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BACKGROUND & AIMS Alcohol-related hepatitis (AH) encompasses a high mortality. AH might be a concomitant event in patients with acute variceal bleeding (AVB). The current study aimed to assess the prevalence of AH in patients with AVB and to compare the clinical outcomes of AH patients to other alcohol-related liver disease (ALD) phenotypes and viral cirrhosis. METHODS Multicentre, observational study including 916 patients with AVB falling under the next categories: AH (n = 99), ALD cirrhosis actively drinking (d-ALD) (n = 285), ALD cirrhosis abstinent from alcohol (a-ALD) (n = 227) and viral cirrhosis (n = 305). We used a Cox proportional hazards model to calculate adjusted hazard ratio (HR) of death adjusted by MELD. RESULTS The prevalence of AH was 16% considering only ALD patients. AH patients exhibited more complications. Forty-two days transplant-free survival was worse among AH, but statistical differences were only observed between AH and d-ALD groups (84 vs. 93%; p = 0.005), when adjusted by MELD no differences were observed between AH and the other groups. At one-year, survival of AH patients (72.7%) was similar to the other groups; when adjusted by MELD mortality HR was better in AH compared to a-ALD (0.48; 0.29-0.8, p = 0.004). Finally, active drinkers who remained abstinent presented better survival, independently of having AH. CONCLUSIONS Contrary to expected, AH patients with AVB present no worse one-year survival than other patients with different alcohol-related phenotypes or viral cirrhosis. Abstinence influences long-term survival and could explain these counterintuitive results.

Patients admitted with acute variceal bleeding (AVB) and Child-Pugh C score (CP-C) or Child-Pugh B plus active bleeding at endoscopy (CP-B+AB) are at high risk for treatment failure, rebleeding, and mortality. A preemptive transjugular intrahepatic portosystemic shunt (p-TIPS) has been shown to improve survival in these patients, but its use in clinical practice has been challenged and not routinely incorporated. The present study aimed to further validate the role of preemptive TIPS in a large number of high-risk patients. This multicenter, international, observational study included 671 patients from 34 centers admitted for AVB and high risk of treatment failure. Patients were managed according to current guidelines, and use of drugs and endoscopic therapy (D+E) or p-TIPS was based on individual center policy. p-TIPS in the setting of AVB is associated with a lower mortality in CP-C patients compared with D+E (1 year mortality 22% vs. 47% in D+E group; P = 0.002). Mortality rate in CP-B+AB patients was low, and p-TIPS did not improve it. In CP-C and CP-B+AB patients, p-TIPS reduced treatment failure and rebleeding (1-year cumulative incidence function probability of remaining free of the composite endpoint: 92% vs. 74% in the D+E group; P = 0.017) and development of de novo or worsening of previous ascites without increasing rates of hepatic encephalopathy. Conclusion: p-TIPS must be the treatment of choice in CP-C patients with AVB. Because of the strong benefit in preventing further bleeding and ascites, p-TIPS could be a good treatment strategy for CP-B+AB patients.

Stilbenes are naturally scarce high-added-value plant compounds with chemopreventive, pharmacological and cosmetic properties. Bioproduction strategies include engineering the metabolisms of bacterial, fungal and plant cell systems. Strikingly, one of the most effective strategies consists in the elicitation of wild grapevine cell cultures, which leads to vast stilbene resveratrol accumulation in the extracellular medium. The combination of both cell culture elicitation and metabolic engineering strategies to produce resveratrol analogs proved more efficient for the hydroxylated derivative piceatannol than for the dimethylated derivative pterostilbene, for which human hydroxylase HsCYP1B1- and grapevine O-methyltransferase VvROMT-transformed cell cultures were respectively used. Rose orcinol O-methyltransferase (OOMT) displays enzymatic properties, which makes it an appealing candidate to substitute VvROMT in the combined strategy to enhance the pterostilbene production level by engineered grapevine cells upon elicitation. Here we cloned a Rosa hybrida OOMT gene, and created a genetic construction suitable for Agrobacterium-mediated plant transformation. OOMT's ability to catalyze the conversion of resveratrol into pterostilbene was first assessed in vitro using protein extracts of agroinfiltrated N. benthamiana leaves and transformed grapevine callus. The grapevine cell cultures transformed with RhOOMT produced about 16?mg/L culture of pterostilbene and reached an extracellular distribution of up to 34% of total production at the best, which is by far the highest production reported to date in a plant system. A bonus large resveratrol production of ca. 1500-3000?mg/L was simultaneously obtained. Our results demonstrate a viable successful metabolic engineering strategy to produce pterostilbene, a resveratrol analog with enhanced pharmacological properties.

The present study was designed to investigate the functional status of 2 adrenoceptors (2AR) in two models of chronic inflammatory disease: Liver cirrhosis (LC) and osteoarthritis (OA). The 2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte 2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13 +/- 4 mmHg, CHILD 7 +/- 2 and MELD 11 +/- 4 scores), OA patients (n=30, 84% Kellgren-Lawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 10(-9) to 10(-4) mM), and 2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. 2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the 2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the 2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes.

Background & Aims The use of non-selective beta-blockers has been associated with lower rates of infection and reduced infection-associated morbidity in patients with cirrhosis. However, it is unknown if these drugs modify the systemic inflammatory response to circulating bacterial DNA. Methods Results Sixty-three patients with cirrhosis were included during an episode of decompensation by ascites. Thirty of those patients were on beta-blockers. Blood samples were obtained after each patient had been in the supine position for at least 30 minutes in a quiet atmosphere. Bacterial DNA, serum cytokines, nitric oxide, and LPS were determined. Phagocytic and oxidative burst activities were determined in polymorphonuclear cells from the patients. The detection rate of bacterial DNA in the blood was the same (33%) for patients not treated and treated with non-selective beta-blockers. Patients naive to non-selective beta-blockers showed significantly higher serum levels of IL6, IFN-gamma and IL10 in response to the presence of bacterial DNA. Patients treated with non-selective beta-blockers showed higher basal inflammatory activity that did not change with the presence of bacterial DNA. Monocytes and granulocytes from patients treated with non-selective beta-blockers showed a significantly increased phagocytic capacity in the presence of bacterial DNA. Conclusions In patients with cirrhosis, chronic treatment with beta-blockers is associated with a higher unstimulated production of serum cytokines and an increased phagocytic activity in the presence of bacterial DNA.

Background: To analyse the clinical, epidemiological, microbiological and prognostic differences of pyogenic liver abscess (PLA) in older (>= 65 years of age) versus younger patients (= 65 years) for comparison of clinical, epidemiological and microbiological characteristics as well as treatment. Results: Of 98 patients analysed, 40 patients were younger than 65, and 58 were aged 65 or older. Significant associations in the older group were found with female sex (adjusted odds ratio [ORa] 9.0; 95% CI 1.4, 56), non-cryptogenic origin (ORa 14.5; 95% CI 1.6, 129), absence of chronic liver disease (ORa 14; 95% CI 1.3, 155), Escherichia coli infection (ORa 7.7; 95% CI 1.03, 58), and incidence of complications (ORa 2.3; 95% CI 1.04, 5.4). Mortality was 8.2% overall, although all deaths occurred in the older group (8/58; 13.8%) (p = 0.02). Discussion: Our results are in consonance with other published studies. Older patients with PLA tend to present more anomalies in the biliary tract (Kai et. al, World J Gastroenterol 18: 2948-295, 2012, Rahimian et. al, Clin Infect Dis 39: 1654-9, 2004, Seeto, Medicine (Baltimore) 75: 99-113, 1996, Kao et. al, Aliment Pharmacol Ther 36: 467-76, 2012, Lai et. al, Gastroenterology 146: 129-37, 2014), while younger patients are more often male and present more commonly with previous liver disease (especially related to alcohol) and cryptogenic PLA. Conclusion: In patients aged 65 or older, PLA was more common in women and in those with a history of biliary disease, and E. coli was the most frequent bacterium. Mortality was also higher in the older group.

IntroductionPatients with cirrhosis by hepatitis C virus infection treated with -blockers (BB) have been shown to have a reduced incidence of hepatocellular carcinoma (HCC). Also, an association between propranolol therapy and lower incidence of other tumors has been described.AimTo analyze the incidence of HCC according to BB treatment in cirrhosis of any cause.Patients and methodsCirrhotic patients included in the program for early detection of HCC were followed. Patients' data were prospectively registered, including transplantation and death. Patients were classified as chronically taken or not BB and the proportions of patients who remained free of tumor from the diagnosis of cirrhosis until the end of follow-up were compared using Kaplan-Meier analysis and the Breslow test.ResultsA total of 173 patients (73 treated and 100 untreated BB) were followed. The median duration of follow-up was 11 years. There were no differences between both groups in the overall survival, number of deaths, or liver transplant.Overall, 28 patients developed HCC during the follow-up, 20 patients who were untreated and eight patients treated with BB. The cumulative proportion of cases of HCC between untreated and treated with BB from the diagnosis of cirrhosis was statistically significant (6 vs. 3%, at 5 years; 19 vs. 6% at 10 years; 24 vs. 16% at 15 years; P=0.048). Multivariate analyses showed BB intake as the only significant variable associated with the development of HCC.ConclusionCirrhotic patients treated with BB have a lower cumulative probability of developing HCC during the 10 years after the diagnosis of cirrhosis.

Use of non-steroidal anti-inflammatory drugs in cirrhosis has been associated with impairment of renal function based on its ability to inhibit the renal production of prostaglandins. Renal effects of dipyrone in patients with cirrhosis have not been evaluated. We aimed to assess the renal effect of therapeutic doses of dipyrone used for short periods of time in patients with cirrhosis. Twenty-nine patients with cirrhosis were included in an observer-blind clinical trial. Patients were randomized to receive three times a day oral acetaminophen (500mg; N=15) or dipyrone (575mg; N=14) for 72hr. Serum and urine samples were obtained at baseline, 48 and 72hr, and cystatin C, creatinine, aldosterone, 6-keto-Prostaglandin-F1 alpha and prostaglandin E2 were measured. Cystatin C and creatinine levels remained comparable in patients treated with acetaminophen and dipyrone. Urine and serum prostaglandins concentrations were significantly decreased at 72hr in patients treated with dipyrone regardless of the status of ascites. One patient with ascites treated with dipyrone required a paracentesis and developed renal insufficiency. We conclude that dipyrone and acetaminophen did not reduce renal function when used for short periods of time (up to 72hr) in patients with cirrhosis. However, considering that dipyrone lowered renal vasodilator prostaglandins synthesis, acetaminophen appears as the safest choice with respect to kidney function in cirrhosis.

Purpose: Some new staging systems in hepatocellular carcinoma (HCC) have been described in the last years. The aim of this study was to compare the survival-predicting capacity of some variables and the prognostic classifications. Methods: Demographic, clinical, analytical variables and tumour characteristics were collected in a study including 115 patients with HCC. Predictors of survival were identified using the Kaplan-Meier test and the Cox model. Comparison between different staging systems was carried out. Results: The 1-, 2- and 3-year estimated survival was 65%, 45% and 30%, respectively. Child-Pugh score and alpha-fetoprotein level greater than 400 UI/l were independent predictors of survival in the Cox model. Although all systems correctly differentiated between patients regarding survival (Kaplan-Meier, log rank < 0.05 for all), the Barcelona Clinic Liver Cancer (BCLC) showed a better discriminatory ability than the other evaluated scores. In addition, the independent homogenizing ability and stratification value of BCLC was better than that of other systems. On the contrary, model for end-stage liver disease (MELD) showed the worst results. Conclusions: Child-Pugh score and alpha-fetoprotein levels were the only independent predictors of survival in patients with HCC. Child-Pugh score showed a better prediction value for survival when compared with MELD. BCLC is more accurate than the other prognostic models evaluated in this investigation.