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ABSTRACT: Direct-acting antiviral drugs (DAAs) are currently replacing antiviral therapy for Hepatitis C infection. Treatment related side effects are even worse and the emergence of resistant viruses must be avoided because of the direct-antiviral action. Altogether it remains a challenge to take treatment decisions in a clinical setting with cost restrictions. Genetic host factors are hereby essential to implement an individualized treatment concept. In recent years results on different genetic variants have been published with a strong association with therapy response, fibrosis and treatment-related side effects. Polymorphisms of the IL28B gene were identified as accurate predictors for therapy response and spontaneous clearance of HCV infection and are already used for diagnostic decisions. For RBV-induced side effects, such as hemolytic anemia, associations to genetic variants of inosine triphosphatase (ITPA) were described and different SLC28 transporters for RBV-uptake have been successfully analyzed. Fibrosis progression has been associated with variants of Vitamin D receptor (VDR) and ABCB11 (bile salt export pump). Cirrhotic patients especially have a high treatment risk and low therapy response, so that personalized antiviral treatment is mandatory. This review focuses on different host genetic variants in the pathogenesis of Hepatitis C at the beginning of a new area of treatment.
Viruses 12/2012; 4(12):3281-302. · 1.50 Impact Factor
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Monika Rau,
Felix Stickel,
Stefan Russmann,
Christine Manser,
Philip Becker,
Michael Weisskopf,
Johannes Schmitt,
Michael T Dill,
Jean-François Dufour,
Darius Moradpour,
David Semela,
Beat Müllhaupt, Andreas Geier
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ABSTRACT: BACKGROUND & AIMS: In the last decade pegylated interferon-α (Peg-INF-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed to study genetic determinants of RBV kinetics, efficacy and treatment associated anemia. METHODS: We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726 and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101 and followed regarding treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients RBV serum levels were additionally measured during treatment. RESULTS: Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ⩾ 3 g/dl during treatment in genotype (relative risk (RR)=2.1, 95%CI 1.3-3.5) as well as in allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as in allelic analyses (RR=2.0, 95% CI 1.1-3.4). CONCLUSIONS: The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV induced anemia and treatment response may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.
Journal of Hepatology 11/2012; · 9.26 Impact Factor
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MMW Fortschritte der Medizin 07/2012; 154(13):63-7; quiz 68-9.
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ABSTRACT: Increased serum bile salt levels have been associated to a single-nucleotide polymorphism in the bile salt export pump (BSEP; ABCB11) in several acquired cholestatic liver diseases but there is little evidence in alcoholic liver disease (ALD). Furthermore, a crosstalk between vitamin D and bile acid synthesis has recently been discovered. Whether this crosstalk has an influence on the course of ALD is unclear to date. Our aim was to analyse the role of genetic polymorphisms in BSEP and the vitamin D receptor gene (NR1I1) on the emergence of cirrhosis in patients with ALD. Therefore, 511 alcoholic patients (131 with cirrhosis and 380 without cirrhosis) underwent ABCB11 genotyping (rs2287622). Of these, 321 (131 with cirrhosis and 190 without cirrhosis) were also tested for NR1I1 polymorphisms (bat-haplotype: BsmI rs1544410, ApaI rs7975232 and TaqI rs731236). Frequencies of ABCB11 and NR1I1 genotypes and haplotypes were compared between alcoholic patients with and without cirrhosis and correlated to serum bile salt, bilirubin and aspartate aminotransferase levels in those with cirrhosis. Frequencies of ABCB11 and NR1I1 genotypes and haplotypes did not differ between the two subgroups and no significant association between genotypes/haplotypes and liver function tests could be determined for neither polymorphism. We conclude that ABCB11 and NR1I1 polymorphisms are obviously not associated with development of cirrhosis in patients with ALD.
Mutagenesis 04/2012; 27(5):567-72. · 3.18 Impact Factor
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ABSTRACT: Expression of hepatobiliary transporters is decreased during endotoxemia. Reduction of Mrp2 is mediated by IL-1β-dependent signals but underlying mechanisms are still unclear. YB-1 is a predominantly cytoplasmic protein that translocates to the nucleus in response to various stimuli. Previously we have shown that YB-1 down-regulates Mrp2 expression in vitro. Therefore we investigated the potential role of YB-1 as regulator of hepatic acute phase genes.
Liver sections from LPS-injected rats (20 h) were stained with YB-1-specific antibodies. Real-time RT-PCR quantification was performed for Mrp2, MMP-2 and YB-1. YB-1 protein was quantified from IL-1β- or TNFα-stimulated rat hepatoma cells (FaO) and the localization of a YFP-YB-1-CFP fusion protein was visualized by confocal microscopy in HepG2 human hepatocellular carcinoma cells. ChIP-assays and EMSA were performed to analyze YB-1 binding to DNA promoter elements.
In endotoxemic livers Mrp2 mRNA was down-regulated by 80%, while YB-1 mRNA expression increased 2.5-fold. Immunohistochemical staining showed a marked up-regulation and predominant nuclear localization of YB-1 protein in LPS challenged rats. In FAO cells IL-1β incubation increased cytoplasmic YB-1 protein content up to 16h. IL-1β stimulation resulted in a 6-fold up-regulation of endogenous YB-1 in the nuclear compartment, which occurred within 90min. In accord with these findings nuclear fluorescence was detected with a YFP-YB-1-CFP fusion protein introduced in HepG2 cells. In addition to DNA binding studies with endotoxemic rat liver tissue, ChIP assays revealed an IL-1β-dependent increase of YB-1 binding to the Mrp2-promoter in FAO cells.
YB-1 is activated during the hepatic acute phase response. IL-1β promotes a rapid nuclear YB-1 protein shuttling in hepatoma cells within 90 min and a transcriptional induction thereafter. This biphasic response may explain the IL-1β-mediated suppression of Mrp2 expression in endotoxemic rats.
European journal of cell biology 02/2012; 91(6-7):533-41. · 3.31 Impact Factor
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Johannes Schmitt,
Martin Roderfeld,
Karim Sabrane,
Pan Zhang,
Yinghua Tian,
Joachim C Mertens,
Pascal Frei,
Bruno Stieger,
Achim Weber,
Beat Müllhaupt,
Elke Roeb, Andreas Geier
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ABSTRACT: Fibrogenesis represents the universal response of the liver to chronic liver injury. Complement factor C5 has been linked to fibrosis in murine toxic liver injury and human chronic hepatitis C. C5 may also play a central role in chronic cholestatic disorders, since the BA receptor FXR has been characterized as an activator of the C3 gene. We aimed to investigate, whether C5 deficiency is able to prevent biliary fibrosis in the mouse bile-duct-ligation model. BDL for 1-4 weeks was performed in either Hc(0)/Hc(0) mice (deficient for C5) or WT controls. BA levels were measured by RIA. Histological examination included H&E, sirius-red and immunohistochemistry. mRNA expression was quantified by RT-PCR. Protein expression levels were determined by Western blotting or ELISA. Enzymatic MMP-activity was analysed by zymography. One week BDL leads to fibrosis in WT (F2.0 ± 0), while it is almost absent in Hc(0)/Hc(0) mice (F0.5 ± 0.5). No differences in fibrosis can be detected at week-4. Together with delayed fibrogenesis at week-1, fibrotic markers are decreased in Hc(0)/Hc(0) mice. Expression of the inflammatory cytokine TNF-α is decreased in Hc(0)/Hc(0) mice. In parallel C5 deficiency leads to an attenuated peribiliary infiltration of CD45(+) cells in fibrotic areas together with decreased MMP-9 expression and gelatinase activity. The present study proves a functional role of C5 during biliary fibrogenesis. C5 deficiency leads to attenuated inflammation and normalized MMP-9 activity concomitantly with a significant reduction of fibrosis. C5 appears to be an attractive target for future therapeutic intervention in chronic cholestatic liver disease.
Biochemical and Biophysical Research Communications 02/2012; 418(3):445-50. · 2.48 Impact Factor
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Katharina Baur,
Joachim C Mertens,
Johannes Schmitt,
Rika Iwata,
Bruno Stieger,
Pascal Frei,
Burkhardt Seifert,
Heike A Bischoff Ferrari,
Arnold von Eckardstein,
Beat Müllhaupt, Andreas Geier
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ABSTRACT: Chronic hepatitis C infection is a major cause of end-stage liver disease. Therapy outcome is influenced by 25-OH vitamin D deficiency. To further address this observation, our study investigates the impact of the vitamin D receptor (NR1I1) haplotype and combined effects of plasma vitamin D levels in a well-described cohort of hepatitis C patients.
A total of 155 chronic hepatitis C patients were recruited from the Swiss Hepatitis C Cohort Study for NR1I1 genotyping and plasma 25-OH vitamin D level measurement. NR1I1 genotype data and combined effects of plasma 25-OH vitamin D level were analysed regarding therapy response (sustained virological response).
A strong association was observed between therapy non-response and the NR1I1 CCA (bAt) haplotype consisting of rs1544410 (BsmI) C, rs7975232 (ApaI) C and rs731236 (TaqI) A alleles. Of the HCV patients carrying the CCA haplotype, 50.3% were non-responders (odds ratio [OR] 1.69, 95% CI 1.07, 2.67; P=0.028). A similar association was observed for the combinational CCCCAA genotype (OR 2.94, 95% CI 1.36, 6.37; P=0.007). The combinational CCCCAA genotype was confirmed as an independent risk factor for non-response in multivariate analysis (OR 2.50, 95% CI 1.07, 5.87; P=0.034). Analysing combined effects, a significant impact of low 25-OH vitamin D levels on sustained virological response were only seen in patients with the unfavourable NR1I1 CCA (bAt) haplotype (OR for non-SVR 3.55; 95% CI 1.005, 12.57; P=0.049).
NR1I1 vitamin D receptor polymorphisms influence response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C and exert an additive genetic predisposition to previously described low 25-OH vitamin D serum levels.
Antiviral therapy 12/2011; 17(3):541-7. · 3.16 Impact Factor
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Katharina Baur,
Joachim C Mertens,
Johannes Schmitt,
Rika Iwata,
Bruno Stieger,
Jyrki J Eloranta,
Pascal Frei,
Felix Stickel,
Michael T Dill,
Burkhardt Seifert,
Heike A Bischoff Ferrari,
Arnold von Eckardstein,
Pierre-Yves Bochud,
Beat Müllhaupt, Andreas Geier
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ABSTRACT: Decreased vitamin D levels have been described in various forms of chronic liver disease and associated with advanced fibrosis. Whether this association is a cause or consequence of advanced fibrosis remains unclear to date.
To analyse combined effects of 25-OH vitamin D plasma levels and vitamin D receptor gene (VDR; NR1I1) polymorphisms on fibrosis progression rate in HCV patients.
251 HCV patients underwent VDR genotyping (bat-haplotype: BsmI rs1544410 C, ApaI rs7975232 A and TaqI rs731236 A). Plasma 25-OH vitamin D levels were quantified in a subgroup of 97 patients without advanced fibrosis. The VDR haplotype and genotypes as well as plasma 25-OH vitamin D levels were associated with fibrosis progression.
The bAt[CCA]-haplotype was significantly associated with fibrosis progression >0.101 U/year (P = 0.007; OR = 2.02) and with cirrhosis (P = 0.022; OR = 1.84). Forty-five percent of bAt[CCA]-haplotype patients were rapid fibrosers, 21.1% were cirrhotic. Likewise, ApaI rs7975232 CC genotype was significantly associated with fibrosis progression and cirrhosis. Lower plasma 25-OH vitamin D levels were significantly associated with fibrosis progression >0.101 U/year in F0-2 patients (P = 0.013). Combined analysis of both variables revealed a highly significant additive effect on fibrosis progression with 45.5% rapid fibrosers for bAt[CCA]-haplotype and 25-OH vitamin D < 20 μg/L compared with only 9.1% for the most favourable combination (P = 0.006). In multivariate analysis, the bAt-haplotype was an independent risk factor for fibrosis progression (P = 0.001; OR = 2.83).
Low 25-OH vitamin D plasma levels and the unfavourable VDR bAt[CCA]-haplotype are associated with rapid fibrosis progression in chronic HCV patients. In combination, both variables exert significant additive effects on fibrosis progression.
Liver international: official journal of the International Association for the Study of the Liver 12/2011; 32(4):635-43. · 3.82 Impact Factor
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Katharina Baur,
Joachim C. Mertens,
Johannes Schmitt,
Rika Iwata,
Bruno Stieger,
Jyrki J. Eloranta,
Pascal Frei,
Felix Stickel,
Michael T. Dill,
Burkhardt Seifert,
Heike A. Bischoff Ferrari,
Arnold Eckardstein,
Pierre‐Yves Bochud,
Beat Müllhaupt, Andreas Geier
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ABSTRACT: Background
Decreased vitamin D levels have been described in various forms of chronic liver disease and associated with advanced fibrosis. Whether this association is a cause or consequence of advanced fibrosis remains unclear to date.AimsTo analyse combined effects of 25-OH vitamin D plasma levels and vitamin D receptor gene (VDR;NR1I1) polymorphisms on fibrosis progression rate in HCV patients.Methods251 HCV patients underwent VDR genotyping (bat-haplotype: BsmI rs1544410 C, ApaI rs7975232 A and TaqI rs731236 A). Plasma 25-OH vitamin D levels were quantified in a subgroup of 97 patients without advanced fibrosis. The VDR haplotype and genotypes as well as plasma 25-OH vitamin D levels were associated with fibrosis progression.ResultsThe bAt[CCA]-haplotype was significantly associated with fibrosis progression >0.101 U/year (P = 0.007; OR = 2.02) and with cirrhosis (P = 0.022; OR = 1.84). Forty-five percent of bAt[CCA]-haplotype patients were rapid fibrosers, 21.1% were cirrhotic. Likewise, ApaI rs7975232 CC genotype was significantly associated with fibrosis progression and cirrhosis. Lower plasma 25-OH vitamin D levels were significantly associated with fibrosis progression >0.101 U/year in F0–2 patients (P = 0.013). Combined analysis of both variables revealed a highly significant additive effect on fibrosis progression with 45.5% rapid fibrosers for bAt[CCA]-haplotype and 25-OH vitamin D < 20 μg/L compared with only 9.1% for the most favourable combination (P = 0.006). In multivariate analysis, the bAt-haplotype was an independent risk factor for fibrosis progression (P = 0.001; OR = 2.83).Conclusion
Low 25-OH vitamin D plasma levels and the unfavourable VDR bAt[CCA]-haplotype are associated with rapid fibrosis progression in chronic HCV patients. In combination, both variables exert significant additive effects on fibrosis progression.
Liver international: official journal of the International Association for the Study of the Liver 12/2011; 32(4):635 - 643. · 3.82 Impact Factor
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ABSTRACT: To design a new score on risk assessment for orthotopic liver transplantation (OLT) based on both donor and recipient parameters.
The balance of waiting list mortality and posttransplant outcome remains a difficult task in the era of the model for end-stage liver disease (MELD).
Using the United Network for Organ Sharing database, a risk analysis was performed in adult recipients of OLT in the United States of America between 2002 and 2010 (n = 37,255). Living donor-, partial-, or combined-, and donation after cardiac death liver transplants were excluded. Next, a risk score was calculated (balance of risk score, BAR score) on the basis of logistic regression factors, and validated using our own OLT database (n = 233). Finally, the new score was compared with other prediction systems including donor risk index, survival outcome following liver transplantation, donor-age combined with MELD, and MELD score alone.
Six strongest predictors of posttransplant survival were identified: recipient MELD score, cold ischemia time, recipient age, donor age, previous OLT, and life support dependence prior to transplant. The new balance of risk score stratified recipients best in terms of patient survival in the United Network for Organ Sharing data, as in our European population.
The BAR system provides a new, simple and reliable tool to detect unfavorable combinations of donor and recipient factors, and is readily available before decision making of accepting or not an organ for a specific recipient. This score may offer great potential for better justice and utility, as it revealed to be superior to recent developed other prediction scores.
Annals of surgery 11/2011; 254(5):745-53; discussion 753. · 7.90 Impact Factor
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ABSTRACT: Several molecular changes in colorectal adenomas provide the basis of the adenoma-carcinoma sequence. We investigated the expression of xenobiotic ATP-binding cassette (ABC) transporters in humans and in ApcMin mice and conducted functional studies estimating the importance of the expression changes. Twenty-nine adenomas from 21 patients and eight adenomas from four ApcMin mice were analyzed using Western blotting and quantitative Real-time polymerase chain reaction (RT-PCR). Adjacent healthy tissue served as control for each polyp. Breast cancer resistance protein (BCRP) was significantly downregulated in human colorectal adenomas (to 28 ± 35% of adjacent healthy tissue). This was in line with data from ApcMin mice adenomas, where downregulation was significant as well (to 58 ± 34%). In parallel, quantitative RT-PCR showed BCRP mRNA downregulation in human adenomas (to 17 ± 31%). Basal multidrug resistance-associated protein 2 expression was low and did not change in adenomas; multidrug resistance transporter 1 expression also did not differ between adenomas and healthy tissue. In a functional study, ApcMin mice received radioactively labelled 2-amino-1-methyl-6-phenylimidazo[4,5-β] pyridine (PhIP), a food colon carcinogen and substrate of BCRP, by oral gavage with analysis of PhIP accumulation and DNA adduct formation 48 hr later. In this setting, we could demonstrate a higher carcinogen concentration in adenomas of ApcMin mice (181 ± 113% of normal tissue) including immunohistochemical detection of PhIP-DNA adducts. We conclude that significant transcriptional downregulation of BCRP/Bcrp leads to higher carcinogen concentrations in colorectal adenomas of mice and men. This might promote the adenoma-carcinoma sequence by higher genotoxic effects. The results indicate a possible role of transporter deficiencies in susceptibility for colon carcinoma.
International Journal of Cancer 08/2011; 129(3):546-52. · 5.44 Impact Factor
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ABSTRACT: We analyzed the first 100 patients who underwent liver transplantation by Model for End-Stage Liver Disease (MELD) allocation, and compared the outcome of patients on the waiting list and after orthotopic liver transplantation with the last 100 patients who underwent transplantation prior to the introduction of the MELD system in July 2007. MELD allocation resulted in decreased waiting list mortality (386 versus 242 deaths per 1000 patient-years, P < 0.0001) and the transplantation of sicker recipients (uncorrected median MELD score 13.5 versus 20, P = 0.003). Recipient posttransplant morbidity was significantly higher, mainly caused by increased percentage of renal failure requiring renal replacement therapy (13 versus 46%, P < 0.0001). However, kidney function recovered in most cases within 6 months after OLT. Hospital mortality remained similar in both groups (6% versus 9%). Patient 1-year survival was 91% versus 83% (pre-MELD versus MELD era, P = 0.2154), graft 1-year survival was 88% versus 78% (P = 0.1013), respectively. Costs accumulated were significantly higher after introduction of the MELD policy (US $81,967 versus US $127,453, a 55% increase, P = 0.02) with a strong correlation with the individual MELD score (P < 0.0001). The MELD system addresses the goal of fairness well. However, the postoperative course appears more difficult in the MELD era with increased financial burden, but reasonable patient and graft survival. This is the inevitable price to balance justice and utility in liver graft allocation.
Liver Transplantation 06/2011; 17(6):674-84. · 3.39 Impact Factor
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ABSTRACT: To investigate the effects of sorafenib when combined with radiofrequency ablation treatment in liver tissue, the necrosis volume, tissue repair and hepatocellular growth signals were analyzed in rats. Radiofrequency ablation (RFA) is a widely applied treatment for hepatocellular carcinoma (HCC). Radiofrequency ablation is combined with the multi-tyrosinkinase-inhibitor sorafenib in ongoing clinical trials. Whether this combination treatment affects liver tissue repair is unknown.
Male Sprague Dawley (SD) rats received RFA or sham puncture with concomitant sorafenib (5mg/kg qd from day 2) or vehicle. Necrosis volume was calculated from resected specimens. Proliferation and micro vessel density were determined by Ki67 and CD31 immunofluorescence, respectively. mRNA expression of hepatocyte growth factor (HGF), epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) was quantified.
While ablation size was identical in all treatment groups at day 1, sorafenib treated animals showed sustained necroses (219 ± 24 vs. 88 ± 52 mm(3) in controls; P = 0.03), elevated alanine aminotransferase (ALT) and elevated glutamate dehydrogenase (GLDH) (76 ± 37 vs. 47 ± 58 mm(3); P=0.50) at day 3. By day 7 necrosis volumes equalized for the treatment groups. Ki67 and CD31 staining showed reduced proliferation and micro vessel density at days 1 and 3 following sorafenib. Growth factors HGF and EGF were significantly overexpressed in liver tissue after sorafenib.
Sorafenib initially promotes necrosis after RFA in liver tissue. The delay in tissue repair is overcome at day 7 presumably by transient compensatory overexpression of growth signals. Based on these data from animal studies further investigation of adjuvant sorafenib in humans is warranted.
European journal of radiology 05/2011; 81(7):1601-6. · 2.65 Impact Factor
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ABSTRACT: Liver transplantation is the only curative therapy for many liver diseases, mostly chronic liver diseases, occasionally also in acute or fulminant liver failure. Currently, about 100 liver transplantatations are performed each year in Switzerland. Clichy criteria are used for acute liver failure. Liver transplantation for liver cirrhosis improves survival if the Meld-Score is above 15. 5- and 10-year-survival after liver transplantation are 71% and 61%, respectively. With increasing survival after liver transplantation, the management of drug side effects in the late postoperative course becomes important.
Therapeutische Umschau 04/2011; 68(4):219-24.
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ABSTRACT: INTRODUCTION: Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED: This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed. EXPERT OPINION: Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease.
Expert Opinion on Drug Metabolism & Toxicology 02/2011; 7(4):411-25. · 3.12 Impact Factor
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Andreas Geier
Journal of Hepatology 01/2011; 55(2):273-5. · 9.26 Impact Factor
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ABSTRACT: The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of non-alcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver disease.
Biological Chemistry 12/2010; 391(12):1441-9. · 2.96 Impact Factor
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Rika Iwata,
Katharina Baur,
Bruno Stieger,
Joachim C Mertens,
Ann K Daly,
Pascal Frei,
Julia Braun,
Athanasios Vergopoulos,
Felix Stickel,
Karim Sabrane,
Ina V Martin,
Johannes Schmitt,
Oliver Goetze,
Chris P Day,
Beat Müllhaupt, Andreas Geier
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ABSTRACT: Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) μmol/l compared with 3.5 (1-61) μmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.
Clinical Science 09/2010; 120(7):287-96. · 4.61 Impact Factor
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ABSTRACT: To investigate the frequency of gastroenterological diseases in the etiology and the efficacy of proton pump inhibitors (PPIs) in the treatment of cardiac syndrome X (CSX) as a subform of non-cardiac chest pain (NCCP).
We investigated 114 patients with CSX using symptom questionnaires. A subgroup of these patients were investigated regarding upper gastrointestinal disorders (GIs) and treated with PPI. Patients not willing to participate in investigation and treatment served as control group.
Thirty-six patients denied any residual symptoms and were not further evaluated. After informed consent in 27 of the remaining 78 patients, we determined the prevalence of disorders of the upper GI tract and quantified the effect of treatment with pantoprazole. We found a high prevalence of gastroenterological pathologies (26/27 patients, 97%) with gastritis, gastroesophageal reflux disease (GERD) and acid reflux as the most common associated disorders. If treated according to the study protocol, these patients showed a significant improvement in the symptom score. Patients treated by primary care physicians, not according to the study protocol had a minor response to treatment (n = 19, -43%), while patients not treated at all (n = 26) had no improvement of symptoms (-0%).
Disorders of the upper GI tract are a frequent origin of CSX in a German population and can be treated with pantoprazole if given for a longer period.
World Journal of Gastroenterology 12/2008; 14(42):6506-12. · 2.47 Impact Factor
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ABSTRACT: Primary sclerosing cholangitis (PSC) is an important liver disease with major morbidity and mortality. The diagnosis of PSC is confirmed by magnetic resonance cholangiopancreaticography, and endoscopic retrograde cholangiopancreaticography is performed in patients needing therapeutic endoscopy. As a result of the unknown cause of the disease, current medical therapies are unsatisfactory. Nevertheless, high-dose ursodeoxycholic acid should be recommended for treatment of PSC patients because there is a trend toward increased survival. Dominant bile duct stenoses should be treated endoscopically. However, liver transplantation continues to be the only therapeutic option for patients with advanced disease. Estimation of prognosis and timing of liver transplantation should be determined individually for each PSC patient on the basis of all results. The diagnosis and treatment of cholangiocarcinoma (CC) still remain a challenge in PSC patients. Early diagnosis of CC certainly is a prerequisite for successful treatment with surgical resection or innovative strategies such as neoadjuvant radiochemotherapy with subsequent orthotopic liver transplantation. Therefore, endoscopic techniques such as cholangioscopy and/or intraductal ultrasound may be useful diagnostic tools in patients with stenoses suspicious for malignancy.
Liver Transplantation 07/2008; 14(6):735-46. · 3.39 Impact Factor
