Search

Background and Aims: The aim of the study was to evaluate the risk of hepatocellular carcinoma (HCC) development after treatment with direct-acting antivirals (DAAs) and to compare HCC occurrence in these patients with that among patients treated with interferon (IFN)-based therapies. Methods: We analyzed a large cohort with chronic hepatitis C virus patients for the onset of new HCC after DAA treatment. A historical IFN-treated cohort was investigated for comparison. Results: A total of 819 patients were included in the DAA group. The median follow-up period was 263 days (0–1,001). Twenty-five patients (3.6 HCCs/100 person-years; 3.1%) were diagnosed with de novo HCC within the time of observation. No patient without cirrhosis had developed HCC. Patients with newly diagnosed HCC were mostly male, older, and treatment-experienced and had a lower 12-week sustained virologic response (SVR12) rate and higher levels of liver inflammation markers. The median time to HCC was 312 days (0–880). Investigation of the subcohort of 269 cirrhotic patients yielded an HCC rate of 8.9 HCCs/100 person-years. In this cohort, non-SVR12 was an independent risk factor for de novo HCC (HR 4.48; 95% CI 1.51–13.12; p = 0.007). Twenty-four patients (96%) with new HCC were Child-Pugh class A and 17 (68%) were diagnosed in early BCLC stage A. For the IFN-treated patients, we calculated an overall risk of HCC occurrence of 1.3/100 person-years (19 patients out of 351; 5.4%). The median time to diagnosis was 38.8 months (0–113). Conclusion: The de novo HCC rates did not differ between the DAA-treated patients and those who received IFN. Achievement of SVR is of utmost importance for HCC prevention.

Eine Cholezystolithiasis (CCL) ist haufig und betrifft 15–20 % der erwachsenen Bevolkerung. In 10–15 % der Patienten mit CCL kommt es zu einer Choledocholithiasis (CDL) als Folge einer Steinmigration aus der Gallenblase. Die endoskopische Therapie der CDL mittels endoskopischer retrograder Cholangiopankreatikographie (ERCP) hat weitgehend die chirurgische Steinentfernung abgelost und die Mortalitat bei endoskopisch behandelbaren Erkrankungen halbiert. Bei der Cholangitis sowie bei der biliaren Pankreatitis mit begleitender Cholangitis ist eine ERCP notfallmasig indiziert. Vor der Steinextraktion erfolgt in westlichen Landern standardmasig eine endoskopische Sphinkterotomie (EST), jedoch zeigt die in Asien favorisierte Sphinkteroplastie mittels hydrostatischer Ballondilatation vergleichbare Ergebnisse. Die Steinextraktion erfolgt mittels Steinextraktionskorbchen oder Steinextraktionsballonkatheter. Bei groseren Gallengangsteinen ist haufig eine Lithotripsie notwendig. Hierzu stehen die unterschiedlichen Verfahren der mechanischen oder elektrohydraulischen Lithotripsie bzw. Laserlithotripsie zur Verfugung. Der aktuelle Artikel behandelt die Indikationsstellung und technische Durchfuhrung der endoskopischen Therapie der CDL sowie das Komplikationsmanagement in besonderen Fallen.

BACKGROUND & AIMS Hepatocyte death is an important factor in development and progression of cirrhosis. Cytokeratin 18-based serum markers reflecting apoptotic (M30) and overall epithelial cell death (M65 and M65EpiDeath) have been used as prognostic parameters for survival in patients with acute liver failure. However, there has been no trial investigating M30, M65 and M65EpiDeath as survival parameters in patients with cirrhosis and acute-on-chronic liver failure. METHODS Patients with cirrhosis were enrolled and followed until death, liver transplantation or last contact. M30, M65 and M65EpiDeath serum levels were quantified in patient's sera. RESULTS Three hundred and thirty-one patients were screened and 211 patients could be included in this study. The median duration of follow-up was 322 days with a range of 1-1382 days. All three cell death parameters correlated with the extent of the severity of the disease. However, M65EpiDeath was the only of the three parameters which was associated with the severe complications of cirrhosis including ascites, spontaneous bacterial peritonitis and hepatorenal syndrome. Additionally, M65EpiDeath was the only cell death parameter which was independently from liver function and its surrogate parameter such as Child-Pugh score and the model of end-stage liver disease associated with overall survival. CONCLUSIONS Epithelial cell death reflected by M65EpiDeath serum levels is an indicator for the severity of cirrhosis and a prognostic survival parameter in cirrhotic patients.

We have recently shown that major alterations of serum sphingolipid metabolites in chronic liver disease associate significantly with the stage of liver fibrosis in corresponding patients. In the current study we assessed via mass spectrometry serum concentrations of sphingolipid metabolites in a series of 122 patients with hepatocellular carcinoma (HCC) compared to an age- and sex-matched series of 127 patients with cirrhosis. We observed a highly significant upregulation of long and very long chain ceramides (C16-C24) in the serum of patients with HCC as compared to patients with cirrhosis (P < 0.001). Accordingly, dihydro-ceramides, synthetic precursors of ceramides and notably sphingosine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) were upregulated in patients with HCC (P < 0.001). Especially the diagnostic accuracy of C16-ceramide and S1P, assessed by receiver operating curve (ROC) analysis, showed a higher area under the curve (AUC) value as compared to alpha fetoprotein (AFP) (0.999 and 0.985 versus 0.823, P < 0.001 respectively). In conclusion, serum levels of sphingolipid metabolites show a significant upregulation in patients with HCC as compared to patients with cirrhosis. Particularly C16-ceramide and S1P may serve as novel diagnostic markers for the identification of HCC in patients with liver diseases. Our data justify further investigations on the role of sphingolipids in HCC.

During endoscopic retrograde cholangiopancreatography (ERCP), a guidewire is used to cannulate biliary strictures and allow for therapeutic interventions. The aim of this study was to assess the success of stricture cannulation using a combination of a flexible guidewire and a stable nitinol wire vs. a novel, single, stiff-shaft, flexible-tip guidewire.Consecutive patients who were scheduled for ERCP for biliary obstruction were randomized to undergo the procedure with either a 260-cm long, angled-tip hydrophilic wire in combination with a nitinol wire as required (standard group), or a novel, 270-cm guidewire featuring a hyperflexible, hydrophilic tip with a stiff shaft (novel group). At unsuccessful negotiation of the stricture, patients in the standard group were switched to the novel guidewire and vice versa ("crossover"). Successful cannulation (primary success: as assigned; final success: after "crossover"), procedure time, and total number of wires needed per procedure were compared.A total of 222 patients were randomized and 197 were included in the study (97 in the standard group and 100 in the novel group). The primary success rate was significantly higher in the novel group (94/100, 94 %) compared with the standard group (77/97, 79 %; P = 0.00041), and final success was similar. Mean time (median, interquartile range) to stricture cannulation was 11.2 minutes (6.3, 3.7 - 14.6) in the standard group and 8.1 minutes (2.5, 0.9 - 7.7) in the novel group (P 0.0001). The mean total procedure time was 31.2 minutes (24.6, 16.5 - 40.8) vs. 24.3 minutes (16.9, 10.0 - 31.5), respectively (P = 0.0011). There were no complications observed with either of the guidewires.A guidewire that features a flexible tip with a stable shaft could replace the use of a combination of flexible and stable guidewires and increase the success rate of stricture cannulation while decreasing the procedure time.ClinicalTrials.gov Identifier: NCT 01382680.

Background & Aims Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug–drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS. Methods Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1-infected patients patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily and pegylated interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analysed by liquid chromatography–electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase chain-reaction. Results Median (range) telaprevir plasma concentrations of TW 4, 8 and 12 were 3970 (1980–4430) ng/ml and 2520 (1870–8730) ng/ml in patients after OLT and ciclosporin- or tacrolimus-based IS, respectively, as compared to 2790 (1870–3140) in non-OLT patients (P = 0.3). In one patient with tacrolimus-based IS, telaprevir dose had to be adjusted to achieve virological response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8 and 12 in patients with and without IS. Conclusions Telaprevir drug monitoring may be necessary in patients with tacrolimus-based IS in patients with HCV graft infection after OLT.

Summary Background Vitamin D is involved in many biological processes. The role of vitamin D in patients with hepatocellular carcinoma (HCC) remains inconclusive, although there is evolving evidence that vitamin D may modulate cancer development and progression. Aim To evaluate serum vitamin D as prognostic parameter in HCC, we performed a prospective cohort study. Methods HCC patients were prospectively recruited and 25-hydroxyvitamin D3 (25(OH)D3) levels were determined. 25(OH)D3 levels were compared to stages of cirrhosis and HCC stages with nonparametric Kruskal–Wallis tests and Spearman correlations in 200 HCC patients. The association of the 25(OH)D3 levels and overall survival (OS) was assessed in uni- and multivariate Cox regression models. Results Two-hundred patients with HCC were included. The mean follow-up time was 322 ± 342 days with a range of 1–1508 days. Nineteen patients underwent liver transplantation and 60 patients died within the observation time. The mean serum 25(OH)D3 concentration was 17 ± 13 ng/mL with a range of 1–72 ng/mL. 25(OH)D3 serum levels negatively correlated with the stage of cirrhosis as well as with stages of HCC. Patients with severe 25(OH)D3 deficiency had the highest mortality risk (hazard ratio 2.225, 95% confidence interval 1.331–3.719, P = 0.002). Furthermore, very low 25(OH)D3 levels were associated with mortality independently from the MELD score and high alpha-Fetoprotein levels (>400 ng/mL) in a multivariate Cox regression model. Conclusions We conclude that 25(OH)D3 deficiency is associated with advanced stages of hepatocellular carcinoma and it is a prognostic indicator for a poor outcome.

Background & Aims: Soluble CD163 (sCD163) is shed in the blood circulation by activated macrophages, correlates strongly with the hepatic venous pressure gradient (HVPG) and is thereby a good indicator of portal hypertension. It is unknown whether sCD163 correlates with the risk of variceal bleeding and overall survival (OS) in patients with liver cirrhosis. We performed a prospective study to investigate if sCD163 serum levels correlate with the risk of variceal bleeding and OS in cirrhotic patients. Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death or last contact. At the day of inclusion in the study, blood samples were taken and sCD163 serum levels were assessed by ELISA (enzyme-linked immunosorbent assay). The time until the end points death and variceal bleeding was assessed and the risks of death or variceal bleeding were calculated with uni- and multivariate Cox regression analyses. Results: High sCD163 levels (>4100 ng/L) were associated with death independently of the MELD (model of end stage liver disease) score, CRP (C-reactive protein), age and gender. Furthermore, high sCD163 levels were associated with gastrointestinal bleeding independently of the variceal stage and red spots. Conclusions: The sCD163 serum level is a new independent noninvasive risk factor for death and variceal bleeding in cirrhotic patients. 2013 European Association for the Study of the Liver. Published

Immunotherapy in cancer is a recent and very promising approach, namely the inhibition of the PD/programmed death-ligand 1 (PD-L1) axis. Here we aimed to investigate the prognostic value of a soluble form of PD-L1 in hepatocellular carcinoma (HCC) patients.HCC patients were prospectively recruited and soluble programmed death-ligand 1 (sPD-L1) levels were determined. sPD-L1 levels were compared to stages of cirrhosis and HCC. The association of the sPD-L1 levels and overall survival (OS) was assessed.Two hundred fifteen patients with HCC were prospectively included. The median serum sPD-L1 concentration in patients with HCC was 0.5 ng/ml (range 0.03-6.04). Soluble PD-L1 levels positively correlated with the stage of cirrhosis and with stages of HCC. Furthermore, sPD-L1 correlated positively with a marker of macrophage activation (sCD163) and inflammation (C-reactive protein). The cut-off for high-level sPD-L1 (0.8 ng/ml) was defined by sPD-L1 levels determined in a healthy control cohort. Patients with high serum sPD-L1 concentrations had an increased mortality risk (hazard ratio 3.340, 95 % confidence interval 1.609-6.934, P0.001), while very low PD-L1 levels seem to come along with better prognosis. High sPD-L1 levels were associated with mortality independently from cirrhosis stage, alpha-fetoprotein and sCD163 levels in a multivariate Cox regression model.We conclude that a high sPD-L1 level is a possible prognostic indicator for a poor outcome in HCC patients. The predictive value of sPD-L1 levels for a successful anti-PD1/PD-L1 therapy should be investigated in the future.

Background MicroRNA-122 is a liver specific microRNA and is elevated in the sera of patients with chronic hepatitis C virus infection. Hepatic microRNA-122 levels have been described to be reduced in patients with non-response to antiviral treatment with pegylated interferon-α and ribavirin. Aim Assessment of differences in serum microRNA-122 levels in patients with sustained virological response and non-response. Methods RNA was extracted from pretreatment serum samples and microRNA-122 and microRNA-16 levels were measured by quantitative PCR and compared in patients with sustained virological response and non-response. Results The levels of microRNA-122 and microRNA-16 in the sera did not differ between patients with sustained virological response and non-response. Conclusion Serum microRNA-122 is not a suitable marker for treatment response prediction to combination therapy with pegylated interferon-α and ribavirin in patients with chronic hepatitis C virus infection.

a b s t r a c t Background: Reduction of necroinflammatory activity is a major goal of antiviral therapy of patients with chronic hepatitis B. Serum ALT does not detect all forms of cell death. Objectives: To analyze dynamics of novel serum cell death markers for apoptosis and necrosis in associ- ation with virologic response to nucleos(t)ide (Nuc) analogue treatment. Study design: Quantification of the M30-apoptosis neoepitope and the cytokeratin-18 (M65-necrosis) serum levels before and during treatment of patients with chronic hepatitis B with Nuc (n = 26). Results: Before treatment, M30-apoptotic activity was significantly correlated with M65-necrosis and fibrosis but not with serum ALT. During therapy with Nucs, cell death parameters M30-apoptosis, M65- necrosis, and ALT declined in association with virologic response. The most frequent cell death pattern was simultaneous decline of ALT and M30-apoptosis which occurred more frequently in patients with HBs- Antigen decline than in patients with HBs-Antigen increase during treatment (87.5% vs. 40.0%; p = 0.024). ALT decline in association with increase of M30 apoptosis was frequent in patients with HBs-Antigen increase during treatment (36.3%) but was not observed in patients with HBs-Antigen decline during treatment. Conclusion: Decline of cell death parameters in association with decline of HBV-DNA and HBs-Antigen indicates a reduction in overall cell death activity during Nuc treatment supporting the concept that response to Nuc therapy reduces necroinflammatory activity and progression of liver disease. © 2011 Elsevier B.V. All rights reserved.

The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection.RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis.Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA.The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver.

Background & Aims: Thrombopoietin receptor agonists are a new class of compounds licenced for the treatment of immune thrombocytopenic purpura. They are currently being studied for patients with thrombopenia in advanced liver disease or under therapy for hepatitis C. There are indications that the risk for development of portal vein thrombosis in patients with advanced liver cirrhosis might be increased under therapy with thrombopoietin receptor agonists. We report a case of a patient with Child class B liver cirrhosis with concurrent immune thrombocytopenic purpura that developed portal vein thrombosis under therapy with the thrombopoietin receptor agonist romiplostim. Methods: A 50-year-old woman with hepatitis C virus associated immune thrombocytopenic purpura and Child class B liver cirrhosis presented in our emergency with rapidly evolving hydropic decompensation and general malaise. For immune thrombocytopenic purpura, the patient was started on the thrombopoietin receptor agonist romiplostim nine months ago. Results: During hospitalization, the platelet count was measured above 330,000/ll and partial portal vein thrombosis was diagnosed by imaging studies. The thrombotic event was assumed to be associated with the romiplostim treatment for immune thrombocytopenic purpura via excessive elevation of platelet count. After anticoagulation with heparin and cessation of romiplostim treatment, complete recanalisation of the portal vein was achieved. Conclusions: We conclude that romiplostim should be used with precaution in patients with hepatitis C-associated immune thrombocytopenic purpura and advanced liver cirrhosis as the risk for thrombotic complications may increase significantly. 2011 European Association for the Study of the Liver. Published

Introduction Interferon alpha (IFN) down regulates CD81 expression on peripheral blood mononuclear cells (PBMC) in patients with chronic hepatitis C virus (HCV) infection. Aim of our study was to investigate whether amantadine alters IFN associated down regulation of CD81 expression on PBMC in patients with chronic hepatitis C. Methods Nineteen patients with chronic HCV infection received peginterferon alpha-2a/ribavirin (SOC) for 48 weeks. Patients were randomised to 12 weeks amantadine therapy ( n = 12) or no additional treatment ( n = 7). FACS analysis of CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was performed at baseline, week (TW) 4, TW12, and TW24 of antiviral therapy. Results A significant decline of CD81 expression was observed on CD4(+), CD8(+), and CD56(+) cells ( p = 0.011, p p = 0.015, respectively) but not on CD19(+) cells ( p > 0.2). CD81 expression on CD4(+), CD8(+), CD19(+), and CD56(+) cells was not different between patients treated with SOC plus amantadine and patients treated with SOC alone. Conclusion The current study confirms that CD81 expression is down regulated by SOC on CD4(+), CD8(+) and CD56(+) cells. Amantadine treatment was not associated with CD81 expression. Interaction between amantadine and CD81 is unlikely to be involved in potential antiviral activity of amantadine in chronic HCV infection.

356 Background: The aim of the study was to evaluate the risk of HCC development after treatment with direct-acting antivirals (DAA) and to compare hepatocellular carcinoma (HCC) occurrence to patients treated with interferon (IFN)-based therapies. Methods: We analyzed a large cohort with chronic HCV patients for the onset of new hepatocellular carcinoma after DAA treatment. A historic interferon treated cohort was investigated for comparison. Results: 819 patients were included in the DAA group, 269 (32.8%) had established cirrhosis. Median follow up was 263 days (0-1001). 25 patients (3.1%) were diagnosed with de novo HCC within the observation time. All of these patients had established cirrhosis. Patients with new HCC were mostly male, older, treatment experienced, had a lower SVR12 rate and higher levels of liver inflammation markers. Investigation of the subcohort of 269 cirrhotic patients yielded a HCC rate of 9.3% during the follow-up of approximately one year. Non-SVR12 was an independent risk factor for de novo HCC (OR 4.983, 1.39-17.88, 0.014). Most HCCs were diagnosed in early stage BCLC A. In the historical cohort of 351 IFN treated patients the rate of de novo HCC was 5.4% overall and 11.8% in patients with already established cirrhosis (n = 68). In the multivariate analysis failed SVR (OR 5.386, 1.155-25.108, p = 0.032) remained an independent risk factor for de novo HCC. In a combined analysis of all patients (DAA and IFN treated) in a multivariate approach male gender, failed SVR and cirrhosis were independent factors for HCC development. Conclusions: DAA treatment in cirrhotic patients does not seem to reduce the risk of HCC development in the short term. HCC rates were not different between DAA-treated patients and those who received interferon. Achievement of SVR seems to be the most important aim to prevent HCC development.

Die nichtalkoholische Fettlebererkrankung (NAFLD) mit Ausbildung einer Steatohepatitis (NASH) und die chronische Hepatitis-C-Virus-(HCV-)Infektion sind die haufigsten Ursachen fur Leberzirrhose und hepatozellulares Karzinom (HCC). Die Entstehung der NAFLD/NASH ist mit Insulinresistenz, Diabetes mellitus Typ 2, Dyslipidamie und Adipositas assoziiert. In der Normalbevolkerung liegt die Pravalenz der NAFLD bei 20–30%, bei Patienten mit chronischer Hepatitis C bei 40–80%. Die Steatosis hepatis bei Patienten mit chronischer Hepatitis C steht in Zusammenhang mit viralen Faktoren wie Genotyp-3-Infektion und metabolischen Faktoren wie Diabetes mellitus und einem erhohten Body-Mass-Index. HCV kann durch direkte und indirekte Interaktion mit zellularen Signalwegen eine Steatosis hepatis auslosen. Die klinische Bedeutung liegt in einem erhohten Leberzirrhose- und HCC-Risiko und einem schlechteren Ansprechen auf eine antivirale Therapie bei nicht mit Genotyp 3 infizierten Patienten. Die Therapie der Steatosis hepatis bei Patienten mit chronischer Hepatitis C besteht in einer viralen Eradikation und in der Behandlung der Adipositas und der Insulinresistenz.

A main target of specifically targeted antiviral therapy for hepatitis C (STAT-C) is the NS3-protease, which has key functions in the hepatitis C virus (HCV) replication cycle. HCV/NS3-protease inhibitors have shown high antiviral activity in vitro and in patients with chronic hepatitis C. Protease-resistant HCV variants occurred rapidly in patients receiving protease-inhibitor monotherapy. The development of resistance can be best explained by selection of preexisting resistant variants, which grow out under selective pressure. Numerous mutations associated with resistance were identified. Clinical trials showed that protease-resistant strains are sensitive to interferon and that a triple combination of protease inhibitors, peginterferon, and ribavirin may improve the sustained virologic response rate compared with standard peginterferon/ribavirin combination therapy. Overall, it can be anticipated that successful treatment with protease inhibitors will require either combination therapy with peginterferon/ribavirin or a combination of STAT-C compounds with distinct modes of action and resistance patterns.

Addition of ribavirin to interferon alfa treatment has substantially increased sustained virologic response rates in patients with chronic hepatitis C (CHC). Ribavirin acts as an RNA virus mutagen in vitro, thereby leading to error catastrophe. However, data in CHC are controversial.The nonstructural (NS) 5B quasi-species heterogeneity was analyzed in Huh7 cells harboring a subgenomic hepatitis C virus (HCV) replicon system treated with ribavirin or levovirin. Accordingly, NS5B quasi-species were studied in 14 patients with CHC who received ribavirin alone or combined with pegylated interferon alfa both at baseline and during the first weeks of therapy. Analysis of NS3 quasi-species served as control.Cultivation of HCV replicon cells with ribavirin led to higher NS5B mutational frequencies compared with levovirin-treated or untreated cells (P.05). Patients receiving ribavirin monotherapy showed higher overall mutational frequencies within NS3 and NS5B during therapy as compared with baseline (P.01). Proportions of ribavirin-specific G-to-A and C-to-T transitions increased (P.01). Paired analysis confirmed significant mean increases of mutational frequencies of approximately 5%. Ribavirin serum concentrations were positively correlated with mutational frequency changes (P.05). In patients receiving combination therapy, a decrease of NS5B mutational frequencies ( approximately 10%) and lower proportions of G-to-A and T-to-C mutations (P.01) were detectable.Ribavirin, but not its L-enantiomer levovirin, is a mutagen in HCV replicon cells. In patients with CHC, ribavirin monotherapy exhibits a moderate mutagenic effect early during therapy that is not detectable in combination with pegylated interferon alfa.

Background & aimsVitamin D, best known to regulate bone mineralization, has numerous additional roles including regulation inflammatory pathways. Recently, an increased incidence of 25-hydroxyvitamin D3 (25(OH)D3) deficiency has been found in subjects suffering from liver diseases. We here investigated if low vitamin D levels might be associated with prognosis, inflammation and infectious complications in patients with cirrhosis.MethodsWe performed a prospective cohort study investigating the relation between 25(OH)D3 levels and stages of cirrhosis, mortality and complications of cirrhosis, including infections.Results251 patients with cirrhosis were enrolled into the present prospective cohort study. 25(OH)D3 levels were quantified by radioimmunoassay from serum samples obtained at study inclusion. The mean follow-up time was 411 ± 397 days with a range of 1-1382 days. 30 (12.0%) patients underwent liver transplantation and 85 (33.8%) individuals died within the study. The mean serum 25(OH)D3 concentration was 8.93 ± 7.1 ng/ml with a range of 1.0 to 46.0 ng/ml. 25(OH)D3 levels differed significantly between Child Pugh scores and showed a negative correlation with the model of end stage liver disease (MELD) score. Patients with decompensated cirrhosis and infectious complications, had significantly lower 25(OH)D3 levels compared to subjects without complications. Low 25(OH)D3 was associated with mortality in uni- as well as multivariate Cox regression models.Conclusions25(OH)D3 deficiency is associated with advanced liver disease and low 25(OH)D3 levels are an indicator for a poor outcome and are associated with infectious complications.

We read with interest the recent paper by Angeli et al 1 investigating the acute-on-chronic liver failure classification in comparison to the acute kidney injury classification as a prognostic parameter in patients with decompensated cirrhosis. Higher stages of acute-on-chronic liver failure were accompanied with mortality and more frequently bacterial infections were identified in patients with multiorgan failure in this large cohort of patients. It is well known that patients with cirrhosis are at high risk for bacterial infections and bacterial infections are common causes of hepatic decompensations.2 Infectious complications significantly impair patients’ prognosis.2 ,3 However, especially hospital acquired infections are associated with high mortality.3 A common additional challenge is the worldwide …

In patients with chronic hepatitis C, alanine aminotransferase (ALT) levels do not accurately reflect the extent of liver inflammation. The discrepancy between ALT level and liver damage could be related to the mode of cell death. In the present study, we quantified serum levels of apoptotic cytokeratin 18 (CK-18) neoepitopes that are generated by activated caspases during apoptosis. Apoptotic CK-18 neoepitopes were quantified by enzyme linked immunosorbent assay in sera from patients with chronic hepatitis C and elevated ALT levels (n = 72), patients with chronic hepatitis C and persistently normal ALT levels (n = 27) and healthy controls (n = 19). Serum CK-18 neoepitope levels were strongly correlated with ALT (r = 0.659, P < 0.0001) and the histology activity index (r = 0.374, P < 0.001). Patients with chronic hepatitis C and persistently normal ALT levels had higher apoptotic CK-18 neoepitope levels than healthy controls (P = 0.03) but lower levels than patients with chronic hepatitis C and elevated ALT levels (P < 0.001). Highest serum CK-18 neoepitope levels were observed in patients with cirrhosis (P = 0.002). Hence apoptotic CK-18 neoepitopes in serum of patients with chronic hepatitis C are associated with ALT level and histological liver damage. Serum apoptotic CK-18 neoepitope levels are elevated both in patients with chronic hepatitis C and elevated ALT levels as well as in patients with normal ALT levels indicating that also patients with chronic hepatitis C and normal ALT have an increased hepatocyte loss by apoptosis.

The antiviral efficacy of amantadine in patients with chronic hepatitis C is controversial. In this randomized, prospective, placebo-controlled, multicenter trial, triple therapy with interferon alfa (IFN-alpha)-2a plus ribavirin and amantadine (amantadine group) was compared with combination therapy IFN-alpha plus ribavirin (control group). Four hundred previously untreated patients with histologically proven chronic hepatitis C were randomly allocated to treatment with amantadine sulphate (100 mg twice daily orally) or a matched placebo together with IFN-alpha induction plus ribavirin (1,000-1,200 mg/day orally) for 48 weeks. The primary end point was sustained virologic response (SVR) defined as undetectable serum hepatitis C virus (HCV) RNA (100 copies/mL) 24 weeks after the end of treatment. SVR was observed in 52% of the amantadine group and in 43.5% of the control group (P =.11). Among patients with HCV genotype 1 infection, the corresponding SVR rates were 39% and 31%, respectively. The virologic on-treatment response rate in week 24 was significantly higher in the amantadine group as compared with the control group (70% vs. 59%, respectively, P =.016). This beneficial effect was mainly related to HCV type 1-infected patients (63% vs. 47%, respectively, P =.012). Independent factors associated with SVR, according to multiple logistic regression analysis, were amantadine treatment, low baseline HCV RNA, platelet counts (/=250/nL), pretreatment ALT quotient/=3, and GGT level (28 U/L) as well as HCV genotypes other than 1. In conclusion, although we could not demonstrate a significant advantage of the triple regimen in univariate analysis, multivariate analysis offers arguments that amantadine should be considered as a potential anti-HCV drug in future studies.

INTRODUCTION European data on outcome and follow-up of long-term lamivudine treatment are sparse. Moreover, little is known about predictors for sustained virologic response and for development of drug resistance in patients with lamivudine monotherapy. Patients and methods : 39 patients (17 HBeAg+, 22 HBeAg-) were treated with lamivudine for a median duration of 2.5 years (range: 0.5-4). Outcome to therapy and predictors for response and drug resistance were analyzed retrospectively. RESULTS None of the patients lost HBsAg. In 14 of 17 initially HBeAg positive patients the HBeAg status was available at the end of treatment. Loss of HBeAg was observed in 8 patients and 7 of these 8 patients seroconverted to anti-HBe. Five of 6 patients with HBeAg seroconversion and a post-treatment follow-up period showed sustained HBeAg seroconversion. In HBeAg negative patients virologic response (serum HBV DNA< or =1 x 10(5) copies/ml) was observed in 12 of 22 patients after a median treatment period of 2.5 years. Post-treatment follow-up data were available in only 2 patients, one of which remained below 1 x 10(5) HBV DNA copies/ml for one year. Resistance emerged in 15 of 36 patients with available serum HBV DNA data after a median treatment period of 2 years. CONCLUSION The present retrospective study confirms international data for lamivudine treatment in a central European setting. Lamivudine therapy achieved disease control in more than 50 % of patients treated for chronic hepatitis B. Baseline predictors could neither be identified for sustained virologic response nor for the development of drug resistance.

Fully covered self-expandable metal stents (FCSEMS) are increasingly used for treatment of benign common bile duct (CBD) stricture or leakage, but dislodgement of FCSEMS is frequent. To compare dislocation rate and clinical outcome of a standard fixed cell structure FCSEMS (S-FCSEMS) to a novel FCSEMS with an unfixed cell structure (N-FCSEMS). We performed a retrospective analysis of all patients with FCSEMS insertion for benign biliary disease at our Hospital from 03/2008 to 03/2014. Both stent types N-FCSEMS and S-FCSEMS were applied as available unrelated to the indication. Twenty-nine patients (S-FCSEMS: 18, N-FCSEMS: 11) were included. Stent placement was technically successful in 28/29 (96.6 %) patients; stent removal was successful in 26/27 (96.2 %). Two patients with N-FCSEMS were excluded due to unsuccessful placement and withdrawal of consent for stent removal, respectively. Stent migration into the duodenum (distal migration) was observed in 9/18 (50 %) in the S-FCSEMS group compared to 0/9 in the N-FCSEMS (p

Background: The variety of rendezvous (RV) procedures has recently been extended by EUS- and PTCD-guided procedures as a complementary means to conventional ERCP. We have identified indication criteria and the potential of biliary PTCD-guided vs. EUS-guided RV. Methods: Consecutive patients with bile duct obstruction who underwent RV were included. In all, ERCP alone was unable to achieve treatment success. Indication, technical success, and outcome in PTCD- vs. EUS-guided RV were retrospectively compared to identify criteria that indicate preference of RV technique. Site of obstruction, clinical scenario (stenosis with abscess vs. no abscess) and reason for previous failure of ERC were evaluated. Results: In 32 patients, three different indications for RV procedures were identified: First, a one-step access to assist in failed ERCP (type 1, intra-ductal RV); second, temporary drainage for prolonged treatment of complex biliary disease (type 2, intra-ductal RV), and drainage of cholangio-abscess with re-establishing bile outflow (type 3, intra-abscess RV). Indication of PTCD- vs. EUS-guided rendezvous was competitive in type 1, but exclusive in favor of PTCD in types 2 and 3. The site of biliary obstruction indicated the anatomic location of RV procedures. Conclusions: This classification may help to define inclusion criteria for prospective studies on biliary RV procedures. Choice of therapeutic strategy depends on the anatomic location of the biliary obstruction and the type of the biliary lesion. PTCD-guided RV might improve outcome in cholangio-abscess.

SummaryBackground Proton pump inhibitors (PPI) are widely used in patients with liver diseases. Within the last years, there have been concerns about the PPI use as they may promote infections in patients with cirrhosis. Aim As there are sparse data of the prognostic relevance of PPI treatment, to perform a prospective study investigating the relation of PPI treatment and overall survival (OS) in cirrhotic individuals. Methods Patients with cirrhosis were enrolled and followed prospectively. The primary end point was OS. PPI treatment and additional clinical and laboratory data were assessed at the day of the study inclusion. The time until the end point death was assessed and the individual risks were calculated with Cox regression analyses. Results A total of 272 patients were included and 213 individuals (78.3%) were on PPI treatment. In multivariate logistic regression analysis, PPI treatment was associated with higher MELD scores (P = 0.027) and ascites (P = 0.039). In a multivariate Cox regression model, PPI use was an independent predictor of mortality (hazard ratio 2.330, 95% confidence interval 1.264–4.296, P = 0.007) in addition to the model of end-stage liver disease (MELD) score, hepatocellular carcinoma and hepatic decompensation. Conclusions PPI use is an independent risk factor for mortality in patients with cirrhosis. Although a causative role for increased mortality in patients taking PPI is still missing, the prescription of PPI in cirrhotics should be considered carefully taking into account its potential adverse effects.

BackgroundAutotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.MethodsPatients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.Results270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, PConclusionSerum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients.

Anemia is a common complication in several types of cancer including hepatocellular carcinoma (HCC). The prognostic potential of hemoglobin (Hb) levels has not yet been investigated in HCC patients. One hundred and ninety-nine patients were prospectively recruited and Hb levels were determined. Hb levels were compared to the stages of liver cirrhosis and HCC stages. The association of the Hb levels and overall survival (OS) was assessed by univariate and multivariate Cox regression models. The relation of Hb levels and OS was further validated in an independent cohort of 87 HCC patients. Hb levels negatively correlated with the stage of liver cirrhosis (model of end stage liver disease score and Child-Pugh stage) and differed between stages of HCC. Low Hb levels (≤ 13 g/dl) were associated with higher mortality in the test [hazard ratio (HR) 2.422, 95 % confidence interval (CI) 1.357-4.322, P = 0.003] as well in the validation cohort (HR 2.486, 95 % CI 1.097-5.632, P = 0.029) in univariate Cox regression model. Low Hb levels were associated with mortality independently from the tumor stage, age, gender and the C-reactive protein levels in a multivariate Cox regression model. Anemia should be considered as a risk factor for mortality in HCC patients.

The serum cell death parameters M30 and M65 and the macrophage activation marker sCD163 (soluble CD163) are elevated in patients with acute and chronic liver diseases. However, their diagnostic and prognostic potential in patients with hepatocellular carcinoma (HCC) has not yet been investigated.Serum levels of M30, M65, and sCD163 were measured in two cohorts of HCC patients and a cohort of cirrhotic patients. The parameters were compared between patients with and without HCC and the overall survival (OS) times according to M30, M65, and sCD163 were assessed.M30 and M65 levels were higher in HCC patients than in cirrhotic patients (both p0.001). M65 was an independent parameter for non-invasive identification of HCC patients by logistic regression analysis and could supplement AFP (alpha-fetoprotein) and abdominal ultrasound in non-invasive detection of HCC patients. High M65 serum levels as well as high sCD163 concentrations were associated with an impaired prognosis in univariate Cox regression analysis. The sCD163 level was associated with OS independently of the CLIP (Cancer of the Liver Italian Program) score, the BCLC (Barcelona Clinic Liver Cancer) stage, and the CRP (C-reactive protein) level in a multivariate Cox regression model.Serum M65 has the potential as a new diagnostic parameter for HCC and serum sCD163 is a new prognostic parameter in HCC patients.

Background The identification of new biomarkers to predict the aggressiveness of hepatocellular carcinoma (HCC) and supplement the current set of prognosis and treatment algorithms is an important clinical need. Extracellular microRNAs (miRNAs) circulating in the blood are a new class of highly promising disease markers. Aim Here we investigated the prognostic potential of miR-1 and miR-122 in sera from patients with HCC. Methods RNA was extracted from 195 sera of HCC patients and 54 patients with liver cirrhosis, obtained at the time of study enrolment. miR-1 and miR-122 levels were correlated with overall survival (OS), Cancer of the Liver Italian Program (CLIP) score, Barcelona Clinic Liver Cancer stage, clinical chemistry parameters and tumor specific treatment. Results Patients with higher miR-1 and miR-122 serum levels showed longer OS than individuals with lower miR-1 and miR-122 serum concentrations (hazard ratio [HR] 0.440, 95% confidence interval [CI] 0.233–0.831, P = 0.011 for miR-1 and HR 0.493, 95% CI 0.254–0.956, P = 0.036 for miR-122, respectively). Serum miR-1 and miR-122 concentrations did not differ significantly between patients with HCC and liver cirrhosis. An age-, sex-, tumor stage and treatment-adjusted multivariate Cox regression analysis revealed that miR-1 serum levels (HR 0.451, 95% CI 0.228–0.856, P = 0.015) were independently associated with OS, whereas serum miR-122 was not. miR-1 serum levels showed no relevant correlation with clinical chemistry liver parameters, whereas serum miR-122 correlated with clinical chemistry parameters of hepatic necroinflammation, liver function and synthetic capacity. Conclusion Our data indicate that serum miR-1 is a new independent parameter of OS in HCC patients and may therefore improve the predictive value of classical HCC staging scores.

Background and Aims: Soluble CD 163 (sCD163) is shed in the blood circulation by activated macrophages, correlates strongly with the hepatic venous pressure gradient (HVPG) and is thereby a good indicator for portal hypertension. It is unknown if sCD163 correlates with the risk of variceal bleeding and overall survival (OS) in patients with liver cirrhosis. We performed a prospective study to investigate if sCD163 serum levels correlate with the risk of variceal bleeding and with OS in cirrhotic patients. Methods: Patients with liver cirrhosis were prospectively enrolled and followed until death or last contact. At the day of inclusion into the study blood samples were taken and the sCD163 serum levels were assessed by ELISA (Enzyme-linked immunosorbent assay). The time until the end points death and variceal bleeding were assessed and the risks of death or variceal bleeding were calculated with uni- and multivariate Cox regression analyses. Results: High sCD163 levels (>4100ng/l) corresponding to a HVPG >10mmHg were associated with variceal bleeding and death independently from the MELD (model of end stage liver disease) score, age and sex. Furthermore, high sCD163 levels were independent from the variceal stage associated with gastrointestinal bleeding. Conclusions: The sCD163 serum level is a new independent non-invasive risk factor for death and variceal bleeding in cirrhotic patients.