Gender and gut microbiota composition determine hepatic bile acid, metabolic and inflammatory response to a single fast-food meal in healthy adults.

BACKGROUND & AIMS: Regular consumption of fast-food (FF) as a form of typical Western style diet is associated with obesity and the metabolic syndrome, including its hepatic manifestation nonalcoholic fatty liver disease. Currently, it remains unclear how intermittent excess FF consumption may influence liver metabolism. The study aimed to characterize the effects of a single FF binge on hepatic steatosis, inflammation, bile acid (BA), glucose and lipid metabolism. METHODS: Twenty-five healthy individuals received a FF meal and were asked to continue eating either for a two-hour period or until fully saturated. Serum levels of transaminases, fasting BA, lipid profile, glucose and cytokine levels as well as transient elastography and controlled attenuation parameter (CAP; to assess hepatic steatosis) were analyzed before (day 0) and the day after FF binge (day 1). Feces was collected prior and after the FF challenge for microbiota analysis. RESULTS: The FF meal induced a modest increase in CAP, which was accompanied by a robust increase of fasting serum BA levels. Surprisingly, levels of cholesterol and bilirubin were significantly lower after the FF meal. Differentiating individuals with a relevant delta BA (>1 µmol/l) increase vs. individuals without (delta BA ≤1 µmol/l), identified several gut microbiota, as well as gender to be associated with the BA increase and the observed alterations in liver function, metabolism and inflammation. CONCLUSION: A single binge FF meal leads to a robust increase in serum BA levels and alterations in parameters of liver injury and metabolism, indicating a novel metabolic aspect of the gut-liver axis.

Long-term outcome of patients with advanced pancreatic cancer treated with sequential chemotherapies before the era of modern combination therapy protocols.

INTRODUCTION: Patients (pts) with locally advanced (LAPC) or metastatic pancreatic ductal adenocarcinoma (mPDAC) have a dismal prognosis. Recently, new combination chemotherapies such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated superiority over gemcitabine monotherapy. However, a substantial proportion of pts cannot tolerate these intensive front-line protocols. Moreover, the long-term superiority of multiagent protocols over less intensive strategies remains to be shown. To provide a benchmark for future studies, we analyzed the outcome of patients with LAPC or mPDAC treated at the West German Cancer Center before the FOLFIRINOX/nab-paclitaxel + gemcitabine era. METHODS: This retrospective analysis included 201 consecutive pts with LAPC and mPDAC treated between 2007 and 2011. Efficacy parameters were correlated with type of chemotherapy, number of treatment lines and clinicopathological parameters. RESULTS: Gemcitabine monotherapy was given as first-line therapy in 51.1%, whereas 48.9% received combination chemotherapies such as gemcitabine/oxaliplatin or FOLFOX. Patients received a median of two lines of treatment, with 54.8% receiving second-line and 37.9% receiving third- and further-line therapies. There was no significant difference between gemcitabine monotherapy and combination therapies. Despite moderate activity of first-line treatment, median overall survival for LAPC was 11.3 months and 8.7 months for mPDAC. Multivariate analysis identified age and number of treatment lines as prognostic markers. CONCLUSION: The long-term outcome of unselected pts with LAPC and mPDAC treated before the introduction of aggressive multiagent chemotherapy protocols compares favorably with the results of contemporary benchmark trials. This suggests a multifactorial benefit from interdisciplinary care provided over sequential treatment lines at high volume expert centers.

Effects of the Mammalian Target of Rapamycin Inhibitor Everolimus on Hepatitis C Virus Replication In Vitro and In Vivo.

BACKGROUND: The influence of immunosuppressants on hepatitis C virus (HCV) re-infection after liver transplantation, particularly mammalian target of rapamycin inhibitors, remains unclear. The aim of our study was to analyze the influence of everolimus (EVR) on HCV replication activity in the context of underlying molecular mechanisms, with focus on the pro-myelocytic leukemia protein (PML). METHODS: HCV viral load was recorded in 40 patients with post-transplant HCV re-infection before and 8 weeks after introduction of EVR. An HCV cell culture replicon system for genotype (GT) 1b, GT2b, and GT3a was used to compare the influence of EVR on HCV replication for the respective genotypes in vitro. Fluorescence-activated cell-sorting analysis was used to test for effects on cell proliferation. PML expression was silenced with the use of small hairpin RNA constructs, and PML expression was quantified by means of quantitative real-time polymerase chain reaction. RESULTS: In patients with HCV, the viral load of GT1a and GT1b was hardly affected by EVR, whereas the viral load was reduced in patients with GT2a (P ≤ .0001) or GT3 infection (P ≤ .05). In vitro EVR impairs HCV replication activity of GT2a and GT3a up to 60% (P ≤ .0005), whereas in GT1b cells, HCV replication activity is increased by 50% (P ≤ .005). Replicon cell viability was not impaired. HCV replication activity is impaired in the absence of PML, which can be reversed by overexpression of PML isoforms. Furthermore, in the absence of PML, the effect of EVR on HCV replication activity is nearly abrogated. CONCLUSIONS: The mammalian target of rapamycin inhibitor EVR influences HCV replication via PML. The herein presented results suggest a genotype-dependent benefit for an EVR-based immunosuppressive regimen in patients with GT2a or GT3 re-infection after liver transplantation.

Diagnostic value of diffusion-weighted imaging (DWI) for the assessment of the small bowel in patients with inflammatory bowel disease.

AIM: To evaluate diffusion-weighted imaging (DWI) compared to standard magnetic resonance imaging (sMRI) in the assessment of inflammatory lesions of the small bowel. MATERIALS AND METHODS: Two readers retrospectively analysed MRI images of the small bowel including DWI followed by capsule endoscopy (CE) and ileocolonoscopy (ICS) in 30 consecutive patients with a suspected or established diagnosis of inflammatory bowel disease. Small bowel CE and the combination of CE + ICS were used as the standards of reference. Inflammatory lesions of the small bowel detected at endoscopy were compared with the findings of (1) sMRI alone (MRI without DWI), (2) DWI alone, and (3) sMRI in combination with DWI (sMRI + DWI). The sensitivity, specificity, and accuracy were calculated for all three readouts. The results of the three readouts were compared with each other. RESULTS: Using CE + ICS as the standard of reference, the mean sensitivity and specificity for the detection of inflammatory lesions of the small bowel at sMRI were 55.2% and 99.5%, at DWI 60% and 99%, and at sMRI + DWI 70% and 99%. Interobserver agreement between the two readers was very good (k=0.87-0.95). Two lesions in different patients were only detected at DWI. CONCLUSION: DWI of the small bowel not only allowed for the detection of inflammatory lesions with high accuracy, but also enabled the identification of additional lesions that were not found using sMRI alone.

Treatment of fulminant acute Hepatitis B with nucles(t)id analogues is safe and does not lead to secondary chronification of Hepatitis B.

Background: Acute hepatitis B virus (HBV) infection is still a major cause of acute liver failure (ALF), necessitating a high rate of emergency liver transplantation (LTx). Acute infection is followed by high viral replication rates leading to hepatocyte death and, ultimately, ALF. The objective of treating HBV-induced ALF thus is to eliminate, or significantly suppress, HBV replication and therefore reduce cell death and support regeneration. Objective: In this retrospective study, we want to evaluate the timing, the safety, and the long-term virological outcome of this approach. Methods/results: In this study, we included 32 patients (16 female and 16 males; median age 39.5 years) with ALF due to hepatitis B, who were transferred to the university hospital Essen, Germany between January 2009 and December 2013. Before treatment, transaminases were highly elevated, bilirubin was increased, and elevated international normalized ratio (INR) revealed impaired liver function. HBV-DNA and HBsAg were positive. All 32 patients received oral antiviral treatment (3 lamivudine, 21 entecavir, and 8 tenofovir) between 1 day and 4 months after diagnosis of acute hepatitis B. One patient died, 2 were transplanted, one died shortly after LTx the other patient survived after LTx. These 3 patients received treatment in a state of advanced liver failure, and 1 patient 4 months after initial diagnosis of hepatitis B. Twenty-nine patients survived without LTx. Five patients were discharged without further follow-up. All 24 remaining patients became HBV-DNA negative in median of 100 days. Twenty-two patients were followed further, and all patients lost their HBsAg in median of 108 days. Sixteen of the 22 patients experienced a seroconversion to anti-HBs in median of 137 days. Four patients who were followed for 1 more year after HBsAg did not develop anti-HBs. None of the patients developed chronic hepatitis B. Conclusion: Immediate treatment of HBV-induced ALF with nucleos(t)id-analogues (NUCs) appears save and prevents LTx and death, and there is no indication for increased chronicity.

[Hepatic steatosis : Differential diagnostics and current aspects]. / Hepatische Steatosen : Differenzialdiagnostik und aktuelle Aspekte.

The frequency of non-alcoholic fatty liver disease (NAFLD) has continously increased over the last few decades in parallel with the increasing prevalence of metabolic syndrome. With the increasing frequency of obesity and type 2 diabetes an increase in non-alcoholic steatohepatitis (NASH) is also to be expected. The NASH-associated liver cirrhosis and primary hepatocellular carcinoma (HCC) are indications for liver transplantation (LTX), which is gaining importance in Germany. In contrast, liver cirrhosis as a result of alcoholic steatohepatitis (ASH) is already the leading cause for LTX in Germany. A significant number of patients with ASH cirrhosis develop HCC. Less common causes of hepatic steatosis are secondary and include chemotherapy-associated steatohepatitis (CASH). In this article the causes, diagnostics and novel therapeutic approaches for the various forms of steatosis are discussed.

Diagnostics and treatment of a severe humoral rejection after liver transplantation: donor-specific antibodies as a still underestimated cause of graft failure.

BACKGROUND: Donor-specific antibodies (DSAs) are increasingly being considered a cause of complications after liver transplant (LT). However, neither monitoring of DSAs nor the appropriate therapeutic procedures for humoral graft damage are yet standardized. Here we report a case of DSA-positive humoral rejection after LT that was successfully treated with plasmapheresis and immunoglobulins. METHODS: Human leukocyte antigen (HLA)-specific DSAs were detected by Luminex bead assay. Patient characteristics, laboratory values, and data about the patient's general condition were documented from April 2013 to June 2015. CASE REPORT: Eighteen months after LT, a 54-year-old man experienced severe hepatopathy with rapidly increasing transaminase activity and total bilirubin levels. Histologic findings were inconclusive, demonstrating chronic cholestasis and minimal positive staining for C4 d. However, an analysis for anti-HLA antibodies detected DSAs against HLA class II molecules with high mean fluorescence intensity. The patient underwent 8 courses of plasmapheresis, resulting in sustained amelioration of his condition and decreases in bilirubin levels and transaminase activity. CONCLUSION: De novo DSAs can be responsible for graft failure after LT. Thus, procedures aimed at detecting DSAs are recommended, and regular monitoring of DSAs after LT is important for individualized risk management. Plasmapheresis is an efficient therapeutic procedure for DSA-associated graft failure.

Hepatic expression of proteasome subunit alpha type-6 is upregulated during viral hepatitis and putatively regulates the expression of ISG15 ubiquitin-like modifier, a proviral host gene in hepatitis C virus infection.

The interferon-stimulated gene 15 (ISG15) plays an important role in the pathogenesis of hepatitis C virus (HCV) infection. ISG15-regulated proteins have previously been identified that putatively affect this proviral interaction. The present observational study aimed to elucidate the relation between ISG15 and these host factors during HCV infection. Transcriptomic and proteomic analyses were performed using liver samples of HCV-infected (n = 54) and uninfected (n = 10) or HBV-infected controls (n = 23). Primary human hepatocytes (PHH) were treated with Toll-like receptor ligands, interferons and kinase inhibitors. Expression of ISG15 and proteasome subunit alpha type-6 (PSMA6) was suppressed in subgenomic HCV replicon cell lines using specific siRNAs. Comparison of hepatic expression patterns revealed significantly increased signals for ISG15, IFIT1, HNRNPK and PSMA6 on the protein level as well as ISG15, IFIT1 and PSMA6 on the mRNA level in HCV-infected patients. In contrast to interferon-stimulated genes, PSMA6 expression occurred independent of HCV load and genotype. In PHH, the expression of ISG15 and PSMA6 was distinctly induced by poly(I:C), depending on IRF3 activation or PI3K/AKT signalling, respectively. Suppression of PSMA6 in HCV replicon cells led to significant induction of ISG15 expression, thus combined knock-down of both genes abrogated the antiviral effect induced by the separate suppression of ISG15. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation. PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of HCV infection. Therefore, the proteasome might be involved in the enigmatic interaction between ISG15 and HCV.

[Relevance of Ablation Therapies for HCC: "A Real Bridging" for Liver Transplantation?]. / Stellenwert der ablativen Tumortherapie beim HCC: "eine reale Brücke" zur Lebertransplantation?

BACKGROUND: The utilisation of interventional ablation procedures in the context of bridging and downstaging plans for hepatocellular carcinomas before liver transplantation is increasing. The aim of the present study was to summarise current data for the application of bridging and downstaging procedures before liver transplantation. METHODS: The present study is based on an extensive investigation of the literature in PubMed. RESULTS of controlled trials, cohort studies, meta-analyses and reviews were included. RESULTS: Recommendations for the usage of bridging procedures for hepatocellular carcinomas within the Milan criteria and an expected waiting time of more than 6 months until transplantation depend on the size of the lesions and have a low level of evidence. After successful downstaging of hepatocellular carcinomas beyond the Milan criteria into the range of the Milan criteria liver transplantation is recommended with a low level of evidence, as well. CONCLUSION: Randomised controlled trials, clearly proving the success of bridging and downstaging procedures, are not available at the time and are not awaited for ethical reasons. Due to the uncomplicated application and low risk for therapy-associated complications, interventional procedures for bridging and downstaging are accepted and recommended.

Microarrays-Enabled Hypothesis Generation: The Suspect Role of FNBP-1 in Neuropsychiatric Pathogenesis Associated with HIV and/or HCV Infection.

OBJECTIVE: The spectrum of neuropsychiatric illness (NI) associated with the Human Immunodeficiency Virus (HIV) and/or the Hepatitis C Virus (HCV) is far reaching and significantly impacts the clinical presentation and outcome of infected persons; however, the etiological and pathophysiological background remains partially understood. The present work was aimed to investigate the potential significance of formin binding protein 1 (FNBP-1)-dependent pathways in NI-pathogenesis by elaborating on previous microarray-based research in HIV and/or HCV-infected patients receiving interferon-α (IFN-α) immunotherapy via a rigorous data mining procedure. METHODS: Using microarray data of peripheral whole blood (PB) samples obtained from HCV mono-infected persons (n=25, Affymetrix® HG-U133A_2) 12 h before and after the 1st dose of pegylated IFN-α (PegIFN-α), we re-applied the same analytical algorithm that we had developed and published in an earlier study with HIV/HCV co-infected subjects (N=28, Affymetrix® HG-U133A), in order to evaluate reproducibility of potential NI-related molecular findings in an independent cohort. RESULTS: Among 28 gene expression profiles (HIV/HCV: N=9 vs. HCV: N=19) selected by applying different thresholds (a Mean Fold Difference value (MFD) in gene expression of ≥ 0.38 (log2) and/or P value from <0.05 to ≤ 0.1) FNBP-1 was identified as the only overlapping marker, which also exhibited a consistent upregulation in association with the development of NI in both cohorts. Previous functional annotation analysis had classified FNBP-1 as molecule with significant enrichment in various brain tissues (P<0.01). CONCLUSION: Our current findings are strongly arguing for intensifying research into the FNBP-1-related mechanisms that may be conferring risk for or resistance to HIV- and/or HCV-related NI.

Performance characteristics of the VERSANT hepatitis C virus RNA 1.0 (kPCR) assay.

HCV RNA assays are of central importance for virological diagnostics and for clinical planning and monitoring of an antiviral combination treatment of chronic HCV infections. The objective of the pre-market evaluation of the VERSANT HCV RNA 1.0 Assay (kPCR) was to collect analytical performance data for this new method of HCV RNA quantification and to compare them with the high standards that exist in this context. The assay exhibited a specificity of 100%. The mean intra- and inter-assay imprecision was 14.1% and 14.6%, respectively. The detection limit was determined to be 16IU/ml (95% confidence interval: 11.9-30.6IU/ml) and consequently corresponded to the manufacturer's claims (i.e. 15IU/ml). The test exhibited linearity for all HCV genotypes in a broad range from 15 to 10(8)IU HCV RNA/ml. Hence, the kPCR assay in general is well suitable for HCV RNA determinations in clinical practice. However, in a methodological comparison, a considerable under-quantification of the concentrations of HCV genotype 2 and 3 isolates was detected. Provided that the assay's manufacturer will quickly remedy this shortcoming, the VERSANT HCV RNA 1.0 (kPCR) can be called a completely reliable technique for HCV RNA quantification in routine virological diagnostics.

Quantitative assessment of small bowel motility in patients with Crohn's disease using dynamic MRI.

BACKGROUND: Assessment of motility alterations by functional magnetic resonance imaging (MRI) contributes to improved evaluation of inflammatory bowel disease. The aim of the study was to quantify motility in inflammatory bowel segments and to compare motility alterations with MR-based parameters for activity of inflammation in Crohn's disease (CD). METHODS: Thirty consecutive patients with CD underwent bowel MRI which included a dynamic sequence for automatic generation of parametric maps facilitating quantification of bowel motility. Mean motility score (MMS) of small bowel segments with signs of inflammation was measured and compared with MMS of the whole gastrointestinal tract (GI tract). MRI-based score of inflammatory activity and lesion length were correlated with the MMS ratio of inflammatory small bowel lesion and whole GI tract. KEY RESULTS: Inflammatory bowel segments showed a mean value of MMSs of 1080, whereas the whole GI tract showed a mean value of MMSs of 2839 (p < 0.0001). Decrease in motility ranged between 20 and 87% in inflammatory bowel segments compared to the MMS of the whole GI tract. The MMS ratio of an inflammatory small bowel segment and whole GI tract showed negative correlation with MR activity score (r = -0.5921, p = 0.0003) and length of the lesion (r = -0.3495, p = 0.0462). CONCLUSIONS & INFERENCES: Quantitative assessment of motility alterations by means of motility scoring in small bowel segments affected by CD provides additional information on inflammatory activity.

[Comparison of extracorporeal liver assist devices - albumin dialysis versus plasma exchange - in acute-on-chronic liver failure]. / Vergleich extrakorporaler Leberunterstützungsverfahren - Albumin-Dialyse versus Plasmaaustausch - bei akut-auf-chronischem Leberversagen.

BACKGROUND AND AIM: Extracorporeal liver assist devices are besides causal and symptomatic approaches important therapeutic options in acute-on-chronic (AOC) liver failure. In this retrospective analysis, albumin dialysis was compared to therapeutic plasma exchange (TPA) under various aspects. PATIENTS AND METHODS: Data from 20 patients per group (10 women, 10 men in each group, mean age 51 ±â€…12,6 years and 48,2 ±â€…15,2 years, respectively) treated over a period of 3 months were analyzed. During the first treatment, 5 sessions of dialysis were performed (week 1) for both procedures, 3 more sessions were completed in the second and in the third week each. Data were acquired on days 1, 8, 13, 20, 28 and 90. RESULTS: After 28 days, 13 out of 20 patients following albumin dialysis and 7 out of 20 patients following plasma exchange had survived (p = 0,11). After 90 days, 10 patients following albumin dialysis and 5 patients following plasma exchange were alive (p = 0,19). Degree of hepatic encephalopathy (HE) had not improved significantly. Rates of complication (infections, bleeding or system clotting) were similar under both procedures. CONCLUSION: Extracorporeal liver assist devices can be considered equally well as a therapeutic option in acute-on-chronic liver failure. Differences in 90-day survival were not observed in our study.

Tacrolimus as a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis.

BACKGROUND: More recently, autoimmune pancreatitis (AIP) in association with IgG4-positive cholangitis (IAC) has been recognised as a new and challenging entity. Currently, initiation of high dose steroids (e.g., prednisolone 0.5 - 1 mg/kg/day) followed by a steroid dose taper in combination with purine antagonists (e.g., azathioprine or 6-mercaptopurine) after resolution has been recommended as standard therapy. CASE REPORT: A 68-year-old male patient was referred to our institution in February 2012 for therapy evaluation of a steroid-dependent course of autoimmune pancreatitis type 1 with IgG4-associated cholangitis. Since the first diagnosis in March 2011, the patient was treated with high-dose steroids with good response. Whenever steroids were tapered down to a daily dose <20 mg, cholestatic liver enzymes increased dramatically despite concurrent immunosuppressive therapy primarily with azathioprine and 6-MP thereafter. Therefore, we restarted steroid therapy (1 mg/kg/day) in combination with tacrolimus achieving a target level of 5 - 7 ng/mL. During the down-tapering phase, follow-up examinations presented a patient in good general condition without jaundice. Moreover, liver and pancreatic enzymes and also immunoglobulins returned to normal values without any evidence of relapse up today (66 weeks). CONCLUSION: In this case, the combination of steroids with tacrolimus seems to be a reasonable alternative in a patient with steroid-dependent and thiopurine-refractory autoimmune pancreatitis with IgG4-associated cholangitis. To date, this is the first description of such a therapeutic approach for this entity.

Long-term stimulation of Toll-like receptor 3 in primary human hepatocytes leads to sensitization for antiviral responses induced by poly I:C treatment.

Chronic hepatitis C infection is associated with increased expression of interferon-sensitive genes (ISGs) in the liver, which is, paradoxically, correlated with the nonresponse to interferon (IFN)-based therapies. In the present study PHHs were isolated from HCV-infected or uninfected patients and stimulated with the TLR1-9 ligands for 6-24 h. Expression of cytokines and ISGs was determined by ELISA and qRT-PCR. A comparative analysis was performed for TLR3 signalling, which was also correlated with single nucleotide polymorphisms (SNPs) related to HCV pathogenesis. TLR-activated PHHs produced pro-inflammatory and anti-inflammatory cytokines, whereas IFNs were exclusively induced by TLR3 stimulation. Here, IL-29 and IL-28A were significantly highly expressed than IFN-α and IFN-ß. TLR3-induced IFN response was enhanced in hepatocytes isolated from patients with HCV infection. This hyper-responsiveness could be mimicked in naïve PHHs consistently stimulated with low dose of poly I:C, but not Guardiquimod. The higher responsiveness in PHH isolated from HCV-infected patients could be partially explained by higher frequencies of unfavourable SNP alleles of different SNPs associated with HCV progression and treatment outcome. These data suggest that durable activation of TLR3 but not TLR7, by low doses of viral replicative intermediates, increases the sensitivity to viral invasion. These findings shed new light on the relevance of TLR3 in the pathogenesis of HCV and may provide a possible explanation for the increased ISG expression during chronic HCV infection, the so-called IFN paradox.

[Drug-induced liver injury as predominant cause of acute liver failure in a monocenter study]. / Medikamentös-toxische Schädigung als wichtigste Ätiologie des akuten Leberversagens.

BACKGROUND AND AIM: Clinical course and mortality of acute liver failure (ALF) are determined by its causes. Traditionally, fulminant hepatitis B infection (HBV) was thought to be the predominant etiology of ALF in Germany. However, recent studies, conducted in American and European cohorts pointed to drug-induced liver injury (DILI) as the major cause. Aim of this study was to identify currently predominant etiologies of ALF in a monocenter study at a leading transplant center in Germany. PATIENTS AND METHODS: The data of 161 patients admitted with ALF from 1/2002 to 12/2012 were analyzed retrospectively. All patients fulfilled the criteria of the "Acute Liver Failure Study Group Germany" (international normalized ratio (INR) ≥ 1.5, hepatic encephalopathy ≥ stage 1). RESULTS: DILI was the leading cause of ALF in this cohort. About 20 % of ALF patients with DILI died or received liver transplantats. Mortality rate was highest in ALF patients with unknown etiology and those without specific therapy available. CONCLUSIONS: In Europe ALF etiologies exhibit a North-South divide. In Germany the most common cause for ALF is idiosyncratic pharmacological intoxication followed by acute hepatitis B.

Toll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigen.

It has been recently shown that Toll-like receptor (TLR) signalling in murine nonparenchymal liver cells (NPCs) is suppressed in the presence of Hepatitis B virus surface antigen (HBsAg). It is not clear, however, whether this is also relevant for the adaptive immune responses and how this effect is mediated. Peripheral blood mononuclear cells (PBMCs) from Hepatitis B virus (HBV) patients and controls were stimulated by TLR ligands in the absence or presence of autologous serum. Interestingly, TLR-mediated cytokine expression (Interleukin-6 and -10) as well as TLR3-induced interferon (IFN) expression in PBMCs of HBV patients was significantly higher than in the healthy volunteers, showing a negative correlation with the levels of HBsAg. In addition, TLR3-mediated IFN-γ production was inhibited in the presence of HBV-containing serum. To mechanistically analyse this observation, murine Kupffer cells (KCs) and sinusoidal endothelial cells (LSECs) were stimulated with TLR3 ligands in the presence or absence of HBsAg. Mixed lymphocyte reactions were performed to study T-cell activation induced by TLR-stimulated NPCs. Gene expression of cytokines and TLR3 was analysed by quantitative rt-PCR, and activation of transcription factors was assessed by Western blot or reporter gene assays. TLR-induced expression of interferon γ, interferon sensitive genes and proinflammatory cytokines in murine KCs and LSECs was efficiently suppressed in the presence of HBsAg, whereas the expression of anti-inflammatory cytokines was enhanced. Activation of NFκB, IRF-3 and MAPKs in these liver cells was potently suppressed by HBsAg. T-cell activation mediated through TLR3-stimulated KCs or LSECs was suppressed by HBsAg which could be reverted by anti-IL-10 antibodies. These findings may, at least in part, explain how HBV evades innate and adaptive immune responses to maintain a persistent infection.