POSTERS 8.55±3.47, in patients with grade I EV: 2.72±0.83 and 8.82±3.41, in patients with grade II EV: 3±0.67 and 9.88±2.85 and respectively in patients with grade III EV: 2.81±0.61 and 9.14±2.52. The mean liver stiffness values, as well as the splenohepatic index were not significant different in patients without and those with EV (2.76±0.79 vs. 2.89±0.70 m/s, p = 0.36 and 8.55±3.47 vs. 9.49±2.92 m/s, p = 0.12, respectively). Also, the mean liver stiffness values and splenohepatic index were not significant different in patients without and with grade 1 EV vs. those with significant EV (2.74±0.80 m/s vs. 2.94±0.65 m/s, p = 0.11 and 8.65±3.42 vs. 9.67±2.77 m/s, p = 0.06, respectively). Conclusion: Our preliminary data suggest that ARFI measurements in the liver and splenohepatic index can not predict the presence and the severity of EV in cirrhotic patients. 192 THE EXCESS MORTALITY ASSOCIATED WITH BETA-BLOCKER THERAPY IN PATIENTS WITH DIURETIC INTOLERANT ASCITES CAN BE EXPLAINED BY WORSENING NEUTROPHIL DYSFUNCTION N.J. Taylor, A. Nishtala, R.D. Abeles, J.A. Wendon, Y. Ma, D.L. Shawcross. Institute of Liver Studies, King’s College Hospital, London, UK E-mail:
[email protected] Background and Aims: Neutrophil phagocytic dysfunction is associated with an increased risk of infection and mortality in patients with cirrhosis. Beta-blockers have been shown to be associated with poor survival in patients with refractory ascites (Serste´ et al. Hepatology 2010), possibly through increased susceptibility to infection. Our aim was to determine if betablockade in patients with diuretic refractory ascites had a deleterious effect on neutrophil phagocytic dysfunction and if this was mediated through decreased phosphorylation of p38-MAPK, a pathway critical to neutrophil activation. Methods: Neutrophils were isolated from a cohort of 82 patients with cirrhosis and controls, and followed-up over a 24-month period. Phagocytosis was analysed by flow cytometry using FITClabelled E. coli and oxidative burst was determined by the percentage of CD16-Phycoerytherin labelled neutrophils producing reactive oxygen species (ROS) at rest and after stimulation with opsonised E. coli. Neutrophil volume was measured using flow cytometry. Clinical data, blood biochemistry, arterial ammonia and microbial cultures were collected prospectively. Neutrophil basal levels of total and phosphorylated p38-MAPK were measured. Results: Patients had a median age of 53 (42.5–61), 27% were female and 41% were on antibiotics. Eleven patients suffered diuretic resistant ascites with a median MELD score of 22 (16–23) compared to 17 (12–24) in cirrhotics without diuretic resistant ascites. Neutrophil phagocytic capacity was significantly impaired in patients with cirrhosis compared to controls (p = 0.0027); with no correlation observed between liver disease severity scores and the presence of ascites. In patients with diuretic resistant ascites beta-blocker administration was associated with a further deterioration in phagocytic capacity 49.2% (35.9–63.2) compared to 81.1% (59.4–87.7) in patients not beta-blocked (p = 0.04). Phagocytic impairment correlated with increasing plasma concentrations of ammonia (p = 0.02), IgG (p = 0.005), and decreasing neutrophil count (p = 0.003). Resting neutrophil production of ROS, a measure of neutrophil activation, was significantly increased in patients with hepatic encephalopathy and was associated with increasing cell volume. Conclusions: Beta-blockers are associated with a significant decline in neutrophil phagocytic capacity in patients with diuretic intolerant ascites who are already functionally immunosuppressed. This may explain the excess mortality associated with these drugs in this cohort of patients.
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193 DECREASE OF PORTAL PRESSURE VIA TIPS CORRECTS CONTRACTILE MECHANISMS IN GASTRIC MUCOSA OF HUMAN CIRRHOSIS J. Trebicka1 , A. Krag2 , C. Wix1 , M. Granzow1 , S. Klein1 , B. Appenrodt1 , S. Saller1 , J. Heller1 , T. Sauerbruch1 . 1 Internal Medicine I, University of Bonn, Bonn, Germany; 2 Department of Gastroenterology, University Hospital Hvidovre, Copenhagen, Denmark E-mail:
[email protected] Background: In portal hypertension and cirrhosis vasodilation in splanchnic vessels is maintained despite high vasoconstrictor levels. Increased beta-arrestin-2 expression and defective vasoconstriction via RhoA/Rho-kinase are at least partially responsible for this effect. We have previously shown that changes in contractile pathways can be also assessed in the gastric mucosa of these patients (EASL 2010). Here, we investigated whether this is modified by TIPS insertion. Methods: Gastric mucosa biopsies were collected from 52 patients with liver cirrhosis (eighteen with TIPS), as well as from 12 noncirrhotic controls. Mucosal mRNA levels of RhoA, Rho-kinase, eNOS and beta-arrestin-2 were investigated by Taqman-PCR. Activity of eNOS was assessed as its phosphorylation at serin-1177, and activity of Rho-kinase as phosphorylation of its substrate, moesin, at threonine-558, using Western blot with phospho- and site-specific antibodies. Results: In the mucosa of cirrhotic patients we found two-fold increased mRNA levels of eNOS and beta-arrestin-2 compared to controls (p < 0.01). TIPS insertion doubled mRNA-levels of Rhokinase and decreased mRNA-levels of beta-arrestin-2 by 50% in gastric mucosa (p < 0.05). eNOS phosphorylation was increased and Rho-kinase activity was decreased in cirrhotic patients assessed as phosphorylation of its subtrate moesin, when compared to noncirrhotic controls. However, there wa no difference between TIPS and non-TIPS cirrhotics. Discussion: Our findings show that mechanisms leading to splanchnic hypocontractility in cirrhosis can be detected in the gastric mucosa. Lowering of portal pressure due to TIPS insertion shifts transcription of proteins towards contractile intracellular pathways. Thus, we have a tool to investigate interventions targeting splanchnic vasculature in man. 194 TIPS-PROCEDURE DOES NOT CHANGE ENDOTOXIN LEVELS IN BLOOD OF PATIENTS WITH ALCOHOLIC LIVER CIRRHOSIS J. Trebicka1 , A. Krag2 , S. Gansweid1 , B. Appenrodt1 , P. Schiedermaier1 , T. Sauerbruch1 , U. Spengler1 . 1 Internal Medicine I, University of Bonn, Bonn, Germany; 2 Department of Gastroenterology, University Hospital Hvidovre, Copenhagen, Denmark E-mail:
[email protected] Background: Endotoxins represent a factor contributing to portal hypertension. It has been shown in experimental and human cirrhosis that portal hypertension promotes bacterial translocation, which in turn increases serum endotoxin levels. Thus, we investigated whether the decrease of portal pressure after TIPSinsertion leads to a drop of serum endotoxin levels. Methods: 15 patients with alcoholic liver cirrhosis receiving TIPS for refractory ascites were investigated. During the TIPS procedure and at an invasive control two weeks later, portal and central venous blood samples were taken and endotoxin levels measured via a chromogenic limulus-Assay. Results: Prior to TIPS-insertion we didnot find any significant difference in endotoxin levels between portal (0.35±0.3 ng/mL) and central venous blood (0.30±0.2 ng/mL). Before TIPS, portal endotoxin levels correlated positively with MELD-Score (p = 0.02) and age (p = 0.03), and inversely with systolic arterial pressure (p = 0.009) and portal vein flow velocity (p = 0.016). After TIPSinsertion portal pressure decreased by 21% (19.9±3.1 and
Journal of Hepatology 2011 vol. 54 | S61–S208
