Search

El articulo recoge el conjunto de medidas propuestas por la SEPD, la AEEH, GETECCU y la AEG que pretenden servir de ayuda a los servicios en su reincorporacion a la actividad habitual. Hemos confeccionado una serie de recomendaciones practicas respecto al manejo y a la reintroduccion progresiva de la actividad asistencial. Estas recomendaciones estan guiadas por la escasa y cambiante evidencia disponible y seran objeto de futuras actualizaciones, en base a las necesidades diarias y la disponibilidad del material fungible para adecuarse a las mismas; y se podran implementar en cada servicio en funcion de la incidencia acumulada de SARS-CoV-2 en cada region y de la carga que la epidemia ha ocasionado en cada uno de los hospitales. Los objetivos generales de estas recomendaciones son: • Proteger a nuestros pacientes de los riesgos de la infeccion por SARS-CoV-2 y prestarles una atencion de calidad. • Proteger a todos los profesionales sanitarios de los riesgos de la infeccion por SARS-CoV-2. • Recuperar el normal funcionamiento de nuestros servicios en un entorno de riesgo continuado de infeccion por SARS-CoV-2.

[Introduction] Despite the direct-acting antiviral therapy has dramatically decreased the likelihood of having liver-related complications and extrahepatic outcomes, the risk of developing hepatocellular carcinoma (HCC) is not totally eliminated after sustained virological response (SVR). We aimed to develop an easy-to-apply strategy to be adopted in clinical practice for accurately classifying the HCC risk in hepatitis C virus patients after SVR., [Methods] Prospective and multicenter study enrolling hepatitis C virus patients with advanced fibrosis (transient elastography [TE] > 10 kPa) or cirrhosis by ultrasound showing SVR. They were followed up until HCC, liver transplantation, death, or until October 2020, which occurred first, with a minimum follow-up period of 6 months after SVR (follow-up: 49 [interquartile range 28–59] months)., [Results] Patients with cirrhosis by ultrasound represented 58% (611/1,054) of the overall cohort. During the study, HCC occurrence was 5.3% (56/1,054). Multivariate analyses revealed that Fibrosis-4 (FIB-4) > 3.25 (hazard ratio [HR] 2.26 [1.08–4.73]; P = 0.030), TE (HR 1.02 [1.00–1.04]; P = 0.045) and cirrhosis by ultrasound (HR 3.15 [1.36–7.27]; P = 0.007) predicted HCC occurrence. Baseline HCC screening criteria (TE > 10 kPa or cirrhosis) identified patients at higher risk of HCC occurrence in presence of FIB-4 > 3.25 (8.8%; 44/498) vs FIB-4 < 3.25 (2.4%; 12/506), while those with only FIB > 3.25 had no HCC (0%; 0/50) (logRank 22.129; P = 0.0001). A combination of baseline FIB-4 > 3.25 and HCC screening criteria had an annual incidence >1.5 cases per 100 person-years, while the rest of the groups remained 3.25 and HCC screening criteria remained at the highest risk of HCC occurrence (13.7% [21/153] vs 4.9% [9/184]; logRank 7.396, P = 0.007)., [Discussion] We demonstrated that a two-step strategy combining FIB-4, TE, and ultrasound could help stratify HCC incidence risk after SVR.

Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life threatening liver failure. However, chronic injury has also been reported with a variable frequency, with a range from 3.4% to 39% of patients after 6-12 months after stopping the implicated agent. This wide range is probably related to various definition of chronic liver injury and variable selection of the DILI patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear. Although rare vanishing bile duct syndrome, is associated with unfavorable prognosis with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and as a common final stage the development of cirrhosis, portal hypertension and its complications. A new type of cancer immunotherapy, check point inhibitors can apart from the acute autoimmune like phenotype also lead to sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have significant impact on health-related quality of life but very little is known on its psychological consequences in the long-term. Further investigations on the psychological disability in patients with chronic DILI particularly in those with chronic outcome are clearly needed in studies with structured long-term follow-up and periodic quality of live surveys.

Resumen La incorporacion de los antivirales de accion directa al tratamiento de la hepatitis C cronica permite simplificar el diagnostico y seguimiento del paciente, optimizando los recursos asistenciales (consultas y pruebas) dedicados al abordaje de la enfermedad. El objetivo fue estimar el impacto economico derivado de esta simplificacion. La optimizacion de recursos asistenciales se estimo, mediante el metodo Delphi, a partir de un panel de 36 expertos clinicos espanoles, y de las guias de practica clinica. Los costes unitarios (€ en 2017) de los recursos sanitarios considerados se obtuvieron de fuentes espanolas. La simplificacion del proceso, asi como la coordinacion entre el medico especialista, enfermeria y el servicio de farmacia, generarian unos ahorros por paciente de 591,17 €. Asimismo, se estima que la duracion media de las consultas seria inferior con regimenes diarios de 1 solo comprimido que con regimenes de mas de 1 comprimido al dia. Informacion sobre el suplemento: este articulo forma parte del suplemento titulado “El valor de la simplicidad en el tratamiento de la hepatitis C”, que ha sido patrocinado por Gilead. © 2019 Elsevier Espana, S.L.U. Todos los derechos reservados.

BACKGROUND AND OBJECTIVES: Corticosteroids are often empirically used to treat idiosyncratic hepatotoxicity with severe features. Interestingly, intravenous methylprednisolone (MP) is increasingly being recognized as being responsible for liver injury. We aimed to characterize MP-induced liver injury by analyzing demographical, clinical, laboratory and outcome data of three MP-induced hepatotoxicity cases and compared this information with that of previously published cases. CASE SERIES: Three females with multiple sclerosis (MS) were treated intravenously with MP, mean daily dose 767 mg. Liver damage occurred 2 to 6 weeks after exposure. Severity was mild to moderate. Two patients suffered positive rechallenge. LITERATURE REVIEW: We identified 50 published cases of MP hepatotoxicity. Most of these cases were female (86%) and main treatment indications were MS (29 cases) and Graves' ophthalmopathy (13 cases). Hepatocellular damage predominated and mean time to onset was 6 weeks. Four patients died and rechallenge occurred in 19 cases. CONCLUSION: MP pulses can induce severe liver injury, often with an autoimmune phenotype, particularly in patients with MS and Graves' ophthalmopathy. Consequently, these patient groups should have liver tests monitored when treated with MP to provide safer patient care.

Background and objective The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain. Patients and methods Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naive subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018. Results The GLE/PIB effectiveness was 100% (CI95%: 96.2–100%) in the mITT population and 94.1% (CI95%: 87.5–97.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35 ± 103.60€ compared to 1689.42€ and 2007.89€ of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95€ and 1689.42€ of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources. Conclusions 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.

[Background and Aim] Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD)., [Methods] Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years)., [Results] Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these., [Conclusions] The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death., This project has been partially funded by the ‘Consejería de Salud de la Junta de Andalucía’ (PI-0075-2014) and the ‘Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III’ (PI19/01404, PI16/01842, PI17/00535 and GLD19/00100).

Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 × 10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.

INTRODUCTION: Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments. METHODS: Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation. RESULTS: Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseline significantly higher alkaline phosphatase (ALP) (P = 0.01) and lower platelets (P = 0.03) than fibrates. Both treatments significantly decreased ALP, gamma-glutamyl transferase (GGT), and transaminases and improved Globe score. Albumin and immunoglobulin type M improved in the fibrates group. ALP decrease was higher under fibrates, whereas alanine aminotransferase decline was higher under OCA. Although baseline transaminases and GGT were higher in patients with OCA plus fibrates, significant ALP, GGT, alanine aminotransferase, and Globe score improvement were observed during triple therapy. Adverse events were reported in 14.7% of patients (21.3% OCA; 17.6% fenofibrate; 10.7% bezafibrate), mainly pruritus (10.1% with OCA). Discontinuation was more frequent in fenofibrate treatment mainly because of intolerance or adverse events. DISCUSSION: Second-line therapy with OCA or fibrates improves hepatic biochemistry and the GLOBE score in primary biliary cholangitis patients with suboptimal response to ursodeoxycholic acid. Simultaneous treatment with OCA and fibrates improved ALP as well.

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and Latin American DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a twofold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤ 15 days in 12 patients (21%) and one patient developed ALF within 7 days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤ 15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.

Background Herbal and dietary supplements (HDS) consumption, a growing cause of hepatotoxicity, is a common practice among Latin-American populations. Objectives: To evaluate clinical, laboratory features and outcome in HDS-hepatotoxicity included in the Latin America-Drug Induced Liver Injury (LATINDILI) Network. Methods A total of 29 adjudicated cases of HDS hepatotoxicity reported to the LATINDILI Network from October 2011 through December 2019 were compared with 322 DILI cases due to conventional drugs and 16 due to anabolic steroids as well as with other series of HDS-hepatotoxicity. Results From 367 DILI cases, 8% were attributed to HDS. An increasing trend in HDS-hepatotoxicity was noted over time (p = .04). Camellia sinensis, Herbalife® products, and Garcinia cambogia, mostly used for weight loss, were the most frequently adjudicated causative agents. Mean age was 45 years (66% female). Median time to onset was 31 days. Patients presented typically with hepatocellular injury (83%) and jaundice (66%). Five cases (17%) developed acute liver failure. Compared to conventional medications and anabolic steroids, HDS hepatotoxicity cases had the highest levels of aspartate and alanine transaminase (p = .008 and p = .021, respectively), had more re-exposure events to the culprit HDS (14% vs 3% vs 0%; p = .026), and had more severe and fatal/liver transplantation outcomes (21% vs 12% vs 13%; p = .005). Compared to other DILI cohorts, less HDS hepatotoxicity cases in Latin America were hospitalized (41%). Conclusions HDS-hepatotoxicity in Latin-America affects mainly young women, manifests mostly with hepatocellular injury and is associated with higher frequency of accidental re-exposure. HDS hepatotoxicity is more serious with a higher chance of death/liver transplantation than DILI related to conventional drugs.

Resumen El articulo recoge el conjunto de medidas propuestas por la SEPD, la AEEH, el GETECCU y la AEG que pretenden servir de ayuda a los servicios en su reincorporacion a la actividad habitual. Hemos confeccionado una serie de recomendaciones practicas respecto al manejo y a la reintroduccion progresiva de la actividad asistencial. Estas recomendaciones estan guiadas por la escasa y cambiante evidencia disponible y seran objeto de futuras actualizaciones en base a las necesidades diarias y a la disponibilidad del material fungible para adecuarse a ellas, y se podran implementar en cada servicio en funcion de la incidencia acumulada de SARS-CoV-2 en cada region y de la carga que la epidemia ha ocasionado en cada uno de los hospitales. Los objetivos generales de estas recomendaciones son: a) Proteger a nuestros pacientes de los riesgos de la infeccion por SARS-CoV-2 y prestarles una atencion de calidad. b) Proteger a todos los profesionales sanitarios de los riesgos de la infeccion por SARS-CoV-2. c) Recuperar el normal funcionamiento de nuestros servicios en un entorno de riesgo continuado de infeccion por SARS-CoV-2.

Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of fourteen promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n=192 and =81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n=55 and =92) and DILI patients (n=98, =28, and =143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total keratin 18 (K18), caspase cleaved K18 (ccK18), glutathione S-transferase alpha (GSTα), alpha fetoprotein (AFP), arginase-1 (ARG1), osteopontin (OPN), sorbitol dehydrogenase (SDH), fatty acid binding protein (FABP1), cadherin-5 (CDH5), macrophage colony stimulating factor receptor (MCSFR), paraoxonase 1 (PON1, normalized to prothrombin protein), and leucocyte cell-derived chemotaxin-2 (LECT2). Most candidate biomarkers were significantly altered in DILI cases compared to healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase (ALT) than miR-122 and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among the healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplant within 6 months of DILI-onset. Prediction of prognosis among DILI patients using Model for End-stage Liver Disease (MELD) was improved by incorporation of K18 and MCSFR levels. Conclusion: GLDH appears to be more useful than miR-122 in identifying DILI patients. K18, OPN and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management.

Drug-induced liver injury (DILI) occurs in a small fraction of individuals exposed to drugs, herbs or dietary supplements and is a relatively rare diagnosis compared with other liver disorders. DILI can be serious, resulting in hospitalization and even life-threatening liver failure, death or need for liver transplantation. Toxic liver damage usually presents as an acute hepatitis viral-like syndrome or as an acute cholestasis that resolves upon drug discontinuation. However, un-resolving chronic outcome after acute DILI can ensue in some subjects, the mechanisms and risk factors for this particular evolution being yet scarcely known. Furthermore, the definition of chronicity after acute DILI is controversial, regarding both the time frame of liver injury persistence and the magnitude of the abnormalities required. Besides this, in some instances the phenotypes and pathological manifestations are those of chronic liver disease at the time of DILI diagnosis. These include non-alcoholic fatty liver disease, vascular lesions, drug-induced autoimmune hepatitis, chronic cholestasis leading to vanishing bile duct syndrome and even cirrhosis, and some drugs such as amiodarone or methotrexate have been frequently implicated in some of these forms of chronic DILI. In addition, all of these DILI phenotypes can be indistinguishable from those related to other etiologies, making the diagnosis particularly challenging. In this manuscript we have critically reviewed the more recent data on chronicity in DILI with a particular focus on the epidemiology, mechanisms and risk factors of atypical chronic DILI phenotypes.

The purpose of this review was to analyze the current evidence regarding the incidence, mechanisms, and outcomes of drug-induced liver injury (DILI) and hepatotoxicity in patients with metabolic syndrome and nonalcoholic fatty liver disease. DILI is a complex clinical entity. Although uncommon, its incidence and diagnosis have been rising in recent years as basic research and clinical databases provide information about its etiology, clinical course, and prognosis. The prevalence of metabolic syndrome and non-alcoholic fatty liver disease is on the rise in western countries. Recently, features of the metabolic syndrome have been identified as factors affecting the phenotype and evolution of DILI, both in pre-clinical and clinical research. In the present review, we summarize current evidence regarding the influence of features of metabolic syndrome in the presentation, clinical course, and prognosis of DILI.

OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged >= 65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged >= 80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin = 75 years (2.59 (1.16-5.83); P = 0.02) and albumin = 75 years) or those with advanced liver disease (albumin

[Background & Aims] Non-alcoholic fatty liver disease (NAFLD) could play a catalytic role in the development of metabolic comorbidities, although the magnitude of this effect in metabolically healthy patients with NAFLD remains unclear. We assessed the role of biopsy-proven NAFLD on the risk of developing type 2 diabetes mellitus (T2DM) and other metabolic comorbidities (arterial hypertension [AHT], and dyslipidemia) in metabolically healthy patients., [Methods] We included 178 metabolically healthy—defined by the absence of baseline T2DM, AHT, dyslipidemia—patients with biopsy-proven NAFLD from the HEPAmet Registry (N = 1,030). Hepamet fibrosis score (HFS), NAFLD fibrosis score, and Fibrosis-4 were calculated. Follow-up was computed from biopsy to the diagnosis of T2DM, AHT, or dyslipidemia., [Results] During a follow-up of 5.6 ± 4.4 years, T2DM occurred in 9% (16/178), AHT in 8.4% (15/178), low HDL in 9.6% (17/178), and hypertriglyceridemia in 23.6% (42/178) of patients. In multivariate analysis, significant fibrosis predicted T2DM and AHT. Independent variables related to T2DM appearance were significant fibrosis (HR 2.95; 95% CI 1.19–7.31; p = 0.019), glucose levels (p = 0.008), age (p = 0.007) and BMI (p = 0.039). AHT was independently linked to significant fibrosis (HR 2.39; 95% CI 1.14–5.10; p = 0.028), age (p = 0.0001), BMI (p = 0.006), glucose (p = 0.021) and platelets (p = 0.050). The annual incidence rate of T2DM was higher in patients with significant fibrosis (4.4 vs. 1.2 cases per 100 person-years), and increased in the presence of obesity, similar to AHT (4.6 vs. 1.1 cases per 100 person-years). HFS >0.12 predicted the risk of T2DM (25% [4/16] vs. HFS, [Conclusion] Metabolically healthy patients with NAFLD-related significant fibrosis were at greater risk of developing T2DM and AHT. HFS >0.12, but not NAFLD fibrosis score or Fibrosis-4, predicted the occurrence of T2DM., [Lay summary] Patients with biopsy-proven non-alcoholic fatty liver disease and significant fibrosis were at risk of developing type 2 diabetes mellitus and arterial hypertension. The risk of metabolic outcomes in patients with significant fibrosis was increased in the presence of obesity. In addition to liver biopsy, patients at intermediate-to-high risk of significant fibrosis by Hepamet fibrosis score were at risk of type 2 diabetes mellitus., This project has been partially funded by the “Consejería de Salud de la Junta de Andalucía” (PI-0075-2014), the “Spanish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III” (PI19/01404, PI16/01842 and PI17/00535) and “Gilead” (GLD19/00100).

[Background] chronic liver disease (CLD) patients often present thrombocytopenia (TCP) and when severe, it may prevent them from undergoing necessary invasive procedures due to an increased bleeding risk. The lack of scientific evidence makes it impossible to determine key aspects of the current management and associated healthcare burden of these patients in Spain., [Purpose] to gain insight into the current situation of patients with CLD-associated severe TCP undergoing invasive procedures in Spain, based on the experience of clinical experts. Methods: national Delphi study involving 32 medical experts., [Results] the estimated prevalence of CLD-associated severe TCP is approximately 5,967, with an annual incidence of 1,148 new patients. Patients undergo a median of 1 (0-3) invasive procedures/year. Platelet transfusions (PTs) are the standard option to raise platelet counts and are associated with significant burden. The achievement of target platelet levels (≥ 50 x 109/l) after a transfusion is not routinely measured. The lack of effectiveness and short life span of transfused platelets can lead to procedure cancellations and bleeding events, which potentially affect patient outcomes. Adverse events occur in 1-25 % of patients, including mild (febrile and allergic reactions) and severe events (e.g., transfusion-related acute lung injury). Between 5-15 % of patients are unfit to receive PTs and approximately 3 % are treated off-label with thrombopoietin receptor agonists., [Conclusions] this study provides a snapshot of the current situation in Spain, highlighting that the current management is poorly standardized and suboptimal in some cases. The results suggest the benefit of developing a consensus document to address some of these shortcomings and to advance in the search for alternatives to PTs., This study was funded by Shionogi Inc.

Background and Aims: Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. Methods: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analyzed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n=144), HEV antigen (Ag) and anti- HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in 8 patients. Results: Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age 61 years. Underlying hepatic diseases (OR=23.4, p20 folds upper limit of normal (OR=10.9, p=0.002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). Conclusions: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels. The present study has been supported by grants of the Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional FEDER (contract numbers: FIS PI0274-2016, PI-0285- 2016, PI 18-01804, PI 18-00901, PT17/0017/0020, CM17/00243, JR16/00015, B-0002-2019, UMA-18-FEDERJA-193 and by the Agencia Española del Medicamento. SCReN and CIBERehd are funded by Instituto de Salud Carlos III. European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network, IMI2-Translational Safety Biomarker Pipeline (TransBioLine). The funding sources had no involvement in the study design, in the collection, analysis, and interpretation of data, in the writing of the report or in the decision to submit the manuscript for publication

Summary Background Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. Methods We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. Findings The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST −14 IU/L [–91 to 64; p=0·728] and for ALT −8 IU/L [–49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [–804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. Interpretation Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. Funding Horizon 20/20 European programme.

Drug-induced liver injury (DILI) is a rare, unpredictable, and potentially serious adverse reaction. It is induced by many drugs, herbs, and dietary supplements and represents a diagnostic challenge to clinicians. Older people (aged 65 years and older) are often polymedicated, and their declining physiological function affects drug pharmacokinetics. There is no consistent evidence that age is a general risk factor for DILI; however, age might be a risk factor with specific medications, with antimicrobials and cardiovascular drugs being the most likely medications to cause DILI in older people. Ageing influences DILI phenotypes, making cholestatic damage and chronic DILI more likely. In older people with DILI, comorbidities act as confounding causes and account for higher mortality unrelated to the liver. There are no specific therapies for DILI and supportive measures are still the mainstay of management. This Review highlights current advances and gaps in DILI epidemiology, mechanisms, and diagnosis that are pertinent to older individuals.

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are a leading cause of drug-induced liver injury (DILI) across the world. Ibuprofen is one of the most commonly used and safest NSAIDs, nevertheless reports on ibuprofen-induced hepatotoxicity are available. Aim To analyse previously published information on ibuprofen-induced liver injury for a better characterisation of its phenotypic expression. Method A systematic search was performed and information on ibuprofen-induced liver injury included in case series and case reports, in terms of demographic, clinical, biochemical and outcome data, was analysed. Results Twenty-two idiosyncratic ibuprofen hepatotoxicity cases were identified in the literature, suggesting a very low prevalence of this type of DILI. These patients had a mean age of 31 years and 55% were females. Mean cumulative dose of ibuprofen and time to onset were 30 g and 12 days, respectively. Hepatocellular injury was the most frequently involved liver injury pattern. Six cases developed vanishing bile duct syndrome. Full recovery occurred in 11 patients after a mean time of 14 weeks, whereas five cases evolved to acute liver failure leading to death/liver transplantation. Conclusions When assessing potential hepatotoxicity cases, physicians should keep in mind that ibuprofen has been associated with hepatotoxicity in the literature. Ibuprofen-associated DILI presents commonly as hepatocellular damage after a short latency period. Published reports on ibuprofen hepatotoxicity leading to liver failure resulting in liver transplantation or death are available. However, due to the apparent low absolute risk of ibuprofen-induced liver complications, ibuprofen can be regarded as an efficacious and safe NSAID.

HEPAmet Registry., [Background & Aims] Fibrosis affects prognoses for patients with nonalcoholic fatty liver disease (NAFLD). Several non-invasive scoring systems have aimed to identify patients at risk for advanced fibrosis, but inconclusive results and variations in features of patients (diabetes, obesity and older age) reduce their diagnostic accuracy. We sought to develop a scoring system based on serum markers to identify patients with NAFLD at risk for advanced fibrosis., [Methods] We collected data from 2452 patients with NAFLD at medical centers in Italy, France, Cuba, and China. We developed the Hepamet fibrosis scoring system using demographic, anthropometric, and laboratory test data, collected at time of liver biopsy, from a training cohort of patients from Spain (n = 768) and validated the system using patients from Cuba (n = 344), Italy (n = 288), France (n = 830), and China (n = 232). Hepamet fibrosis score (HFS) were compared with those of previously developed fibrosis scoring systems (the NAFLD fibrosis score [NFS] and FIB-4). The diagnostic accuracy of the Hepamet fibrosis scoring system was assessed based on area under the receiver operating characteristic (AUROC) curve, sensitivity, specificity, diagnostic odds ratio, and positive and negative predictive values and likelihood ratios., [Results] Variables used to determine HFS were patient sex, age, homeostatic model assessment score, presence of diabetes, levels of aspartate aminotransferase, and albumin, and platelet counts; these were independently associated with advanced fibrosis. HFS discriminated between patients with and without advanced fibrosis with an AUROC curve value of 0.85 whereas NFS or FIB-4 did so with AUROC values of 0.80 (P = .0001). In the validation set, cut-off HFS of 0.12 and 0.47 identified patients with and without advanced fibrosis with 97.2% specificity, 74% sensitivity, a 92% negative predictive value, a 76.3% positive predictive value, a 13.22 positive likelihood ratio, and a 0.31 negative likelihood ratio. HFS were not affected by patient age, body mass index, hypertransaminasemia, or diabetes. The Hepamet fibrosis scoring system had the greatest net benefit in identifying patients who should undergo liver biopsy analysis and led to significant improvements in reclassification, reducing the number of patients with undetermined results to 20% from 30% for the FIB-4 and NFS systems (P < .05)., [Conclusions] Using clinical and laboratory data from patients with NAFLD, we developed and validated the Hepamet fibrosis scoring system, which identified patients with advanced fibrosis with greater accuracy than the FIB-4 and NFS systems. the Hepamet system provides a greater net benefit for the decision-making process to identify patients who should undergo liver biopsy analysis.

[Background] recent evidence suggests a causal link between serum uric acid and the metabolic syndrome, diabetes mellitus, arterial hypertension, and renal and cardiac disease. Uric acid is an endogenous danger signal and activator of the inflammasome, and has been independently associated with an increased risk of cirrhosis., [Aim and methods] six hundred and thirty-four patients from the nation-wide HEPAMET registry with biopsy-proven NAFLD (53% NASH) were analyzed to determine whether hyperuricemia is related with advanced liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Patients were divided into three groups according to the tertile levels of serum uric acid and gender., [Results] the cohort was composed of 50% females, with a mean age of 49 years (range 19-80). Patients in the top third of serum uric acid levels were older (p = 0.017); they had a higher body mass index (p < 0.01), arterial blood pressure (p = 0.05), triglyceridemia (p = 0.012), serum creatinine (p < 0.001) and total cholesterol (p = 0.016) and lower HDL-cholesterol (p = 0.004). According to the univariate analysis, the variables associated with patients in the top third were more advanced steatosis (p = 0.02), liver fibrosis (F2-F4 vs F0-1; p = 0.011), NASH (p = 0.002) and NAS score (p = 0.05). According to the multivariate logistic regression analysis, the top third of uric acid level was independently associated with steatosis (adjusted hazard ratio 1.7; CI 95%: 1.05-2.8) and NASH (adjusted hazard ratio 1.8; CI 95%: 1.08-3.0) but not with advanced fibrosis (F2-F4) (adjusted hazard ratio 1.09; CI 95%: 0.63-1.87)., [Conclusion] higher levels of serum uric acid were independently associated with hepatocellular steatosis and NASH in a cohort of patients with NAFLD. Serum uric acid levels warrants further evaluation as a component of the current non-invasive NAFLD scores of histopathological damage.

Background & Aims We performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China. Methods We collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method. Results Most cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76–52.03), followed by mixed injury (28.30%; 95% CI 27.73–28.87) and cholestatic injury (20.31%; 95% CI 19.80–20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy's Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86–26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher. Conclusions In a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.

BACKGROUND AND AIM A small but significant proportion of patients with normal body mass index show non-alcoholic fatty liver disease (NAFLD). Oxidized low-density lipoprotein (LDL) is a powerful immunogenic molecule, which causes oxidative stress and produces antibodies (oxLDL-ab). We aimed to analyze the role of oxLDL-ab on histological features in lean-NAFLD patients. METHODS Seventy-two biopsy-proven NAFLD patients were included. Lean patients showed body index mass of

espanolIntroduccion: en los ultimos anos, numerosos articulos relacionan el uso de los inhibidores de la bomba de protones (IBP) con posibles efectos adversos serios que han creado cierta alarma social. Objetivo: el objetivo de este trabajo es revisar la literatura de cara a elaborar un documento institucional de posicionamiento de la Sociedad Espanola de Patologia Digestiva (SEPD) sobre la seguridad de los IBP a largo plazo. Material y metodos: se ha realizado una revision exhaustiva de la literatura orientada a la presentacion de conclusiones tras una valoracion critica sobre los siguientes temas: a) indicaciones actuales de los IBP; b) deficit de vitamina B12 y alteraciones neurologicas; c) deficit de magnesio; d) fracturas oseas; e) infecciones entericas y neumonias; f) interaccion con los derivados de las tienopiridinas; y e) complicaciones en pacientes cirroticos. Resultados: las indicaciones actuales de los IBP no han variado en los ultimos anos y estan bien establecidas. No se recomienda la realizacion de un cribado generalizado de los niveles de vitamina B12 en todos los pacientes tratados de forma cronica con estos medicamentos; sin embargo, si parece necesario controlar los niveles de magnesio al inicio del tratamiento y monitorizarlos en pacientes con toma de otros farmacos que puedan inducir hipomagnesemia. Existe mayor riesgo de fracturas oseas, aunque no se puede concluir que esta asociacion sea causal. La asociacion IBP e infeccion por Clostridium difficile es debil o moderada y el riesgo de neumonia es bajo. En pacientes con riesgo cardiovascular y tratados con derivados de las tienopiridinas -dada la ausencia de evidencias definitivas en relacion a posibles interacciones medicamentosasparece que lo prudente sea sopesar adecuadamente los riesgos gastrointestinales y los riesgos cardiovasculares de cada paciente; cuando el riesgo gastrointestinal sea moderado/alto, debemos ejercer una accion terapeutica de prevencion efectiva utilizando un IBP. En cirroticos descompensados deben ser indicados con cautela. Conclusiones: los IBP son farmacos seguros y los beneficios de su empleo, tanto a corto como a largo plazo superan los posibles efectos secundarios, siempre que la indicacion, dosis y duracion sean las adecuadas. EnglishIntroduction: In the last few years a significant number of papers have related the use of proton-pump inhibitors (PPIs) to potential serious adverse effects that have resulted in social unrest. Objective: The goal of this paper was to provide a literature review for the development of an institutional position statement by Sociedad Espanola de Patologia Digestiva (SEPD) regarding the safety of long-term PPI use. Material and methods: A comprehensive review of the literature was performed to draw conclusions based on a critical assessment of the following: a) current PPI indications; b) vitamin B12 deficiency and neurological disorders; c) magnesium deficiency; d) bone fractures; e) enteric infection and pneumonia; f) interactions with thienopyridine derivatives; e) complications in cirrhotic patients. Results: Current PPI indications have remained unchanged for years now, and are well established. A general screening of vitamin B12 levels is not recommended for all patients on a PPI; however, it does seem necessary that magnesium levels be measured at therapy onset, and then monitored in subjects on other drugs that may induce hypomagnesemia. A higher risk for bone fractures is present, even though causality cannot be concluded for this association. The association between PPIs and infection with Clostridium difficile is mild to moderate, and the risk for pneumonia is low. In patients with cardiovascular risk receiving thienopyridines derivatives it is prudent to adequately consider gastrointestinal and cardiovascular risks, given the absence of definitive evidence regardin potential drug-drug interactions; if gastrointestinal risk is found to be moderate or high, effective prevention should be in place with a PPI. PPIs should be cautiously indicated in patients with decompensated cirrhosis. Conclusions: PPIs are safe drugs whose benefits outweigh their potential side effects both short-term and long-term, provided their indication, dosage, and duration are appropriate.

Background & Aims Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Mitochondrial SH3BP5 (also called SAB) and phosphorylation of c-Jun N-terminal kinase (JNK) mediate the hepatotoxic effects of APAP. We investigated the involvement of steroidogenic acute regulatory protein (STARD1), a mitochondrial cholesterol transporter, in this process and sensitization by valproic acid (VPA), which depletes glutathione and stimulates steroidogenesis. Methods Nonfasted C57BL/6J mice (control) and mice with liver-specific deletion of STARD1 (Stard1ΔHep), SAB (SabΔHep), or JNK1 and JNK2 (Jnk1+2ΔHep) were given VPA with or without APAP. Liver tissues were collected and analyzed by histology and immunohistochemistry and for APAP metabolism, endoplasmic reticulum (ER) stress, and mitochondrial function. Adult human hepatocytes were transplanted into Fah−/−/Rag2−/−/Il2rg−/−/NOD (FRGN) mice to create mice with humanized livers. Results Administration of VPA before administration of APAP increased the severity of liver damage in control mice. The combination of VPA and APAP increased expression of CYP2E1, formation of NAPQI-protein adducts, and depletion of glutathione from liver tissues of control mice, resulting in ER stress and the upregulation of STARD1. Livers from control mice given VPA and APAP accumulated cholesterol in the mitochondria and had sustained mitochondrial depletion of glutathione and mitochondrial dysfunction. Inhibition of ER stress, by administration of tauroursodeoxycholic acid to control mice, prevented upregulation of STARD1 in liver and protected the mice from hepatoxicity following administration of VPA and APAP. Administration of N-acetylcysteine to control mice prevented VPA- and APAP-induced ER stress and liver injury. Stard1ΔHep mice were resistant to induction of ALF by VPA and APAP, despite increased mitochondrial levels of glutathione and phosphorylated JNK; we made similar observations in fasted Stard1ΔHep mice given APAP alone. SabΔHep mice or Jnk1+2ΔHep mice did not develop ALF following administration of VPA and APAP. The ability of VPA to increase the severity of APAP-induced liver damage was observed in FRGN mice with humanized liver. Conclusions In studies of mice, we found that upregulation of STARD1 following ER stress mediates APAP hepatoxicity via SH3BP5 and phosphorylation of JNK1 and JNK2., We acknowledge the support from grants SAF2014–57674R, SAF-2015–69944R, and SAF2017–85877R from Plan Nacional de I+D, Spain, and by the CIBEREHD; the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health (NIH); the NIH R01DK06715 and the USC Research Center for Liver Diseases P30DK485522 Instrumentation (NK), as well as support from AGAUR of the Generalitat de Catalunya SGR-2017–1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network, and the Fundación BBVA.

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related deaths worldwide. Up to 80% of patients with HCC have concomitant cirrhosis as a result of hepatitis B or C virus, alcohol abuse, or non-alcoholic steatohepatitis.

Background & Aims In phase 3 trials and real-world settings, smaller proportions of patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have a sustained virologic response 12 weeks after treatment (SVR12) with the combination of sofosbuvir and velpatasvir than in patients without cirrhosis. It is unclear whether adding ribavirin to this treatment regimen increases SVRs in patients with genotype 3 HCV infection and cirrhosis. Methods We performed a phase 2 trial of 204 patients with genotype 3 HCV infection and compensated cirrhosis (mean age 51 ± 7.4 years) at 29 sites in Spain from August 19, 2016 through April 18, 2017. Patients were assigned to groups given sofosbuvir and velpatasvir for 12 weeks (n = 101) or sofosbuvir and velpatasvir plus ribavirin for 12 weeks (n = 103). The primary efficacy end point was SVR12. Results The overall rates of SVR12 were 91% (92 of 101; 95% CI 84–96) for the sofosbuvir–velpatasvir group and 96% (99 of 103; 95% CI 90–99) for the sofosbuvir–velpatasvir plus ribavirin group. In the sofosbuvir–velpatasvir group, a smaller proportion of patients with baseline resistance-associated substitutions (RASs) in nonstructural protein 5A (NS5A) achieved an SVR12 (84%) than did patients without (96%). In the sofosbuvir–velpatasvir plus ribavirin group, baseline RASs had less effect on the proportion of patients with an SVR12 (96% for patients with baseline RASs; 99% for patients without). The most common adverse events (which occurred in ≥10% of patients) were asthenia (12%) in the sofosbuvir–velpatasvir group and asthenia (27%), headache (24%), and insomnia (12%) in the sofosbuvir–velpatasvir plus ribavirin group. Conclusions Consistent with findings from previous studies, a high rate of patients (91% and 96%) with genotype 3 HCV infection and compensated cirrhosis achieved an SVR12 with sofosbuvir and velpatasvir, with or without ribavirin. Of patients treated with sofosbuvir and velpatasvir without ribavirin, fewer patients with baseline NS5A RASs achieved an SVR12 compared with patients without baseline NS5A. ClinicalTrials.gov NCT02781558.

Background & Aims: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. Methods: Twenty-two males (70±8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150±50mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. Results: From 1993 to 2013, 22 patients were retrieved. Latency was 163±97days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18±13×ULN, ALP 0.7±0.7×ULN and total serum bilirubin 14±10mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). Conclusions: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient. Fil: Bessone, Fernando. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Lucena, M. L.. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; España Fil: Roma, Marcelo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina Fil: Stephens, Camilla. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; España Fil: Medina Cáliz, Inmaculada. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; España. Universidad de Málaga; España Fil: Frider, Bernardo. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; Argentina Fil: Tsariktsian, Guillermo. Ministerio de Defensa. Ejército Argentino. Hospital Militar Central Cirujano Mayor "Dr. Cosme Argerich"; Argentina Fil: Hernández, Nelia. Universidad de la República; Uruguay Fil: Bruguera, Miquel. Liver Unit; España Fil: Gualano, Gisela. Hospital Alejandro Posadas; Argentina Fil: Fassio, Eduardo. Hospital Alejandro Posadas; Argentina Fil: Montero, Joaquin. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Reggiardo, María V.. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Ferretti, Sebastian Eduardo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Colombato, Luis. Hospital Británico de Buenos Aires; Argentina Fil: Tanno, Federico. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Ferrer, Jaime. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Zeno, Lelio. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Tanno, Hugo. Universidad Nacional de Rosario. Facultad de Ciencias Médicas; Argentina Fil: Andrade, Raúl J.. Universidad de Málaga; España. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas ; España

Background & Aims The current definition of the pattern of liver injury in hepatotoxicity (DILI) is given by the R (ratio) value, dividing alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in upper limits of normal at DILI onset. We aimed to explore the validity of using aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) as biomarkers of hepatocelullar and cholestatic damage, respectively, when calculating the R value. Methods Clinical, laboratory and histological data from 588 DILI episodes included in the Spanish DILI Registry were analyzed. Linear regression analysis was performed to establish the most appropriate cut-off points for hepatocellular and cholestatic patterns when calculating R with AST and GGT. Results The overall agreement between ALT/ALP and AST/ALP was 76%, with 96%, 61% and 41% agreement in the hepatocellular (R ≥ 5), cholestatic (R ≤ 2) and mixed groups respectively (P

Resumen Introduccion GIDEON es un estudio internacional prospectivo, no intervencionista, que evaluo la seguridad de sorafenib en pacientes con carcinoma hepatocelular (CHC) no resecable en la practica clinica diaria, incluidos pacientes Child-Pugh B. Objetivos Analisis de datos recogidos en Espana sobre seguridad y efectividad de sorafenib y los patrones de tratamiento. Metodos Se recogieron los datos demograficos y de la enfermedad, la dosis inicial usada, los acontecimientos adversos emergentes del tratamiento (AA) y las modificaciones de dosis a lo largo del seguimiento. Se valoraron la supervivencia global y el tiempo hasta la progresion de la enfermedad. La eficacia y la seguridad se analizaron en funcion de la clasificacion Child-Pugh y la dosis inicial. Resultados Se incluyo a 143 pacientes de 19 hospitales espanoles. El 24,5% eran pacientes Child-Pugh B. El 90,9% de los pacientes recibio una dosis inicial de 400 mg/12 h. En pacientes Child-Pugh A se modifico mas frecuentemente la dosis y la duracion del tratamiento fue mas larga. La incidencia de AA y de aquellos relacionados con el farmaco fue similar en los pacientes Child-Pugh A y B, aunque los AA graves fueron mas frecuentes en los pacientes Child-Pugh B. Los mas frecuentes fueron diarrea, fatiga y eritrodisestesia palmo-plantar. La mediana de supervivencia global fue de 384 dias, y superior en pacientes Child-Pugh A (593 vs. 211 dias en Child-Pugh B); la mediana hasta la progresion de la enfermedad fue de 177 dias, similar en ambos subgrupos. Conclusion El perfil de seguridad de sorafenib en pacientes espanoles con CHC no resecable es independiente de la funcion hepatica. El estado Child-Pugh no parece influir en el enfoque de dosificacion de sorafenib ni en el tiempo hasta la progresion, pero si parece ser un fuerte predictor de la supervivencia.

RESUMEN En el año 2016 se detectó en la provincia de Málaga un brote de hepatitis A en pacientes con características epidemiológicas especiales, con un predominio de sujetos del sexo masculino. Presentamos 51 casos de hepatitis A aguda con una media de edad de 35,7 años, el 90% varones, con un 55% de casos que reconocían haber mantenido relaciones sexuales con otros hombres en los últimos dos meses. La mitad de ellos requirieron ingreso hospitalario por coagulopatía significativa en el momento del diagnóstico, sin evolución a fallo fulminante, ni encefalopatía en ningún caso. Cuatro casos presentaban ascitis al diagnóstico. Este brote se suma a otros dos publicados en Reino Unido y Holanda con un número de casos similar y epidemiológicamente muy parecidos, lo cual refuerza la importancia de la vigilancia epidemiológica y la necesidad de vacunación en esta población de riesgo, así como de campañas informativas a la población para prevenir la enfermedad. ABSTRACT In 2016, an outbreak of hepatitis A was identified in the Malaga province among patients with specific epidemiological characteristics, which were predominantly males. This is a report of 51 subjects with acute hepatitis A and a mean age of 35.7 years, 90% were male and 55% of cases were men who had had sex with other men within the last two months. Half of them required hospitalization for significant coagulopathy at diagnosis and no cases progressed to fulminant failure or encephalopathy. Four patients had ascites at the time of diagnosis. This outbreak adds to those reported in the United Kingdom and the Netherlands with a similar number of cases and epidemiology. These studies highlight the importance of epidemiological surveillance, the need for vaccination in this particular at risk population and the need for informative campaigns in order to prevent this disease.

Background Metabolically healthy obesity (MHO) shows a reduced risk compared with obese patients with adverse metabolic conditions. Lean people suffering some metabolic derangements also have non-alcoholic fatty liver disease (NAFLD)-related outcomes compared with non-obese subjects with a few metabolic risks. Aim To define the impact of the metabolic status on the NAFLD-related outcomes, beyond the presence of obesity. Methods We designed a multicentre cross-sectional study, including 1058 biopsy-proven NAFLD patients. Metabolically healthy status was strictly defined by the lack of metabolic risk factors (diabetes mellitus, low HDL, hypertriglyceridemia, arterial hypertension). Non-alcoholic steatohepatitis (NASH) and significant fibrosis (F2-F4) were identified by liver biopsy. Chronic kidney disease epidemiology collaboration equation was calculated for kidney function and the atherogenic index of plasma (AIP) for cardiovascular risk. Results Metabolically healthy (OR 1.88; P = 0.050) and unhealthy obesity (OR 3.47: P < 0.0001), and unhealthy non-obesity (OR 3.70; P < 0.0001) were independently associated with NASH together with homeostatic model assessment (HOMA), ALT, and platelets. Significant fibrosis was more frequently observed in the presence of adverse metabolic conditions in obese (OR 3.89; P = 0.003) and non-obese patients (OR 3.92; P = 0.002), and independently associated with platelets, albumin, ALT, HOMA, and age. The number of metabolic factors determined the risk of NASH and significant fibrosis. Glomerular filtration rate was lower in unhealthy (91.7 +/- 18) than healthy metabolism (95.6 +/- 17) (P = 0.007). AIP was higher in adverse metabolic conditions (P = 0.0001). Metabolically unhealthy non-obesity showed higher liver damage (NASH 55.8% vs 42.4%; P P < 0.0001) and cardiovascular risk (P < 0.0001) than healthy obesity. Conclusions Metabolic unhealthy status showed a greater impact on NASH, significant fibrosis, kidney dysfunction, and atherogenic profile than obesity. However, metabolically healthy obesity was not a full healthy condition. We should focus our messages especially on patients with adverse metabolic conditions.

Hyperammonemia is a metabolic condition characterized by elevated levels of ammonia and a common event in acute liver injury/ failure and chronic liver disease. Even though hepatic ammonia levels are potential predictive factors of patient outcome, easy and inexpensive methods aiming at the detection of liver ammonia accumulation in the clinical setting remain unavailable. Thus, herein we have developed a morphological method, based on the utilization of Nessler A s reagent, to accurately and precisely detect the accumulation of ammonia in biological tissue. We have validated our method against a commercially available kit in mouse tissue samples and, by using this modified method, we have confirmed the hepatic accumulation of ammonia in clinical and animal models of acute and chronic advanced liver injury as well as in the progression of fatty liver disease. Overall, we propose a morphological method for ammonia detection in liver that correlates well with the degree of liver disease severity and therefore can be potentially used to predict patient outcome. This work was supported by grants from NIH (USDepartment of Health and Human services)-R01AT001576 (to S.C.L., J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), MINECO: SAF20145 4658-R and SAF2014-52097-R integrado en el Plan Estatal de Investigacion Cientifica y Tecnica y Innovacio 2013-2016 cofinanciado con Fondos FEDER to M.L.M.-C and J.M.M. respectively, Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigacion Cientifica y Tecnica y Innovacion 2013-2016 cofinanciado con Fondos FEDER (toM.L.M.-C and J.M.M),EITB. BIO15/CA/014, Asociacion Espanola contra el Cancer (T.C.D, P.F-Tand M.L.M-C). Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III.Thefunders had no role in study design,datacollection and analysis,decision to publish,or preparation of the manuscript.

Summary Background We have observed an increase in hepatotoxicity (DILI) reporting related to the use of anabolic androgenic steroids (AAS) for bodybuilding. Aim To characterise phenotype presentation, outcome and severity of AAS DILI. Methods Data on 25 cases of AAS DILI reported to the Spanish (20) and Latin-American (5) DILI Registries were collated and compared with previously published cases. Results AAS DILI increased from representing less than 1% of the total cases in the Spanish DILI Registry in the period 2001–2009 to 8% in 2010–2013. Young men (mean age 32 years), requiring hospitalisation, hepatocellular injury and jaundice were predominating features among the AAS cases. AAS DILI caused significantly higher bilirubin values independent of type of damage when compared to other drug classes (P = 0.001). Furthermore, the cholestatic AAS cases presented significantly higher mean peak bilirubin (P = 0.029) and serum creatinine values (P = 0.0002), compared to the hepatocellular cases. In a logistic regression model, the interaction between peak bilirubin values and cholestatic damage was associated with the development of AAS-induced acute kidney impairment (AKI) [OR 1.26 (95% CI: 1.035–1.526); P = 0.021], with 21.5 ×ULN being the best bilirubin cut-off point for predicting AKI risk (AUCROC 0.92). No fatalities occurred. Conclusions Illicit recreational AAS use is a growing cause of reported DILI that can lead to severe hepatic and renal injury. AAS DILI is associated with a distinct phenotype, characterised by considerable bilirubin elevations independent of type of damage. Although hepatocellular injury predominates, acute kidney injury develops in cholestatic cases with pronounced jaundice.

Chronic hepatitis C virus infection is usually asymptomatic. The severity of the hepatic lesion in these patients at diagnosis varies and, from the histopathologic point of view, most have mild disease. A series of factors have been described that correlate with the progression of fibrosis in patients with mild fibrosis: age at diagnosis, the duration of the infection, male sex, HIV coinfection, transaminase levels during follow-up, alcohol consumption, metabolic factors such as diabetes and overweight, necroinflammatory activity in the initial biopsy, and the degree of steatosis. In patients with genotype 1 hepatitis C infection, the standard treatment has been pegylated interferon and ribavirin. However, response rates are markedly increased by concomitant use of first-generation protease inhibitors, boceprevir or telaprevir. In patients with moderate fibrosis, these drugs are well tolerated, in addition to being effective. Currently, dual therapy should be reserved for patients with good baseline predictive factors of response and/or contraindications for treatment with telaprevir or boceprevir. In patients with genotypes other than genotype 1, the standard treatment continues to be the combination of pegylated interferon and ribavirin, although the development of new direct-acting antiviral agents such as sofosbuvir and simeprevir will change the strategies used in these patients. The decision to wait for the new treatments is complex because their release date is unknown; likewise, their high cost will limit the possibilities for their use.

Background and Aim Obesity is an important health-care problem in developed countries. It is considered a multisystemic disease, but it may also affect the liver, thus provoking non-alcoholic fatty liver disease. This disease has been less extensively studied among children than among adults. We propose to analyze the prevalence of hepatic steatosis among a pediatric population within an area in southern Europe besides the variables associated with its development and severity. Methods Cross-sectional study carried out on a population of children aged 6–14 years inclusive, using abdominal ultrasound as a method to determine the presence and severity of hepatic steatosis; in addition, anthropometric and blood-tested parameters were examined to determine which of these were associated with steatosis. Results One hundred forty-four children were analyzed, 84 male (58.3%). Steatosis was detected in 50 children (34.7%; 95% confidence interval [CI]: 26.0–42.0%). In six of these cases (12%), elevated aminotransferase levels were recorded. Factors found to be associated with steatosis were body mass index ≥ 99th percentile (odds ratio [OR] 3.58, 95% CI 1.16–15.6) and the level of alanine aminotransferase (ALT) (OR 1.08, 95% CI 1.03–1.13), while its severity was associated with ALT (OR 1.17, 95% CI 1.09–1.28). A level of ALT

BACKGROUND: There is a clear need for better biomarkers of drug-induced-liver-injury (DILI). AIMS: We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI. METHODS: We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.

Drug-induced liver damage is one of the most complex liver diseases due to its similar presentation to other acute or chronic liver processes, its potential severity and the absence of specific biomarkers to confirm diagnosis, which is based on clinical suspicion and exclusion of alternative causes. Because the drug development process fails to completely screen out hepatotoxic molecules and identify susceptible individuals, postmarketing pharmacovigilance remains essential. Hepatotoxicity registries are the ideal instrument for systematic and continual data collection, using preestablished criteria based on consensus. The present article briefly describes the contributions of the Spanish Hepatotoxicity Registry and those of other international registries. Hopefully, Latin American registries will be incorporated into existing initiatives, which will stimulate research and improve understanding of the complex mechanisms involved in this adverse reaction.