Limited expression of TLR9 on T cells and its functional consequences in patients with nonalcoholic fatty liver disease

We demonstrated a limited expression of Toll-like receptor 9 (TLR9) and interferon gamma (IFN-γ) production by T cells in patients with simple steatosis (SS). The limited expression of TLR9 on T cells was directly associated with lower liver necroinflammatory activity and fibrosis, and lower antrophometric and biochemical alterations of nonalcoholic fatty liver disease. Besides, co-stimulation of T cell activation via TLR9 induced a limited number of IFN-γ-producing CD8+ T cells in SS patients. Accordingly, these patients showed a low frequency of circulating type 1 CD8+ cells whereas additional pro-inflammatory signals may be responsible for the higher frequency observed at baseline in the context of steatohepatitis.Fil: Alegre, Nadia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: García, Cecilia Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Billordo, Luis Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Ameigeiras, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Poncino, Daniel. Sanatorio Municipal Dr. Julio Méndez. Servicio de Gastroenterología; ArgentinaFil: Benavides, Javier. Hospital Británico de Buenos Aires; ArgentinaFil: Colombato, Luis. Hospital Británico de Buenos Aires; ArgentinaFil: Cherñavsky, Alejandra Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentin

Fatty liver disease, an emerging etiology of hepatocellular carcinoma in Argentina

AIM To investigate any changing trends in the etiologies of hepatocellular carcinoma (HCC) in Argentina during the last years. METHODS A longitudinal cohort study was conducted by 14 regional hospitals starting in 2009 through 2016. All adult patients with newly diagnosed HCC either with pathology or imaging criteria were included. Patients were classified as presenting non-alcoholic fatty liver disease (NAFLD) either by histology or clinically, provided that all other etiologies of liver disease were ruled out, fatty liver was present on abdominal ultrasound and alcohol consumption was excluded. Complete follow-up was assessed in all included subjects since the date of HCC diagnosis until death or last medical visit. RESULTS A total of 708 consecutive adults with HCC were included. Six out of 14 hospitals were liver transplant centers (n = 484). The prevalence of diabetes mellitus was 27.7%. Overall, HCV was the main cause of liver disease related with HCC (37%) including cirrhotic and non-cirrhotic patients, followed by alcoholic liver disease 20.8%, NAFLD 11.4%, cryptogenic 9.6%, HBV 5.4% infection, cholestatic disease and autoimmune hepatitis 2.2%, and other causes 9.9%. A 6-fold increase in the percentage corresponding to NAFLDHCC was detected when the starting year, i.e., 2009 was compared to the last one, i.e., 2015 (4.3% vs 25.6%; P < 0.0001). Accordingly, a higher prevalence of diabetes mellitus was present in NAFLD-HCC group 61.7% when compared to other than NAFLD-HCC 23.3% (P < 0.0001). Lower median AFP values at HCC diagnosis were observed between NAFLD-HCC and non-NAFLD groups (6.6 ng/mL vs 26 ng/mL; P = 0.02). Neither NAFLD nor other HCC etiologies were associated with higher mortality. CONCLUSION The growing incidence of NAFLD-HCC documented in the United States and Europe is also observed in Argentina, a confirmation with important Public Health implications.Fil: Piñero, Federico. Hospital Universitario Austral; Argentina. Sanatorio de la Trinidad San Isidro; ArgentinaFil: Pages, Josefina. Hospital Universitario Austral; ArgentinaFil: Marciano, Sebastián. Hospital Italiano; ArgentinaFil: Fernández, Nora. Hospital Británico de Buenos Aires; ArgentinaFil: Silva, Jorge. Provincia de San Juan. Hospital Rawson; ArgentinaFil: Anders, Margarita. Hospital Alemán; ArgentinaFil: Zerega, Alina. Sanatorio Allende; ArgentinaFil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Ameigeiras, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: D'amico, Claudia. Centro Especialidades Médicas Ambulatorias Mar del Plata; ArgentinaFil: Gaite, Luis. Clínica de Nefrología de Santa Fe; ArgentinaFil: Bermúdez, Carla. Hospital Italiano; ArgentinaFil: Cobos, Manuel. Hospital Alemán; ArgentinaFil: Rosales, Carlos. Provincia de San Juan. Hospital Rawson; ArgentinaFil: Romero, Gustavo. Gobierno de la Ciudad de Buenos Aires. Hospital de Gastroenterología "Dr. Carlos B. Udaondo"; ArgentinaFil: McCormack, Lucas. Hospital Alemán; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Reggiardo, Virginia. Gobierno de Santa Fe. Hospital Provincial del Centenario; ArgentinaFil: Colombato, Luis. Hospital Británico de Buenos Aires; ArgentinaFil: Gadano, Adrián Carlos. Hospital Italiano; ArgentinaFil: Silva, Marcelo. Hospital Universitario Austral; Argentin

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)

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

Historia natural de la Hepatitis C

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Hepatitis Crónica C. Primer Tratamiento

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Alterations in response to resistin induced oxidative stress in circulating leukocytes from patients with nonalcoholic fatty liver disease (NAFLD)

We previously demonstrated that Resistin (RES) decrease reactive oxygen species levels (ROS) in peripheral blood mononuclear cells (PBMC) in non-NAFLD, but not in NAFLD patients. To further evaluate RES effects on oxidative stress and on antioxidant defenses (Aox) in PBMC from NAFLD patients, PBMC were cultured in presence/absence of RES (20 ng/ml) for 24h. PBMC from NAFLD patients had higher baseline ROS levels (1353 ± 498 vs. 468 ± 89, vs. non-NAFLD cells). In addition, PBMC from NAFLD patients showed lower superoxide dismutase (SOD) and glutathione reductase (GRd) activities, and higher glutathione peroxidase activity (p <0.05) than non-NAFLD PBMC. 24h incubation with RES induced an increase in catalase and GRd activities (p<0.01), and a decrease in SOD activity (p< 0.05) and glutathione content (p<0.05) in non-NAFLD PBMC. However, RES could not modulate enzymatic activities in PBMC from NALFD patients. In conclusion, RES presence favored the decrease in ROS in non-NAFLD PBMC by modulating Aox enzymes and GSH redox state, but not in PBMC from NAFLD patients. Redox signaling alterations would favor the inflammatory state and the progression of NALFD. The regulatory mechanisms controlled by Res could be used as potential therapeutic targets in NAFLD patients.Fil: García, Cecilia Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Piotrowsky, Barbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Baz, Placida. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Benavidez, Javier. Hospital Británico de Buenos Aires; ArgentinaFil: Colombato, Luis. Hospital Británico de Buenos Aires; ArgentinaFil: Poncino, Daniel Alberto. Sanatorio Dr. “Julio Méndez”; ArgentinaFil: García, Daniel. Sanatorio Dr. “Julio Méndez”; ArgentinaFil: Fraga, César Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular. Universidad de Buenos Aires. Facultad Medicina. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Cherñavsky, Alejandra Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; Argentina2019 Annual Meeting “Redox homeostasis: from signaling to damage”FerraraItaliaSociety for Free Radical Research Europ