Publications by authors named "Hans Dieter Nischalke"

74 Publications

A genetic variant in toll-like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis.

Liver Int 2021 09 27;41(9):2139-2148. Epub 2021 Jun 27.

Department of Internal Medicine I, University Hospital, University of Bonn, Bonn, Germany.

Background & Aims: Bacterial translocation drives liver disease progression. We investigated whether functional genetic variants in toll-like receptor 5 (TLR5), the receptor for bacterial flagellin, affect the risk for hepatocellular carcinoma (HCC).

Methods: Healthy controls (n = 212), patients with alcohol abuse without liver disease (n = 382), and patients from a discovery cohort of alcohol-associated cirrhosis (n = 372 including 79 HCC cases), a validation cohort of alcohol-associated cirrhosis (n = 355 including 132 HCC cases), and a cohort of cirrhosis due to nonalcoholic steatohepatitis (NASH) (n = 145 including 62 HCC cases) were genotyped for the TLR5 rs5744174 and rs5744168 polymorphisms. Chemokine levels were measured by ELISA in patients' sera and supernatants of flagellin-stimulated healthy monocytes.

Results: Frequency of the TLR5 rs5744174 TT genotype was similar in healthy controls (33%), controls with alcohol abuse (34%), and patients with alcohol-associated cirrhosis in the discovery (28%), validation (33%), and NASH cohort (31%). The TT genotype was enriched in patients with versus without HCC in the discovery, validation, and NASH cohort (41% vs 25%; 39% vs 29%; 40% vs 24%; p < .05 each). This genotype remained a risk factor for HCC (OR = 1.9; p = .01) after multivariate correction for age, gender, diabetes, and carriage of the PNPLA3 148M variant. Interleukin-8 induction in monocytes from healthy controls and serum levels of interleukin-8 and CXCL1 from cirrhotic patients with the TT genotype were significantly increased versus C allele carriers.

Conclusion: The TLR5 rs5744174 polymorphism, affecting immune response to flagellin, is linked to occurrence of HCC in cirrhosis caused by steatohepatitis.
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http://dx.doi.org/10.1111/liv.14980DOI Listing
September 2021

Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1.

Gastroenterology 2020 10 16;159(4):1276-1289.e7. Epub 2020 Jun 16.

Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Germany.

Background And Aims: Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease.

Methods: We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068).

Results: In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020).

Conclusions: In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.
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http://dx.doi.org/10.1053/j.gastro.2020.06.014DOI Listing
October 2020

Role of regulatory T cells and checkpoint inhibition in hepatocellular carcinoma.

Cancer Immunol Immunother 2019 Dec 13;68(12):2055-2066. Epub 2019 Nov 13.

Department I of Internal Medicine, University Hospital of Bonn (UKB), Venusberg-Campus-1, 53127, Bonn, Germany.

Immune checkpoint inhibition suggests promising progress for the treatment of advanced hepatocellular carcinoma (HCC). However, the underlying cellular mechanisms remain unclear because liver cancer cells apparently do not upregulate inhibitory checkpoint molecules. Here, we analysed whether regulatory T cells (Tregs) can alternatively trigger checkpoint inhibition pathways in HCC. Using flow cytometry we analysed expression of checkpoint molecules (PD-1, PD-L1, CTLA-4, GITR, Tim-3) on peripheral CD4CD25Foxp3 Tregs and their secretion of inhibitory mediators (IL-10, IL-35, TGF-beta, galectin-9) in 116 individuals (50 patients with HCC, 41 non-tumour bearing liver disease controls, 25 healthy controls). Functional activity of Tregs on T effector cells (IFN-gamma production, cytotoxicity) was characterized in vitro using a lectin-dependent cellular cytotoxicity (LDCC) assay against checkpoint inhibitor-negative P815 target cells. Unlike liver patients without malignancy and healthy controls, the frequency of checkpoint inhibitor-positive Tregs inversely correlated to age of patients with HCC (PD-L1, p = 0.0080; CTLA-4, p = 0.0029) and corresponded to enhanced numbers of Tregs producing IL-10 and IL-35 (p < 0.05 each). Tregs inhibited IFN-gamma secretion and cytotoxicity of CD8 T cells when added to LDCC against P815 cells. Treg-induced inhibition of IFN-gamma secretion could be partially blocked by neutralizing PD-1 and PD-L1 antibodies specifically in HCC patients. In HCC peripheral Tregs upregulate checkpoint inhibitors and contribute to systemic immune dysfunction and antitumoural activity by several inhibitory pathways, presumably facilitating tumour development at young age. Blocking PD-L1/PD-1 interactions in vitro selectively interfered with inhibitory Treg -T effector cell interactions in the patients with HCC and resulted in improved antitumoural activity also against checkpoint inhibitor-negative tumour cells.
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http://dx.doi.org/10.1007/s00262-019-02427-4DOI Listing
December 2019

The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu.

J Mol Med (Berl) 2019 11 21;97(11):1589-1600. Epub 2019 Oct 21.

Department of Internal Medicine I, University Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.

The I148M variant of the Patatin-like phospholipase domain-containing 3 (PNPLA3) protein is associated with an increased risk for liver inflammation and hepatocellular carcinoma (HCC), but the underlying mechanism is unknown. We hypothesized that enhanced CXC chemokine secretion mediates hepatic inflammation that accelerates development of HCC. Expandable primary human (upcyte®) hepatocytes and human PLC/PRF/5 hepatoma cells were lentivirally transduced with both PNPLA3 I148M variants and stimulated with lipids. Cytokine levels in culture supernatant and patient sera (n = 80) were analyzed by ELISA. Supernatants were assessed in transmigration experiments, tube formation, and proliferation assays. In vitro, lipid stimulation of transduced hepatocytes dose-dependently induced the production of interleukin-8 and CXCL1 in hepatocytes carrying the PNPLA3 148M variant. In line, sera from PNPLA3 148M-positive patients with alcoholic liver cirrhosis contained higher levels of interleukin-8 and CXCL1 than patients with wild-type PNPLA3. Supernatants from lipid-stimulated hepatocytes with the PNPLA3 148M variant induced enhanced migration of white blood cells, angiogenesis, and cell proliferation in comparison with supernatants from wild-type hepatocytes via CXC receptors 1 and 2. Increased production of interleukin-8 and CXCL1 by hepatocytes carrying the PNPLA3 148M variant contributes to a pro-inflammatory and tumorigenic milieu in patients with alcoholic liver disease. KEY MESSAGES: The PNPLA3 148M variant is associated with cirrhosis and hepatocellular carcinoma. Lipid stimulation of hepatocytes with this variant induces IL-8 and CXCL1. Supernatants from hepatocytes with this variant promote migration and angiogenesis. Sera from patients with this variant contained enhanced levels of IL-8 and CXCL1. The PNPLA3 148M variant contributes to a tumorigenic milieu via IL-8 and CXCL1.
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http://dx.doi.org/10.1007/s00109-019-01836-3DOI Listing
November 2019

Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers.

Hepatology 2020 07 20;72(1):88-102. Epub 2020 May 20.

Departments of Gastroenterology and Hepatology, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland.

Background And Aims: Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC.

Approach And Results: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (OR , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10 ).

Conclusions: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.
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http://dx.doi.org/10.1002/hep.30996DOI Listing
July 2020

The ATG16L1 gene variant rs2241880 (p.T300A) is associated with susceptibility to HCC in patients with cirrhosis.

Liver Int 2019 12 11;39(12):2360-2367. Epub 2019 Sep 11.

Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Jena, Germany.

Background And Aims: Protein and organelle turnover by autophagy is a key component to maintain cellular homeostasis. Loss of the autophagy protein ATG16L1 is associated with reduced bacterial killing and aberrant interleukin-1β production, perpetuating inflammation and carcinogenesis. Here we hypothesized that the functional p.T300A gene variant in ATG16L1 is associated with an increased risk for hepatocellular carcinoma (HCC) in cirrhosis.

Methods: A case-control study was performed using a prospective derivation cohort (107 patients with HCC and 101 controls) and an independent validation cohort (124 patients with HCC and 108 controls) of patients with cirrhosis of any aetiology. ATG16L1 p.T300A (rs2241880) and PNPLA3 p.I148M (rs738409) variants were determined by real-time PCR.

Results: The G allele of the ATG16L1 p.T300A variant was more frequent in patients with HCC compared to controls without HCC in the derivation cohort (0.62 vs. 0.51, P = .022) and in the validation cohort (0.59 vs. 0.50, P = .045). In combined analysis, the odds ratios (OR) were 1.76 (95% CI: 1.07-2.88) for G allele positivity and 2.43 (95% CI: 1.37-4.31) for p.T300A G allele homozygosity. This association was independent from the presence of a PNPLA3 variant, which was also associated with HCC (OR 2.10; 95% CI: 1.20-3.66), and it remained significant after adjustment for male sex, age and aetiology in multivariate analysis.

Conclusion: The common germ-line ATG16L1 gene variant is a risk factor for HCC in patients with cirrhosis. Personalized strategies employing the genetic risk conferred by ATG16L1 and PNPLA3 may be used for risk-based surveillance in cirrhosis.
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http://dx.doi.org/10.1111/liv.14239DOI Listing
December 2019

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

Gut 2019 06 1;68(6):1099-1107. Epub 2018 Aug 1.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objective: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.

Design: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.

Results: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)).

Conclusion: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.
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http://dx.doi.org/10.1136/gutjnl-2018-316228DOI Listing
June 2019

Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis.

Am J Gastroenterol 2018 10 13;113(10):1475-1483. Epub 2018 Mar 13.

Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland. Medical Department 1, University Hospital Dresden, TU Dresden, Dresden, Germany. Department of Internal Medicine I, University of Bonn, Bonn, Germany. Department of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany. Hepatology Section, Division of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. Department of Gastroenterology, University Hospital Halle/Saale, Halle, Germany. Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. Department of Medicine II, Saarland University Medical Center, Homburg, Germany. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK. Medical Department 1, University of Erlangen, Nuremberg, Bavaria, Germany. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany. Department of Clinical Toxicology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Institute of Laboratory Animal Science, University of Zurich, Schlieren, Switzerland. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. These authors have contributed equally to the presented work and share premier authorship: Felix Stickel, Stephan Buch. These authors have contributed equally to the presented work and share senior authorship: Pierre Deltenre, Thomas Berg, Marsha Y. Morgan, and Jochen Hampe.

Objectives: Variants in patatin-like phospholipase domain-containing 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), and membrane bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) are risk factors for the development of alcohol-related cirrhosis. Within this population, PNPLA3 rs738409 is also an established risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to explore possible risk associations of TM6SF2 rs58542926 and MBOAT7 rs641738 with HCC.

Methods: Risk variants in PNPLA3, TM6SF2, and MBOAT7 were genotyped in 751 cases with alcohol-related cirrhosis and HCC and in 1165 controls with alcohol-related cirrhosis without HCC. Association with the risk of developing HCC was analyzed using multivariate logistic regression.

Results: The development of HCC was independently associated with PNPLA3 rs738409 (OR 1.84 [95% CI 1.55-2.18], p = 1.85 × 10) and TM6SF2 rs58542926 (OR 1.66 [1.30-2.13], p = 5.13 × 10), using an additive model, and controlling the sex, age, body mass index, and type 2 diabetes mellitus; the risk associated with carriage of MBOAT7 rs641738 (OR 1.04 [0.88-1.24], p = 0.61) was not significant. The population-attributable fractions were 43.5% for PNPLA3 rs738409, 11.5% for TM6SF2 rs58542926, and 49.9% for the carriage of both the variants combined.

Conclusions: Carriage of TM6SF2 rs58542926 is an additional risk factor for the development of HCC in people with alcohol-related cirrhosis. Carriage of both PNPLA3 rs738409 and TM6SF2 rs58542926 accounts for half of the attributable risk for HCC in this population. Genotyping will allow for more precise HCC risk-stratification of patients with alcohol-related cirrhosis, and genotype-guided screening algorithms would optimize patient care.
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http://dx.doi.org/10.1038/s41395-018-0041-8DOI Listing
October 2018

Relative Ascites Polymorphonuclear Cell Count Indicates Bacterascites and Risk of Spontaneous Bacterial Peritonitis.

Dig Dis Sci 2017 09 9;62(9):2558-2568. Epub 2017 Jun 9.

Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany.

Background And Aims: Absolute polymorphonuclear (PMN) counts in ascites define spontaneous bacterial peritonitis (SBP), a severe form of bacterial infection in liver cirrhosis. Bacterascites, another form of ascites infection, can progress to SBP or may resolve spontaneously but is not reflected by absolute PMN counts. We investigated whether the relative ascites PMN count (the absolute PMN count divided by the absolute leukocyte count) provides additional information to detect bacterascites or predict SBP.

Methods: Hospitalized patients with liver cirrhosis requiring paracentesis were stratified with respect to a diagnosis of bacterascites and SBP with a prospective follow-up for 1 year. Diagnostic power of relative PMN counts in ascites was evaluated by receiver operating characteristics curves.

Results: At inclusion, we observed 28/269 (10%) and 43/269 (16%) episodes of BA and SBP, respectively. Unlike absolute PMN counts, relative PMN counts in ascites were significantly elevated in bacterascites (p = 0.001). During follow-up, 16 and 30 further episodes of BA and SBP were detected, respectively. Relative PMN counts increased significantly once patients developed BA (p = 0.001). At a threshold of 0.20 for the relative PMN count, sensitivity, specificity, positive and negative predictive values for bacterascites which required antibiotic treatment were 83, 75, 26 and 98%, respectively (p < 0.001). Furthermore, a relative PMN count in ascites ≥0.13 and MELD score >17 was independent factors associated with occurrence of SBP during follow-up.

Conclusion: The relative PMN count is a cheap immunological marker linked to bacterascites and future SBP, which may help to stratify patients according to their risk of infection.
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http://dx.doi.org/10.1007/s10620-017-4637-4DOI Listing
September 2017

Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART).

PLoS One 2017 8;12(6):e0178685. Epub 2017 Jun 8.

Department of Internal Medicine I, Rheinische Friedrich-Wilhelms University Bonn, Bonn, Germany.

Hepatic steatosis can occur with any antiretroviral therapy (cART). Although single nucleotide polymorphisms (SNPs) have been identified to predispose to alcoholic and non-alcoholic fatty liver disease, their role for treatment-associated steatosis in HIV-positive patients remains unclear. We determined the frequency of PNPLA3 (rs738409), CSPG3/NCAN (rs2228603), GCKR (rs780094), PPP1R3B (rs4240624), TM6SF (rs8542926), LYPLAL1 (rs12137855) and MBOAT7 (rs626283) by RT-PCR in 117 HIV-positive patients on cART and stratified participants based on their "controlled attenuation parameter" (CAP) into probable (CAP: 215-300 dB/m) and definite (CAP >300 dB/m) hepatic steatosis. We analyzed CAP values and routine metabolic parameters according to the allele frequencies. Sixty-five (55.6%) and 13 (11.1%) patients were allocated to probable and definite steatosis. CAP values (p = 0.012) and serum triglycerides (p = 0.043) were increased in carriers of the GCKR (rs780094) A allele. Cox logistic regression identified triglycerides (p = 0.006), bilirubin (p = 0.021) and BMI (p = 0.068), but not the genetic parameters as risk factors for the occurrence of hepatic steatosis. Taken together, according to the limited sample size, this exploratory study generates the hypothesis that genetic polymorphisms seem to exert minor effects on the risk for fatty liver disease in HIV-positive patients on cART. Nevertheless, SNPs may modify metabolic complications once metabolic abnormalities have developed. Hence, subsequent analysis of a larger cohort is needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178685PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464588PMC
September 2017

Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy.

PLoS Pathog 2017 May 15;13(5):e1006373. Epub 2017 May 15.

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

Innate lymphocyte cells (ILCs), a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV)-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(-) individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI) tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+)ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+) patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+) and HIV(-) individuals.
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http://dx.doi.org/10.1371/journal.ppat.1006373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444854PMC
May 2017

Influence of genetic variations in the SOD1 gene on the development of ascites and spontaneous bacterial peritonitis in decompensated liver cirrhosis.

Eur J Gastroenterol Hepatol 2017 Jul;29(7):800-804

aDepartment of Internal Medicine I bInstitute of Experimental Immunology, University of Bonn cGerman Center for Infection Research, partner site Bonn-Cologne, Bonn dDepartment of Medicine II, Saarland University Medical Center, Homburg, Germany eFaculty of Health Sciences, University of Southern Denmark, Odense, Denmark fEuropean Foundation for Chronic Liver Failure gInstitute for Bioengineering of Catalonia, Barcelona, Spain.

Background: The balance between generation and elimination of reactive oxygen species by superoxide dismutase (SOD) is crucially involved in the pathophysiology of liver cirrhosis. Reactive oxygen species damage cells and induce inflammation/fibrosis, but also play a critical role in immune defense from pathogens. As both processes are involved in the development of liver cirrhosis and its complications, genetic variation of the SOD1 gene was investigated.

Patients And Methods: Two SOD1 single nucleotide polymorphisms (rs1041740 and rs3844942) were analyzed in 49 cirrhotic patients undergoing liver transplantation. In addition, 344 cirrhotic patients with ascites were analyzed in a cohort of 521 individuals in terms of the relationship of these polymorphisms with spontaneous bacterial peritonitis (SBP).

Results: Although rs3844942 showed no associations with complications of cirrhosis, we observed a significant association between rs1041740 and the presence of ascites and SBP in the discovery cohort of patients with cirrhosis. Importantly, the association with SBP was not confirmed in the validation cohort of patients with ascites. By contrast, a trend toward lower SBP rates was observed in carriers of rs1041740. In this cohort, rs1041740 was not associated with survival.

Conclusion: These data suggest a complex role of SOD1 in different processes leading to complications of liver cirrhosis. rs1041740 might be associated with the development of ascites and possibly plays a role in SBP once ascites has developed.
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http://dx.doi.org/10.1097/MEG.0000000000000878DOI Listing
July 2017

Increased peripheral CD4 regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C.

J Hepatol 2017 05 29;66(5):888-896. Epub 2016 Dec 29.

Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany.

Background & Aims: CD4 regulatory T cells (Tregs) expand during chronic hepatitis C virus (HCV) infection, inhibit antiviral immunity and promote fibrosis. Direct-acting antiviral agents (DAA) have revolutionized HCV therapy. However, it is unclear if Tregs are normalized after DAA-induced HCV elimination.

Methods: We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3 CD25 CD4 T cells were studied by multi-color flow cytometry and co-culture inhibition assays.

Results: Frequencies and activation status of Foxp3 CD25 CD4 T cells remained elevated above those of normal controls in both treatment groups even long-term after HCV elimination. Co-culture assays indicated a dose-response relationship for functional inhibition of autologous CD4 effector T cells and confirmed that activation of Tregs remained largely unchanged over the observation period. Unlike IFN-free regimens, SOF plus IFN/ribavirin induced a transiently increased frequency of Foxp3 CD25 CD4 T cells at EOT (5.0% at baseline to 6.1% at EOT; p=0.001). These Foxp3 CD25 CD4 T cells co-expressed the activation markers glycoprotein A repetitions predominant (GARP; p=0.012) and tumor necrosis factor receptor superfamily, member 4 (OX-40; p=0.001) but showed unchanged in vitro inhibitory activity.

Conclusion: Although IFN-based DAA therapy induced transient expansion of activated Foxp3 CD25 CD4 T cells, neither IFN-based nor IFN-free DAA regimens normalized frequencies and activation status of Tregs one year after viral elimination. Persistence of immunosuppressive Tregs may thus contribute to complications of liver disease even long-term after HCV cure.

Lay Summary: In chronic hepatitis C virus (HCV) infection, CD4 regulatory T cells (Tregs) can reduce antiviral immune responses, promote liver fibrosis and may increase the risk for liver cancer, because they gradually expand during disease. Modern direct-acting antiviral agents (DAA) can "cure" hepatitis C in almost all treated patients. However, our study shows that DAA do not normalize the increased frequency and activation status of Tregs even long-term after HCV elimination. Tregs may persistently modulate functions of the immune system even after "cure" of hepatitis C.
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http://dx.doi.org/10.1016/j.jhep.2016.12.019DOI Listing
May 2017

Antibiotic resistance in healthcare-related and nosocomial spontaneous bacterial peritonitis.

Eur J Clin Invest 2017 Jan 7;47(1):44-52. Epub 2016 Dec 7.

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

Background: Spontaneous bacterial peritonitis (SBP) can be life threatening in patients with liver cirrhosis. In contrast to community-acquired SBP, no standard treatment has been established for healthcare-related and nosocomial SBP.

Materials And Methods: We prospectively collected healthcare-related and nosocomial SBP cases from March 2012 till February 2016 at the Department of Internal Medicine I of the University of Bonn and analysed the prevalence of antibiotic resistance among the isolated bacteria. SBP was diagnosed according to international guidelines. Ciprofloxacin, ceftriaxone and meropenem were used as reference substance for resistance to quinolones, third-generation cephalosporins and carbapenems, respectively.

Results: Ninety-two SBP episodes in 86 patients were identified: 63 episodes (69%) were nosocomial. Escherichia coli, Klebsiella species, enterococci and streptococci were most frequently isolated. Frequencies of these microorganisms were comparable for healthcare-related and nosocomial SBP (14% vs. 11%, 14% vs. 8%, 14% vs. 5% and 10% vs. 6%, respectively). In general, antibiotic resistance was higher in isolates from nosocomial than from healthcare-related SBP (50% vs. 18% for quinolones, 30% vs. 11% for piperacillin-tazobactam; P > 0·05), but comparable concerning third-generation cephalosporins (30% vs. 33%). All microorganisms were sensitive to carbapenems apart from nosocomial infections with Enterococcus faecium (n = 3) and Candida albicans (n = 1) due to intrinsic resistance or lack of microbiological efficacy, respectively. No multidrug-resistant microorganisms were detected. Resistance to initial antibiotic treatment affected 30-day survival negatively (18% vs. 68%; P = 0·002).

Conclusion: Resistance to initial antibiotic treatment was associated with increased mortality. With resistance to cephalosporins being frequent, piperacillin-tazobactam or carbapenems might be preferred as treatment of SBP.
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http://dx.doi.org/10.1111/eci.12701DOI Listing
January 2017

IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C.

PLoS One 2016 1;11(9):e0162068. Epub 2016 Sep 1.

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

Background: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity.

Methods: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used.

Results: Following stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals.

Conclusions: Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008784PMC
July 2017

A variant in the nuclear dot protein 52kDa gene increases the risk for spontaneous bacterial peritonitis in patients with alcoholic liver cirrhosis.

Dig Liver Dis 2016 Jan 28;48(1):62-8. Epub 2015 Sep 28.

Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research, Germany.

Background: Spontaneous bacterial peritonitis is frequently a fatal infection in patients with liver cirrhosis. We investigated if nuclear dot protein 52kDa (NDP52), a negative regulator of toll-like receptor (TLR) signalling and autophagy adaptor protein, might be involved.

Methods: Two cohorts comprising 152 (derivation cohort) and 198 patients (validation cohort) with decompensated liver cirrhosis and 168 healthy controls were genotyped for the rs2303015 polymorphism in the NDP52 gene and prospectively followed-up for spontaneous bacterial peritonitis.

Results: Overall, 57 (38%) patients in the derivation cohort and 77 (39%) in the validation cohort had spontaneous bacterial peritonitis. Cirrhosis was due to alcohol abuse in 57% of the derivation and 66% of the validation cohort. In patients with alcoholic cirrhosis, patients with spontaneous bacterial peritonitis had an increased frequency of the NDP52 rs2303015 minor variant in the derivation (p=0.04) and in the validation cohort (p=0.01). Multivariate analysis confirmed this minor variant (odds ratio 4.7, p=0.002) and the TLR2 -16934 TT variant (odds ratio 2.5, p=0.008) as risk factors for spontaneous bacterial peritonitis. In addition, presence of the NDP52 minor variant affected survival negatively.

Conclusion: Presence of the NDP52 rs2303015 minor variant increases the risk for spontaneous bacterial peritonitis in patients with alcoholic cirrhosis.
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http://dx.doi.org/10.1016/j.dld.2015.09.011DOI Listing
January 2016

A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis.

Nat Genet 2015 Dec 19;47(12):1443-8. Epub 2015 Oct 19.

Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Cliniques Universitaires de Bruxelles (CUB) Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.

Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
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http://dx.doi.org/10.1038/ng.3417DOI Listing
December 2015

Hypoxia impairs anti-viral activity of natural killer (NK) cells but has little effect on anti-fibrotic NK cell functions in hepatitis C virus infection.

J Hepatol 2015 Dec 20;63(6):1334-44. Epub 2015 Aug 20.

Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Bonn, Germany. Electronic address:

Background & Aims: Natural killer (NK) cells have been shown to exert anti-viral as well as anti-fibrotic functions in hepatitis C virus (HCV) infection. Previous studies, however, analyzed NK cell functions exclusively under atmospheric oxygen conditions despite the fact that the liver microenvironment is hypoxic. Here, we analyzed the effects of low oxygen tension on anti-viral and anti-fibrotic NK cell activity.

Methods: Peripheral (n=34) and intrahepatic (n=15) NK cells from HCV(+) patients as well as circulating NK cells from healthy donors (n=20) were studied with respect to anti-viral and anti-fibrotic activity via co-culture experiments with HuH7 replicon cells and hepatic stellate cells, respectively.

Results: Anti-viral activity of resting NK cells from healthy controls was not affected by hypoxia. However, hypoxia significantly reduced the response of healthy NK cells to cytokine stimulation. In contrast to healthy controls, we observed resting and cytokine activated peripheral NK cells from HCV patients to display a significantly decreased anti-viral activity when cultured at 5% or 1% oxygen, suggesting HCV NK cells to be very sensitive to hypoxia. These findings could be confirmed when intrahepatic NK cells were tested. Finally, we show that anti-fibrotic NK cell activity was not affected by low oxygen tension.

Conclusions: Our results show that anti-viral function of NK cells from HCV(+) patients is critically affected by a hypoxic microenvironment and, therefore, indicate that in order to obtain an accurate understanding of intrahepatic NK cell anti-HCV activity, the laboratory modelling should take into account the liver specific levels of oxygen.
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http://dx.doi.org/10.1016/j.jhep.2015.08.008DOI Listing
December 2015

The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites.

Clin Chem Lab Med 2015 Nov;53(12):2031-9

Background: Diagnosis of spontaneous bacterial peritonitis (SBP) is based on a differential ascites leukocyte count which does not provide prognostic information. We performed a pilot study to assess calprotectin in ascites as an alternative diagnostic and prognostic marker.

Methods: We collected ascites from patients with liver cirrhosis from March 2012 to July 2013. Routine clinical and laboratory data of the patients were recorded. Ascites calprotectin levels were determined by ELISA.

Results: Overall, we collected 120 ascites samples from 100 patients with liver cirrhosis and from eight patients with malignant peritoneal effusion as disease control. Samples without infection had significantly lower calprotectin levels (median 34 ng/mL, range 5-795) than SBP samples (median 928 ng/mL, range 21-110,480; p<0.001) and malignant effusions (median 401, range 47-2596 ng/mL; p<0.001). In non-infected ascites, calprotectin levels were higher in Child-Pugh stage B versus C (median 57 ng/mL vs. 17 ng/mL; p<0.001) and in alcoholic versus viral cirrhosis (median 37 ng/mL vs. 10 ng/mL; p=0.015). The ratio of ascites calprotectin to total protein was a better marker for SBP than calprotectin alone (AUROC=0.93; p<0.001; sensitivity 93%, specificity 79%; positive predictive value 60%; negative predictive value 97%). In addition, high levels of the ratio to total protein were associated with poor 30-day survival (p=0.042).

Conclusions: The ratio of ascites calprotectin to total protein may be a promising new diagnostic and prognostic marker in patients with liver cirrhosis and SBP and should be evaluated further.
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http://dx.doi.org/10.1515/cclm-2015-0284DOI Listing
November 2015

Low ascitic fluid protein does not indicate an increased risk for spontaneous bacterial peritonitis in current cohorts.

J Hepatol 2015 Aug 24;63(2):527-8. Epub 2015 May 24.

Department of Internal Medicine I, Bonn University Hospital, Bonn, Germany.

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http://dx.doi.org/10.1016/j.jhep.2015.03.040DOI Listing
August 2015

PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease.

Am J Gastroenterol 2015 Jun 12;110(6):846-56. Epub 2015 May 12.

Division of Gastroenterology and Hepatology, University of Alabama, Birmingham, Alabama, USA.

Objectives: The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity.

Methods: Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses.

Results: Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients.

Conclusions: PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.
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http://dx.doi.org/10.1038/ajg.2015.137DOI Listing
June 2015

Spontaneous bacterial peritonitis: The clinical challenge of a leaky gut and a cirrhotic liver.

World J Hepatol 2015 Mar;7(3):304-14

Philipp Lutz, Hans Dieter Nischalke, Christian P Strassburg, Ulrich Spengler, Department of Internal Medicine I, University of Bonn, D-53129 Bonn, Germany.

Spontaneous bacterial peritonitis (SBP) is a frequent, life-threatening bacterial infection in patients with liver cirrhosis and ascites. Portal hypertension leads to increased bacterial translocation from the intestine. Failure to eliminate invading pathogens due to immune defects associated with advanced liver disease on the background of genetic predisposition may result in SBP. The efficacy of antibiotic treatment and prophylaxis has declined due to the spread of multi-resistant bacteria. Patients with nosocomial SBP and with prior antibiotic treatment are at a particularly high risk for infection with resistant bacteria. Therefore, it is important to adapt empirical treatment to these risk factors and to the local resistance profile. Rifaximin, an oral, non-absorbable antibiotic, has been proposed to prevent SBP, but may be useful only in a subset of patients. Since novel antibiotic classes are lacking, we have to develop prophylactic strategies which do not induce bacterial resistance. Farnesoid X receptor agonists may be a candidate, but so far, clinical studies are not available. New diagnostic tests which can be carried out quickly at the patient's site and provide additional prognostic information would be helpful. Furthermore, we need tools to predict antibiotic resistance in order to tailor first-line antibiotic treatment of spontaneous bacterial peritonitis to the individual patient and to reduce mortality.
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http://dx.doi.org/10.4254/wjh.v7.i3.304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381159PMC
March 2015

A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis.

Dig Liver Dis 2014 Nov 30;46(11):1047-50. Epub 2014 Jul 30.

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

Background: In mice, the farnesoid X receptor is involved in bacterial translocation, which can result in spontaneous bacterial peritonitis in patients with cirrhosis. We investigated if polymorphisms in the farnesoid X receptor gene influence the risk for spontaneous bacterial peritonitis.

Methods: Laboratory and clinical data of 293 cirrhotic patients with ascites and 226 healthy controls were prospectively collected. The rs56163822, rs11110390 and rs12313471 polymorphisms of the farnesoid X receptor were determined.

Results: 115 (39%) patients had spontaneous bacterial peritonitis. Distribution of all farnesoid X receptor genotypes matched the Hardy-Weinberg equilibrium. Patients with spontaneous bacterial peritonitis had a higher frequency of the rs56163822 GT genotype (7.0%) than patients without (1.7%, OR=4.4, p=0.02). This genotype was confirmed as predictor of spontaneous bacterial peritonitis by binary logistic regression analysis (OR=6.8, p=0.018).

Conclusion: The farnesoid X receptor rs56163822 GT genotype increases the risk for spontaneous bacterial peritonitis in cirrhotic patients with ascites.
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http://dx.doi.org/10.1016/j.dld.2014.07.008DOI Listing
November 2014

A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease.

J Hepatol 2014 Nov 16;61(5):1073-9. Epub 2014 Jun 16.

Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany. Electronic address:

Background & Aims: The genetic background of alcoholic liver diseases and their complications are increasingly recognized. A common polymorphism in the neurocan (NCAN) gene, which is known to be expressed in neuronal tissue, has been identified as a risk factor for non-alcoholic fatty liver disease (NAFLD). We investigated if this polymorphism may also be related to alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC).

Methods: We analysed the distribution of the NCAN rs2228603 genotypes in 356 patients with alcoholic liver cirrhosis, 126 patients with alcoholic HCC, 382 persons with alcohol abuse without liver damage, 362 healthy controls and in 171 patients with hepatitis C virus (HCV) associated HCC. Furthermore, a validation cohort of 229 patients with alcoholic cirrhosis (83 with HCC) was analysed. The genotypes were determined by LightSNiP assays. The expression of NCAN was studied by RT-PCR and immunofluorescence microscopy.

Results: The frequency of the NCAN rs2228603 T allele was significantly increased in patients with HCC due to ALD (15.1%) compared to alcoholic cirrhosis without HCC (9.3%), alcoholic controls (7.2%), healthy controls (7.9%), and HCV associated HCC (9.1%). This finding was confirmed in the validation cohort (15.7% vs. 6.8%, OR=2.53; 95%CI: 1.36-4.68; p=0.0025) and by multivariate analysis (OR=1.840; 95%CI: 1.22-2.78; p=0.004 for carriage of the rs2228603 T allele). In addition, we identified and localised NCAN expression in human liver.

Conclusions: NCAN is not only expressed in neuronal tissue, but also in the liver. Its rs2228603 polymorphism is a risk factor for HCC in ALD, but not in HCV infection.
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http://dx.doi.org/10.1016/j.jhep.2014.06.006DOI Listing
November 2014

CD27(+)CD56Bright natural killer cells may be involved in spontaneous clearance of acute hepatitis C in HIV-positive patients.

AIDS 2014 Aug;28(13):1879-84

Department of Internal Medicine I, University of Bonn, German Center for Infection Research (DZIF), Bonn, Germany.

Objective: The objective of this study was to analyse the potential role of CD27 in natural killer (NK) cell-mediated control of hepatitis C virus (HCV) infection in HIV-positive patients.

Design: Frequency of CD27-expressing CD56 NK cells was analysed in HIV mono-infected individuals and HIV-positive patients with acute or chronic hepatitis C. Anti-HCV activity of CD27(+) and CD27(-) NK cells was compared.

Methods: NK cell mediated inhibition of HCV replication was analysed using the HUH7 HCV Replicon model. NK cell phenotype and interferon (IFN) secretion was studied by flowcytometry.

Results: High frequency of CD27(+)CD56 NK cells is associated with spontaneous clearance of acute hepatitis C in HIV-positive patients. Accordingly, we found CD27(+)CD56 NK cells to display strong anti-HCV activity.

Conclusion: Our results underline the important role of NK cells in modulating outcome of HCV infection.
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http://dx.doi.org/10.1097/QAD.0000000000000355DOI Listing
August 2014

Impact of rifaximin on the frequency and characteristics of spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites.

PLoS One 2014 8;9(4):e93909. Epub 2014 Apr 8.

Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research.

Background: Rifaximin is a non-absorbable antibiotic used to prevent relapses of hepatic encephalopathy which may also be a candidate for prophylaxis of spontaneous bacterial peritonitis (SBP).

Aim: To detect the impact of rifaximin on the occurrence and characteristics of SBP.

Methods: We prospectively studied all hospitalized patients that underwent a diagnostic paracentesis in our department from March 2012 to April 2013 for SBP and recorded all clinical data including type of SBP prophylaxis, prior use of rifaximin, concomitant complications of cirrhosis, as well as laboratory results and bacteriological findings. Patients were divided into the following three groups: no antibiotic prophylaxis, prophylaxis with rifaximin or with systemically absorbed antibiotic prophylaxis.

Results: Our study cohort comprised 152 patients with advanced liver cirrhosis, 32 of whom developed SBP during the study period. As expected, our study groups differed regarding a history of hepatic encephalopathy and SBP before inclusion into the study. None of the 17 patients on systemic antibiotic prophylaxis developed SBP while 8/27 patients on rifaximin and 24/108 without prophylaxis had SBP (p = 0.02 and p = 0.04 versus systemic antibiotics, respectively). In general, episodes of SBP were similar for patients treated with rifaximin and those without any prophylaxis. However, Escherichia coli and enterococci were dominant in the ascites of patients without any prophylaxis, while mostly klebsiella species were recovered from the ascites samples in the rifaximin group.

Conclusion: Rifaximin pretreatment did not lead to a reduction of SBP occurrence in hospitalized patients with advanced liver disease. However, the bacterial species causing SBP were changed by rifaximin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093909PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979735PMC
January 2015

An effective interferon-gamma-mediated inhibition of hepatitis C virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis C in human immunodeficiency virus-positive patients.

Hepatology 2014 Mar 21;59(3):814-27. Epub 2014 Jan 21.

Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Bonn, Germany.

Unlabelled: Hepatitis C virus (HCV) coinfection is an increasing health problem in human immunodeficiency virus-positive (HIV(+) ) individuals. However, a considerable proportion of HIV(+) patients manage to overcome acute hepatitis C (AHC) spontaneously. In the present study, we analyzed the role of natural killer (NK) cells in modulating the course of AHC in HIV(+) patients. Twenty-seven HIV(+) patients with AHC (self-limited course: n = 10; chronic course: n = 17), 12 HIV(+) patients with chronic hepatitis C (CHC), 8 HIV monoinfected individuals, and 12 healthy controls were studied. NK cells were phenotypically analyzed by flow cytometry. Interferon-gamma (IFN-γ) secretion, degranulation (CD107a), and anti-HCV (= inhibition of HCV replication) activity of NK subpopulations were analyzed using the HuH7A2 HCVreplicon cell system. NK cell frequency did not differ significantly between HIV(+) patients with chronic and self-limited course of AHC. However, we found NK cells from patients with self-limiting infection to be significantly more effective in inhibiting HCV replication in vitro than NK cells from patients developing CHC. Of note, antiviral NK cell activity showed no significant correlation with NK cell degranulation, but was positively correlated with IFN-γ secretion, and blocking experiments confirmed an important role for IFN-γ in NK cell-mediated inhibition of HCV replication. Accordingly, NK cells from patients that spontaneously cleared the virus displayed a stronger IFN-γ secretion than those developing chronic infection. Finally, we observed high expression of NKG2D and NKp46, respectively, to be associated with self-limiting course of aHCV. Accordingly, we found that blocking of these NK cell receptors significantly impaired antiviral NK cell activity.

Conclusion: Our data suggest a strong IFN-γ-mediated antiviral NK cell response to be associated with a self-limited course of AHC in HIV(+) patients.
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http://dx.doi.org/10.1002/hep.26782DOI Listing
March 2014
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