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Background: Patients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP., Methods/design: The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥ 15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014., Discussion: Preventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms., Trial Registrations: German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.

Background: TNFα levels are increased in liver cirrhosis even in the absence of infection, most likely owing to a continuous endotoxin influx into the portal blood. Soluble TNFα receptors (sTNFR type I and II) reflect release of the short-lived TNFα, because they are cleaved from the cells after binding of TNFα. The aims were to investigate the circulating levels of soluble TNFR-I and -II in cirrhotic patients receiving TIPS., Methods: Forty-nine patients with liver cirrhosis and portal hypertension (12 viral, 37 alcoholic) received TIPS for prevention of re-bleeding (n = 14), therapy-refractory ascites (n = 20), or both (n = 15). Portal and hepatic venous blood was drawn in these patients during the TIPS procedure and during the control catheterization two weeks later. sTNFR-I and sTNFR-II were measured by ELISA, correlated to clinical and biochemical characteristics., Results: Before TIPS insertion, sTNFR-II levels were lower in portal venous blood than in the hepatic venous blood, as well as in portal venous blood after TIPS insertion. No significant differences were measured in sTNFR-I levels. Hepatic venous levels of sTNFR-I above 4.5 ng/mL (p = 0.036) and sTNFR-II above 7 ng/mL (p = 0.05) after TIPS insertion were associated with decreased survival. A multivariate Cox-regression survival analysis identified the hepatic venous levels of sTNFR-I (p = 0.004) two weeks after TIPS, and Child score (p = 0.002) as independent predictors of mortality, while MELD-score was not., Conclusion: Hepatic venous levels of sTNFR-I after TIPS insertion may predict mortality in patients with severe portal hypertension.

Background/aims: In cirrhosis portal hypertension can promote bacterial translocation and increase serum endotoxin levels. Vice versa, endotoxin aggravates portal hypertension by induction of systemic and splanchnic vasodilation, and by triggering hepatic inflammatory response via tumor necrosis factor α (TNFα). However, the hepatic elimination of endotoxin in cirrhotic patients with severe portal hypertension, in the absence of acute complications, has not been investigated so far., Methods: Twenty patients with alcoholic liver cirrhosis received transjugular intrahepatic portosystemic shunt at an event-free interval for either refractory ascites or recurrent bleeding. During the transjugular intrahepatic portosystemic shunt procedure portal and hepatic venous blood samples were obtained and endotoxin levels were measured by a chromogenic limulus-assay. In 16 of these patients an enzyme-linked immunosorbent assay was used to measure levels of the soluble TNFα-receptors sTNF-R55 and sTNF-R75., Results: Portal venous endotoxin levels correlated with portal vein velocity (P=0.03) and arterial systolic blood pressure (P=0.007). Portal endotoxin levels correlated with portal venous sTNF-R75-levels (P=0.039; r=0.521) and hepatic venous sTNF-R55-levels (P=0.009; r=0.669). Hepatic venous levels of both sTNF-R55 and sTNF-R75 correlated directly with the model for end-stage liver disease-score, and inversely with cholinesterase. However, we did not find significant differences in endotoxin levels nor in sTNF-R55-levels and sTNF-R75-levels between portal and hepatic venous blood., Conclusion: Endotoxin levels correlated with hemodynamic derangement in cirrhotic severe portal hypertension, and with levels of soluble TNFα-receptors. Soluble TNFα-receptor levels correlated with the severity of liver dysfunction. However, in this study an endotoxin concentration gradient across the liver was absent, suggesting negligible primary hepatic endotoxin elimination in the absence of complications.

Objective: To examine the relationship of both the unstimulated and the postprandial portal blood flow (PVF) to the time of day and to determine its intra-individual reproducibility over time in patients with liver cirrhosis., Material and Methods: In 24 cirrhotic patients, 27 PVF measurements were performed during 24 h on day 0 and day 7 using Doppler ultrasound. Three standard liquid meals were given orally. On day 7, the baseline hepatic venous pressure gradient (HVPG) was also measured., Results: Circadian area under the time curve of PVF was highly reproducible within individuals (r=0.959, p<0.001). It did not correlate with HVPG. Cosinor analysis showed a significant circadian rhythm of PVF (acrophase at 11:44 and amplitude of 9.44%). Maximal postprandial increase in PVF was significantly higher in the morning than at noon or in the evening., Conclusions: PVF is subject to a circadian rhythm and postprandial portal hyperemia shows a diurnal variability. Both are highly reproducible.

Background/aim: Kidney function and portal pressure have prognostic relevance in nonshunted patients with cirrhosis. Since insertion of a transjugular intrahepatic portosystemic shunt (TIPS) reduces portal pressure and may improve the renal function, the aim of the present study was to investigate the prognostic role of renal impairment and portal hemodynamics in patients with compensated cirrhosis electively shunted due to recurrent variceal hemorrhages., Methods: Data of 101 consecutive and prospectively followed patients with compensated cirrhosis (bilirubin <5 mg/dl) undergoing elective TIPS due to recurrent variceal bleeding (45 died, and 8 were transplanted during the follow-up period) were evaluated in a multivariate Cox model., Results: Creatinine and sodium were identified as the only independent predictors of survival in this model. The 90th percentile of creatinine (>1.7 mg/dl) defined a subgroup with a similar poor prognosis as the 90th percentile of the model for end-stage liver disease (MELD) score. Neither baseline nor post-TIPS portal pressure correlated with the long-term outcome., Conclusions: In compensated patients undergoing TIPS due to variceal bleeding, renal impairment indicates a poor prognosis. Portal hemodynamic parameters are not predictive of survival in TIPS patients., (Copyright 2003 S. Karger AG, Basel)

Objective: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) is increasingly used to treat complications of portal hypertension, but proven tools for risk assessment of early mortality are lacking., Design: The prospective evaluation of a new 60-day mortality score., Patients and Methods: In a tertiary medical centre, 30 consecutive TIPSS patients were analysed for early mortality predictors, such as Child-Pugh score, TIPSS urgency (elective: > or = 36 h or emergency: < 36 h after variceal bleeding), comorbidity (Acute Physiology and Chronic Health Evaluation [APACHE]-II) and clinical data. Main predictors (P< 0.01) in this group (group-1: Child-Pugh score 10A, 10B, 10C) were graded (1, 2 or 3 points representing low, medium and high risk, respectively) and summarized as a Bonn TIPSS early mortality (BOTEM) score. This score was then tested prospectively in the next 73 TIPSS patients (group-2: Child-Pugh score 14A, 42B, 17C)., Results: Group 1 early mortality (30%) depended primarily on bilirubin (P< 0.005), APACHE-II (P < 0.001) and TIPSS urgency (P< 0.001). Added risk points (1, 2, 3) for bilirubin (< 3 mg/dl, 3-6 mg/dl, > 6 mg/dl, respectively), APACHE-II (< 10, 10-20, > 20 points, respectively) and urgency (elective, emergency, active bleeding, respectively) represented individual BOTEM score points. BOTEM was the best mortality predictor (P< 0.001); < or = / > 6 score points was the optimal cut-off, with 56% sensitivity, 100% specificity, 100% positive predictive value, 84% negative predictive value and 87% accuracy. In group 2, early mortality (8.2%) was again best predicted by BOTEM (P < 0.01) with the same cut-off and 67% sensitivity, 99% specificity, 80% positive predictive value, 97% negative predictive value and 96% accuracy., Conclusion: BOTEM score based on bilirubin, comorbidity and TIPSS-urgency predicts rather reliably post-TIPSS 60-day mortality and might optimize TIPSS treatment.

Tobacco cessation interventions are cost effective therapies in the secondary prevention of coronary heart and chronic obstructive pulmonary diseases which however are rarely used in Germany. Therefore the frequency and the degree of tobacco addiction, the previous treatment of tobacco abuse and the present motivation for smoking cessation of all patients treated within one month in a department of cardiology/pneumology were assessed. 255 of 264 admitted patients (39 % women, 61 % men, mean age 65 +/- 13 years) were evaluated. 33/255 patients (13 %) were smokers, 110/255 (43 %) were former smokers and 112/255 (44 %) patients never smoked. 25/33 (76 %) of the smoking patients met the criteria of nicotine dependence and 8/33 (24 %) the criteria of nicotine abuse of the DSM-IV. According to the Fagerström-Nicotine-Dependence-Test (FTND) 6/33 (18 %) smokers were low nicotine dependent (FTND 0 - 3 points), 24/33 (73 %) smokers were moderate nicotine dependent (FTND 4 - 7 points) and 3/33 (9 %) smokers were high nicotine dependent (FTND 8 - 10 points). 8/33 patients (24 %) agreed in, 8/33 patients (24 %) were undecisive with regard to and 17/33 (52 %) smokers refused smoking cessation treatment during their hospital stay. There was no difference in the FTND between patients willing to stop smoking and patients which were undecisive or unwilling to stop smoking. 27/33 (82 %) patients were pointed to the existence of a tobacco induced disease by physicians, 14/33 (42 %) had received informations about smoking cessation, 7/33 (21 %) had received nicotine substitution and 3/33 (9 %) other treatments (smoking cessation training, acupuncture) in the past. Motivation for and realization of smoking cessation interventions should be considered as important tasks of the psychosomatic or addiction primary care in private practices and hospitals.

Background: Lanreotide, a new long-acting somatostatin analogue, has been shown to inhibit the meal-stimulated increase of splanchnic blood flow in healthy volunteers. To date, similar data in patients with liver cirrhosis have not been available. We have examined the effect of lanreotide compared with placebo on meal-stimulated portal blood flow in patients with liver cirrhosis using Doppler ultrasound., Methods: 20 cirrhotic patients (placebo n = 12, lanreotide n = 8) with proven portal hypertension were studied after an overnight fast. Lanreotide, at a dose of 100 microg/h, was infused intravenously over 7 h after a 1-hour basal period. In parallel to the intravenous infusion, a liquid test meal (Ensure plus, 1.5 kcal/min) was perfused for 7 h through an intraduodenal tube at a rate of 3 ml/min. Blood pressure, heart rate and portal vein blood flow (PVF, ml/min, Doppler technique) were determined at regular intervals., Results: Baseline PVF amounted to 725 +/- 182 ml/min in the placebo and to 917 +/- 252 ml/min in the lanreotide group (n.s.). The meal-stimulated increase in PVF was blunted by lanreotide (AUC, % x min): 62,709.6 +/- 6,817 (placebo) vs. 45,237 +/- 2,507 (lanreotide), p < 0.05. Lanreotide also blunted the postprandial increase in heart rate for the first 2 h of meal perfusion., Conclusions: Because of potent inhibition of postprandial splanchnic hyperemia in patients with liver cirrhosis, lanreotide may be useful in the treatment of complications of portal hypertension., (Copyright 2002 S. Karger AG, Basel)

Objective: This study was undertaken to investigate to what extent continuous infusion of a galactose-based microbubble contrast agent (Levovist) allows evaluation of the portal vascular system in patients with portal hypertension and for whom baseline unenhanced color Doppler sonography was nondiagnostic., Subjects and Methods: We performed color Doppler sonography at baseline and during IV Levovist infusion (4 g, 300 mg/min). First, we measured the duration of portal vein visualization during Levovist infusion in 15 patients in whom unenhanced color Doppler sonography failed to show the portal confluence from a subcostal view. This duration of improved portal conspicuity was termed "diagnostic window." We then compared in 30 patients enhanced color Doppler sonographic findings with conventional imaging methods, including portography (n = 14), helical CT (n = 4), or gadolinium-enhanced MR angiography (n = 12), and we recorded the investigator's confidence in the color Doppler sonographic result before and after Levovist infusion., Results: The diagnostic window achieved by the Levovist infusion was 13.6 +/- 0.9 min. At baseline, color Doppler sonography was nondiagnostic in 19 patients. The diagnostic confidence level was low in all the remaining 11 patients. During Levovist infusion, color Doppler sonography remained nondiagnostic only in two of 30 patients. The confidence level was low in five patients and high in 23 patients. In 26 of these 28 patients, echo-enhanced color Doppler sonographic findings were confirmed by reference methods., Conclusion: The continuous infusion of Levovist achieved a sufficient echo enhancement from the portal vascular bed and allowed a valid diagnostic color Doppler sonographic examination in portal hypertensive patients for whom color Doppler sonography would otherwise be nondiagnostic.

Background & Aims: Angiotensin II receptor antagonists have been proposed as new drugs for portal hypertension. This randomized, placebo-controlled, double-blind study aimed to assess the effect of the angiotensin II receptor antagonist irbesartan on portal and systemic hemodynamics and renal function in patients with cirrhosis., Methods: Thirty-six patients with cirrhosis and portal hypertension received 150 mg/d irbesartan or placebo for 1 week. Systemic hemodynamics, kidney and liver function parameters were recorded regularly; hepatic venous pressure gradient and plasma renin were assessed on days 0 and 7., Results: Irbesartan reduced the hepatic venous pressure gradient by 12.2% +/- 6.6% (P < 0.05) and mean arterial pressure by 5.3% +/- 4.0% in 13 of 18 verum patients. In 4 (22%) verum patients, arterial hypotension, accompanied by significant renal impairment, required withdrawal of irbesartan. In these patients, baseline plasma renin (P < 0.002) and cystatin C (P < 0.001) levels were higher, and creatinine clearance (P < 0.02), serum sodium (P < 0.01), and albumin (P < 0.05) were lower than in patients who tolerated irbesartan. Four of five patients with baseline renin >900 microU/mL developed treatment-limiting hypotension., Conclusions: The angiotensin II receptor antagonist irbesartan is not advisable in patients with advanced cirrhosis and high plasma renin because it may induce arterial hypotension and only moderately reduces portal pressure.

Objective: The aim of this study was to evaluate the hemodynamic effects of octreotide in patients treated with transjugular intrahepatic portosystemic stent shunt in relation to plasma levels of octreotide and glucagon and the correlation between portal pressure and noninvasive Doppler parameters., Methods: In 15 fasting patients, we i.v. administered isotonic sodium chloride followed by octreotide 25 microg/h and 100 microg/h, each over 1 h. We measured portal pressure (PP) directly and portal vein blood flow velocity by Doppler ultrasound simultaneously and calculated portal vascular resistance (PVR) and portal venous flow (PVF). Blood samples were taken for glucagon and octreotide (mean +/- SE)., Results: Octreotide reduced PP (120': -7.7+/-2.2%, p < 0.01 vs baseline; 180': - 11.4+/-2.1%, p < 0.01 vs baseline) and PVF (120': -21.7+/-31.7%, p < 0.01 vs baseline; 180': -11.6+/-18.1%, p < 0.05 vs baseline). Glucagon decreased with the increase in octreotide levels and showed a correlation with the decrease in PP and with PVF. In patients with a high PVR, we found a close inverse correlation between PP and portal vein blood flow velocity (r = -0.83, p = 0.03) as well as Cl (r = 0.81, p = 0.05), whereas poor correlation was found in patients with low PVR., Conclusions: Octreotide caused a dose-related, moderate but sustained reduction in PP in patients with transjugular intrahepatic portosystemic stent shunt. PVR seems to be an important parameter that influences the efficacy of octreotide and the relation between PP and noninvasive Doppler parameters.