated tubulin. Treatment with PCI-24781 resulted in decreased expression of Muc4, an intramembrane ligand for erbB2, in BTC cells. PCI-24781 had more effect on inhibiting growth of BTC cells than SAHA. In addition, PCI-24781 effectively inhibited the growth of gemcitabine-resistant cells. MiRNA profiling revealed that the expression of several miRNAs were significantly altered in GBCa in the BK5.erbB2 mouse compared to normal gallbladder, including up-regulated miR21, which was down-regulated by PCI-24781.Conclusion: These results indicate that PCI-24781 potently inhibits the growth of BTC cells by decreasing erbB2 expression and activity as well as regulating altered miRNA expression. PCI-24781 may have potential value as a novel chemotherapeutic agent against human BTC in which erbB2 is overexpressed.

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

2012-02-13

Abstract: Background & Aims: Intestinal dysbiosis and bacterial translocation is 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 Firmicutesand 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.

The Effect of Steroid Pretreatment of Deceased Organ Donors on Liver Allograft Function: A Blinded Randomized Placebo Controlled Trial - Accepted Manuscript

2012-02-13

Abstract: Background: Brain death associated inflammatory response contributes to increased risk of impaired early liver allograft function, which might be counter balanced by steroid pre-treatment of the organ donor.Aim: The aim of this randomized controlled trial was to elucidate whether steroid pretreatment of liver donors improves early liver allograft function and 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 six hours before recovery of organs. The primary endpoint was the concentration slope of transaminases within the first week. The secondary end point included survival and biopsy confirmed acute rejection (BCAR) within three 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 thirteen in the placebo group within three years after engraftment (RR=0.63 95%CI [0.29, 1.36], p=0.31). Eleven recipients experienced 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.Conclusion: Steroid pre-treatment of organ donors did not improve outcomes after liver transplantation. (controlled-trials.com number ISRCTN78828338)

Hepatocellular carcinoma in nonalcoholic fatty liver disease: An emerging menace - Accepted Manuscript

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

Abstract: 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 noncirrhotic 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 the 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.

Lack of TGFβ Production by Hepatitis C Virus-Specific T Cells during HCV Acute Phase is Associated with HCV Clearance in HIV co-infection - Accepted Manuscript

2012-02-13

Abstract: Background & Aims: Immunity and genetic factors govern recovery from acute hepatitis C virus (HCV) infection. No predictive factors have yet been identified in patients coinfected with the human immunodeficiency virus (HIV). We investigated whether early T cell responses to HCV producing transforming-growth-factor beta (TGFβ) 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 analyzed peripheral HCV-specific TGFβ-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 15 months 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 TGFβ-producing CD4+ and/or CD8+ T cells were detected in 8/24 (33%) patients. Lack of anti-HCV TGFβ+ cells was characteristic of healthy donors and Group A, except in 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 TGFβ+ cells was associated with persistent viremia in 6/8 cases (p=0.005). This profile remained stable over time. Such TGFβ 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 TGFβ-producing T cells are a new marker independent of the IL-28B gene polymorphism, predicting the lack of spontaneous or therapeutic HCV clearance.

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

2012-02-13

Abstract: 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 to 6.Methods: The study consisted of 7 days of monotherapy with TMC435 (200 mg 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 endpoint at Day 8, the mean (±standard error) change in plasma HCV ribonucleic acid (log10 IU/mL) from baseline was 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.

Adult hepatoblastoma: Learning from children - Accepted Manuscript

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

Summary: Background & Aims: 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 diagnosing adult hepatoblastoma discussed.Methods: Case reports of adult hepatoblastoma identified by a PubMed search of the English, French, German, Italian, and Spanish literature through March 2011 were reviewed.Results: Forty-five cases of hepatoblastoma were collected. Age at presentation was variable. Survival was uniformely 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 characterized by malignant appearing mesenchymal components. Surgical management is the cornerstone of therapy in children and also appears to confer an improved prognosis in adults.Conclusion: 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.

Authors Response - Accepted Manuscript

Uzma Asghar, Tim Meyer — 2012-02-10

Do EASL and mRECIST responses have independent effects on survival in hepatocellular carcinoma patients treated with transarterial embolization? - Accepted Manuscript

Weijuan Wang, Yan Zhao, Guohong Han, Daiming Fan — 2012-02-10

A Predictive Model of Treatment Outcome in Patients with Chronic HCV Infection Using IL-28B and PD-1 Genotyping - Accepted Manuscript

2012-02-09

Abstract: Background& aims: The arrival 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 (IL-28B 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 IL-28B polymorphisms, Killer immunoglobulin-like receptors (KIR) and HLA genes. A multivariate logistic regression analysis and a 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, IL-28B C/C genotype was the most significant factor predicting a SVR to treatment in all HCV genotypes (74.5%). In IL-28B C/C patients, the presence of PD-1.3/A allele increased the probability for a SVR to 93.3%. Moreover, when this analysis was made only with patients infected by HCV-1, the predictive value of IL-28B 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 IL-28B C/C genotype. Both markers in conjunction could be a useful tool, more relevant in some cases than HCV genotype in clinical practice.

Mechanistic biomarkers in acute liver injury: Are we there yet? - Uncorrected Proof

Danielle Adebayo, Rajeshwar P. Mookerjee, Rajiv Jalan — 2012-02-09

Although the outcome of acute liver failure (ALF) has improved due to developments in the general intensive care techniques, mortality rates without transplantation in patients who fulfil poor prognostic criteria are still in excess of 80%. Besides N-acetylcysteine, there are no specific treatment options for ALF that occurs on the background of acetaminophen (APAP) toxicity. Also, strategies to limit progression of acute liver injury in patients who are progressing to ALF remain an unmet need. Further difficulties in the management of patients with ALF are the lack of biomarkers that may indicate progression of liver failure early as decision making regarding listing for transplantation in patients with ALF is challenging. At present, the criteria that are used to list patients for urgent transplantation lack sensitivity . Therefore, the paper by Antoine and colleagues in the present issue of the Journal is welcome as it starts to address these two areas of unmet need.

EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolisation - Accepted Manuscript

Tim Meyer, Amy Kirkwood, Roopinder Gillmore — 2012-02-09

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

2012-02-07

Abstract: 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 larger 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 8 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 3 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.Conclusion: 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.

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

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 five 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 - Accepted Manuscript

2012-02-07

Abstract: 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 in comparison to normal age-appropriate tissues.Results: Serum iron indices indicate iron overload and excess non-transferrin bound iron in gestational alloimmune liver disease. Diseased liver showed significantly reduced hepcidin, hemojuvulin, and transferrin gene expression compared to normal fetal and neonatal liver. Those extrahepatic tissues that are typically involved with 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 normal capacity of various tissues to import non-transferrin-bound iron and not export cellular iron.

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

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.

Focus - Uncorrected Proof

Scott L. Friedman — 2012-02-07

A silent partner no longer – Sinusoidal endothelial cells in liver homeostasis and disease A study in this month’s issue of the Journal illustrates the growing appreciation for how non-parenchymal cells – in this case liver sinusoidal endothelial cells – contribute to disease. The term ‘non-parenchymal cells’ refers not only to endothelial cells and macrophages, but also to hepatic stellate cells and a host of resident lymphocytes and immune cells within the liver, which collectively comprise approximately 40% of the total number of liver cells. Stellate cells have garnered most of our attention in the past decade because of their major contribution to fibrogenesis, and because of ready methods to isolate and characterize the cells. Moreover, stellate cells love to grow in culture and thus even mixed non-parenchymal cell cultures invariably become dominated by stellate cells when plated in the presence of serum. Macrophages, which in liver have been traditionally called “Kupffer cells” based on the late 19th Century description by Kupffer , are also well appreciated. Moreover, we have adopted an increasingly nuanced understanding of their heterogeneity and divergent functions as a result of the identification of many cell surface markers, and advances in flow cytometry methods .

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

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 at finding 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 .

Diagnostic and Therapeutic Potential of miRNA Signatures in Patients with Hepatocellular Carcinoma - Accepted Manuscript

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

Abstract: 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.

Futility and Rationing in Liver Retransplantation: When and How Can We Say No? - Accepted Manuscript

Scott W. Biggins — 2012-02-06

Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution - Uncorrected Proof

P. 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.

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

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.

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

2012-02-06

Abstract: Background & Aims: The diagnosis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is limited by the need for liver biopsy. We aimed to test 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 103 U/L, 15.4 ng/ml and 104 pg/ml), patients with non-NASH NAFLD (263 U/L, 18.9 ng/ml and 249pg/ml) and NASH (418 U/L, 19.4 ng/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 cutoffs of 203 and 670 U/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.

Non-Invasive Diagnosis of Hepatocellular Carcinoma ⩽ 2 cm in Cirrhosis. Diagnostic accuracy Assessing Fat, Capsule and Signal Intensity at Dynamic MRI - Accepted Manuscript

2012-02-06

Abstract: Backgroundand aims: To prospectively assess the diagnostic accuracy of the incorporation of additional MRI parameters to those based on contrast enhancement pattern for the diagnosis of solitary nodules between 5-20 mm 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 5-20 mm in diameter by screening 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 58.2 and 96.4%, respectively. Capsule was present in 45 HCC and in 2 non-HCC lesions. Intralesional fat was detected in 24 nodules; 5 nodules were non-HCC. Finally, the presence of capsule and fat was present 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 in the contrast enhancement pattern, while other characteristics at MRI do not increase the diagnostic accuracy.

Decreased infectivity of nucleoside analogs-resistant hepatitis B virus mutants - Accepted Manuscript

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

Abstract: 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 pseudoparticles 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.Conclusion: Based on this study, we found that envelope substitutions modulate viral protein expression, HDV coating and viral infectivity. These envelope modifications provide novel insight regarding the features of emerging HBV variants during antiviral therapies and suggest that such mutants are less prone to transmission than their WT counterpart.

Phase II study of concurrent transarterial chemoembolization and sorafenib for patients with unresectable hepatocellular carcinoma - Uncorrected Proof

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.

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 - Accepted Manuscript

2012-02-06

Abstract: Background: 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 analysed from two studies in which treatment-naive patients received peginterferon alfa-2a (40KD) 180μg/week plus ribavirin 1000/1200mg/day for 48 weeks. 558 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; per category, the proportion of patients with undetectable HCV RNA at week 12 was calculated and of these, the proportion with an SVR.Results: Overall, 88% of RVR patients and 43% 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 ⩾3log10, ⩾2log10, ⩾1log10, or <1log10 drop to week 4. In patients HCV RNA positive at week 4, SVR rates were 67% for those negative at week 12 versus 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 ⩾3log10 drop in HCV RNA at week 4 have a high probability of achieving an SVR.

Is a Liver Biopsy Necessary in Alcoholic Hepatitis? - Accepted Manuscript

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

A Phase 1, Randomized, Placebo-Controlled, Three-Day, Dose-Ranging Study of GS-5885, an NS5A Inhibitor, in Patients with Genotype 1 Hepatitis C - Accepted Manuscript

2012-02-06

Abstract: Background & Aims: GS-5885 is an inhibitor of the hepatitis C virus (HCV) NS5A protein and exhibits potent suppression of genotype 1 HCV replicons. The safety, tolerability, pharmacokinetics, antiviral activity, and resistance profile of once-daily GS-5885 doses of 1-90 mg were evaluated in patients with chronic genotype 1 HCV.Methods: Genotype 1 HCV-infected patients were randomized to 3 days of once-daily (QD) dosing with placebo (n=12) or GS-5885 1 mg (n=10), 3 mg (n=10), 10 mg (n=20), 30 mg (n=10), or 90 mg (n=10). Plasma samples for pharmacokinetics, HCV RNA, and NS5A sequencing were collected through Day 14.Results: GS-5885 was well tolerated and resulted in median maximal reductions in HCV RNA ranging from 2.3 log10 IU/mL (1 mg QD) to 3.3 log10 IU/mL (10 mg QD in genotype 1b and 30 mg QD). Emax modeling indicated GS-5885 30 mg was associated with >95% of maximal antiviral response to HCV genotype 1a. HCV RNA reductions were generally more sustained among patients with genotype 1b versus 1a. Three of 60 patients had a reduced response and harbored NS5A-resistant virus at baseline. NS5A sequencing identified residues 30 and 31 in genotype 1a, and 93 in genotype 1b as the predominant sites of mutation following GS-5885 dosing. Plasma pharmacokinetics were consistent with QD dosing.Conclusions: During 3 days of monotherapy, low doses of GS-5885 demonstrated significant antiviral activity in genotype 1a and 1b HCV-infected patients. GS-5885 is currently being evaluated in combination direct antiviral regimens with and without peginterferon.

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

2012-02-06

Abstract: Background & Aims: We aimed to improve 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: 148 consecutive cirrhotic patients with Child-Pugh score⩾B8 and without hepatocellular carcinoma were prospectively included and followed for 182 days. The primary endpoint 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%. CRP range was 1-240 mg/L (median 25mg/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). 42 patients died within the first 6 months of follow-up. Short-term mortality was associated with extrahepatic comorbidities (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). Of 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 comorbidities (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 3 variables taken together for predicting death was 0.80 (AUROC).Conclusion: In Child-Pugh score⩾B8 cirrhotic patients, persistent CRP levels⩾29mg/L predicted short-term mortality independently of age, MELD, and comorbidities, and better than infection or clinically-assessed SIRS.

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

2012-02-06

Abstract: Background & aims: In a previous study, advanced fibrosis was associated with worsening efficacy of antiviral therapy in HCV-transplant patients. We aimed to assess 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 2 non-contemporaneous cohorts of post-LT naïve patients treated with pIFN-RBV: Group 1 (n=44), a historical cohort of patients treated in 2005-07 and Group 2 (n=70), patients treated more recently (2007-10), 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.

IL28B and PNPLA3 Polymorphisms Affect Histological Liver Damage in Patients with Non-alcoholic Fatty Liver Disease - Accepted Manuscript

2012-02-06

Abstract: Background and 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 rs 12979860 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 rs 12979860 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 rs 12979860 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 on multivariate logistic regression analysis.Conclusions: In NAFLD patients, IL28B rs 12979860 CC genotype, together with PNPLA3 rs738409 GG, is associated with the severity of liver damage.

Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolization (TACE) using DCBeads. Implications for clinical practice and trial design - Accepted Manuscript

2012-02-06

Abstract: Background: TACE improves survival of properly selected HCC patients. 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.Aim: 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).Patients/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/June 2010.Results: 104 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, 6 post-treatment recurrences. After a median follow up of 24.5 months, 38 patients had died, two patients had received transplantation and 24 sorafenib because of untreatable tumour progression. Median survival of the cohort was 48.6 months (95%CI: 36.9-61.2), while it was 54.2 months in BCLC stage A and 47.7 months in stage B. Median survival after censoring follow-up at the time of transplant/sorafenib was 47.7 (95%CI: 37.9-57.5) months.Conclusion: These data validate the safety of DEB-TACE and expose that the survival expectancy applying current selection criteria and technique is better than that previously reported. A 50% survival at 4 years should be considered when suggesting treatment for patients fitting into controversial scenarios such as expanded criteria for transplantation/resection for multifocal HCC.

TACE treatment in hepatocellular carcinoma: what should we do now? - Accepted Manuscript

2012-01-27

Genetic testing for hepatocellular carcinoma: an ambitious goal still to achieve - Accepted Manuscript

Enrico Galmozzi, Massimo Colombo — 2012-01-27

Liver transplantation for severe alcoholic hepatitis saves lives - Accepted Manuscript

Andrew K. Burroughs — 2012-01-27

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

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.

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

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

Molecular epidemiology in HCV-related hepatocellular carcinoma: first steps - Accepted Manuscript

Augusto Villanueva, Xavier Forns, Josep M. Llovet — 2012-01-25

Abstract: Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, P(combined) = 1.27 × 10(-13), odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 × 10(-14), odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection.

The option of HBIG-free prophylaxis against recurrent HBV - Uncorrected Proof

Alyson N. Fox, Norah A. Terrault — 2012-01-23

Since the early 1990’s, hepatitis B immune globulin (HBIG) has been central to the prevention of hepatitis B virus (HBV) recurrence after liver transplantation. When used in combination with oral nucleos(t)ide analogues, HBIG prevents reinfection with HBV in ⩾90% of transplant recipients. While HBIG is highly efficacious, its use is undermined by its high cost. Because of this limitation, there have been many studies of alternative regimens seeking to minimize the dose or duration of HBIG without sacrificing low HBV recurrence rates. Toward that goal, lower dose intramuscular HBIG in combination with oral nucleos(t)ide analogues has been shown to be highly efficacious in preventing disease recurrence and represents a significant cost savings when compared with high dose intravenous administration. The withdrawal of HBIG after a defined course of combination HBIG and oral antivirals has also been shown to be effective, particularly if combination antiviral therapy is used. The ability to achieve undetectable HBV DNA levels pre-transplantation in the majority of patients may contribute to the high efficacy of these HBIG “light” regimens. Additionally, the success of antiviral rescue therapy for those patients who fail prophylaxis and develop recurrent HBV infection post-transplant has provided the impetus to move increasingly towards HBIG-free approaches. New techniques to detect occult HBV in hepatic and extrahepatic sites may allow clinicians to define a subgroup of patients in whom withdrawal of HBIG or all prophylaxis may be applicable.

Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression - Uncorrected Proof

2012-01-18

Background & Aims: Superimposed infection and/or inflammation precipitate renal failure in cirrhosis. This study aimed at testing the hypothesis that increased gut bacterial translocation in cirrhosis primes the kidney to the effect of superimposed inflammation by upregulating expression of Toll-like receptor 4 (TLR4), NFκB, and cytokines. A well-characterized bile-duct ligated (BDL) model of cirrhosis, which develops renal failure following superimposed inflammatory insult with LPS, was used and selective gut decontamination was performed using norfloxacin.Methods: Sprague–Dawley rats were studied: Sham, Sham+LPS; BDL, BDL+LPS; an additional BDL and BDL+LPS groups were selectively decontaminated with norfloxacin. Plasma biochemistry, plasma renin activity (PRA) and cytokines and, protein expression of TLR4, NFκB, and cytokines were measured in the kidney homogenate. The kidneys were stained for TLR4, TLR2, and caspase-3. Endotoxemia was measured using neutrophil burst and LAL assays.Results: The groups treated with norfloxacin showed significant attenuation in the increase in plasma creatinine, plasma and renal TNFα and renal tubular injury on histology. The increased renal protein expression of TLR4, NFκB, and caspase-3 in the untreated animals was significantly attenuated in the norfloxacin treated animals. PRA was reduced in the treated animals and severity of endotoxemia was reduced.Conclusions: The results show for the first time that the kidneys in cirrhosis show an increased expression of TLR4, NFκB, and the pro-inflammatory cytokine TNFα, which makes them susceptible to a further inflammatory insult. This increased susceptibility to LPS can be prevented with selective decontamination, providing novel insights into the pathophysiology of renal failure in cirrhosis.

A novel biliary stent loaded with 125I seeds in patients with malignant biliary obstruction: Preliminary results versus a conventional biliary stent - Corrected Proof

2012-01-18

Background & Aims: Stenting is a palliative therapy method for relieving malignant biliary obstruction. The aim of this study was to evaluate the safety and effectiveness of an irradiation stent compared to a conventional biliary stent in patients with biliary obstruction caused by both primary and metastatic adenocarcinomas.Methods: Participants were randomly assigned to receive treatment with a biliary irradiation stent (irradiation stent group) or a conventional biliary stent (control group). After stent implantation, the outcomes were measured in terms of relief of obstructive jaundice, survival time, complications related to the procedure. A p value of less than 0.05 indicated a significant difference.Results: The stents were successfully placed in all the 23 patients. The obstructive jaundice was relieved in all patients except three in the control group. The median and mean overall survivals in the irradiation stent group were higher than those in the control group (7.40months versus 2.50months, 8.03months versus 3.36months, p=0.006). The patients with stent patent at 3, 6, and 12months in the irradiation stent group were 11 (91.7%), 7 (58.3%), and 1 (8.3%), respectively. While in the control group, 4 (36.4%), 1 (9.1%), and 0 (0%), respectively. There were no significant differences in the complications related to stent insertion between the two groups.Conclusions: This interim analysis shows that treatment with the biliary intraluminal irradiation stent in patients with biliary obstruction caused by adenocarcinomas appears safe and technically feasible, has benefits in relieving jaundice, and seems to extend survival when compared to a conventional biliary stent.

Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity - Corrected Proof

2012-01-18

Background & Aims: Full length keratin-18 (FL-K18) and High Mobility Group Box-1 (HMGB1) represent circulating indicators of necrosis during acetaminophen (APAP) hepatotoxicity in vivo. In addition, the caspase-cleaved fragment of K18 (cK18) and hyper-acetylated HMGB1 represent serum indicators of apoptosis and immune cell activation, respectively. The study aim was to assess their mechanistic utility to establish the balance between apoptosis, necrosis, and immune cell activation throughout the time course of clinical APAP hepatotoxicity.Methods: HMGB1 (total, acetylated) and K18 (apoptotic, necrotic) were identified and quantified by novel LC–MS/MS assays in APAP overdose patients (n=78).Results: HMGB1 (total; 15.4±1.9ng/ml, p<0.01, acetylated; 5.4±2.6ng/ml, p<0.001), cK18 (5649.8±721.0U/L, p<0.01), and FL-K18 (54770.2±6717.0U/L, p<0.005) were elevated in the sera of APAP overdose patients with liver injury compared to overdose patients without liver injury and healthy volunteers. HMGB1 and FL-K18 correlated with alanine aminotransferase (ALT) activity (R2=0.60 and 0.58, respectively, p<0.0001) and prothrombin time (R2=0.62 and 0.71, respectively, p<0.0001). Increased total and acetylated HMGB1 and FL-K18 were associated with worse prognosis (King’s College Criteria) or patients that died/required liver transplant compared to spontaneous survivors (all p<0.05–0.001), a finding not reflected by ALT and supported by ROC analysis. Acetylated HMGB1 was a better predictor of outcome than the other markers of cell death.Conclusions: K18 and HMGB1 represent blood-based tools to investigate the cell death balance clinical APAP hepatotoxicity. Activation of the immune response was seen later in the time course as shown by the distinct profile of acetylated HMGB1 and was associated with worse outcome.

A randomized trial of 48 versus 24 weeks of combination pegylated interferon and ribavirin therapy in genotype 6 chronic hepatitis C - Corrected Proof

Pham Thi Thu Thuy, Chalermrat Bunchorntavakul, Ho Tan Dat, K. Rajender Reddy — 2012-01-18

Background & Aims: Genotype 6 chronic hepatitis C (HCV) is encountered predominantly in Southeast Asia and data on optimal treatment strategy is limited. This study was aimed at assessing the rate and predictors of sustained virological response (SVR) in genotype 6 chronic HCV following 48 and 24weeks of pegylated interferon and ribavirin therapy.Methods: This investigator-initiated, open-label randomized trial was conducted in Vietnam between 2008 and 2010. One hundred and five treatment-naïve HCV genotype 6 patients were randomized to either 48-week (N=70) or 24-week (N=35) duration of pegylated interferon (PEG-IFN) alfa-2a 180 mcg/week and ribavirin (RBV) 15mg/kg/day; 92 patients completed the study (63 in the 48-week and 29 in the 24-week group, respectively). Primary outcome was sustained virological response (SVR) as intention-to-treat analysis.Results: There was no statistical difference in SVR between 48-week and 24-week treated groups (71% vs. 60%, respectively; p=0.24). In the 48-week and 24-week treatment groups, 81% and 80% of cases achieved rapid virological response (RVR) (p=0.86), and 86% and 80% achieved complete early virological response (p=0.45). Among those patients with RVR, SVR was in 86% (48-weeks), and 75% (24-weeks) of cases, whereas following non-RVR, only 8% of cases had an SVR with 48-week treatment duration.Conclusions: Overall, RVR was achieved in the majority of genotype 6 patients and, in those patients, similar and high rates of SVR were noted following 24-week and 48-week therapy. This observation, however, needs validation in a larger study to demonstrate non-inferiority of the shorter duration therapy. In non-RVR patients, even 48-week therapy achieved low SVR rates.

Efficacy of non-selective β-blockers as adjunct to endoscopic prophylactic treatment for gastric variceal bleeding: A randomized controlled trial - Uncorrected Proof

2012-01-18

Background & Aims: Gastric variceal obturation (GVO) therapy is the current treatment of choice for gastric variceal bleeding (GVB). However, the efficacy of non-selective β-blockers (NSBB) in the secondary prevention of GVB is still debatable. This study aimed at evaluating the efficacy of additional NSBB to repeated GVO in the secondary prevention of GVB.Methods: From April 2007 to March 2011, 95 patients with GVB after primary hemostasis using GVO were enrolled. Repeated GVO were performed until GV eradication. Forty-eight and 47 patients were randomized into the GVO alone group (Group A) and the GVO+NSBB group (Group B), respectively. Primary outcomes in terms of re-bleeding and overall survival were analyzed by multivariate analysis.Results: After a mean follow-up of 18.10months in group A, 26 patients bled and 20 died. In group B, 22 patients bled and 22 died after a mean follow-up of 20.29months. The overall re-bleeding and survival rates analyzed by the Kaplan–Meier method were not different between the two groups (p=0.336 and 0.936, respectively). The model of end-stage liver disease (MELD) score and main portal vein thrombosis (MPT) were independent determinants of re-bleeding while MPT and re-bleeding were independent factors of mortality by time-dependent Cox-regression model. Asthenia was the most common adverse event and was higher in group B (p<0.001).Conclusions: Adding NSBB therapy to repeated GVO provides no benefit for the secondary prevention of bleeding and mortality in patients with GVB.

Development of the bile ducts: Essentials for the clinical hepatologist - Uncorrected Proof

Mario Strazzabosco, Luca Fabris — 2012-01-16

Several cholangiopathies result from a perturbation of developmental processes. Most of these cholangiopathies are characterised by the persistence of biliary structures with foetal configuration. Developmental processes are also relevant in acquired liver diseases, as liver repair mechanisms exploit a range of autocrine and paracrine signals transiently expressed in embryonic life. We briefly review the ontogenesis of the intra and extrahepatic biliary tree, highlighting the morphogens, growth factors, and transcription factors that regulate biliary development, and the relationships between developing bile ducts and other branching biliary structures. Then, we discuss the ontogenetic mechanisms involved in liver repair, and how these mechanisms are recapitulated in ductular reaction, a common reparative response to many forms of biliary and hepatocellular damage. Finally, we discuss the pathogenic aspects of the most important primary cholangiopathies related to altered biliary development, i.e. polycystic and fibropolycystic liver diseases, Alagille syndrome.