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Accurate HCV prevalence estimates are necessary for guiding elimination policies. Our aim was to determine the HCV prevalence and assess the cost-effectiveness of a screen-and-treat strategy in the Spanish population. A population-based, cross-sectional study (PREVHEP-ETHON Cohort, Epidemiological sTudy of Hepatic infectiONs; NCT02749864) was performed from July 2015-April 2017. Participants from three Spanish regions were selected using two-stage conglomerate sampling, and stratified by age, with randomized subject selection. Anthropometric and demographic data were collected, and blood samples were taken to detect anti-HCV antibodies/quantify HCV RNA. The cost-effectiveness of the screening strategies and treatment were analysed using a Markov model. Among 12 246 participants aged 20-74 (58.4% females), the overall anti-HCV prevalence was 1.2% (95% CI 1.0-1.4), whereas the detectable HCV-RNA prevalence was 0.3% (0.2-0.4). Infection rates were highest in subjects aged 50-74 years [anti-HCV 1.6% (1.3-1.9), HCV RNA 0.4% (0.3-0.6]. Among the 147 anti-HCV + subjects, 38 (25.9%) had active infections while 109 (74.1%) had been cleared of infection; 44 (40.4%) had cleared after antiviral treatment, whereas 65 (59.6%) had cleared spontaneously. Overall, 59.8% of the anti-HCV + participants were aware of their serological status. Considering a cost of treatment of €7000/patient, implementing screening programmes is cost-effective across all age cohorts, particularly in patients aged 50-54 (negative incremental cost-effectiveness ratio which indicates a cost-saving strategy). The current HCV burden is lower than previously estimated, with approximately 25% of anti-HCV + individuals having an active infection. A strategy of screening and treatment at current treatment prices in Spain is cost-effective across all age cohorts.

Background: we aimed to assess the influence of metabolic syndrome on fibrosis regression (using liver-stiffness measurement (LSM) and serological scores) and the relationship with the expression of lysyl oxidase-like-2 as a potential goal of antifibrotic therapy. Methods: We included 271 patients treated with Direct Antiviral Therapy (DAAs) in our hospital who achieved a sustained virological response (SVR), physical examination, blood tests, and LSM were made at baseline (B) and 24 months (24 M) after SVR. Hemodynamic studies and transjugular liver biopsies were performed on 13 patients. Results: At B, 68 patients were F1 (25.1%), F2 n = 59 (21.7%), F3 n = 44 (16.05%), and 100 were F4 (36.9%). Although the LSM (absolute value) improved in 82% of patients (n = 222), it progressed in 17.5% of patients (n = 48). At 24 M, 48 patients met the metabolic syndrome (MetS) criteria and there was an increase in patients with a BMI of &gt, 25 kg/m2 (p &lt, 0.001). At B and 24 M, a BMI of &gt, 25 kg/m2 is a risk factor for significant fibrosis or steatosis at 24 M (p &lt, 0.05) and progression on LSM (p &lt, 0.001), as well as MetS at B and 24 M (OR 4.1 IC (1.4&ndash, 11.7), p = 0.008, and OR 5.4 IC (1.9&ndash, 15.4), p = 0.001, respectively). Regarding the correlation between LSM and the liver biopsy, we found that only six out of 13 patients had a matching LSM and biopsy. We found a statistically significant decrease in LOXL2 levels at 24 M with respect to B (p &lt, 0.001) with higher serological value in patients with elastography of &gt, 9 kPa vs. &lt, 9 kPa (p = 0.046). Conclusion: Regression of LSM was reached in 82% of patients. Downregulated LOXL2 was demonstrated post-SVR, with overexpression in cirrhotic patients being a potential therapy goal in selected patients.

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH., Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Portal sinusoidal vascular disease is a presinusoidal cause of portal hypertension (PHT) of unknown etiology, characterized by typical manifestations of PHT (esophageal varices, ascites, portosystemic collaterals), plaquetopenia and splenomegaly with a gradient of portal pressure slightly increased, according to the presinusoidal nature of the PHT. A few cases in the literature have shown a relationship between oxaliplatin and the development of presinusoidal portal hypertension, years after the chemotherapy for colorectal cancer (therefore, different to sinusoidal obstruction syndrome). There are three mechanisms through which oxaliplatin can cause sinusoidal damage: 1) damage at the level of endothelial cells and stimulates the release of free radicals and depletion of glutathione transferase, with altering the integrity of the sinusoidal cells. The damage in the endothelial sinusoidal cells allows to erythrocytes to across into the Dissé space and formation of perisinusoidal fibrosis, 2) the appearance of nodular regenerative hyperplasia is favored by the chronic hypoxia of the centrilobular areas and, finally, 3) oxaliplatin can generate an obliteration of the blood capillaries and zones of parenchymal extinction. These three facts can develop, in a minority of cases, the appearance of a presinusoidal increase of portal pressure, which typically appears years after the completion of chemotherapy and sometimes is underdiagnosed until variceal bleeding, ascites or encephalopathy appear. The knowledge of this pathology is essential to be able to perform an early diagnostic and consult to the hepatologist. Funding: This research received an external funding of CI18/67/02 Acuerdo de cooperación en el programa de becas de investigación científica de IDIVAL de JANSSEN-CILAG, S.A.

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure. Funding: This research was funded by NEXT-VAL grant 15/12 from Health Research Institute Marques de Valdecilla (IDIVAL).

Chronic hepatitis C infection (HCV) activates a systemic cell-mediated immune response characterized by the production of IFN? and an innate immune response addressed by the activation of TLR signaling. We aimed to investigate whether HCV eradication by direct acting antivirals (DAA) leads to a recovery in cell-mediated immune response and TLR expression and functionality. Blood samples were obtained in HCV infected patients before DAA treatment and at week +48 after the end of treatment. Results were compared to healthy controls. Cell surface expression of TLR8 was assessed on peripheral blood mononuclear cells (PBMCs) by flow cytometry. Freshly isolated PBMCs were cultured with specific TLR8 agonists and intracellular production of cytokines was determined by flow-cytometry after ex vivo TLR8 activation with ssRNA 40. Production of IFN?, IL2 and IL17 was assessed by flow cytometry in T cells after polyclonal activation. Included were 50 HCV-infected patients and 15 controls. TLR8 expression in PBMCs was significantly increased before treatment and recovered normal levels at week +48. Production of IL1b, IL6 and TNF? dependent on the activation of TLR8 in PBMCs was also increased in patients before DAA treatment, with a significant reduction at week +48. Combined expression of IFN? and IL2 in CD4+ T cells in HCV-infected patients was significantly increased compared to controls and recovered normal levels at week +48. DAA-mediated clearance of HCV is associated with a decreased expression and activation of TLR8 in PBMCs until healthy control levels which is accompanied by a reduction in the Th1 response. This research was funded by the Instituto de Salud Carlos III (ISCIII), grant number PIE15/00079.

Resumen Epidemiologia La hepatitis C es una infeccion virica que afecta a unos 180 millones de personas en el mundo. Se trata de la primera causa de trasplante hepatico en nuestro pais. Historia natural La evolucion natural de la enfermedad es la aparicion de cirrosis y el aumento del riesgo de desarrollo de cancer hepatocelular. Manifestaciones clinicas Es una enfermedad silente, cuyo diagnostico mediante signos clinicos supone detectarla en fases avanzadas, es por ello de gran importancia el desarrollo de programas de cribado. Diagnostico El diagnostico inicial se realiza mediante anticuerpos anti-VHC y se confirma demostrando la replicacion virica. Indicacion de tratamiento Se establece tras la evaluacion del grado de fibrosis. Las nuevas tecnicas de evaluacion no invasiva de la fibrosis y la ecografia de ultima generacion permiten una estadificacion precisa y rapida de la enfermedad. Antiviricos de accion directa La incorporacion de los agentes antiviricos de accion directa al arsenal terapeutico frente al VHC ha supuesto un gran avance que permite obtener elevadas tasas de curacion, evitando el empleo de interferon y ribavirina.

Resumen Concepto La hepatitis es una enfermedad del higado de etiologia multifactorial que se caracteriza por la existencia de necrosis hepatocelular e inflamacion. Clasificacion Segun su curso evolutivo pueden ser agudas, cronicas o fulminantes. En esta actualizacion nos centraremos fundamentalmente en las producidas por agentes viricos, que son la causa mas frecuente de hepatitis. Hepatitis B Describiremos con detalle la etiopatogenia, epidemiologia, la historia natural, las manifestaciones clinicas, el diagnostico, el tratamiento y las estrategias de prevencion de la infeccion por el virus de la hepatitis B. Otras hepatitis viricas Posteriormente se destacaran los aspectos mas relevantes de otras hepatitis viricas (hepatitis A, D y E).

Pyogenic granuloma (PG) is a polypoid lobular capillary hemangioma rarely described in the stomach. We report two cases aged 72 and 66 years. A review of the literature on gastric PG, including the present cases, yielded ten patients. There were six males and four females. The age of the patients ranged from 35 to 82 years with a mean of 58.9 years. The lesions were all solitary, except one case of multiple lesions in the corpus and antrum. PG can be located in any part of the stomach. The most common site was the antrum. The mean maximum diameter of the lesions was 14.5mm (range 7-30mm). Most lesions were pedunculated. Pain or discomfort (epigastric, right upper quadrant or chest), upper gastrointestinal bleeding, and melena were the most common clinical symptoms. Iron deficiency anemia was the rule, often requiring blood transfusion. Five patients underwent snare polypectomy, four endoscopic mucosal resection, and one laser irradiation. The follow-up ranged from two weeks to two years. There were no recurrences. Pathologists should be familiar with this condition in order to avoid overdiagnosis as a malignant vascular tumor.

AIM To evaluate the long-term outcome of an acute hemodynamic response-guided protocol in which acute responders to intravenous propranolol received traditional nonselective beta-blockers (NSBBs) and acute nonresponders received carvedilol. METHODS Retrospective review of a protocol for primary prophylaxis of variceal bleeding guided by the acute hemodynamic response to intravenous propranolol. Fifty-two acute responders treated with traditional NSBB (i.e. propranolol or nadolol) were compared with 24 acute nonresponders receiving carvedilol. A second hemodynamic study was performed in 27 and 13 patients, respectively. The primary endpoint was development of first or further decompensation. Secondary endpoints included death from any cause, association between acute and chronic hemodynamic response, and baseline clinical and laboratory variables related to the acute hemodynamic response. RESULTS Acute responders and acute nonresponders presented similar 1, 2, and 3-year probabilities of first decompensation (NSBB: 0%, 13.7%, 26.1% vs carvedilol: 0%, 20%, 20%, P = 0.968) or further decompensation (21.2%, 26.1%, 40.9% vs 21.2%, 50.0%, 50.0%, P = 0.525). A previous episode of hepatic encephalopathy was the only independent predictor of decompensation [hazard ratio (95% confidence interval): 8.03 (2.76-23.37)]. Mortality rates were similar in acute responders and acute nonresponders with compensated (P = 0.428) or decompensated cirrhosis (P = 0.429). No clinical, laboratory, endoscopic or hemodynamic parameter predicted the acute hemodynamic response. In patients receiving traditional NSBB, the acute and chronic changes of hepatic venous pressure gradient were correlated (r = 0.59, P = 0.001). Up to 69.2% of acute nonresponders gained chronic response with carvedilol. CONCLUSION Early identification and treatment with carvedilol of acute nonresponders to intravenous propranolol improves the clinical outcome of this high-risk group of patients, probably due to its greater effects for reducing portal pressure.

Background Toll-like receptor 7 (TLR7) is an endosomal TLR that is activated by single-stranded RNA, including endogenous microRNAs (e.g., let-7b). Increased hepatic expression of TLRs, microRNAs, and inflammatory mediators is linked to ethanol (EtOH) exposure and to alcoholic liver disease (ALD). ALD invovles chronic hepatic inflammation that can progress to alcoholic hepatitis (AH), a particularly severe form of ALD. This study aimed to investigate TLR7 expression in patients with different liver disease phenotypes and in mouse liver following alcohol exposure. Methods Hepatic mRNA expression was determined by RNA sequencing of liver tissue from patients with liver disease or normal liver tissue. Mice were exposed to subchronic EtOH followed by administration of the TLR7 agonist imiquimod. Primary human hepatocytes were exposed to EtOH or imiquimod in vitro. Results RNAseq analysis revealed that hepatic expression of TLR7 and let-7b microRNA, an endogenous TLR7 ligand, was significantly increased in AH patients. Hepatic expression of TLR7 and let-7b positively correlated with hepatic IL-8 mRNA expression. In mice, EtOH increased hepatic TLR7 mRNA expression and enhanced imiquimod-induced expression of the pro-inflammatory mediators TNFα, MCP-1, and iNOS. In vitro, EtOH significantly increased hepatocyte TLR7 mRNA and the TLR7 agonist, imiquimod, induced hepatocyte expression of TNFα and IL-8 mRNA. EtOH also increased the release of let-7b in microvesicles from hepatocytes, suggesting that EtOH can increase the expression of both the receptor and its endogenous ligand. Conclusions These studies suggest that increased TLR7 signaling caused by increased expression of TLR7 and its endogenous ligand let-7b may contribute to the enhanced inflammatory response associated with AH.

Identifying patients at high risk for acute kidney injury (AKI) during hospitalization among patients admitted with severe alcoholic hepatitis (AH) is an unmet clinical need. We performed a multicentric prospective cohort study using data from 4 different cohorts on well-characterized patients hospitalized with severe AH. Data collected on 773 AH patients from 4 cohorts across the globe were randomly split into test (n = 390) and validation (n = 383) cohorts. We found that 32% of the patients developed inpatient AKI in the test cohort. Approximately 60% of patients met criteria for systemic inflammatory response syndrome (SIRS) at admission. Hepatic encephalopathy, SIRS, and Model for End-Stage Liver Disease score at admission predicted inpatient AKI with odds ratios of 3.86, 2.24, and 1.14, respectively. The AKI risk score developed using these predictors stratified risk of inpatient AKI to low (score3), moderate (3-4), and high (4). These findings were replicated in the validation cohort. In the whole study cohort, patients with AKI had a lower 90-day survival (53% versus 77%; P0.001). Those with AKI risk score of4 had significantly lower 90-day survival as compared with those with risk scores between 3 and 4 and3 (47% versus 68% versus 88%; P0.001). In conclusion, AKI occurs frequently in AH patients and negatively impacts short-term mortality. The AKI risk score is useful in identifying patients at high risk for inpatient AKI and may be useful for developing new therapeutic strategies to prevent AKI in patients with AH.

Sterile inflammation after tissue damage is a ubiquitous response, and yet has the highest amplitude in the liver. This has major clinical consequences with alcoholic and non-alcoholic steatohepatitis (ASH and NASH) accounting for the majority of liver disease in industrialized countries, and both lacking therapy. Requirements for sustained sterile inflammation include increased oxidative stress, and activation of the HIF-1α signaling pathway. We demonstrate the ability of digoxin, a cardiac glycoside, to protect from liver inflammation and damage in ASH and NASH. Digoxin was effective in maintaining cellular redox homeostasis, and suppressing HIF-1α pathway activation. A proteomic screen revealed that digoxin binds pyruvate kinase M2 (PKM2), and independent of PKM2 kinase activity results in chromatin remodeling and down-regulation of HIF-1α transactivation. These data identify PKM2 as a mediator and therapeutic target for regulating liver sterile inflammation, and demonstrate a novel role for digoxin which can effectively protect the liver from ASH and NASH.

This work presents the design, construction and testing of a new embedded sensor system for monitoring concrete curing. A specific mote has been implemented to withstand the aggressive environment without affecting the measured variables. The system also includes a real-time monitoring application operating from a remote computer placed in a central location. The testing was done in two phases: the first in the laboratory, to validate the functional requirements of the developed devices; and the second on civil works to evaluate the functional features of the devices, such as range, robustness and flexibility. The devices were successfully implemented resulting in a low cost, highly reliable, compact and non-destructive solution., This work has been supported by the Spanish Centre for the Development of Industrial Technology (CDTI) and FEDER funds under grant IDI-20100440 and sponsored by AZVI Inc., Aertec Ingenieria y Desarrollo Inc. and Geolen Ingenieria Inc.

OBJECTIVES: Prisons are major reservoirs of hepatitis C virus (HCV) in which a therapeutic approach has been particularly difficult so far. Our aim was to create a permanent program of HCV elimination in a prison based on a "test and treat" strategy. METHODS: This open-label clinical trial was conducted in the Spanish prison "El Dueso" between May 2016 and July 2017. Viremic patients were treated with a ledipasvir-sofosbuvir regimen (8-12 weeks) according to the 2015 Spanish Guidelines. A teleconsultation program was established to follow-up patients from the hospital. Non-responders were submitted for a phylogenetic analysis and offered retreatment. An evaluation of new cases of HCV infection was performed every 6 months and upon release in all inmates. RESULTS: 847 (99.5%) inmates accepted to participate. HCV antibodies were present in 110 (13.0%) and 86 (10.2%) had detectable viremia. Most of them were genotype 1 or 3 (82.6%) and had

Background & Aims: Antiviral therapy with interferon and ribavirin (double therapy) is associated with a significant risk of developing bacterial infections in patients with hepatitis C-related cirrhosis. The addition of telaprevir or boceprevir seems to increase this risk but there are no studies yet to compare the infection rate between both treatments. We aimed to assess rate, type and predictive factors of infection in cirrhotic patients undergoing triple or double antiviral therapy. Methods: This was a retrospective analysis of prospectively collected data. 167 patients with hepatitis C-related cirrhosis undergoing triple therapy (cohort A) and 81 receiving double therapy (cohort B) were enrolled in the study. Only Child-Pugh A patients were included. Results: The infection rate was significantly higher for patients in cohort A as compared to those in cohort B (25% vs. 9%, p = 0.001). Interestingly, respiratory tract infections were significantly more frequent in patients in cohort A (12% vs. 1%; p = 0.049). The use of triple antiviral therapy was the only predictive factor of infection. Severe infections were also more frequent in patients in cohort A, but the difference did not reach the level of significance (13% vs. 6%, p = 0.123). Conclusions: Triple therapy carries a higher risk of infections in patients with cirrhosis and changes the pattern of infection in this subpopulation. Further studies are needed in order to establish the underlying mechanism of this event. 2014 European Association for the Study of the Liver. Published

Liver fibrosis is a common consequence of chronic liver injury and is a key determinant of liver-associated morbidity and mortality. Identification of new mechanisms of fibrosis, including disease-specific molecular drivers, remains relevant to reveal novel biomarkers and therapeutic targets. Recently, greater accessibility to more advanced molecular methods that can assess changes in epigenetic regulation has stimulated more research investigating the epigenetic landscape of liver fibrosis. Such studies have revealed changes in DNA methylation, histone acetylation, and microRNAs that regulate the fibrogenic response to injury including hepatic stellate cell activation. The aim of this review is to briefly introduce the general mechanisms and epigenetic regulation of liver fibrosis and to familiarize the reader with the chief epigenetic mechanisms implicated as drivers of liver fibrosis.

Introduction Iron is simultaneously an essential and potentially toxic micronutrient linked to oxidative stress, bacterial infection and systemic inflammation. The liver plays a key role in iron homeostasis through synthesis of the serum transporter, transferrin, and the iron hormone hepcidin. Dysregulation of iron parameters is common in patients with severe alcoholic hepatitis and serum transferrin has been associated with outcome in patients with decompensated alcohol-related liver disease. The aim of this study was to examine the relationship between parameters of iron metabolism and outcome in patients with severe alcoholic hepatitis. Method Ferritin, transferrin, iron, transferrin saturation (TSAT) and hepcidin were measured in baseline, pre-treatment, serum samples from 202 randomly selected patients with severe alcoholic hepatitis (AH) recruited prospectively via the STOPAH trial. Hepatic transferrin mRNA expression was assessed in 27 additional AH subjects. Results Compared to population-based normal ranges AH patients had diminished serum transferrin (median 93 mg/dl), but increased ferritin (median 625 ng/dl) and TSAT (median 69.8%). Transferrin was negatively correlated with MELD (r=-0,26; p Conclusion Our findings demonstrate that parameters of iron metabolism, particularly transferrin as a negative acute phase reactant, are strongly associated with outcome in severe AH. Moreover, the performance of transferrin in predicting 28 day mortality is comparable to the commonly used scoring systems. Further studies are needed to determine factors influencing transferrin availability in AH. Disclosure of Interest None Declared

Objectives Effective oral therapies for hepatitis B and C have recently been developed, while there are no approved pharmacological therapies for alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD). We hypothesise that fewer advances in fatty liver diseases could be related to disparities in research attention. Methods We developed the Attention-to-Burden Index (ABI) that compares the research activities during 2010–2014, and an estimate of disease burden of these 4 major liver diseases. The resulting ratio reflects either overattention (positive value) or inadequate attention (negative value) compared with disease burden. The mean research attention and disease burden were calculated from 5 and 6 different parameters, respectively. The efficacy rate of current pharmacological therapies was assessed from published clinical trials. Findings The mean research attention for hepatitis B and C was 31% and 47%, respectively, while NAFLD and ALD received 17% and 5%. The overall burden was 5% and 28% for hepatitis B and C, and 17% and 50% for NAFLD and ALD. The calculated ABI for hepatitis B and C revealed a +6.7-fold and +1.7-fold overattention, respectively. NAFLD received an appropriate attention compared with its burden, while ALD received marked inadequate attention of −9.7-fold. The efficacy rate of current pharmacological agents was 72% for hepatitis B, 89% for hepatitis C, 25% for non-alcoholic steatohepatitis and 13% for alcoholic hepatitis. Importantly, we found a positive correlation between the mean attention and the efficacy rate of current therapies in these 4 major liver diseases. Interpretation There are important disparities between research attention and disease burden among the major liver diseases. While viral hepatitis has received considerable attention, there is a marked inadequate attention to ALD. There is a critical need to increase awareness of ALD in the liver research community.

[Abstract] Background and Aims. Hepatitis C (HCV) therapy with Sofosbuvir (SOF)/Simeprevir (SMV) in clinical trials and real‐world clinical practice, showed high rates of sustained virological response (SVR) in non‐cirrhotic genotype (GT)‐1 and GT‐4 patients. These results were slightly lower in cirrhotic patients. We investigated real‐life effectiveness and safety of SOF/SMV with or without ribavirin (RBV) in a large cohort of cirrhotic patients. Methods. This collaborative multicentre study included data from 968 patients with cirrhosis infected with HCV‐GT1 or 4, treated with SOF/SMV±RBV in 30 centres across Spain between January‐2014 and December‐2015. Demographic, clinical, virological and safety data were analysed. Results. Overall SVR was 92.3%; the majority of patients were treated with RBV (62%) for 12 weeks (92.4%). No significant differences in SVR were observed between genotypes (GT1a:94.3%; GT1b:91.7%; GT4:91.1%). Those patients with more advanced liver disease (Child B/C, MELD≥10) or portal hypertension (platelet count≤100×109/L, transient elastography≥21 Kpa) showed significantly lower SVR rates (84.4%‐91.9%) than patients with less advanced liver disease (93.8%‐95.9%, P

Background & Aims (i) To describe the demographic, clinical, virological and histological characteristics of the patients undergoing evaluation for indication of triple therapy against hepatitis C virus genotype 1, and to identify the reasons why candidate patients are excluded; and (ii) to evaluate the characteristics of the healthcare environment related to treatment. Methods Observational, prospective and multi-centred study involving 16 hospitals of Spain. Data were collected on 1122 patients receiving attention in the outpatient clinics between June and December 2012. Results Of the 1122 patients evaluated, 769 were finally included in this study; 27% (211/769) had contraindications to the therapy. Of those without contraindications, 54% (301/558) did not receive the treatment, and so, only about a third of the patients (33%–257/769) underwent therapy. The reasons for not initiating therapy were as follows: patient refusal (30%), mild disease/awaiting new treatments (34%), restrictions by the health service (30%), other reasons (6%). In univariate analyses, the probability of receiving treatment was related to: age

Background & Aims: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. Methods: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index

Cryptosporidium localization to the stomach is uncommon. We report a case of a 56-year-old, HIV-positive, male patient with severe immunosuppression after antiretroviral treatment dropout who presented with epigastric discomfort, nausea and vomiting. The abdominal CT with contrast showed an important concentric thickening of the gastric antrum wall. Upper gastrointestinal endoscopic evaluation revealed lack of distensibility of the gastric wall and marked thickening, stiffness, distortion, and erosions of mucosal folds involving the antrum region. The endoscopy was clinically reported as gastric malignancy suggestive of lymphoma. The histopathologic diagnosis was cryptosporidiosis. To our knowledge, gastric cryptosporidiosis simulating malignancy has not been previously described. This type of lesion should be included in the differential diagnosis of AIDS patients with lesions simulating gastric malignancy.

Resumen La hepatitis cronica por el virus de la hepatitis C afecta a casi 180 millones de personas en el mundo. La infeccion por el virus de la hepatitis C es curable. Hasta hace 1 ano, el unico tratamiento de la hepatitis por virus de la hepatitis C genotipo 1 consistia en la combinacion de interferon pegilado y ribavirina con una modesta eficacia (40–50%). La llegada de los nuevos agentes antivirales directos, como el telaprevir, ha supuesto una autentica revolucion en la terapia de esta infeccion, un cambio de paradigma. Supone un incremento en las probabilidades de respuesta (80%) y la posibilidad de reducir la duracion del tratamiento en mas de la mitad de los pacientes. Se han desarrollado nuevas reglas de parada del tratamiento con el fin de evitar el desarrollo de resistencias. Finalmente, debemos prestar atencion al desarrollo de efectos secundarios potencialmente graves, en especial la anemia y las alteraciones cutaneas.

BACKGROUND & AIMS Pretransplant renal failure is commonly reported to be a poor prognostic indicator affecting survival after liver transplantation (LT). However, whether the impact of renal failure on patient outcome varies according to the aetiology of the underlying liver disease is largely unknown. METHODS We investigated the association between renal failure at the time of LT and patient outcome in patients with alcoholic liver disease (ALD) (n = 6920), non-alcoholic steatohepatitis (NASH) (n = 2956) and hepatitis C (HCV) (n = 14 922) using the United Network for Organ Sharing (UNOS) database between February 2002 and December 2013. A total of 24 798 transplant recipients were included. RESULTS The presence of renal failure was more frequently seen in patients with ALD (23.95%) and NASH (23.27%) compared to patients with HCV (19.38%) (P < 0.001). In multivariate analysis, renal failure was an independent predictor of poor survival. Renal failure showed detrimental effect on patient survival in the overall series (HR = 1.466, P < 0.0001). Importantly, the impact of renal failure was less marked in patients with ALD (HR = 1.31, P < 0.0001) than in patients with NASH (HR = 1.73, P < 0.0001) or HCV (HR = 1.52, P < 0.0001). Despite a higher model for end-stage liver disease (MELD) score at the time of LT, ALD patients with renal failure had better long-term prognosis than non-ALD patients. CONCLUSIONS Renal failure at the time of LT conferred a lower patient and graft survival post-LT. However, renal failure has less impact on the outcome of patients with ALD than that of patients with non-alcoholic liver disease after LT.

Hepatitis C therapy in the era of the newer direct-acting antiviral agents has radically changed our treatment schemes by achieving very high rates of sustained virological response. However, treatment with direct antiviral agents fails in a subgroup of patients. This group of so-called difficult-to-treat individuals is the subject of this paper, which reviews the causes of virological failure, their clinical implications, and some final recommendations.

A patient receiving a liver graft needs to be treated with immunosuppressive drugs to avoid rejection. These kinds of drugs predispose the patient to the reactivation of latent infections such as tuberculosis (TB). Therefore, it is necessary to establish treatment regimens to prevent this. We retrospectively analyzed all consecutive patients undergoing liver transplantation (LT) at our center between January 1, 2000 and December 31, 2010. Latent tuberculosis infections (LTBIs) were diagnosed with positive tuberculin skin test results. After LT, infected patients were treated with isoniazid for 6 months; the treatment began soon after transplantation, and the patients were followed until the end of the study. During this period, 53 patients had LTBI data. All these patients were treated with isoniazid after LT. The median observation period after LT was 52 months (range = 12-129 months). No cases of TB reactivation were reported during follow-up. Only 4 patients presented alterations in liver enzymes related to this treatment, and they showed clear improvement after the treatment was stopped. None of these patients showed severe graft dysfunction. In conclusion, preventive isoniazid appears to be a safe drug for use in LTBI patients after LT. The treatment may be established just after LT without important graft dysfunction or severe consequences for the patient. Liver Transpl, 2012. © 2012 AASLD.

Nowadays, the retreatment of patients with Hepatitis C virus (HCV) genotype 3 (GT3) especially cirrhotic, who have already been treated with regimens containing a NS5A inhibitor represents a challenge. Use a novel retreatment option for patients with a difficult approach. We present three case reports of retreatment with a new combination of Direct-acting antivirals (DAAs), Sofosbuvir, Elbasvir/ Grazoprevir in patients with GT3 with a previous failure with Sofosbuvir/Ledipasvir. All the cases achieved sustained virologic response (SVR) at week +12 without adverse effects. In our experience, this combo may represent an effective and safe option for these patients.

The consumption of alcoholic beverages is harmful to human health. In recent years, consumption patterns of alcoholic beverages have changed in our society, and binge drinking has generalized. It is considered to be a socio-sanitary problem with few known consequences in terms of individual and third-party social impacts (in the form of violence or traffic accidents) and its organic impact (affects the liver and other organs and systems, such as the nervous and cardiovascular systems) and represents an important financial burden due to its increasing economic impact. This review provides a global approach to binge drinking and emphasizes its epidemiological character, the effect of this type of consumption and the possible management of a problem with an increasing tendency in our society.

Background and rational. Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220). Results. The mean patient age was 55 years, 67% male. Type of prior response was 22% naive, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%), respectively. Sixty-five percent were non-CC IL28B genotype. Week-12 sustained virologic response (SVR12) was significantly higher among F2-naive patients (78%) compared with F3/F4-naive patients (60%; p = 0.039) and among F2 non-responders (67%) compared with F3/F4 non-responders (42%; p = 0.014). SVR12 among relapsers was remarkably high in both groups (F2:89% vs. F3/F4:78%). Severe anemia and thrombocytopenia were more frequent among patients with F3/F4 than those with F2 (p < 0.01). Overall, 132 patients (22%) discontinued treatment: 58 due to adverse effects, 42 due to the stopping-rule, and 32 due to breakthrough. Premature discontinuation was more frequent among patients with F3/F4 (p = 0.028), especially due to breakthrough (p < 0.001). Conclusions. This multicenter study demonstrates high efficacy and an acceptable safety profile with regard to TBT in F2-patients in clinical practice.

AIM: To investigate the plasma levels of betatrophin in patients with cirrhosis. METHODS: Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic, or histological criteria were included. The severity of cirrhosis was classified according to Pugh’s modification of Child’s classification and MELD score. Insulin resistance (IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects. Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay (DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were < 4% and < 10%, respectively. The normal values were between 2 and 17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA (Aviscera Bioscience®). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were < 6% and < 10%, respectively. RESULTS: Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects (P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B (P < 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation (P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification (r = 0.53; P < 0.01) or MELD score (r = 0.45; P < 0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin (r = 0.39; P < 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin (r = -0.41; P < 0.01) or prothrombin time (r = -0.44; P

Background Anaemia is a common side-effect of ribavirin (RBV) use that overwhelms management of hepatitis C when protease inhibitors are added. Aim To assess the pharmacogenomic impact of candidate genes SLC28A2, SLC28A3 and ITPA on anaemia in patients receiving triple therapy. Methods Patients (n = 161) with chronic hepatitis C genotype 1 treated with telaprevir (n = 95) or boceprevir (n = 66) were included. Using RT-PCR we genotyped ITPA (rs1127354, rs7270101) and SLC28A3 (rs56350726, rs10868138) and SLC28A2 (rs11854484). Clinically significant anaemia (CSA) was diagnosed when at least one of the following criteria was observed: (a) haemoglobin Results CSA occurred in 44% (69/157) of patients and was associated with SLC28A2 rs11854484 [CC/CT genotypes: 33% (26/78) vs. TT genotype: 56% (36/64); p = 0.006]. Further, the needed for blood transfusion was related to genotype [CC: 0% (0/18) vs. CT: 13% (8/61) vs. TT: 27% (17/64); p = 0.016]. Similarly, ITPA rs1127354 genotypes [AA/AC: 19% (3/16) vs. CC: 45% (61/135; p = 0.060] were linked to CSA. In multivariate analysis, SLC28A2 rs11854484 TT genotype (OR:2.33;95%CI:1.10–4.95; p = 0.027), female sex (OR:2.54;95% CI:1.13–5.71;p = 0.024) and Hb drop at week 4) OR: 1.36; 95CI%: 1.11–1.67; p = 0.003) were independently associated with CSA. Similarly, ITPA rs1127354 genotypes [AA/AC: 16% (3/19) vs. CC: 63% (85/134); p = 0.0001] and ITPA rs6051702 genotypes [CC/CA: 46% (26/57) vs. CC: 65% (60/93); p = 0.023] were related to Hb drop of >3g/dL at week 4. Conclusions In patients receiving first generation protease inhibitors, genotype SLC28A2 rs11854484 predicts CSA, and helps to identify a subgroup of patients with better tolerance of triple therapy.

The recently released UK Chief Medical Officers Alcohol Guidelines Review set up new restricted limitations in alcohol consumption—14 units, the same amount for both men and women. In parallel, the popular Dry January campaign was launched again, aimed at promoting prolonged abstinence. Are these campaigns enough to give up boozing?

Computerized physician order entry (CPOE) applications are widely used to prevent medical errors. In our center, a CPOE system has been in use since 2009 on both the inpatient and outpatient levels. A new and simple alert was introduced in the CPOE system to notify healthcare providers of the potential risk of viral reactivation when prescribing biological therapies, thereby facilitating the request for a serological profile (hepatitis B surface antigen [HBsAg], anti-HBc, and anti-HBs) in patients who have not had these tests. Between May 2012 and May 2013, a total of 1,076 patients undergoing biological treatment were included in the implementation of the CPOE in our hospital, resulting in the identification of 4 HBsAg-positive and 69 anti-HBc-positive/HBsAg-negative patients, two of them with positive viral loads. Since the implementation of this alert system, over 90% of patients who were prescribed a biological drug (BD) have undergone serological screening to detect hepatitis B virus (HBV) infection. The use of the alert system has increased the screening rate from less than 50% to 94% for HBsAg and from less than 30% to 85% for anti-HBc in patients for whom a BD is prescribed. Six patients received prophylactic antiviral therapy. No patient had HBV reactivation. Conclusion: This study demonstrates the feasibility of implementing a CPOE system that has allowed our hospital to increase the rate of HBV screening. Its use has facilitated the identification of patients at high risk for HBV reactivation and permitted physicians to prescribe prophylactic measures according to current guidelines. (Hepatology 2014;106–113)

TO THE EDITOR: In the clinical opinion update by Hwang et al, the authors reviewed the most important issues related to hepatitis B virus (HBV) screening in patients who are about to receive cytotoxic chemotherapy for the treatment of malignant diseases. This update notes the importance of screening all patients who are going to be treated with anti-CD20 therapy. The authors also point out that this screening should be extended to patients with high risk factors for HBV infection. Then, when a patient who is hepatitis B surface antigen (HBsAg) positive/hepatitis B core antibody (anti-HBc) positive is identified, antiviral treatment should be started just before or at the same time as chemotherapy. In contrast, patients who are HBsAg negative/anti-HBc positive could be carefully observed with ALT and HBV-DNA levels. In the article by Hwang et al, Spain is included as a country with HBV prevalence greater than 2%. We believe this statement is currently obsolete and should be corrected. Because of the universal vaccination program started circa 1992, the HBV prevalence in Spain is now approximately 0.7% (HBsAg positive). However, this 0.7% prevalence in HBsAg does not disqualify, in our opinion, a universal HBsAg screening for all patients scheduled to receive systemic cancer therapy. As Hwang et al succinctly mentioned, previous studies have shown that universal screening for HBsAg is not only cost effective but actually cost saving when compared with no screening or screening only high-risk individuals before starting chemotherapy, particularly when the prevalence of HBsAg in the low-risk population is greater than 0.20%. Finally, one aspect that we miss in this special article is the mention of currently available innovative strategies to facilitate this HBV screening in the hospital setting, where the majority of immunosuppressive therapies are prescribed. We are referring specifically to the use of the computerized physician order entry–based (CPOE) systems that apply to this subject. As we previously have demonstrated, the use of this CPOE system in our hospital increased theHBV screening rate from less than 50% to 94% forHBsAg and from less than 30% to 85% for anti-HBc in patients for whom a biologic drug was prescribed. In conclusion, we consider it reasonable to recommend universal HBsAg (and anti-HBc) screening for all patients scheduled to receive systemic cancer therapies or other immunosuppressive therapies, adding when available or feasible the potential benefits of new tools such as CPOE systems together with educational efforts to improve the HBV screening rates.

P0812 IMPACT OF SVRW12 IN THE DEVELOPMENT OF COMPLICATIONS AND FIBROSIS REGRESSION IN PATIENTS TREATED WITH TRIPLE THERAPY WITH BOCEPREVIR AND TELAPREVIR C. Perello, J. Cabezas, E. Llop, S. Menendez, J. De La Revilla, J. Crespo, J.L. Calleja. Gastroenterology, Hepatology Unit, University Hospital Puerta de Hierro, Majadahonda, Gastroenterology and Hepatology, University Hospital Marques de Valdecilla, Santander, Gastroenterology and Hepatology. CYBERehd, University Hospital Puerta de Hierro, Majadahonda, Spain E-mail: csperello@hotmail.com

Conclusions: Duration of undetectable HCVRNA to end of treatment with this two DAA regimen was associated with SVR. These data suggest that the optimal treatment duration in GT-1binfected patients is between 8 and 12 weeks plus the time required to reach undetectable HCVRNA. There were differences for GT-1aand GT-1b-infected patients, which might reflect differences in viral kinetics at a sub-detectable level and/or differences in the rate of infected cell turnover.