Serious liver injury induced by Nimesulide: an international collaboration study reporting 57 cases

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 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 2-fold 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 seven 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.The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18-00901; PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) research contract from ISCIII and Consejería de Salud de Andalucía, IAA holds a Sara Borrell research contract from the National Health System, ISCIII (CD 20/00083)

Unsuccessful therapy with adefovir and entecavir-tenofovir in a patient with chronic hepatitis B infection with previous resistance to lamivudine: a fourteen-year evolution of hepatitis B virus mutations

<p>Abstract</p> <p>Background</p> <p>Complex mutants can be selected under sequential selective pressure by HBV therapy. To determine hepatitis B virus genomic evolution during antiviral therapy we characterized the HBV quasi-species in a patient who did no respond to therapy following lamivudine breakthrough for a period of 14 years.</p> <p>Case Presentation</p> <p>The polymerase and precore/core genes were amplified and sequenced at determined intervals in a period of 14 years. HBV viral load and HBeAg/Anti-HBe serological profiles as well as amino transferase levels were also measured. A mixture of lamivudine-resistant genotype A2 HBV strains harboring the rtM204V mutation coexisted in the patient following viral breakthrough to lamivudine. The L180M+M204V dominant mutant displayed strong lamivudine-resistance. As therapy was changed to adefovir, then to entecavir, and finally to entecavir-tenofovir the viral load showed fluctuations but lamivudine-resistant strains continued to be selected, with minor contributions to the HBV quasi-species composition of additional resistance-associated mutations. At the end of the 14-year follow up period, high viral loads were predominant, with viral strains harboring the lamivudine-resistance signature rtL180M+M204V. The precore/core frame A1762T and G1764A double mutation was detected before treatment and remaining in this condition during the entire follow-up. Specific entecavir and tenofovir primary resistance-associated mutations were not detected at any time. Plasma concentrations of tenofovir indicated adequate metabolism of the drug.</p> <p>Conclusions</p> <p>We report the selection of HBV mutants carrying well-defined primary resistance mutations that escaped lamivudine in a fourteen-year follow-up period. With the exception of tenofovir resistance mutations, subsequent unselected primary resistance mutations were detected as minor populations into the HBV quasispecies composition during adefovir or entecavir monotherapies. Although tenofovir is considered an appropriate therapeutic alternative for the treatment of entecavir-unresponsive patients, its use was not effective in the case reported here.</p

Diagnosis and treatment of non-alcoholic fatty liver disease: Argentine Association for the Study of Liver Diseases, year 2019

El hígado graso no alcohólico (HGNA) es la enfermedad hepática crónica más frecuente en todo el mundo, con una prevalencia aproximada de 25% a nivel global. Su prevalencia es mucho mayor en pacientes con sobrepeso, obesidad y diabetes tipo 2 y es considerada como la manifestación hepática del síndrome metabólico. El espectro de la enfermedad hepática es muy amplio, desde la esteatosis simple a la esteatohepatitis, fibrosis, cirrosis y sus complicaciones, como el hepatocarcinoma. La mayoría de los pacientes afectados no progresará a la fibrosis avanzada/cirrosis. A pesar de esto, se ha descripto que la hepatopatía es la tercera causa de muerte entre los pacientes con HGNA, luego de las enfermedades cardiovasculares y las malignas. Entre la enorme cantidad de afectados, lo más importante es identificar a los que están en riesgo de evolución a la cirrosis o sus complicaciones y conocer las opciones de diagnóstico y tratamiento. En esta Guía organizada por la Asociación Argentina para el Estudio de las Enfermedades del Hígado se revisan las definiciones, los aspectos epidemiológicos, la historia natural y un enfoque práctico sobre algoritmos posibles para estimar la gravedad de la hepatopatía en cada caso, además de analizar los avances en el tratamiento y recomendaciones para el seguimiento. Es importante señalar que no se han publicado datos sobre incidencia o prevalencia de la enfermedad en población general de Argentina, y se alienta a la realización de los mismos.. Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease worldwide, with an estimated global prevalence of approximately 25%, that is much higher in patients with overweight, obesity and type 2 diabetes. NAFLD is considered as the hepatic manifestation of metabolic syndrome. It has a wide spectrum, from simple steatosis to steatohepatitis, fibrosis, cirrhosis and its complications, such as hepatocellular carcinoma. Most of the affected patients will not evolve to advanced fibrosis or cirrhosis. Despite this, it has been described that the hepatic disease is the third cause of death among patients with nonalcoholic fatty liver, after cardiovascular and malignant diseases. Among the huge number of patients affected, the main challenge is to identify those who are at risk of developing cirrhosis or its complications and to recognize the diagnostic and treatment options. In this Guideline, endorsed by the Argentine Association for the Study of Liver Diseases, the definitions, epidemiological aspects, natural history and a practical approach to possible algorithms to estimate the severity of liver disease in the individual patient are reviewed; in addition to analyzing advances in treatment and proposing recommendations for follow-up. It is important to note that no data on the incidence or prevalence of the disease have been published in the general population of Argentina, and it is encouraged to carry them out.Fil: Fassio, Eduardo. Hospital Nacional Profesor Alejandro Posadas; ArgentinaFil: Dirchwolf, Melisa. Hospital Privado de Rosario; ArgentinaFil: Barreyro, Fernando Javier. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Adrover, Raúl. No especifíca;Fil: Alonso, M. Inés. No especifíca;Fil: Amante, Marcelo. No especifíca;Fil: Ameigeiras, Beatriz. No especifíca;Fil: Barreyro, Fernando J.. No especifíca;Fil: Benavides, Javier. No especifíca;Fil: Bessone, Fernando. No especifíca;Fil: Cairo, Fernando. No especifíca;Fil: Camino, Alejandra. No especifíca;Fil: Cañero Velasco, M. Cristina. No especifíca;Fil: Casciato, Paola. No especifíca;Fil: Cocozzella, Daniel. No especifíca;Fil: Daruich, Jorge. No especifíca;Fil: De Matteo, Elena. No especifíca;Fil: Dirchwolf, Melisa. No especifíca;Fil: Fassio, Eduardo. No especifíca;Fil: Fernández, José Luis. No especifíca;Fil: Fernández, Nora. No especifíca;Fil: Ferretti, Sebastián. No especifíca;Fil: Figueroa, Sebastián. No especifíca;Fil: Galoppo, Marcela. No especifíca;Fil: Godoy, Alicia. No especifíca;Fil: González Ballerga, Esteban. No especifíca;Fil: Graffigna, Mabel. No especifíca;Fil: Guma, Carlos. No especifíca;Fil: Lagues, Cecilia. No especifíca;Fil: Marino, Mónica. No especifíca;Fil: Mendizábal, Manuel. No especifíca;Fil: Mesquida, Marcelo. No especifíca;Fil: Odzak, Andrea. No especifíca;Fil: Peralta, Mirta. No especifíca;Fil: Ridruejo, Ezequiel. No especifíca;Fil: Ruffillo, Gabriela. No especifíca;Fil: Sordá, Juan A.. No especifíca;Fil: Tanno, Mario. No especifíca;Fil: Villamil, Alejandra. No especifíca;Fil: Colombato, Luis. No especifíca;Fil: Fainboim, Hugo. No especifíca;Fil: Gadano, Adrián. No especifíca;Fil: Galoppo, Cristina. No especifíca;Fil: Villamil, Federico. No especifíca

Enhancer decommissioning by Snail1-induced competitive displacement of TCF7L2 and down-regulation of transcriptional activators results in EPHB2 silencing

Transcriptional silencing is a major cause for the inactivation of tumor suppressor genes, however, the underlying mechanisms are only poorly understood. The EPHB2 gene encodes a receptor tyrosine kinase that controls epithelial cell migration and allocation in intestinal crypts. Through its ability to restrict cell spreading, EPHB2 functions as a tumor suppressor in colorectal cancer whose expression is frequently lost as tumors progress to the carcinoma stage. Previously we reported that EPHB2 expression depends on a transcriptional enhancer whose activity is diminished in EPHB2 non-expressing cells. Here we investigated the mechanisms that lead to EPHB2 enhancer inactivation. We show that expression of EPHB2 and SNAIL1 - an inducer of epithelial-mesenchymal transition (EMT) - is anti-correlated in colorectal cancer cell lines and tumors. In a cellular model of Snail1-induced EMT, we observe that features of active chromatin at the EPHB2 enhancer are diminished upon expression of murine Snail1. We identify the transcription factors FOXA1, MYB, CDX2 and TCF7L2 as EPHB2 enhancer factors and demonstrate that Snail1 indirectly inactivates the EPHB2 enhancer by downregulation of FOXA1 and MYB. In addition, Snail1 induces the expression of Lymphoid enhancer factor 1 (LEF1) which competitively displaces TCF7L2 from the EPHB2 enhancer. In contrast to TCF7L2, however, LEF1 appears to repress the EPHB2 enhancer. Our findings underscore the importance of transcriptional enhancers for gene regulation under physiological and pathological conditions and show that SNAIL1 employs a combinatorial mechanism to inactivate the EPHB2 enhancer based on activator deprivation and competitive displacement of transcription factors

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Terapéutica futura

..