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Background & Aims There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Methods Non-cirrhotic HBeAg-negative patients who had received TDF for ≥4years, with suppressed HBV DNA for ≥3.5years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144weeks. Results Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to Week 144. Median HBsAg change in this group was −0.59log 10 IU/ml (range −4.49 to 0.02log 10 IU/ml) vs. 0.21log 10 IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n=9) had either achieved HBsAg loss or had HBV DNA Conclusions This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy. Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA Clinical trial number: NCT01320943.

Background and aim Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, characterized by cognitive deficits that negatively impact patients' quality of life. The mild, minimal hepatic encephalopathy (mHE) can only be detected by psychometric tests and early mHE detection can prevent more severe complications or even survival times. Here, we aimed to investigate the feasibility and validity of the novel-developed electronic number connection test (eNCT), which is designed as a fast and easy-to-perform mHE patient self-test. Methods The eNCT design was inspired by the paper-pencil number connection test version A, showing 25 numbers on the screen (1-25), in a random order. The time required to tap on all digits in the correct order was measured. A total of 238 individuals (112 patients with liver cirrhosis) were enrolled in this study and eNCT times were compared with well-established paper-pencil tests. The Psychometric Hepatic Encephalopathy Score test battery was used to detect mHE and cut-off values for mHE detection by the eNCT were defined. Results Overall, cirrhotic patients showed significantly slower test completion times compared with control participants. The eNCT performance was inversely correlated with Psychometric Hepatic Encephalopathy Score test performance in cirrhotic patients, independent of the HE status. Thirty cirrhotic patients fulfilled the mHE criteria and receiver operating characteristic curve analysis showed high sensitivity (>82%) and specificity (>85%) for mHE detection. Finally, the eNCT showed excellent test-retest reliability (intraclass correlation coefficient=0.94). Conclusion The novel eNCT is a reliable HE self-test to monitor cognitive function and detect cognitive impairment in cirrhotic patients.

Patients with hepatocellular carcinoma (HCC) in cirrhosis have an increased risk for postoperative complications including liver failure. However, there is some evidence that the use of laparoscopy markedly decreases this risk. Patients Between 2010 – 2015, a total of 21 laparoscopic liver resections were performed for HCC in Child-A cirrhosis at our center. Mean MELD score was 9 (6 – 12), and the mean LiMAx was 261 µg/h/kg (101 – 489). All resections were performed by conventional laparoscopy using 4 – 6 trocars. Liver parenchyma was transected using ultrasonic shears. Hilar occlusion was used on demand. In the earlier years, laparoscopic resections were performed occasionally and mainly if tumors were easily accessible. With increasing experience, currently most HCC in cirrhosis are resected laparoscopically. Likewise, 12 out of the 21 resections were performed within the last 12 months, including 2 anatomic left hemihepatectomies. Results Conversion rate, postoperative mortality, and operative revision rate were all 0 %. Four patients (19 %) developed mild complications Clavien-Dindo grade 1 or 2 (ascites, transfusion, pneumonia, renal impairment). One patient (4.8 %) developed a grade 3 event (bile leak, percutaneous drainage). All but 1 early patient underwent R0 resection (95 %). The mean duration of hospital stay was 10.5 days (5 – 21), and the mean duration of ICU stay was 1.8 days (1 – 7). No case of decompensation of liver cirrhosis was observed. In 1 case, a prolonged production of ascites evolved. Conclusion Even in patients with severely impaired liver function, no severe complications and especially no decompensation of cirrhosis was observed. Therefore, in accordance with other single center experiences, liver resection for HCC in cirrhosis should be performed preferentially by laparoscopy.

Background/aim The use of lamivudine for the treatment of chronic hepatitis B (CHB) is limited by high rates of lamivudine resistance. However, it is still in use in many regions. Factors associated with lamivudine resistance development have been studied in only a few European cohorts. The aim of our study was to assess the rate and risk factors for lamivudine resistance in a large real-life European cohort. Patients and methods We retrospectively analyzed patients with CHB treated in three German University centers over up to 12 years. Lamivudine resistance was defined as virologic breakthrough and presence of genotypic lamivudine resistance. The probability of resistance was estimated by Kaplan-Meier analysis and resistance predictors by Cox regression. Results A total of 227 patients were included into the analysis (hepatitis B envelope antigen positive or negative). Rates of lamivudine resistance by years 1-7 were 7, 26, 35, 41, 46, 53, and 55%, respectively. Interestingly, two hepatitis B envelope antigen-negative patients developed resistance during the year 12 of treatment. Independent risk factors for resistance development were hepatitis B virus DNA levels of at least 10 copies/ml before and detectable hepatitis B virus DNA by month 6 of treatment. Conclusion Even after long-term response to lamivudine more than 10 years, resistance may still develop. Our findings further discourage the use of lamivudine for the treatment of CHB.

Background The new directly acting antivirals (DAAs) enable all-oral interferon-free treatment of chronic hepatitis C virus (HCV) infection. We here investigated the effect of DAAs on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C. Methods Twenty-one patients with elevated liver enzymes or advanced fibrosis/compensated cirrhosis caused by recurrent HCV were treated with sofosbuvir either in combination with simeprevir, or in combination with ribavirin or daclatasvir with or without ribavirin for 12 weeks. Biochemical parameters, tacrolimus trough levels, and the maximal liver function capacity (LiMAx) were measured monthly during the treatment and 12 weeks after the end of treatment. Results All patients achieved sustained virological response 12 weeks after the end of the treatment. The transaminases and cholestasis parameters normalized until week 8 of treatment. The mean LiMAx (normal ranges >315 μg/kg/h) increased from 344±142 μg/kg/h before treatment to 458±170 μg/kg/h (P

Background & Aims Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. Methods We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naive patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. Results RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. Conclusions We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

BackgroundIn pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%.ObjectiveThe objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study.MethodsThe German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician.ResultsA total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24–1.43); p

BACKGROUND: There is a clear need for better biomarkers of drug-induced-liver-injury (DILI). AIMS: We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI. METHODS: We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT

Introduction. Beneath tumor grading and vascular invasion, nontumor related risk factors for HCC recurrence after liver transplantation (LT) have been postulated. Potential factors were analyzed in a large single center experience. Material and Methods. This retrospective analysis included 336 consecutive patients transplanted for HCC. The following factors were analyzed stratified for vascular invasion: immunosuppression, rejection therapy, underlying liver disease, age, gender, blood transfusions, tumor biopsy, caval replacement, waiting time, Child Pugh status, and postoperative complications. Variables with a potential prognostic impact were included in a multivariate analysis. Results. The 5- and 10-year patient survival rates were 70 and 54%. The overall 5-year recurrence rate was 48% with vascular invasion compared to 10% without (p<0.001). Univariate analysis stratified for vascular invasion revealed age over 60, pretransplant tumor biopsy, and the application of blood transfusions as significant risk factors for tumor recurrence. Blood transfusions remained the only significant risk factor in the multivariate analysis. Recurrence occurred earlier and more frequently in correlation with the number of applied transfusions. Conclusion. Tumor related risk factors are most important and can be influenced by patient selection. However, it might be helpful to consider nontumor related risk factors, identified in the present study for further optimization of the perioperative management.

Background Elevated IgG4 levels have been reported among patients with primary sclerosing cholangitis. Epidemiological data has only been provided from tertiary centres. Aims To investigate the prevalence of elevated IgG4 levels and to compare prognosis between patients with and without elevated IgG4 levels in serum in two European cohorts of patients with primary sclerosing cholangitis. Methods Serum IgG4-levels were measured in a consecutive series of patients from Berlin, and retrospectively collected in a population-based cohort from Sweden (total N = 345). Cox's proportional hazard analysis was used to calculate relative risks for liver-related death or liver transplantation and cholangiocarcinoma. Results Elevated IgG4 values were demonstrated in 10% of patients. A previous history of pancreatitis, combined intra- and extrahepatic biliary involvement and jaundice were independently associated with elevated IgG4 in multivariate analysis. IgG4 status was not associated with an increased risk for the combined endpoint liver-related death or liver transplantation or cholangiocarcinoma. Conclusion The prevalence of elevated IgG4 values among European patients with primary sclerosing cholangitis is similar to what previously has been reported from the United States. Elevated IgG4 was not associated with an increased risk of liver transplantation or liver-related death or cholangiocarcinoma.

Background & Aims IgG4-related cholangitis is a chronic inflammatory biliary disease that involves different parts of the pancreatobiliary system, but little is known about its mechanisms of pathogenesis. A T-helper (Th) 2 cell cytokine profile predominates in liver tissues from these patients. We investigated whether Th2 cytokines disrupt the barrier function of biliary epithelial cells (BECs) in patients with IgG4-related cholangitis. Methods We assessed the Th2 cytokine profile in bile samples and brush cytology samples from 16 patients with IgG4-related cholangitis and respective controls, and evaluated transcription of tight junction (TJ)–associated proteins in primary BECs from these patients. The effect of Th2 cytokines on TJ-mediated BEC barrier function and wound closure was examined by immunoblot, transepithelial resistance, charge-selective Na + /Cl − permeability, and 4-kDa dextran flux analyses. Results Bile samples from patients with IgG4-related cholangitis had significant increases in levels of Th2 cytokines, interleukin (IL)-4, and IL-5. IL-13 was not detected in bile samples, but polymerase chain reaction analysis of whole-brush cytology samples from patients with IgG4-related cholangitis revealed increased levels of IL-13 mRNA, compared with controls. BECs isolated from the brush cytology samples revealed decreased levels of claudin-1 and increased levels of claudin-2 mRNAs. In vitro, IL-4 and IL-13 significantly reduced TJ-associated BEC barrier function by activating claudin-2–mediated paracellular pore pathways. Th2 cytokines also impaired wound closure in BEC monolayers. Conclusions Th2 cytokines predominate in bile samples from patients with IgG4-related cholangitis and disrupt the TJ-mediated BEC barrier in vitro. Subsequent increases in biliary leaks might contribute to the pathogenesis of chronic biliary inflammation in these patients.

Aim/objectives/background Hepatitis E virus (HEV) is an emerging disease in developed countries. HEV seroprevalence ranges from 3.2 to 10% in Europe, but is higher in endemic areas such as southern France. In Germany, an increasing incidence of HEV infections has been reported recently. Risk factors for the acquisition of HEV are incompletely understood. Methods We screened 295 consecutive patients with chronic liver disease attending the outpatient department at Charite University Hospital for HEV seroprevalence. Epidemiological characteristics were analyzed and patients were questioned for risk factors using a standardized questionnaire. A total of 78 patients without known liver disease were also tested for HEV IgG. Results Out of 295 screened patients, 62 tested positive for HEV-IgG. Overall, 50% of the HEV-positive patients were women and 23.8% had underlying liver cirrhosis. HEV-positive patients were older than HEV-negative patients (mean age 56 vs. 48.6 years). Seroprevalence increased with age from 13% in patients 30-39 years of age to 36.4% in patients 70-79 years of age. Of the total, 46.7% of HEV-IgG-positive patients had contact with domestic animals and 38.3% had received blood transfusions. A total of 50% of the HEV-IgG-positive patients had regularly consumed uncooked meat and 45% had regularly consumed wild game or wild boar, which was significantly more frequent than in HEV-IgG-negative patients. Conclusion HEV-IgG seroprevalence was 21% in a cohort of patients with chronic liver disease and 24.4% in a cohort of patients without known liver disease. The higher seroprevalence found among elderly patients suggests a lifetime accumulation of risk of exposure to HEV. The results from this study imply that regular testing should be performed for HEV in developed countries in case of liver disease of unknown etiology.

Poster-Abstract

Einleitung: Die spontane Ausheilung der HBV-Infektion, der Ubergang in ein asymptomatisches Stadium und der HBs-Antigen-(HBsAg)-Verlust im naturlichen und therapieabhangigen Verlauf treten haufig bei HBeAg-positiven Patienten auf und werden wahrscheinlich durch Faktoren des angeborenen Immunsystems beeinflusst. Mehre Studien belegen die essentielle Bedeutung des Toll-like-Rezeptor-3-(TLR3)-vermittelten Signalwegs. Veranderungen im TLR3-Gen konnen die Effizienz der Signaltransduktion beeinflussen. Deshalb haben wir die Pravalenz der Genotypen der TLR3-Polymorphismen (SNPs) an den Positionen c.-976T/A und c.1234G/A und die Assoziation der Varianten mit dem naturlichen und therapieabhangigen Verlauf der HBV-Infektion untersucht. Methoden: Es wurden 476 kaukasische Patienten mit chronischer Hepatitis B (CHB) und 194 Personen mit spontaner HBs-Antigen-Serokonversion (SC) mit anti-HBs- und anti-HBc-Positivitat ohne fruhere Vakzinierung genotypisiert. In der CHB-Gruppe befanden sich 40% inaktive Trager und 23% HBeAg-positive Patienten. Die TLR3-SNPs wurden mittels Polymerasenkettenreaktion und Schmelzkurvenanalyse erfasst. Ergebnisse: Die Patienten mit SC waren signifikant alter als jene mit CHB (p < 0,001). Es kamen signifikant weniger A-Allele von TLR3 c.-976T/A und c.1234G/A in der SC-Gruppe (SC vs. CHB; c.-976A: 55% vs. 67%, p = 0,003; c.1234A: 44% vs. 60%, p = 0,0002). In der multivariaten Regressionsanalyse waren die A-Alle beider SNPs mit einer geringeren Wahrscheinlichkeit der spontanen SC assoziiert (c.-976A: OR = 0,60 [95% CI: 0,41 – 0,88] p = 0,01; c.1234A: OR = 0.56 [95% CI: 0,38 – 0,83] p = 0,004). Bei inaktiven Tragern wurden ebenfalls weniger A-Allele von c.1234G/A detektiert (inaktiv vs. hochviramisch: 57% vs. 70% p = 0,002). In der CHB-Gruppe war der AA-Genotyp von c.-976 mit der HBe-Antigen-Positivitat assoziiert (OR = 0,41 [95% CI: 0,20 – 0,84] p = 0,015). Schlussfolgerung: Die Polymorphismen c.-976T/A und c.1234G/A im TLR3-Gen sind sowohl mit der spontanen HBs-Antigen-Serokonversion, mit dem inaktiven Tragerstatus als auch mit HBe-Antigen-Positivitat bei Patienten mit chronischer Hepatitis B assoziiert. Der Einfluss dieser Varianten des angeborenen Immunsystems auf die Progredienz der CHB muss in groseren Kohorten und in funktionellen Analysen weiter untersucht werden.

Introduction Hepatitis C virus (HCV) recurrence after liver transplantation (LT) used to be a serious problem in the era of interferon-based treatment. Since the introduction of modern directly acting antivirals, treatment has become easier and shorter. According to published data, in the natural course of hepatitis C infection the duration of antiviral treatment with sofosbuvir (SOF) und ledipasvir (LDV) may be shortened to 12 instead of 24 weeks, using ribavirin (RBV) in addition. Furthermore, the question of whether or not RBV is really necessary, in a 12-week SOF/LDV treatment in the post-transplant setting, is still unanswered. Patients and methods At our institution, 100 liver transplant patients with HCV recurrence underwent interferon-free SOF-based treatment. A total of 51 patients received SOF/LDV with or without RBV. Twenty-nine HCV genotype 1 or 4 patients with histologically proven stage 0-2 fibrosis were treated with SOF/LDV for 12 weeks; another 22 patients with advanced fibrosis (stage 3-4) either received SOF/LDV plus weight-adjusted RBV or prolonged treatment for 24 weeks. Results End of treatment response and sustained virological response (SVR) were achieved in 100% of the 51 patients, irrespective of the treatment group. Patients with prolonged treatment duration or with RBV developed significantly more adverse events (AEs) compared to the SOF/LDV group: 19 (86.4%) vs 8 (27.6%), P

Sorafenib, a receptor tyrosine kinase-inhibitor with anti-proliferative and anti-angiogenic activity, is currently the only approved systemic treatment for patients with hepatocellular carcinoma. It inhibits downstream signaling of VEGFR-2, PDGFR, c-Kit receptors and BRAF. Over the last four years comprehensive experience with sorafenib in this indication has been accumulated. In this review we discuss the current data on the use of sorafenib in patients with advanced HCC including special patient populations such as patients with impaired liver function, patients after transplantation, and others. The most frequent side-effects and practical tips on how to manage them are discussed in detail. In addition, we summarize the current experimental data on the use of sorafenib in combination treatment, e. g., together with transarterial chemoembolisation or other targeted agents.

In patients with chronic hepatitis C virus (HCV) infection, several variants of the interleukin-28B (IL28B) gene have been shown to correlate significantly with a sustained virologic response (SVR). Recent evidence shows that determination of one single IL28B polymorphism, rs12979860, is sufficient for predicting treatment outcome. We examined whether the combined determination of the IL28B single-nucleotide polymorphisms (SNPs), rs12979860, rs8099917, rs12980275, and rs8103142, might improve the prediction of SVR in patients with HCV. In the study cohort, 54% of 942 patients with chronic HCV type 1 infection had SVR. The IL28B SNPs, rs12979860CC and rs8099917TT, correlated significantly with SVR (68% and 62%). The SNPs, rs12980275 and rs8103142, were in strong linkage disequilibrium with rs12979860 and were not included in further analysis. In homozygous carriers of the rs12979860 responder allele C, additional genotyping of the rs8099917 SNP had no effect on response prediction, whereas in carriers of the rs12979860 nonresponder allele, the rs8099917 SNP improved the response prediction. In heterozygous carriers of the rs12979860 nonresponder T allele, SVR rates were 55% in the presence of the rs8099917TT genotype and 40% in patients carrying the rs8099917 TG or GG genotype. Analysis of an independent confirmation cohort of 377 HCV type 1–infected patients verified the significant difference in SVR rates between the combined genotypes, rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (38% versus 21%; P = 0.018). Conclusion: Treatment outcome prediction could not be improved in homozygous carriers of the IL28B rs12979860 C responder allele by the additional determination of the rs8099917 SNP. There is evidence that a significant proportion of heterozygous carriers of the rs12979860 T nonresponder allele can profit with respect to SVR prediction by further determination of the rs8099917 SNP. (HEPATOLOGY 2012;55:1700–1710)

Objectives The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. Methods When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). Results Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. Conclusion DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Supplemental digital content is available in the text., Background Elevated liver enzymes are frequently observed in renal transplant recipients and warrant further exploration. In immunosuppressed patients, hepatitis E virus (HEV) infection may cause chronic hepatitis, cirrhosis, and extrahepatic manifestations such as renal injury. Methods We performed a retrospective cross-sectional study investigating the prevalence, clinical correlates, and outcome of chronic HEV infection in a cohort of renal transplant recipients with elevated liver enzymes. Results Over a period of 30 months, 140 of 1469 renal transplant recipients had elevated liver enzymes, of which serum samples from 98 patients were available to determine HEV status. Seventeen patients were detected with HEV infection, of which 16 developed chronic HEV infection, while 1 patient controlled viremia (prevalence of chronic infection of 16.3%, with a minimum prevalence of 1.1% in the whole cohort). Increased liver stiffness was indicated by an average FibroScan result of 11.2 kPa in these patients. All 16 patients with chronic HEV infection were treated with ribavirin for a mean duration of 3 months. Five patients developed a viral rebound and received a second treatment course, of which 2 controlled HEV replication. Six months after the end of therapy, HEV clearance was achieved in 81.3% of the patients. One patient developed ribavirin resistance. Hemolytic anemia after ribavirin treatment was frequent, requiring blood transfusion in 3 patients. Four patients developed de novo glomerulonephritis, of which 2 were possibly associated with HEV infection. Conclusions This retrospective study showed that prevalence of chronic HEV infection was high in our renal transplant patient cohort and was associated with significant liver impairment and the occurrence of renal injury. Ribavirin treatment was effective and should be initiated early to avoid complications, but the risk of severe hemolytic anemia makes strict monitoring essential.

Background & Aims: V alpha 14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We here describe a role for V alpha 14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-moVA (Tf-mOVA) mice. Methods: Naive ovalbumin-specific class I MHC-restricted T cells (OTI) were adoptively transferred into Tf-mOVA mice in the presence or absence of iNKT-cell agonist alpha-galactosylceramide, after which OTI T-cell priming, antigen-specific cytokine production, cytotoxic killing ability, and liver damage were analyzed. Results: Transfer of OTI cells resulted in robust intrahepatic, antigen-specific proliferation of T cells. OTI T-cells were activated in liver, and antigen-specific effector function was stimulated by coactivation of V alpha 14 iNKT cells using alpha-galactosylceramide. This stimulation was absent in CD1d(-/-)Tf-mOVA mice, which lack Va14 iNKT cells, and was prevented when interferon-gamma and tumor necrosis factor-alpha production by V alpha 14 iNKT cells was blocked. Conclusions: CD1d-restricted V alpha 14 iNKT cells stimulate intrahepatic CD8 T-cell effector responses to antigen expressed in liver. Our findings elucidate a previously unknown intervention point for targeted immunotherapy to autoimmune and possibly infectious liver diseases.

Liver cirrhosis induced by HBV and HCV infections is the main risk factor for the development of hepatocellular carcinoma (HCC). Therefore, prevention of chronic infection with hepatitis viruses and prevention of the development of cirrhosis are essential for the primary prevention of HCC. A consequent vaccination program for HBV is suitable to reduce the rate of infections and the HCC-associated mortality. Since no vaccine is available for HCV, the reduction of risky behaviour and the improvement of hygiene standards are the mainstays for prevention of HCV. An efficient antiviral therapy aimed at the durable suppression of the viral load reduces the risk of progression to cirrhosis and development of HCC in precirrhotic stages of chronic HBV or HCV infections. In cirrhotic patients, the risk of developing HCC remains elevated even if a sustained virological response is achieved, thus requiring further screening with the intention of the early detection of HCC. It is too early to judge whether virological nonresponders profit from continued antiviral therapy. Therefore, the early diagnosis of chronic HBV or HCV infection is the single most important factor for the prevention of HCC. Secondary prevention after surgical resection or local ablative therapy may reduce the frequency of late recurrence. Liver transplantation is today the most effective measure of secondary prevention for selected patients with HCC. Due to its antiproliferative effects, the immunosuppressive drug sirolimus may play a role for secondary prevention of HCC following transplantation.

Liver cirrhosis is characterized by remodeling leading to nodules that are difficult to discern from hepatocellular carcinoma (HCC). Alpha-fetoprotein (AFP) serum levels are used for the screening for HCC, with limited success. We evaluated angiopoietin-2 as a serum marker in patients with cirrhosis and with HCC.In a retrospective study, we measured angiopoietin-2 serum levels in 131 patients with HCC, 180 patients with cirrhosis, and 40 healthy controls. We also determined AFP serum levels in patients with HCC and compared the test characteristics of both serum markers. The expression patterns of angiopoietin-2 were determined by in situ hybridization in healthy and cirrhotic livers as well as in HCC.Angiopoietin-2 serum levels were elevated in patients with liver cirrhosis (P0.0001) compared with healthy controls. Levels were further elevated in patients with HCC compared with healthy controls (P0.0001) and cirrhotic patients (P0.0001). The combination with AFP measurements led to improved discrimination between HCC and cirrhosis. Angiopoietin-2 message was present in tumor cells of HCCs but was absent from hepatocytes of cirrhotic and healthy livers. In cirrhosis, message was detected within the strands of fibrous tissue.Serum angiopoietin-2 levels are elevated in patients with cirrhosis, implicating a possible role of the angiopoietin-Tie-2 system for neoangiogenesis in cirrhosis. Serum levels are further elevated in patients with HCC, suggesting the potential use of angiopoietin-2 as a marker for the detection of cirrhosis and HCC.

Background CTLA4 is an inhibitory receptor expressed on a subset of T lymphocytes. Single nucleotide polymorphisms of the CTLA4 gene have been implicated in autoimmune diseases, including autoimmune hepatitis and primary biliary cirrhosis. In reverse form, CTLA4 variations are associated with chronic infections such as chronic hepatitis B. Methods CTLA4 variations - 318C > T and + 49A>G were analyzed in 2366 patients with chronic liver disease of various etiologies, including 323 patients with chronic hepatitis B virus (HBV) infection, 1181 patients with chronic hepatitis C virus infection, 180 patients with primary biliary cirrhosis, and 127 patients with autoimmune hepatitis, as well as 202 healthy control individuals. Genotyping was performed by melting curve analysis. Results The - 318C>T variation was underrepresented in patients with chronic HBV infection compared with healthy controls (14.6 vs. 25.7%, P= 0.002) and with patients with chronic liver disease of other origin (14.6 vs. 20.7%, P=0.011). Patients with cryptogenic cirrhosis also showed a lower frequency of the - 318T allele than healthy controls (12.0 vs. 25.7%, P=0.014). No association of the + 49G >A variation was found with any diagnosis, including autoimmune hepatitis and primary biliary cirrhosis. Conclusion We describe the association of the CTLA4 -318C>T variation with chronic HBV infection and cryptogenic cirrhosis but find no association of the +49G>A variation with autoimmune liver disease.

Secondary sclerosing cholangitis in critically ill patients (SSC-CIP) is an important differential diagnosis in patients presenting with cholestasis and PSC-like cholangiographic changes in endoscopic retrograde cholangiography (ERC). As a relatively newly described entity, SSC-CIP is still underdiagnosed, and the diagnosis is often delayed. The present study aims to improve the early detection of SSC-CIP and the identification of its complications. A total of 2633 records of patients who underwent or were listed for orthotopic liver transplantation at the University Hospital Charité, Berlin, were analyzed retrospectively. The clinical presentation and outcome (mean follow-up 62.7 months) of the 16 identified SSC-CIP cases were reviewed. Cholestasis was the first sign of SSC-CIP. GGT was the predominant enzyme of cholestasis. Hypercholesterolemia occurred in at least 75% of the patients. SSC-CIP provoked a profound weight loss (mean 18 kg) in 94% of our patients. SSC-CIP was diagnosed by ERC in all patients. The 3 different cholangiographic features detected correspond roughly to the following stages: (I) evidence of biliary casts, (II) progressive destruction of intrahepatic bile ducts, and (III) picture of pruned tree. Biliary cast formation is a hallmark of SSC-CIP and was seen in 87% of our cases. In 75% of the patients, the clinical course was complicated by cholangiosepsis, cholangitic liver abscesses, acalculous cholecystitis, or gallbladder perforation. SSC-CIP was associated with worse prognosis; transplant-free survival was ∼40 months (mean). Because of its high rate of serious complications and unfavorable prognosis, it is imperative to diagnose SSC-CIP early and to differentiate SSC-CIP from other types of sclerosing cholangitis. Specific characteristics enable identification of SSC-CIP. Early cooperation with a transplant center and special attention to biliary complications are required after diagnosis of SSC-CIP.

Introduction: Hepatitis E is an emerging disease in developed countries with an increasing incidence. In developed countries, HEV genotype 3 prevails as a zoonotic disease carried by wild boars or pigs, which usually causes asymptomatic infection. Case Presentation: An asymptomatic HBsAg carrier was tested regularly at a German university hospital and showed no signs of chronic hepatitis B (CHB) activity. At a routine visit, elevated aminotransferases were detected while HBV DNA remained low and the patient was clinically asymptomatic. The laboratory signs of acute hepatitis resolved spontaneously. When aminotransferases returned to normal limits, the patient showed a flare of HBV-replication, which resolved spontaneously. In follow-up, further investigations revealed a resolved hepatitis E (HEV) superinfection causing an acute hepatitis before the HBV flare. No potential risk factors for HEV infection were identified. Conclusions: Elevated aminotransferases in CHB patients are most commonly caused by exacerbation of CHB. Nevertheless, when HBV DNA is not elevated, other reasons should be excluded. Amongst others, superinfection with another hepatotropic virus can be the reason for decompensation of chronic hepatitis B. This case report describes an asymptomatic HEV superinfection followed by a flare in HBV replication in an HBsAg carrier without signs of HBV replication for eight years. In CHB carriers with signs of acute hepatitis, rare causes should be considered as well. HEV should be a part of routine laboratory evaluation for hepatitis flares given the rising number of infections.

The present multicenter phase II trial investigated the combination of TACE and sorafenib for the treatment of HCC. Eligibility criteria included histologically confirmed, unresectable HCC beyond Milan criteria, no extrahepatic spread, Child–Pugh score ≤8 and ECOG PS 0-2. Patients had received no prior therapy for HCC. Sorafenib was given at a dose of 400 mg/bid (interrupted only around TACE). TACE with lipiodol, 50 mg doxorubicin and polyvinyl alcohol (PVA) particles was repeated q6w as long as there was no overall disease progression. Tumor assessment by MRI was performed q6w according to EASL criteria. The primary endpoint was time to progression (TTP). Patients (n = 43) received a mean of 2.6 ± 2.2 TACE interventions (range 0–10). Median TTP was 16.4 months (95 % CI 10.7–∞). Median overall survival (OS) was 20.1 months (95 % CI 17.6–28.2). Disease control rate according to EASL criteria was 74.4 % (7 % complete responses [CRs] + 41.8 % partial responses [PRs] + 25.6 % stable diseases [SDs]). Four patients (9 %) became amenable to either radiofrequency ablation or liver transplantation; 5 (12 %) patients died during the trial. Overall, there were 360 AEs, including 56 grade 3/4 AEs and 39 SAEs. Combination treatment of TACE and sorafenib in the present trial was tolerable and associated with an interesting response rate, TTP and OS. Combination therapies will probably close gaps in the present mono therapy driven treatment guidelines for locally advanced HCC.

Objective Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The majority of patients with HCC have cirrhosis. Beside liver transplantation the resection is an established curative treatment option for patients with HCC in cirrhosis. However, the long term success is limited by a high tumor recurrence rate. Furthermore, by many patients surgical resection is restricted by poor liver function. The purpose of this study was to investigate the influence of patient age on long term outcome after liver resection in patients with HCC in cirrhotic liver. Further purpose was to define the potential prognostic factors. Patients and methods The outcome of 141 patients with liver cirrhosis after curative resection was analyzed using a prospective database. Only patients with postoperative histological assurance of HCC were included in the database. Patients with fibrolamellar HCC were excluded. Results By patients below 70 years of age the 1-, 3- and 5-year survival rates were 78.5%, 56.5% and 47.1%. By patients over 70 years the 1-, 3- and 5-year survival rates were 59.9%, 40.3% and 6.7%. Cumulative survival of the total collective was significant influenced by patient age, Clavien grade, positive lymph vessels, mechanical ventilation and BMI. The overall postoperative morbidity was 44.7%. No intraoperative deaths were observed, but 11 patients (8 older than 70 and 3 younger than 70 years) died during the hospital stay. Clavien grade correlated with preoperative increased GGT, need for intraoperative blood and fresh frozen plasma transfusion. Conclusions Patient age and postoperative complications are more relevant for the outcome than many tumor factors, especially by patients over 70 years of age. In contrast, the prognosis of patients below 70 years of age is significantly better and a 5 year survival rate above 50% could be shown in our patients. However, by carefully selected elderly patients with HCC in cirrhosis an acceptable long term survival is reachable.