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Background/Aims Bariatric surgery can increase the risk of addictive disorders and nutritional deficiencies. The aim of this study was to evaluate the association between bariatric surgery and alcohol use disorder (AUD), alcohol-related liver disease (ALD), and psychiatric disorders associated with AUD. The impact of vitamin D deficiency in these associations was also investigated. Methods A cross-sectional study was performed using the National Inpatient Sample database and its ICD-9 codes information. Diagnostic and comorbidity data from hospital discharges were obtained from patients with bariatric surgery and other abdominal surgeries between 2005 and 2015. The two groups were then compared for alcohol-related outcomes after propensity-score matching. Results The final study cohort included 537,757 patients with bariatric surgery and 537,757 with other abdominal surgeries. The bariatric surgery group had an increased risk of AUD [odds ratio (OR): 1.90; 95% CI: 1.85–1.95], ALD [OR: 1.29; 95% CI: 1.22–1.37], cirrhosis [OR, 1.39; 95% CI: 1.37–1.42], and psychiatric disorders associated with AUD [OR, 3.59; 95% CI: 3.37–3.84]. Vitamin D deficiency did not impact in the association between bariatric surgery and AUD, ALD, or psychiatric disorders associated with AUD. Conclusions Bariatric surgery is associated with an increased prevalence of AUD, ALD, and psychiatric disorders associated with AUD. These associations appear to be independent from vitamin D deficiency. Graphical Abstract

Introduction: Direct-acting antivirals (DAAs) are an opportunity for hepatitis C virus (HCV) elimination. Strategies are needed to diagnose new patients and to attract those diagnosed without evaluation. Patients with other chronic viral diseases who receive satisfactory treatment promote referral of other patients for evaluation. Our aim was to evaluate whether patients who have been treated with DAAs would recommend follow-up and treatment to other patients as well as the characteristics that influence this decision. Patients and methods: Two-hundred and 2 HCV-infected patients treated with DAAs were included. Patients were asked about whether they knew other infected people and their willingness to share their experience. A general satisfaction survey and a specific HCV satisfaction survey were carried out. Demographic, socioeconomic and HCV infection variables were recorded. Results: Despite the fact that 54.4% of the patients reported knowing others infected, 34.2% would not fully agree to share their experience. The analysis of general and specific satisfaction showed that patients who shared their experience mentioned a perception of greater care from the specialist (4.7 ± 0.4 vs. 4.3 ± 0.6, P=.001) and had more information on treatment expectations (4.6 ± 0.5 vs. 4.0 ± 0.7, P=.001) and social support (4.5 ± 0.7 vs. 4.0 ± 0.8, P=.001). Conclusions: The perception by treated patients of general satisfaction with the healthcare process and information about benefits influences the degree of recommendation to other infected people. Knowledge about treatment and perception of improvement in health of treated patients should be enhanced as it can contribute to increasing referrals to specialized consultation.

Resumen Introduccion La infeccion por el virus de la hepatitis C (VHC) es curable en la mayoria de los casos tratados, siendo actualmente una prioridad diagnosticar a todos los infectados. Para ello se necesitan, especialmente en poblaciones de dificil diagnostico, metodos diagnosticos simples, como es el uso de muestras de gotas de sangre seca (GSS), como alternativa a la extraccion de sangre mediante venopuncion. Como paso previo para poder implantarlo como metodo diagnostico de deteccion de pacientes con VHC dentro del Sistema Nacional de Salud se precisa evaluar la precision diagnostica en equipos de uso hospitalario habitual. Metodologia Se evaluaron in vitro y en ensayo de campo muestras de GSS tras ser procesadas en el equipo Cobas 6800, estableciendo una correlacion con el resultado obtenido con sangre completa. Se realizaron pruebas de correlacion y de variabilidad intraensayo de la determinacion con sangre completa y GSS para cuantificar la carga viral del VHC. Resultados En muestras de sangre completa, con una carga viral ≥ 3 log10 UI/ml, se detecto viremia en todos los casos cuando se utilizaron eluciones de 2 gotas (94 detecciones de 95 eluciones de circulos). El rendimiento con 2 gotas fue menor en muestras con Conclusion La determinacion de la carga viral mediante GSS, procesando al menos 2 gotas, es un metodo fiable para el diagnostico de infeccion por el VHC. La estandarizacion del metodo es factible en nuestro equipo Cobas 6800 local, y nuestros resultados respaldan la incorporacion de esta herramienta diagnostica al Sistema Nacional de Salud para facilitar planes de microeliminacion.

Introduction Because hepatitis C virus (HCV) infection is curable in the majority of cases, the diagnosis of all infected patients has become a priority. In difficult-to-diagnose populations, simpler diagnostic methods are required such as the use of dried blood spots (DBS) as an alternative to blood drawn by venipuncture (VP). Before being able to include it as a HCV diagnostic detection method within the Spanish National Health System, the diagnostic accuracy of standard hospital equipment must be evaluated. Methodology DBS samples were evaluated in vitro and in a field test after being processed in the Cobas 6800 system, establishing a correlation with the result by VP. Performance with different viral loads and intra-assay variability was compared. Results In samples with a viral load of >3 log10 IU/ml, viraemia was detected in all cases when at least two blood spot elutions were used (94 detections out of 95 spot elutions). The performance with 2 spots was lower in samples with Conclusion Viral load detection using DBS of at least two spots is a reliable method for HCV diagnosis. The standardisation of the method is feasible and our results support the incorporation of this diagnostic tool in Spain's Public Health System.

Objective Many hepatitis C virus (HCV)-infected patients have a suboptimal diagnosis. Particularly, the characteristics and risk of fibrosis progression of HCV antibody-positive patients without RNA testing are unknown. Methods Patients with a positive HCV antibody performed during 2005-2007 were classified based on RNA request and result until January 2017. Fibrosis was estimated with serologic scores. Results Of the 38 246 HCV tests performed, 791 (2.01%) patients tested positive. At the end of the follow-up (median 128.6 months, range 109.8-145.9), 49.43% (n = 391) of the subjects did not have RNA testing, 13.02% (n = 103) had undetectable RNA, and 37.55% (n = 297) had detectable RNA. After excluding patients without data for AST to platelet ratio index calculation (n = 334), patients without RNA testing (n = 122) compared with RNA undetectable (n = 92) were more frequently men (68.9 versus 46.7%), alcohol (52.6 versus 38.2%) and drug (53.0 versus 39.1%) users, lacking social support (50.4 versus 29.3%), and showed higher basal fibrosis. Patients without RNA testing had a significantly higher increase in the percentage of patients with ≥F2 (P = 0.035) and cirrhosis (P = 0.022). The relative risk for ≥F2 and cirrhosis in patients without RNA testing was 3.03 [95% confidence interval (CI): 1.54-5.98] and 4.31 (95% CI: 1.42-13.10), respectively. Non-RNA request was an independent predictor factor for progression to cirrhosis. Conclusion In our cohort, patients with positive HCV antibody without RNA testing were more likely to be people at risk of social exclusion with an increased risk of fibrosis progression, because non-RNA request was a predictor for cirrhosis. Therefore, we urge support measures and strategies to link to care these difficult-to-treat populations.

Background & Aims Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. Methods This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. Results One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23–37%) on US and 47.7% (95% CI 39–56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38–62%) and 85.3% (95% CI 75–92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. Conclusion While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. Lay summary Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.

BACKGROUND Many patients with chronic hepatitis B virus infection remain infradiagnosed and untreated. In a national health system with unrestricted access to treatment, our aims were to assess the level of compliance with clinical guidelines and the characteristics and risk of fibrosis progression in patients with suboptimal diagnosis. METHODS In a cohort of patients with positive hepatitis B surface antigen from January 2011 to December 2013, data were registered to assess characteristics and compliance with guidelines. For assessing the risk of liver fibrosis, positive hepatitis B surface antigen patients from January 2008 to December 2013 were grouped depending on DNA request. Liver fibrosis was estimated by serological scores. RESULTS Of 41 158 subjects with hepatitis B surface antigen request, 351 (0.9%) tested positive, and DNA was not available from 110 patients (66.4% male, mean 42.4 ± 14.5 years) after a median of 25.6 months (range 12.0-43.5). Most of these patients (76%) were assessed by primary care. Half of the patients (47.2%) showed hypertransaminasemia, at least significant fibrosis, or both conditions. After long follow-up (mean 90.1 ± 45.2 months), these patients had a higher risk of achieving at least significant fibrosis during follow-up (log-rank 8.73; P = 0.003). CONCLUSION In more than one-third of patients with positive hepatitis B surface antigen, DNA was not requested despite showing hypertransaminasemia and significant fibrosis. Patients without DNA request are at high risk of liver fibrosis progression. Thus, educational measures and other strategies are necessary, especially targeting primary care, to improve access to treatment.

hepatitis C patients loss to follow-up in the health care system has been shown to have negative consequences. This study aimed to investigate this issue as regards primary biliary cholangitis.the databases (immunology, biochemistry, clinical reports, drug dispensation, appointments) of 4 reference hospitals in Spain (serving a population of 1,450,000 inhabitants) were analyzed. The diagnosis of primary biliary cholangitis was based on an antimitochondrial antibody titer ≥ 1:80, chronically elevated alkaline phosphatase, and the absence of other liver disease. Patients were classified as lost in the absence of reports indicating a diagnosis, specific medical follow-up, and/or treatment with bile salts.a total of 1372 patients with antimitochondrial antibody titers ≥ 1:80 were included between January 2010 and June 2019. A total of 697 (50.8 %) were classified as having primary biliary cholangitis, and 100 patients (14.3 %; 95 % CI: 11.8-17.2) were identified as lost. Of these, 30 were contacted and retrieved. The median age was 70 years, 93 % were female, median alkaline phosphatase was 185 IU/L, 10 % had pruritus, and 27 % had a transient elastography value9.5 kPa. The disease was confirmed and ursodeoxycholic acid was started in all 30 patients. Death was liver-related in 6 of the 100 patients classified as lost.up to 14.3 % of patients (1 out of 7) with a definitive diagnosis of primary biliary cholangitis remain undiagnosed, thus preventing monitoring and treatment. More than a quarter are at risk of advanced liver disease and its complications. Patients lost in the system must be identified and retrieved, and searching hospital databases is a suitable approach to meet this goal.

[Background & Aims] The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic., [Methods] An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave., [Results] Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%, 17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37)., [Conclusions] The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making., [Lay summary] The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes.

Background In the non-interferon era, many patients still remain untested for hepatitis C virus (HCV) infection. Our aim was to determine if media coverage, number and type of news, can influence the rate of HCV testing. Methods For each calendar year we searched from national, regional and local newspapers for articles published related to HCV between 2001 and 2013 (interferon era) and 2014–2018 (non-interferon era) and the HCV tests performed. Demographics, provider data and test result were collected from patients tested. Results During the studied period, 21 913 press articles were found, and we identified a total of 293 226 HCV tests. A total of 9778 HCV tests from 5237 patients tested positive (1.88%). An inverse correlation was found between media coverage and the number of HCV tests during the interferon era (r2 = −0.558, P = 0.024), where news concerning epidemiology and burden of the disease were more frequent. By contrast, in the non-interferon era a strong correlation was observed (r2 = 0.900, P = 0.019), where news related to treatment prevailed. Conclusion Our results show that media coverage on HCV fluctuate so the type of news. It remains to be prospectively evaluated if well designed publicity campaigns about the benefits of HCV screening and treatment influences on HCV testing.

This study examined the effects of a large-scale flipped learning (FL) approach in an undergraduate course of Digestive System Diseases.This prospective non-randomized trial recruited 404 students over three academic years. In 2016, the course was taught entirely in a Traditional Lecture (TL) style, in 2017 half of the course (Medical topics) was replaced by FL while the remaining half (Surgical topics) was taught by TL and in 2018, the whole course was taught entirely by FL. Academic performance, class attendance and student's satisfaction surveys were compared between cohorts.Test scores were higher in the FL module (Medical) than in the TL module (Surgical) in the 2017 cohort but were not different when both components were taught entirely by TL (2016) or by FL (2018). Also, FL increased the probability of reaching superior grades (scores7.0) and improved class attendance and students' satisfaction.The holistic FL model is more effective for teaching undergraduate clinical gastroenterology compared to traditional teaching methods and has a positive impact on classroom attendances.

Background & Aims: Corticosteroids are the only effective therapy for severe alcohol-associated hepatitis (AH), defined by a model for end-stage liver disease (MELD) score >20. However, there are patients who may be too sick to benefit from therapy. Herein, we aimed to identify the range of MELD scores within which steroids are effective for AH. Methods: We performed a retrospective, international multi-center cohort study across 4 continents, including 3,380 adults with a clinical and/or histological diagnosis of AH. The main outcome was mortality at 30 days. We used a discrete-time survival analysis model, and MELD cut-offs were established using the transform-the-endpoints method. Results: In our cohort, median age was 49 (40-56) years, 76.5% were male, and 79% had underlying cirrhosis. Median MELD at admission was 24 (19-29). Survival was 88% (87-89) at 30 days, 77% (76-78) at 90 days, and 72% (72-74) at 180 days. A total of 1,225 patients received corticosteroids. In an adjusted-survival-model, corticosteroid use decreased 30-day mortality by 41% (hazard ratio [HR] 0.59; 0.47-0.74; p 51. The type of corticosteroids used (prednisone, pred-nisolone, or methylprednisolone) was not associated with sur-vival benefit (p = 0.247). Conclusion: Corticosteroids improve 30-day survival only among patients with severe AH, especially with MELD scores between 25 and 39. Lay summary: Alcohol-associated hepatitis is a condition where the liver is severely inflamed as a result of excess alcohol use. It is associated with high mortality and it is not clear whether the most commonly used treatments (corticosteroids) are effective, particularly in patients with very severe liver disease. In this worldwide study, the use of corticosteroids was associated with increased 30-day, but not 90-or 180-day, survival. The maximal benefit was observed in patients with an MELD score (a marker of severity of liver disease; higher scores signify worse disease) between 25-39. However, this benefit was lost in patients with the most severe liver disease (MELD score higher than 51). (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Direct-acting antivirals (DAAs) are an opportunity for hepatitis C virus (HCV) elimination. Strategies are needed to diagnose new patients and to attract those diagnosed without evaluation. Patients with other chronic viral diseases who receive satisfactory treatment promote referral of other patients for evaluation. Our aim was to evaluate whether patients who have been treated with DAAs would recommend follow-up and treatment to other patients as well as the characteristics that influence this decision.Two-hundred and 2HCV-infected patients treated with DAAs were included. Patients were asked about whether they knew other infected people and their willingness to share their experience. A general satisfaction survey and a specific HCV satisfaction survey were carried out. Demographic, socioeconomic and HCV infection variables were recorded.Despite the fact that 54.4% of the patients reported knowing others infected, 34.2% would not fully agree to share their experience. The analysis of general and specific satisfaction showed that patients who shared their experience mentioned a perception of greater care from the specialist (4.7±0.4 vs. 4.3±0.6, P=.001) and had more information on treatment expectations (4.6±0.5 vs. 4.0±0.7, P=.001) and social support (4.5±0.7 vs. 4.0±0.8, P=.001).The perception by treated patients of general satisfaction with the healthcare process and information about benefits influences the degree of recommendation to other infected people. Knowledge about treatment and perception of improvement in health of treated patients should be enhanced as it can contribute to increasing referrals to specialized consultation.

Objectives: there has been a global increase in the incidence of hepatitis A infection. The aim of this study was to examine the characteristics of the increase in our region and the degree of adherence to the recommended hygienic measures after discharge from hospital. Methods: demographic, clinical and biochemical variables were collected from patients with acute hepatitis A in our health area. The patients were grouped as follows: January 2010 to December 2016 (historical cohort) and January 2017 to October 2017 (recent cohort). A phylogenetic analysis was also performed in the recent cohort. One month after discharge, bacterial growth was evaluated by a culture of the dominant hand imprint and were compared with a control group. Results: a total of 110 cases were registered with a median age of 36.3 years (range 3-89) and 77.3 % were male. The incidence was 0.82/100,000 inhabitants/year and 22.75/100,000 inhabitants/year in the historical and recent cohorts, respectively. Patients in the recent cohort were more frequently male (52.6 % vs. 82.4 %, p = 0.008) and younger (51.7 [3-89] vs. 33.4 [4-74] years, p < 0.001). In addition, 63.8 % of the recent cohort were men who had sex with other men and had unsafe sexual practices (37.5 %). Phylogenetic analysis showed a predominance of genotype A and a high frequency of the VRD 521-2016 sequence. A higher growth of enterobacteria was observed in patients with hepatitis A compared to the control group (7.3 % vs. 1.2 %, p = 0.005), despite specific hygienic measures given at discharge. Conclusions: a recent outbreak of hepatitis A in our area was related with gender, younger age and sexual practices. Hepatitis A infected subjects showed a poor adherence to hygienic measures. Our data suggests the need for policies that encourage preventive actions, particularly vaccination in this high-risk group. This study was partially supported by grants from Fondos FEDER. Dr. M. Hernandez-Guerra is the recipient of a Grant from Instituto de Salud Carlos III (PI14/01243). Sí

Background People attending drug treatment centres have a high burden of hepatitis C virus (HCV) and face barriers to diagnosis and treatment. Dried blood spot (DBS) testing has been proposed to simplify diagnosis, but many patients remain untreated. In this retrospective study, we evaluated the reasons for non-retention in care in an intervention using on-site DBS testing and the effect of telemedicine and decentralized care compared to standard of care among people attending drug treatment centres who were lost to follow-up. Methods In a first phase, retention in care, adherence to treatment, and predictive factors in the DBS testing program of patients in drug treatment centres were analyzed and compared to a cohort of patients treated at the hospital outpatient clinic. Subsequently, in a second phase we evaluated in patients lost to follow-up from drug treatment centres the efficacy of one-step testing and telemedicine linked to a decentralized dispensation of HCV treatment or standard of care. Results Among 512 patients attending drug treatment centres, 467 (91.2%) agreed to be tested and 53.4% (237 patients/444 valid tests) tested positive (46 ± 9 years, 87.3% male) for HCV antibodies. After excluding patients negative for RNA or under surveillance, 178 patients were scheduled to meet with a specialist. Overall, 44 patients did not attend and 25 did not complete the pre-treatment evaluation. The only factor associated with retention in care was patient's knowledge of HCV infection. Treated patients attending drug treatment centres (n = 68) compared to the hospital outpatient clinic cohort (n = 135) had lower rates of treatment adherence. Among the patients who attended drug treatment centres that were lost to follow-up (n = 69), the proportion of patients who completed the program was significantly higher among those assisted by telemedicine than by standard of care (62.5% vs. 24.3%, p = 0.002). Conclusion Although there was a high participation rate in a DBS testing program in drug treatment centres, non-retention in care is a challenge. Importantly, telemedicine linked to a decentralized dispensation of HCV treatment re-engages patients and may be effective for HCV microelimination.

The process of diagnosis and linkage to care in cases of hepatitis C virus (HCV) infection remains an obstacle to disease control. The aims of this study were to evaluate predictive factors for not undergoing RNA testing among patients with positive HCV serology and impact of incorporating an automated electronic alert with recommendations in clinical practice. We collected HCV antibody tests requested from October 2011 to September 2014 to evaluate the rate of RNA testing and predictive factors for not undergoing RNA testing. Since October 2014, an automated alert notification has been implemented to remind physicians for testing RNA after a positive HCV test and referral to specialist care. 41 403 HCV antibody tests were requested from 34 073 patients. 870 (2.55%) patients tested positive. After a median of follow-up of 57.0 months (range 45.6-82.1), 37.6% did not have RNA testing. The independent predictors for not undergoing RNA testing were primary care serology requests (P

Background & Aims The combination of β-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis. Methods We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a β-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding). Results The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group ( P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15–0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group ( P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group ( P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group ( P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis. Conclusions In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185.

Introduction Metabolic syndrome induces endothelial dysfunction, a surrogate marker of cardiovascular disease. In parallel, metabolic syndrome is frequently associated with non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. The aim of the present study was to evaluate intrahepatic endothelial dysfunction related to cyclooxygenase end products and oxidative stress as possible mechanisms involved in the pathophysiology of NAFLD. Materials and Methods Sprague-Dawley rats were fed standard diet (control-diet, CD) or high-fat-diet (HFD) for 6 weeks. Metabolic syndrome was assessed by recording arterial pressure, lipids, glycemia and rat body weight. Splanchnic hemodynamics were measured, and endothelial dysfunction was evaluated using concentration-effect curves to acetylcholine. Response was assessed with either vehicle, L-NG-Nitroarginine (L-NNA), indomethacin, tempol, or a thromboxane receptor antagonist, SQ 29548. We quantified inflammation, fibrosis, oxidative stress, nitric oxide (NO) bioavailability and thromboxane B2 levels. Results HFD rats exhibited metabolic syndrome together with the presence of NAFLD. Compared to control-diet livers, HFD livers showed increased hepatic vascular resistance unrelated to inflammation or fibrosis, but with decreased NO activity and increased oxidative stress. Endothelial dysfunction was observed in HFD livers compared with CD rats and improved after cyclooxygenase inhibition or tempol pre-incubation. However, pre-incubation with SQ 29548 did not modify acetylcholine response. Conclusions Our study provides evidence that endothelial dysfunction at an early stage of NAFLD is associated with reduced NO bioavailability together with increased cyclooxygenase end products and oxidative stress, which suggests that both pathways are involved in the pathophysiology and may be worth exploring as therapeutic targets to prevent progression of the disease.