Reiner Wiest

Publications of Reiner Wiest

• Intestinal bacterial translocation in rats with cirrhosis is related to compromised paneth cell antimicrobial host defense.

  Authors: Zora Teltschik, Reiner Wiest, Julia Beisner, Sabine Nuding, Claudia Hofmann, Juergen Schoelmerich, Charles L Bevins, Eduard F Stange, Jan Wehkamp

  Hepatology (Baltimore, Md.). 11/2011;

  Liver cirrhosis is associated with bacterial translocation (BT) and endotoxemia. Most translocating bacteria belong to the common intestinal microbiota, suggesting a breakdown of intestinal barrierLiver cirrhosis is associated with bacterial translocation (BT) and endotoxemia. Most translocating bacteria belong to the common intestinal microbiota, suggesting a breakdown of intestinal barrier function. We hypothesized that diminished mucosal antimicrobial host defense could predispose to BT. Two rodent models of portal hypertension with increased BT were used, CCl(4) -induced ascitic cirrhosis and 2-day portal vein-ligated (PVL) animals. BT was assessed by standard microbiological techniques on mesenteric lymph nodes. Total RNA was isolated systematically throughout the intestinal tract, and expression of Paneth cell α-cryptdins and β-defensins was determined by real-time quantitative polymerase chain reaction (qPCR). To determine functional consequences, mucosal antimicrobial activity was assessed with a fluorescence-activated cell sorting assay. BT was detectable in 40% of rats with cirrhosis. Compared with the group without BT, these animals exhibited diminished intestinal Paneth cell α-cryptdin 5 and 7 expression. In contrast, PVL was associated with BT in all animals but did not affect antimicrobial peptides. The decrease in Paneth cell antimicrobials was most pronounced in the ileum and the coecum. Other antimicrobials showed no changes or even an induction in the case of BT at different sites. Antimicrobial activity toward different commensal strains was reduced, especially in the distal ileum and the cecum in experimental cirrhosis with BT (excluding PVL). Conclusion: Compromised Paneth cell antimicrobial host defense seems to predispose to BT in experimental cirrhosis. Understanding this liver-gut axis including the underlying mechanisms could help us to find new treatment avenues. (HEPATOLOGY 2011).

• NOD2 gene variants and spontaneous bacterial peritonitis: authors' reply.

  Authors: Tony Bruns, Reiner Wiest, Andreas Stallmach

  Liver international : official journal of the International Association for the Study of the Liver. 11/2011; 32(3):521-2.

• Elevated systemic monocyte chemoattractrant protein-1 in hepatic steatosis without significant hepatic inflammation.

  Authors: Georgi Kirovski, Christoph Dorn, Hanna Huber, Lukas Moleda, Catrin Niessen, Hella Wobser, Doris Schacherer, Christa Buechler, Reiner Wiest, Claus Hellerbrand

  Experimental and molecular pathology. 08/2011; 91(3):780-3.

  Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and the metabolic syndrome. It encompasses a clinico-pathologic spectrum of conditions ranging from simple steatosis toNon-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and the metabolic syndrome. It encompasses a clinico-pathologic spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). The latter develops upon pro-inflammatory cell infiltration and is widely considered as the first relevant pathophysiological step in NAFLD-progression. The chemokine monocyte chemoattractant protein 1 (MCP-1) plays an important role in the progression of hepatic inflammation and fibrosis, and both increased hepatic expression and circulating serum levels have been described in NASH. Here, we aimed to investigate MCP-1 expression in simple hepatic steatosis. Upon feeding a high-fat diet mice developed hepatic steatosis in the absence of significant hepatic inflammation, but elevated hepatic MCP-1 expression compared to control mice fed a standard chow. Interestingly, high-fat diet fed mice had significantly higher MCP-1 serum levels, and MCP-1 mRNA expression was significantly increased in visceral adipose tissue. Furthermore, MCP-1 serum levels were also elevated in patients with ultrasound-diagnosed NAFLD and correlated with the body-mass index and fasting glucose. In conclusion, our data indicate both the liver and adipose tissue as cellular sources of elevated circulating MCP-1 levels already in the early phase of hepatic steatosis. Since MCP-1 derived from visceral adipose tissue reaches the liver via portal circulation at high concentrations it may significantly contribute to the progression of simple steatosis to NASH.

• Soluble CD163 is not increased in visceral fat and steatotic liver and is even suppressed by free fatty acids in vitro.

  Authors: Sabrina Bauer, Thomas S Weiss, Reiner Wiest, Doris Schacherer, Claus Hellerbrand, Stefan Farkas, Marcus N Scherer, Mirko Ritter, Gerd Schmitz, Andreas Schäffler, Christa Buechler

  Experimental and molecular pathology. 08/2011; 91(3):733-9.

  Visceral fat differs from subcutaneous fat by higher local inflammation and increased release of IL-6 and free fatty acids (FFA) which contribute to hepatic steatosis. IL-6 has been shown toVisceral fat differs from subcutaneous fat by higher local inflammation and increased release of IL-6 and free fatty acids (FFA) which contribute to hepatic steatosis. IL-6 has been shown to upregulate the monocyte/macrophage specific receptor CD163 whose soluble form, sCD163, is increased in inflammatory diseases. Here, it was analyzed whether CD163 and sCD163 are differentially expressed in the human fat depots and fatty liver. CD163 mRNA and protein were similarly expressed in paired samples of human visceral and subcutaneous fat, and comparable levels in portal venous and systemic venous blood of liver-healthy controls indicate that release of sCD163 from visceral adipose tissue was not increased. CD163 was also similarly expressed in steatotic liver when compared to non-steatotic tissues and sCD163 was almost equal in the respective sera. Concentrations of sCD163 were not affected when passing the liver excluding substantial hepatic removal/release of this protein. A high concentration of IL-6 upregulated CD163 protein while physiological doses had no effect. However, sCD163 was not increased by any of the IL-6 doses tested. FFA even modestly decreased CD163 and sCD163. The anti-inflammatory mediators fenofibrate, pioglitazone, and eicosapentaenoic acid (EPA) did not influence sCD163 levels while CD163 was reduced by EPA. These data suggest that in humans neither visceral fat nor fatty liver are major sources of sCD163.

• Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn's disease is affected by NOD2/CARD15 genotype.

  Authors: Ana Gutiérrez, Ernst Holler, Pedro Zapater, Laura Sempere, Rodrigo Jover, Miguel Pérez-Mateo, Juergen Schoelmerich, José Such, Reiner Wiest, Rubén Francés

  Inflammatory bowel diseases. 08/2011; 17(8):1641-50.

  Blood translocation of bacterial-DNA has been described in patients with Crohn's disease (CD). The host's immune cell types cooperate to respond against bacterial insults. Some antimicrobial peptidesBlood translocation of bacterial-DNA has been described in patients with Crohn's disease (CD). The host's immune cell types cooperate to respond against bacterial insults. Some antimicrobial peptides are inducible after culture with bacterial products and a linkage has been established between them and NOD2/CARD15. The aim was to test whether defensins and cathelicidin (LL-37) expression and NOD2/CARD15 mutations in blood neutrophils are related to molecular bacterial translocation events in CD patients. Fifty consecutively admitted CD patients and 15 healthy controls were included. Clinical and analytical characteristics of patients were considered. NOD2/CARD15 genotyping, presence of bacterial-DNA, defensin and cathelicidin gene, and protein levels in neutrophils and serum cytokine levels were studied. Twenty patients (40%) presented bacterial-DNA in blood. Eleven were active and 9 were in remission. Bacterial-DNA was not present in controls. NOD2/CARD15 mutations were identified in 25 patients (50%), 15 of which were in remission. Sixty percent of bacterial-DNA(+) and 43% of bacterial-DNA(-) patients showed a NOD2/CARD15 mutation. β-Defensin 2 and LL-37 mRNA and protein levels were upregulated in bacterial-DNA(+) patients. β-Defensin 2 and LL-37 expression correlated with bacterial-DNA concentration only in patients with a wildtype NOD2/CARD15 genotype. Cultured neutrophils of bacterial-DNA(-) patients confirmed the muramyl dipeptide-independent association between DEFB2 and LL-37 with bacterial-DNA concentration in wildtype NOD2/CARD15 patients. Cytokine levels were increased in bacterial-DNA(+) patients and correlated with bacterial-DNA concentration. NOD2/CARD15 genotype did not influence this correlation. β-Defensin 2, LL-37, and proinflammatory cytokines are increased in CD patients with bacterial-DNA in a concentration-dependent manner. NOD2/CARD15 plays a key role in the regulation of this response.

• Systemic and hepatic vein galectin-3 are increased in patients with alcoholic liver cirrhosis and negatively correlate with liver function.

  Authors: Josef Wanninger, Johanna Weigert, Reiner Wiest, Sabrina Bauer, Thomas Karrasch, Stefan Farkas, Marcus N Scherer, Roland Walter, Thomas S Weiss, Claus Hellerbrand, Markus Neumeier, Andreas Schäffler, Christa Buechler

  Cytokine. 06/2011; 55(3):435-40.

  Recently we demonstrated higher galectin-3 in portal venous serum (PVS) compared to hepatic venous serum (HVS) in a small cohort of patients with normal liver function suggesting hepatic removal ofRecently we demonstrated higher galectin-3 in portal venous serum (PVS) compared to hepatic venous serum (HVS) in a small cohort of patients with normal liver function suggesting hepatic removal of galectin-3. Here, galectin-3 was measured by ELISA in PVS, HVS and systemic venous blood (SVS) of 33 patients with alcoholic liver cirrhosis and a larger cohort of 11 patients with normal liver function. Galectin-3 was cleared by the healthy but not the cirrhotic liver, and subsequently HVS and SVS galectin-3 levels were significantly increased in the patients with liver cirrhosis compared to controls. In healthy liver galectin-3 was produced by cholangiocytes and synthesis by hepatocytes was only observed in cirrhotic liver. Hepatic venous pressure gradient did not correlate with galectin-3 levels excluding hepatic shunting as the principal cause of higher SVS galectin-3. Galectin-3 was elevated in all blood compartments of patients with CHILD-PUGH stage C compared to patients with CHILD-PUGH stage A, and was higher in patients with ascites than patients without this complication. Galectin-3 was negatively associated with antithrombin-3 whose synthesis is reduced with worse liver function. Galectin-3 positively correlated with urea and creatinine, and PVS galectin-3 showed a negative association with creatinine clearance as an accepted measure of kidney function. To summarize in the current study systemic, portal and hepatic levels of galectin-3 were found to be negatively associated with liver function in patients with alcoholic liver cirrhosis and this may in part be related to impaired hepatic removal and/or increased synthesis in cirrhotic liver.

• NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis.

  Authors: Tony Bruns, Jack Peter, Philipp A Reuken, Dominik H Grabe, Sonja R Schuldes, Julia Brenmoehl, Jürgen Schölmerich, Reiner Wiest, Andreas Stallmach

  Liver international : official journal of the International Association for the Study of the Liver. 06/2011; 32(2):223-30.

  Spontaneous bacterial peritonitis (SBP) is considered as result of bacterial translocation from the gastrointestinal lumen to the mesenteric lymph nodes and subsequent circulation. Variants of theSpontaneous bacterial peritonitis (SBP) is considered as result of bacterial translocation from the gastrointestinal lumen to the mesenteric lymph nodes and subsequent circulation. Variants of the NOD2 gene contribute to bacterial translocation and were associated with SBP in a recent study. We determined common NOD2 variants by TaqMan polymerase chain reaction and analysed the ascitic fluid neutrophil count and bacterial culture results in 175 prospectively characterized hospitalized patients with decompensated cirrhosis who underwent diagnostic paracentesis in two German centres. Ten patients presented with culture-positive SBP, 19 with culture-negative SBP and six had bacterascites. Minor allele frequencies for R702W, G908R and 1007fs in subjects with sterile non-neutrocytic ascites were 3.2, 2.5 and 2.5% respectively. Patients with SBP [odds ratio (OR) 2.7; P=0.036], culture-positive SBP (OR 6.0; P=0.012) and bacterascites (OR 6.0; P=0.050) were more often carriers of NOD2 variants than patients with sterile non-neutrocytic ascites. The mutations 1007fs and G908R were associated with culture-positive SBP (P ≤ 0.005) and R702W with bacterascites (P=0.014). There was no significant association of NOD2 variants with culture-negative SBP (OR 1.6; P=0.493). In logistic regression, previous SBP, a higher model for end-stage liver disease (MELD) score and the presence of a NOD2 variant were independent predictors of ascitic fluid infection. The median survival was insignificantly shorter in patients with NOD2 variants (268 vs. 339 days; P=0.386). In patients without hepatocellular carcinoma at study entry (N=148), NOD2 was a predictor of survival after adjustment for the MELD score and age (hazard ratio 1.89; P=0.045). NOD2 variants increase the risk for culture-positive SBP and bacterascites in cirrhosis and may affect survival.

• DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH.

  Authors: Erwin Gäbele, Karin Dostert, Claudia Hofmann, Reiner Wiest, Jürgen Schölmerich, Claus Hellerbrand, Florian Obermeier

  Journal of hepatology. 04/2011; 55(6):1391-9.

  Intestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextranIntestinal bacterial overgrowth and increased permeability are features of non alcoholic steatohepatitis (NASH). Bacterial endotoxin has been shown to promote NASH progression. Application of dextran sulfate sodium (DSS) is a colitis model in mice characterized by damage of the intestinal barrier. This study was designed to investigate if application of DSS aggravates experimental NASH. Male C57bl/6 mice were allocated into four experimental groups receiving either (I) standard chow (SC), (II) a high fat (HF) diet, (III) SC+DSS (1% in the drinking water), and (IV) HF+DSS for 12 weeks. DSS treatment caused inflammation and proinflammatory gene expression (IL-1β, IL-17, TNF) in the colon. Expression of colonic antimicrobial peptide Cramp was significantly induced in SC+DSS mice, whereas expression was blocked in the HF+DSS group. Endotoxin levels were elevated in SC+DSS and HF mice but further augmented in the HF+DSS group. In line with this, increased hepatic TLR4 and TLR9 mRNA levels were detected in HF+DSS mice. The histological analysis revealed hepatic steatosis in both HF groups. Hepatic inflammation was more severe in HF+DSS mice, reflected by histology and analysis of proinflammatory gene expression (TNF and MCP-1). HF+DSS mice showed increased hepatic fibrosis by sirius red staining, hepatic collagen I expression, and α-SMA positive cells accompanied by higher p47(phox), TIMP-1, TGF-β, Pai-1, and α-SMA mRNA expression. Induction of an intestinal inflammation in experimental NASH promotes LPS translocation, hepatic inflammation, and fibrogenesis probably due to inhibition of intestinal antimicrobial peptides. These findings underscore the pathophysiological role of the gut-liver axis in the progression of NASH.

• Portal levels of latent transforming growth factor-β are related to liver function in patients with liver cirrhosis.

  Authors: Josef Wanninger, Reiner Wiest, Sabrina Bauer, Markus Neumeier, Kristina Eisinger, Stefan Farkas, Marcus N Scherer, Andreas Schäffler, Christa Buechler

  European journal of gastroenterology & hepatology. 03/2011; 23(3):218-23.

  Transforming growth factor-β1 (TGFβ1) is a short-lived immune suppressive and profibrotic protein. Its latent precursor is relatively stable and may even protect from fibrosis. Latent TGFβ1 isTransforming growth factor-β1 (TGFβ1) is a short-lived immune suppressive and profibrotic protein. Its latent precursor is relatively stable and may even protect from fibrosis. Latent TGFβ1 is synthesized by various tissues including the liver and portal, hepatic, and systemic concentrations of latent TGFβ1 were determined in patients with liver cirrhosis and patients with normal liver function to find out whether circulating levels are affected by liver disease. Latent TGFβ1 was measured in portal venous serum (PVS), hepatic venous serum (HVS), and systemic venous serum (SVS) of 26 patients with liver cirrhosis and nine patients with normal liver function. Latent TGFβ1 was similarly abundant in HVS, PVS,and SVS of patients with liver cirrhosis and controls. There was a strong positive correlation of HVS, PVS, and SVS TGFβ1 to each other. PVS levels of latent TGFβ1 were significantly lower in patients with CHILD-PUGH stage C compared with CHILD-PUGH stage A, SVS levels were modestly and HVS levels tended to be reduced. PVS and SVS TGFβ1 concentrations were also lower in patients with a higher model for end-stage liver disease score. Only PVS concentrations were reduced in patients with massive ascites compared with the patients without ascites. Creatinine clearance as a marker of renal function and parameters of coagulation did not correlate with this cytokine indicating that latent TGFβ1 levels are not linked to kidney function and coagulation. Interleukin-6, which is elevated in patients with liver cirrhosis negatively correlated with latent TGFβ1 in PVS and SVS. In patients with liver cirrhosis splanchnic organ-derived latent TGFβ1 is negatively associated with the liver function.

• Impaired hepatic removal of interleukin-6 in patients with liver cirrhosis.

  Authors: Reiner Wiest, Johanna Weigert, Josef Wanninger, Markus Neumeier, Sabrina Bauer, Sandra Schmidhofer, Stefan Farkas, Marcus N Scherer, Andreas Schäffler, Jürgen Schölmerich, Christa Buechler

  Cytokine. 02/2011; 53(2):178-83.

  Systemic concentrations of interleukin-6 (IL-6) are elevated in patients with liver cirrhosis, and impaired hepatic uptake of IL-6 was suggested to contribute to higher levels in these patients. ToSystemic concentrations of interleukin-6 (IL-6) are elevated in patients with liver cirrhosis, and impaired hepatic uptake of IL-6 was suggested to contribute to higher levels in these patients. To test this hypothesis IL-6 was measured in portal venous serum (PVS), hepatic venous serum (HVS) and systemic venous serum (SVS) of 41 patients with liver cirrhosis and four patients with normal liver function. IL-6 was higher in PVS than HVS of all blood donors and about 43% of portal vein derived IL-6 was extracted by the healthy liver, and 6.3% by the cirrhotic liver demonstrating markedly impaired removal of IL-6 by the latter. Whereas in patients with CHILD-PUGH stage A IL-6 in HVS was almost 25% lower than in PVS, in patients with CHILD-PUGH stage C IL-6 was similarly abundant in the two blood compartments. Ascites is a common complication in cirrhotic patients and was associated with higher IL-6 levels in all blood compartments without significant differences in hepatic excretion. Hepatic venous pressure gradient did not correlate with the degree of hepatic IL-6 removal excluding hepatic shunting as the principal cause of impaired IL-6 uptake. Furthermore, patients with alcoholic liver cirrhosis had higher IL-6 in all blood compartments than patients with cryptogenic liver cirrhosis. Aetiology of liver cirrhosis did not affect hepatic removal rate indicating higher IL-6 synthesis in patients with alcoholic liver cirrhosis. In summary, the current data provide evidence that impaired hepatic removal of IL-6 is explained by hepatic shunting and liver dysfunction in patients with liver cirrhosis partly explaining higher systemic levels.

• Amelioration of portal hypertension and the hyperdynamic circulatory syndrome in cirrhotic rats by neuropeptide Y via pronounced splanchnic vasoaction.

  Authors: Lukas Moleda, Jonel Trebicka, Peter Dietrich, Erwin Gäbele, Claus Hellerbrand, Rainer H Straub, Tilman Sauerbruch, Juergen Schoelmerich, Reiner Wiest

  Gut. 02/2011; 60(8):1122-32.

  Splanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improvesSplanchnic vasodilation triggers the development of the hyperdynamic circulatory syndrome in portal hypertension. Neuropeptide Y (NPY), a sympathetic co-transmitter of norepinephrine, improves contractility in mesenteric arteries of pre-hepatic portal hypertensive rats. Therefore, we investigated the effect of NPY on mesenteric arterial contractility in vitro and in vivo in cirrhotic ascitic rats, as well as the vasoactive pathways involved. All experiments were performed in CCl₄-induced cirrhotic rats with ascites and compared to controls. In vivo haemodynamic characterisation was assessed before and after cumulative application of NPY i.v. using the microspheres technique. In vitro mesenteric arterial perfusion was used to analyse the effect of NPY on the response to α₁-adrenergic, as well as nitrergic stimulation. The NPY effects on vasoactive pathways (RhoA/Rho-kinase and NOS/NO) were analysed by western blot in mesenteric arteries. NPY decreased portal-venous blood flow and reduced portal pressure in cirrhotic rats, without changes in mean arterial pressure. This was accompanied by decreased cardiac output and normalised systemic vascular resistance in cirrhotic rats. By contrast, no significant splanchnic or systemic haemodynamic effect of NPY was seen in controls. NPY enhanced arterial contractility in cirrhotic but not in control rats. Furthermore, NO-mediated vasodilation was reduced to a greater extent than in controls. These findings were paralleled by an increased expression and activity of the constrictive Rho-kinase pathway and decreased activation of vasodilating NOS/NO signalling after NPY administration in mesenteric arteries. NPY exerts marked portal hypotensive effects and ameliorates the hyperdynamic circulation in cirrhotic ascitic rats. This is mediated mainly by a pronounced splanchnic vasoconstriction and reduction in splanchnic blood flow due to enhanced Rho-kinase expression and activity, as well as reduced NOS activation and NO effect.

• Outcome of patients with ischemic-like cholangiopathy with secondary sclerosing cholangitis after liver transplantation.

  Authors: Gabi I Kirchner, Marcus N Scherer, Aiman Obed, Petra Ruemmele, Reiner Wiest, Matthias Froh, Martin Loss, Hans-Juergen Schlitt, Juergen Schölmerich, Cornelia M Gelbmann

  Scandinavian journal of gastroenterology. 11/2010; 46(4):471-8.

  Sclerosing cholangitis in critically ill patients (SC-CIP) with sepsis and acute respiratory distress syndrome (ARDS) is a cholestatic liver disease with a rapid progression to liver cirrhosis andSclerosing cholangitis in critically ill patients (SC-CIP) with sepsis and acute respiratory distress syndrome (ARDS) is a cholestatic liver disease with a rapid progression to liver cirrhosis and hepatic failure. Data on outcome of these patients after liver transplantation (LT) are sparse. Eleven patients (46 ± 12 years; mean labMELD-score: 27 ± 7) with SC-CIP underwent LT. Six patients had severe polytrauma with multiple bone fractures, sepsis and ARDS. Five non-traumatic patients acquired SC-CIP during long-term intensive-care-unit stays due to sepsis and ARDS. Time to diagnosis, the microbiologic results and the survival rates after LT were evaluated. SC-CIP was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) within 3 ± 1 months after manifestation of cholestasis and histologically confirmed in explanted livers. The predominant microorganisms isolated in bile were: Enterococcus and Candida albicans. Mean follow-up after LT was 28 ± 20 months. One female patient (non-traumatic) died due to sepsis 26 days after LT. All other patients left the hospital alive, but two (non-traumatic) patients died from sepsis, and one (traumatic) patient died in a hemorrhagic shock, thereafter. Seven of 11 patients (5 with polytrauma) are still alive and have a good quality of life. The survival of the SC-CIP patients after LT was comparable with that of patients transplanted due to alcoholic liver cirrhosis. SC-CIP develops rapidly within several months. Enterococcus and C. albicans were the main isolated microorganisms in the bile. Sepsis was the main cause of death after LT. Overall, SC-CIP is a good indication for LT in selected patients.

• Role of HSP-90 for increased nNOS-mediated vasodilation in mesenteric arteries in portal hypertension.

  Authors: Lukas Moleda, Lars Jurzik, Matthias Froh, Erwin Gäbele, Claus Hellerbrand, Rainer H Straub, Jürgen Schölmerich, Reiner Wiest

  World journal of gastroenterology : WJG. 04/2010; 16(15):1837-44.

  To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension. Neuronal nitric oxide synthase (nNOS)To explore the role of heat shock protein-90 (HSP-90) for nitrergic vasorelaxation in the splanchnic circulation in rats with and without portal hypertension. Neuronal nitric oxide synthase (nNOS) and HSP-90 were analyzed by immunofluorescence, western blotting and co-immunoprecipitation in the mesenteric vasculature and isolated nerves of portal-vein-ligated (PVL) rats and sham operated rats. In vitro perfused de-endothelialized mesenteric arterial vasculature was preconstricted with norepinephrine (EC(80)) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2-12 Hz, 45V) before and after incubation with geldanamycin (specific inhibitor of HSP-90 signalling, 3 microg/mL) or L-NAME (non-specific NOS-blocker, 10(-4) mol/L). nNOS and HSP-90 expression was significantly increased in mesenteric nerves from PVL as compared to sham rats. Moreover, nNOS and HSP-90 were visualized in mesenteric nerves by immunofluorescence and immunoprecipitation of nNOS co-immunoprecipitated HSP-90 in sham and PVL rats. PNS induced a frequency-dependent vasorelaxation which was more pronounced in PVL as compared to sham rats. L-NAME and geldanamycin markedly reduced nNOS-mediated vasorelaxation abrogating differences between the study groups. The effect of L-NAME and geldanamycin on nNOS-mediated vasorelaxation was significantly greater in PVL than in sham animals. However, no difference in magnitude of effect between L-NAME and geldanamycin was noted. HSP-90 acts as a signalling mediator of nNOS-dependent nerve mediated vascular responses in mesenteric arteries, and the increased nitrergic vasorelaxation observed in portal hypertension is mediated largely by HSP-90.

• Ultrasound-arterioportography (US-AP): A new technical approach to perform detection of liver lesions.

  Authors: Niels Zorger, Ernst-Michael Jung, Andreas G Schreyer, Peter Heiss, René Mueller-Wille, Reiner Wiest, Stefan Feuerbach, Janine Rennert

  Clinical hemorheology and microcirculation. 01/2010; 46(2-3):117-26.

  To show the feasibility of a combination of the advantages of modern contrast enhanced ultrasound (CEUS) with the technique of arterioportography to achieve the highest sensitivity of all differentTo show the feasibility of a combination of the advantages of modern contrast enhanced ultrasound (CEUS) with the technique of arterioportography to achieve the highest sensitivity of all different modalities. Ten patients (9 m, 1 f, age 52-73 years) with suspected hepatocellular carcinoma (HCC) in liver cirrhosis (8 ethyl toxic, 2 hepatitis) were included before transarterial chemo-embolization (TACE). In all patients during a 6-week period a double enhanced MRI (Gd-DTPA and SPIO) was performed. Before TACE a bolus <2 mL ultrasound contrast agent (SonoVue®, Bracco, Milan, Italy) was injected over a selectively placed catheter in the superior mesenteric artery (SMA) and ultrasound of the liver (2.5-4 MHz, LOGIQ 9; GE Healthcare) was performed in arterioportographic phase (US-AP). Two independent readers evaluate number, size and localisation of detected lesion in MRI and US-AP. Additional diagnostic quality of both modalities was determined using a 4-point scale (1: excellent-4: not diagnostic). Differences were analysed for significance using a t-test. Interobserver variability was calculated (κ-value). In all 10 patients (100 %) US-AP was feasible. Diagnostic quality was in all cases between 1-2 for both modalities and readers (MRI standard deviation (SD) -0.51, Sono-AP SD -0.421). US-AP detected with 33.5 vs. 24.5 lesions, significant more lesions than double enhanced MRI (p < 0.022). The interobserver variability was κ -0.965 for MRI and κ -0.898 for US-AP. Conclusion: US-AP for detection of liver lesions is feasible. Using this technique significantly more lesions in patients with hepatocellular carcinoma could be detected in comparison to MRI with liver-specific contrast agent.

• Splanchnic concentrations and postprandial release of visceral adipokines.

  Authors: Reiner Wiest, Lukas Moleda, Stefan Farkas, Markus Scherer, Andrea Kopp, Ulrike Wönckhaus, Christa Büchler, Jürgen Schölmerich, Andreas Schäffler

  Metabolism: clinical and experimental. 11/2009;

  No detailed data are available on hepatic clearance, postprandial release, and distribution profile of metabolically active adipokines in splanchnic blood compartments such as portal and hepaticNo detailed data are available on hepatic clearance, postprandial release, and distribution profile of metabolically active adipokines in splanchnic blood compartments such as portal and hepatic veins. This would be a prerequisite for understanding the role of visceral adipose tissue-derived adipokines in metabolism. Adiponectin, resistin, leptin, and visfatin concentrations were measured by enzyme-linked immunosorbent assay in peripheral veins, arterial blood, hepatic veins, and portal veins in 50 patients with liver cirrhosis undergoing transjugular intrahepatic portosystemic shunt implantation, in 6 patients with normal liver function, and in fasted and fed rats. Adiponectin, leptin, resistin, and visfatin did not differ among blood compartments in normal-weight probands in the fasted state. Adiponectin and leptin levels were similar in patients with and without liver cirrhosis. Systemic visfatin levels were decreased and resistin levels were increased in liver cirrhosis. Visfatin secretion was higher from visceral than from peripheral subcutaneous adipose tissue in liver cirrhosis. There was no hepatic clearance of visfatin. Leptin secretion was higher from peripheral than from visceral adipose tissue. Leptin did not undergo hepatic clearance. Resistin and adiponectin did not differ between blood compartments in liver cirrhosis. Resistin concentrations increased upon feeding in rats, and there was an increase in the postprandial clearance of adiponectin by the liver. A postprandial increase of leptin concentrations was restricted to peripheral adipose tissue in rats. The results give insight into the dynamics of splanchnic adipokine concentrations and help critically interpret data derived from messenger RNA expression studies.

• Analysis of monocyte chemotactic protein-1 gene polymorphism in patients with spontaneous bacterial peritonitis.

  Authors: Erwin Gäbele, Marcus Mühlbauer, Hartwig Paulo, Monika Johann, Christin Meltzer, Franz Leidl, Norbert Wodarz, Reiner Wiest, Jürgen Schölmerich, Claus Hellerbrand

  World journal of gastroenterology : WJG. 11/2009; 15(44):5558-62.

  AIM: To investigate a genetic polymorphism of the monocyte chemotactic protein-1 (MCP-1) gene in patients with spontaneous bacterial peritonitis (SBP). METHODS: MCP-1 genotyping was performed in 23AIM: To investigate a genetic polymorphism of the monocyte chemotactic protein-1 (MCP-1) gene in patients with spontaneous bacterial peritonitis (SBP). METHODS: MCP-1 genotyping was performed in 23 patients with SBP and 83 cirrhotic control patients with non-infected ascites. RESULTS: The frequency of carriers of the G-allele was lower in SBP patients but this difference did not reach statistical significance. However, in the subgroup of patients with alcoholic cirrhosis (n = 80), carriers of the G-allele were significantly less frequent in SBP-patients (38.1%) than in cirrhotic controls (67.8%, P = 0.021). CONCLUSION: In patients with alcoholic liver cirrhosis, the -2518 MCP-1 genotype AA is a risk factor for the development of SBP.

• Secondary peritonitis in cirrhosis: "Oil in fire"

  Authors: Reiner Wiest, Juergen Schoelmerich

  Journal of hepatology. 10/2009;

• ALTERATIONS IN MECHANICAL PROPERTIES OF MESENTERIC RESISTANCE ARTERIES IN EXPERIMENTAL PORTAL HYPERTENSION.

  Authors: Markus Resch, Reiner Wiest, Lukas Moleda, Sabine Fredersdorf, Benjamin Stoelcker, Josef A Schroeder, Juergen Schoelmerich, Dierk H Endemann

  American journal of physiology. Gastrointestinal and liver physiology. 09/2009;

  Splanchnic vasodilation is the pathophysiological hallmark in the development of the hyperdynamic circulatory syndrome in liver cirrhosis and portal hypertension. This has been attributed so farSplanchnic vasodilation is the pathophysiological hallmark in the development of the hyperdynamic circulatory syndrome in liver cirrhosis and portal hypertension. This has been attributed so far mainly to a marked vascular hyporeactivity to endogenous vasoconstrictors. However, myogenic tone and vessel stiffness have not been addressed in mesenteric arteries in liver cirrhosis. Methods: CCl4- - induced ascitic cirrhotic (LC), age-matched control rats and portal-vein-ligated (PVL) as well as sham-operated rats were investigated. Third order mesenteric resistance arteries were studied under no-flow conditions using a pressure myograph measuring media-thickness and lumen diameter in response to incremental increases in intramural pressure, from which wall mechanics were calculated. Electron microscopy was used for investigation of wall ultrastructure, especially the fenestrae in internal elastic lamina (IEL). Results: In PVL animals no significant change in passive vessel strain, stress, media-to-lumen ratio or cross-sectional area was noted. In contrast, in LC rats vessel strain was markedly elevated as compared to healthy control rats indicating a marked reduction in vessel stiffness. In addition, the strain-stress curve was shifted to the right and the elastic modulus in dependency on vessel stress decreased demonstrating predominantly structure-dependent factors to be involved. The media-to-lumen quotient was not significantly altered but cross-sectional area was highly increased in LC rats indicating hypertrophic outward remodeling. These findings were paralleled by enlarged fenestrae in the IEL but no change in thickness of IEL or proportion of extracellular matrix or vascular smooth muscle in LC rats. Conclusion: In long-standing severe portal hypertension such as ascitic LC but not in short-term conditions such as PVL, mesenteric resistance arteries exhibit vascular remodeling and markedly less resistant mechanical properties leading to decreased vessel stiffness accompanied by structural changes in the IEL. This may well contribute to the maintenance and severity of splanchnic arterial vasodilation in liver cirrhosis. Key words: vasodilation, portal hypertension, myogenic tone, mesenteric arteries.

• Systemic chemerin is related to inflammation rather than obesity in type 2 diabetes.

  Authors: Johanna Weigert, Markus Neumeier, Josef Wanninger, Michael Filarsky, Sabrina Bauer, Reiner Wiest, Stefan Farkas, Marcus N Scherer, Andreas Schäffler, Charalampos Aslanidis, Jürgen Schölmerich, Christa Buechler

  Clinical endocrinology. 07/2009;

  SUMMARY Background: The adipokine chemerin modulates the function of innate immune cells and may link obesity and inflammation, and therefore, a possible relation of chemerin to inflammatory proteinsSUMMARY Background: The adipokine chemerin modulates the function of innate immune cells and may link obesity and inflammation, and therefore, a possible relation of chemerin to inflammatory proteins in obesity and type 2 diabetes (T2D) was analysed. As visceral fat contributes to systemic inflammation chemerin was measured in portal (PVS), hepatic (HVS) and systemic (SVS) venous blood of patients with liver cirrhosis. Patients and methods: Systemic chemerin was determined by ELISA in the serum of normal-weight, overweight and T2D males, in the serum of T2D patients of both sexes, and in PVS, HVS and SVS of patients with liver cirrhosis. Results: Circulating chemerin was similar in T2D and obese individuals but was significantly elevated in both cohorts compared to normal-weight individuals. Chemerin positively correlated with leptin, resistin and C-reactive protein (CRP). In T2D chemerin was similar in male and female patients and increased in patients with elevated CRP. Chemerin was similar in PVS and SVS indicating that visceral fat is not a major site of chemerin synthesis. Higher levels of chemerin in HVS demonstrate that chemerin is also released by the liver. Conclusions: Visceral fat is not a major site of chemerin release, and elevated systemic levels of chemerin in obesity and type 2 diabetes seem to be associated with inflammation rather than BMI.

• Transabdominal ultrasound with echoenhancement by contrast media in the diagnosis of hepatocellular carcinoma.

  Authors: Doris Schacherer, Christiane Girlich, Michael E Jung, Reiner Wiest, Juergen Scholmerich

  Digestive diseases (Basel, Switzerland). 01/2009; 27(2):109-13.

  According to the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), ultrasound (US) is the recommended tool for surveillanceAccording to the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), ultrasound (US) is the recommended tool for surveillance of patients at risk of developing hepatocellular carcinoma (HCC). Larger HCCs can be diagnosed with a high accuracy by conventional US. However, the differentiation of smaller malignant lesions in cirrhotic livers can be improved by contrast-enhanced ultrasound (CEUS). Second-generation contrast agents consisting of microbubbles enable us to visualize specific tumor vascularization patterns. With CEUS, it is not only possible to detect and characterize HCC nodules, but to control the effects of ablation techniques of HCC as well, evaluating the former lesion with respect to complete necrosis or residual viable tumor. Limitations of CEUS are its inability to characterize lesions distant to the applicator. Moreover, so far the use of contrast agents in US did not result in increased sensitivity in the detection of small HCCs (<1 cm). Thus, there is currently no indication to use contrast agents to increase the detection rate of HCC in patients undergoing US surveillance.