Quercetin and resveratrol are associated with the downregulation of TNFalpha/NF-kB/inos axis-mediated acute liver injury in rats induced by paracetamol poisoning / La quercetina y el resveratrol están asociados con la regulación decreciente de la lesión hepática aguda mediada por el eje TNF-alfa/NF-kB/inos en ratas inducida por envenenamiento con paracetamol

SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.

El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.

Reacción a fármacos con eosinofilia y síntomas sistémicos (DRESS) / Drug reaction with eosinophilia and systemic symptoms (DRESS)

La reacción a fármacos con eosinofilia y síntomas sistémicos (del acrónimo en inglés DRESS: drug reaction with eosinophilia and systemic symptoms) o síndrome de hipersensibilidad inducida por fármacos (del acrónimo en inglés DIHS: drug induced hypersensitivity syndrome), es una reacción adversa a fármacos (RAF) grave e infrecuente. Los mecanismos involucrados en su fisiopatogenia incluyen diversas alteraciones de las enzimas metabolizadoras de fármacos, con la consecuente acumulación de metabolitos reactivos, la reactivación secuencial de virus de la familia del herpes, la predisposición genética asociada a ciertos alelos de antígenos leucocitarios humanos (HLA) y una respuesta de hipersensibilidad retardada de tipo IV. En la actualidad, se han ido incorporando nuevos fármacos responsables de este cuadro como medicamentos biológicos, inmunosupresores y quimioterápicos. La presentación clínica del DRESS es variable. Tiene una morbimortalidad alta y supone costos elevados en la atención médica. Su tratamiento consiste, en primer lugar, en la suspensión de los fármacos causales o sospechosos de desencadenar el síndrome. Luego, según la gravedad del cuadro, se pueden indicar corticosteroides sistémicos o inmunoglobulina (IGIV) combinada con corticosteroides, plasmaféresis, ciclosporina, micofenolato de mofetilo y rituximab. El objetivo de este trabajo fue realizar una revisión sobre el DRESS y destacar los aspectos nuevos y relevantes de los últimos 5 años.

Drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), is a serious and rare adverse drug reaction. Among the mechanisms involved in its pathophysiology, there are various alterations in drugmetabolizing enzymes with the consequent accumulation of reactive metabolites, sequential reactivation of viruses of the herpes family, genetic predis-position associated with certain HLA, and a type IV hypersensitivity response. Currently, new drugs responsible for this pathology have been incorporated, such as biologicals, immunosuppressants and chemotherapy. The clinical presentation of DRESS is variable. It has a high morbidity and mortality and involves high costs in medical care. Its treatment consists, in the first place, in the suspension of the causal or suspected drugs. Then, depending on severity, systemic corticosteroids or IVIG combined with corticosteroids, plasmapheresis, cyclosporine, mycophenolate mofetil, and rituximab may be indicated.The objective of this work was review DRESS and highlight the new and relevant aspects of the last 5 years.

Protective effect of dietary vitamin E (alpha; Tocopherol) on artemisinin induced oxidative liver tissue damage in rats / Efecto protector de la vitamina E en la dieta (alfa; tocoferol) sobre el daño oxidativo del tejido hepático inducido por artemisinina en ratas

This experiment was designed to study the effects of oral administration of artemether which is the most rapid-acting class of antimalarial drugs and the possible protective effect of vitamin E taken with it on the liver of albino rats. A total of twenty-four adult male albino rats were used in this study and were divided into four groups. Group one served as a control and rats in group two exposed to oral intake of artemether daily for fifteen days. The third and fourth groups treated with artemether plus low and high doses of vitamin E respectively. At the end of the experiment, the rats were sacrificed, and the livers were obtained and processed for histological, biochemical and statistical studies. Histological study of the hepatocytes of rats exposed to artemether showed nearly complete disintegration of most cellular contents except few numbers of mitochondria and rough endoplasmic reticulum. Also, the cytoplasm of these cells had few lysosomes, many vacuoles and irregular nuclei with abnormal distribution of chromatin and were shown. The hepatic sinusoids were dilated and filled with blood and vacuoles and bile ductules were abnormal in its structure. Treatment with low and high doses of vitamin E in concomitant with artemether ameliorated the hepatic histopathological lesions and its parenchyma attained nearly normal structure. As far as biochemical changes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats treated with artemether were significantly elevated as compared to the control. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were significantly increased in the liver in rats treated with artemether. However, vitamin E ameliorated the rise in ALT and AST with decreased MDA concentration and levels of SOD as compared to the corresponding artemether group values. Results of the present suggest that artemether has a harmful and stressful effect on hepatic tissue and the treatment with vitamin E may alleviate this toxicity.

Este experimento fue diseñado para estudiar los efectos de la administración oral de arteméter, la clase de medicamentos antipalúdicos de acción rápida, y el posible efecto protector de la vitamina E en el hígado de ratas albinas. Se utilizaron un total de 24 ratas albinas machos adultas y se dividieron en cuatro grupos. El grupo uno sirvió como control y las ratas en el grupo dos recibieron la dosis oral de arteméter diariamente durante 15 días. Los grupos tres y cuatro fueron tratados con arteméter, más dosis bajas y altas de vitamina E, respectivamente. Al final del experimento, se sacrificaron las ratas y se obtuvieron y procesaron los hígados para estudios histológicos, bioquímicos y estadísticos. El estudio histológico de los hepatocitos de ratas expuestas a arteméter mostró una desintegración casi completa de la mayoría de los contenidos celulares, excepto algunos mitocondrias y retículo endoplásmico rugoso. Además, el citoplasma de estas células tenía pocos lisosomas, muchas vacuolas y núcleos irregulares con distribución anormal de cromatina. Los sinusoides hepáticos estaban dilatados y llenos de sangre y vacuolas, y los conductos biliares tenían una estructura anormal. El tratamiento con dosis bajas y altas de vitamina E en forma concomitante con arteméter mejoró las lesiones histopatológicas hepáticas y su parénquima alcanzó una estructura casi normal. En cuanto a los cambios bioquímicos, la alanina aminotransferasa (ALT) y la aspartato aminotransferasa (AST) en ratas tratadas con arteméter se elevaron significativamente en comparación con el control. Los niveles de superóxido dismutasa (SOD) y malondialdehído (MDA) aumentaron significativamente en el hígado en ratas tratadas con arteméter. Sin embargo, la vitamina E mejoró el aumento de ALT y AST con una disminución de la concentración de MDA y los niveles de SOD en comparación con los valores correspondientes del grupo de arteméter. Los resultados del presente estudio sugieren que el arteméter tiene un efecto dañino y estresante sobre el tejido hepático y el tratamiento con vitamina E puede aliviar esta toxicidad.

Vitamin C administration attenuated artemether induced hepatic injury in rats / La aAdministración de vitamina C atenúa la lesión hepática inducida por artemeter en ratas

This research was designed to investigate the potential protective effect of vitamin C supplementation against hepatocyte ultrastructural alterations induced by artemether (antimalarial drug) administration. Twenty-four adult male albino rats were used in this study and were divided into four groups (n=6). Group I served as a control and rats in group II administrated artemether (4 mg/kg B.W) orally for three consecutive days. Group III administered artemether plus a low dose of vitamin C (2.86 mg/kg/l water) while group IV received artemether plusa high dose of vitamin C (8.56 mg/kg). At the end of the experimental period (14 days), the harvested liver tissues were examined by transmission electron microscopy (TEM), and blood samples were assayed for biomarkers of liver injury and oxidative stress. Artemether significantly (p<0.05) augmented biomarkers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and oxidative stress such as superoxide dismutase (SOD), Glutathione Peroxidase (GPX), and caused degeneration and damage of the rough endoplasmic reticulum and disrupted mitochondria. The blood sinusoids were also damaged with distortion of their canaliculi. Administration of vitamin C showed improvement of liver biomarkers, and liver parenchyma, especially in a high dose of vitamin C.We concludes that vitamin C is a partial protective agent against artemether-induced liver injury.

Esta investigación fue diseñada para investigar el posible efecto protector de la vitamina C contra las alteraciones ultraestructurales de los hepatocitos, inducidas por la administración de arteméter (medicamento antipalúdico). En el estudio se utilizaron 24 ratas albinas macho adultas y se dividieron en cuatro grupos (n = 6). El grupo I fue designado como control y las ratas en el grupo II se adminstró Arteméter (4 mg / kg de peso corporal) por vía oral durante tres días consecutivos. En el grupo III se administró arteméter, además de una dosis baja de vitamina C (2,86 mg / kg / l de agua) mientras que el grupo IV recibió arteméter más una dosis alta de vitamina C (8,56 mg / kg). Al final del período experimental (14 días), los tejidos hepáticos recolectados se examinaron por microscopía electrónica de transmisión (MET), y las muestras de sangre se analizaron en busca de biomarcadores de daño hepático y estrés oxidativo. El arteméter aumentó significativamente (p <0,05) los biomarcadores de daño hepático como alanina aminotransferasa (ALT), aspartato aminotransferasa (AST) y estrés oxidativo como superóxido dismutasa (SOD), glutatión peroxidasa (GPX) y causó degeneración y daño de la retículo endoplásmico rugoso y mitocondrias alteradas. Los sinusoides sanguíneos también fueron dañados con la distorsión de sus canalículos. La administración de vitamina C mostró una mejoría de los biomarcadores hepáticos y el parénquima hepático, especialmente en una dosis alta de vitamina C. Concluimos que la vitamina C es un agente protector parcial contra la lesión hepática inducida por arteméter.

Suppression of hepatic apoptosis induced by acetaminophen using a combination of resveratrol and quercetin: an association of oxidative stress and interleukin-11 / Suspensión de la apoptosis hepática inducida por acetaminofén mediante una combinación de resveratrol y quercetina: una asociación de estrés oxidativo e interleucina-1

We sought to determine whether the combined polyphenolic compounds, resveratrol and quercetin can substantially protect against modulation of hepatic biomarkers of apoptosis and survival, p53-Bax axis and B-cell lymphoma 2 (Bcl-2) in an animal model of acetaminophen-induced acute liver injury via the association of oxidative stress and interleukin-11 (IL-11). The model group of rats received a single dose of acetaminophen (2 g/kg), whereas the protective group of rats was pre-treated for 7 days with combined doses of resveratrol (30 mg/kg) and quercetin (50 mg/kg) before being given a single dose of acetaminophen. All rats were then sacrificed 24 hours post acetaminophen ingestion. Acetaminophen overdose induced acute liver injury as demonstrated by profound liver parenchymal damage and increased levels of the liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Acetaminophen significantly (p<0.05) modulated malondialdehyde (MDA), p53, apoptosis regulator Bax, Bcl-2, IL-11, interleukin-6 (IL-6), ALT, AST, superoxide dismutase (SOD), and glutathione peroxidase (GPx), which were significantly protected by resveratrol plus quercetin. We further demonstrated a significant (p<0.01) correlation between IL-11 scoring and the levels of p53, Bax, Bcl-2, and MDA. Thus, resveratrol plus quercetin effectively protect against acetaminophen-induced apoptosis, which is associated with the inhibition of oxidative stress and IL-11.

En el estudio se intentó determinar si los compuestos polifenólicos combinados, el resveratrol y la quercetina pueden proteger sustancialmente contra la modulación de los biomarcadores hepáticos de apoptosis y supervivencia, el eje p53-Bax y el linfoma de células B 2 (Bcl-2) en un modelo animal de lesión hepática aguda inducida por acetaminofén, a través de la asociación del estrés oxidativo y la interleucina-11 (IL-11). El grupo modelo de ratas recibió una dosis única de acetaminofén (2 g / kg), mientras que el grupo protector de ratas fue tratado durante 7 días con dosis combinadas de resveratrol (30 mg / kg) y quercetina (50 mg / kg) antes de recibir una dosis única de acetaminofén. Todas los animales fueron sacrificados 24 horas después de la ingestión de acetaminofén. La sobredosis de acetaminofén indujo una lesión hepática aguda, como se observó en el daño profundo del parénquima hepático y el aumento de los niveles de las enzimas en la lesión hepática, alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST). Acetaminofén moduló significativamente (p <0.05) malondialdehído (MDA), p53, regulador de apoptosis Bax, Bcl2, IL-11, interleucina-6 (IL-6), ALT, AST, superóxido dismutasa (SOD) y glutatión peroxidasa ( GPx), los que se encontraron significativamente protegidos por el resveratrol y quercetina. Además se determinó una correlación significativa (p <0.01) entre la puntuación de IL-11 y los niveles de p53, Bax, Bcl-2 y MDA. En conclusión, el resveratrol más la quercetina protegen de manera efectiva contra la apoptosis inducida por acetaminofén, asociada con la inhibición del estrés oxidativo y la IL-11.

Implicaciones hepáticas en la pandemia por COVID-19 / Liver implications during the COVID-19 Pandemic

La infección generada por el coronavirus, denominado SARS-CoV-2, llamada coronavirus disease 2019(COVID-19), surgió en China a finales de diciembre de 2019. Actualmente ha sido categorizada como una pandemia por la Organización Mundial de la Salud (OMS). Se han documentado alteraciones de pruebas hepáticas, sin embargo, los estudios se han enfocado en los efectos cardíacos, pulmonares y renales de esta infección. La alteración de pruebas hepáticas en el contexto de COVID-19 puede ser consecuencia de hepatitis viral, toxicidad farmacológica, inflamación o choque. También se considera como un marcador de pronóstico y gravedad de la enfermedad. El impacto de la infección por SARS-CoV-2 en pacientes con enfer-medad hepática preexistente o receptores de trasplante hepático no es claro, y se plantean distintas hipótesis sobre mayor o menor riesgo de enfermedad grave y de descompensación de la enfermedad de base.(AU)

The infection generated by the novel coronavirus SARS-CoV-2, named Coronavirus Disease 2019 (COVID-19) emerged late December of 2019 in China. It is currently categorized as a pandemic by the World Health Organization. Studies have focused on cardiac, pulmonary, and renal effects of this infection, but liver test abnormalities have also been documented. This alteration may be a consequence of viral hepatitis, phar-macological toxicity, inflammation, or shock. It is also considered a marker of prognosis and severity of the disease. The impact of SARS-CoV-2 infection in patients with pre-existing liver disease or liver transplant recipients is unclear, and different hypotheses exist regarding the higher or lower risk of severe disease and decompensation of the underlying disease.

Productos de tabaco calentado con especial referencia a IQOS / Heated tobacco products with special reference to IQOS

Los Productos de Tabaco Calentado (PTC) son nuevos dispositivos de consumo de tabaco que se presentan como un producto de reducción del daño. El más difundido es IQOS de Philip Morris. En el aerosol de IQOS se detectan sustancias tóxicas en menor cantidad y concentración que las detectadas en el humo del cigarrillo convencional, a excepción de algunas. Estas sustancias son capaces de producir enfermedad, con alteración de las células del epitelio bronquial y del endotelio vascular y podría producir nuevos daños, como hepato-toxicidad. La cantidad de nicotina de IQOS es muy similar a los cigarrillos convencionales, por lo que es tan adictivo como el cigarrillo normal. La concentración de sustancias tóxicas emitidas al medio ambiente es menor que las del cigarrillo convencional, pero hay riesgo para la salud de los no fumadores expuestos. La mayoría de las personas usan los PTC como complemento a los cigarrillos convencionales, no como alternativa, transformándose en fumadores duales. IQOS puede crear nuevas generaciones adictas a la nicotina, además de renormalizar el consumo de tabaco en la sociedad. Muchas Sociedades Médicas de Enfermedades Respiratorias en el mundo se han manifestado en contra del uso de los PTC, y han propuesto que deben regirse bajo las mismas políticas regulatorias que se aplican a todos los productos de tabaco, en línea con lo establecido por el Convenio Marco de Control del Tabaco de la OMS.

Heated Tobacco Products (HTP) are new tobacco consumption devices that are presented as a harm reduction product. The most widespread is IQOS by Philip Morris. In the IQOS aerosol, toxic substances are detected in a smaller amount and concentration than those detected in conventional cigarettes, with the exception of some of them. These substances are able of inducing disease. They could modify bronchial epithelial cells and vascular endothelium and could cause additional damages, such as hepatotoxicity The amount of nicotine in IQOS is very similar to conventional cigarettes, so it is as addictive as a normal cigarette. The concentration of toxic substances emitted to the environment is lower than those of conventional cigarettes, but there is a health's risk of exposed non-smokers. Most people use HTP as a complement to conventional cigarettes, not as an alternative, becoming dual smokers. IQOS can create new generations addicted to nicotine, in addition to renormalize the tobacco's use in society. Many Medical Societies of Respiratory Diseases around the world have manifested against the use of HTP, and have proposed that they should be subject to the same regulatory policies that applied to all tobacco products, in line with the WHO Framework Convention on Tobacco Control.

Immunohistopathological and Biochemical Study of the Effects of Dead Nettle (Urtica Dioica) Extract on Preventing Liver Lesions Induced by Experimental Aflatoxicosis in Rats / Estudio inmunohistopatológico y bioquímico de los efectos del extracto de la ortiga mayor (Urtica dioica) en la prevención de lesiones hepáticas inducidas por aflatoxicosis experimental en ratas

ABSTRACT Objective: Aflatoxicosis is a mycotoxicosis infection with an acute or chronic course that forms due to aflatoxins (AFs) in humans and animals. Aflatoxins primarily affect the liver and can lead to histopathological necrosis, fibrosis and hepatocarcinogenesis of the organ. This paper studied the preventive effects of dead nettle leaf (Urtica dioica leaf; UDL) extract on liver lesions that were induced by experimental aflatoxicosis in rats. Methods: A total of 30 rats were separated into three groups of 10 rats each. Experimental group A (control) received normal rat food, experimental group B (AFB1) received 2 mg/kg of AF, and experimental group C (AFB1 + UDL extract) received 2 mg/kg of AF + 2 ml/rat/day of UDL extract. After three months of experimentation, blood and tissue samples were taken from the rats by necropsy to perform chemical and histopathological analyses. Results: According to the biochemical and histopathological findings, antioxidant system activity increased and lipid peroxidation and liver enzyme levels decreased in the group that received UDL extract. Conclusion: The extract of UDL had hepatoprotective effects against aflatoxicosis.

RESUMEN Objetivo: La aflatoxicosis es una infección por micotoxicosis con un curso agudo o crónico producido por aflatoxinas (AF) en seres humanos y animales. Las aflatoxinas afectan principalmente el hígado y pueden conducir a necrosis histopatológica, fibrosis o hepatocarcinogénesis del órgano. En este trabajo se estudiaron los efectos preventivos del extracto de la hoja de ortiga mayor (Urtica dioica l; UDL) sobre las lesiones hepáticas inducidas por aflatoxicosis experimental en ratas. Métodos: Un total de 30 ratas se separaron en tres grupos de 10 ratas cada una. EL grupo experimental A (control) recibió comida normal de ratas; el grupo experimental B (AFB1) recibió 2 mg/kg de AF; y el grupo experimental C (AFB1 + extracto de UDL) recibió 2 mg/kg de AF + 2 ml/rata/día de extracto de UDL. Después de tres meses de experimentación, se tomaron muestras de sangre y tejidos de las ratas en una necropsia encaminada a realizar análisis químicos e histopatológicos. Resultados: Según los hallazgos bioquímicos e histopatológicos, la actividad del sistema antioxidante aumentó, y la peroxidación del lípido y los niveles de la enzima del hígado disminuyeron en el grupo que recibió el extracto de UDL. Conclusión: El extracto de UDL tuvo efectos hepatoprotectores contra la aflatoxicosis.

Aspectos epidemiológicos, clínico-patológicos e diagnóstico precoce da seneciose bovina no Oeste do Rio Grande do Sul / Epidemiological, clinical and pathological aspects and early diagnosis of bovine seneciosis in the Western region of Rio Grande do Sul, Brazil

A ingestão de Senecio spp. (maria-mole) é, possivelmente, a principal causa de morte de bovinos por agentes tóxicos nas regiões central e sul do Rio Grande do Sul. Ao considerar a limitação de informações acerca dessa condição no Oeste do Rio Grande do Sul, esse trabalho objetiva descrever os principais aspectos epidemiológicos e clínico-patológicos da seneciose em bovinos nessa região. O estudo foi realizado por meio da aplicação de questionários em 16 propriedades rurais de municípios da região que apresentaram casos suspeitos da intoxicação em bovinos, de agosto de 2011 a março de 2014. Durante as visitas as propriedades foram coletadas plantas do gênero Senecio para identificação botânica, bem como se procedeu a coleta de fragmentos de fígado através de biópsia transtorácica para confirmação da intoxicação. As espécies de Senecio mais frequentes nas propriedades foram S. brasiliensis e S. heterotrichius. De um total de 88 bovinos, de nove propriedades distintas, que apresentaram falha no ganho de peso, 69 animais (aproximadamente 80%) foram positivos para seneciose crônica por apresentarem lesões características da intoxicação, tais como fibrose periportal (78% dos casos), megalocitose (76% dos casos) e proliferação de ductos biliares (68% dos casos), classificadas entre discretas e acentuadas. O trabalho confirmou a ocorrência da doença, mesmo em bovinos sem sinais clínicos evidentes. Os resultados obtidos nessas avaliações foram fundamentais para orientar proprietários e técnicos quanto às principais características da doença e às formas de controle a serem adotadas. O emprego da biópsia hepática possibilitou o diagnóstico precoce da intoxicação e auxiliou os criadores quanto ao descarte mais criterioso de bovinos e a real situação da intoxicação no rebanho, minimizando as perdas econômicas.(AU)

The ingestion of Senecio spp. (ragwort) is perhaps the leading cause of death of cattle in central and southern Rio Grande do Sul, Brazil. Considering the limited information about this condition in the Western region of Rio Grande do Sul, Brazil, this paper describes main epidemiological clinical and pathological aspects of seneciosis in cattle. The assessments were made through questionnaires on 16 rural properties which had suspected cases of poisoning in cattle, from August 2011 to March 2014. During the visits were evaluated epidemiological aspects of poisoning and performed sample collection of Senecio plants for botanical identification, as well as collection of liver samples using transthoracic biopsy for confirmation of the poisoning. Senecio species most common on farms were S. brasiliensis and S. heterotrichius. From 88 cattle that failed to thrive on nine different farms, 69 animals (about 80%) were positive for chronic seneciosis with periportal fibrosis (78% of cases), megalocytosis (76% of cases) and with bile duct proliferation (68% of cases). Lesions were classified as mild, moderate or marked. The current study confirms the occurrence of this poisoning, even in cattle without evident clinical signs. The use of liver biopsy enabled the early diagnosis of poisoning and helped farmers carefully to dispose affectd cattle, as well as to recognize the real situation of poisoning in the herd and minimize economic losses.(AU)

Fatores associados às reações adversas no tratamento da Tuberculose no município de Dourados, MS / Factors associated with adverse reactions in the treatment of tuberculosis in Dourados, MS

A tuberculose (TB) continua sendo um grave problema de saúde, mesmo existindo tratamento efetivo para o seu controle. A dificuldade de controle da doença está na estreita relação com fatores sociodemográficos, como a miséria, a desnutrição, as condições de moradia em aglomeração e insalubridade. Os esquemas de medicamentos antiTB com dosagens corretas, tempo de uso adequado e adesão integral ao tratamento são os princípios básicos para se alcançar a cura. A associação de medicamentos antiTB acarretam inúmeras Reações Adversas (RAs) que são classificadas, quanto à gravidade, em reações adversas maiores e menores. Objetivo: Estimar a frequência de ocorrência e os fatores associados às RAs no tratamento de TB, no Município de Dourados, MS. Métodos: Trata-se de um estudo epidemiológico prospectivo, de caráter descritivo e analítico. A frequência e o momento da ocorrência das reações adversas no grupo de pacientes indígenas e não indígenas foram analisados por meio de questionário com perguntas sobre os sintomas autorreferidos e exames de avaliação de função hepática, coletados em quatro momentos distintos durante o tratamento (0-15 dias; 30 dias; 60 dias; 180 dias). A análise das alterações nos exames de avaliação hepática foi realizada pelas transaminases AST e ALT. Realizou-se a avaliação de causalidade por meio do algoritmo de Naranjo. O instrumento CAGE foi aplicado aos pacientes para investigar o uso abusivo de álcool. Os dados foram analisados usando-se a distribuição de frequências, teste do χ2 e regressão logística uni e bivariada. Resultados: Dos 117 pacientes acompanhados no seguimento, 66,7 por cento eram do sexo masculino, 35,3 por cento eram indígenas. A média geral de RAs até o final de dois meses de tratamento foi de cinco reações por paciente no grupo de não indígenas, e quatro reações por pessoa no grupo de indígenas...

Tuberculosis (TB) remains a serious health problem even existing effective treatment for its control. The difficulty of controlling the disease is in close relation to sociodemographic factors, such as poverty, malnutrition, overcrowding and unsanitary conditions. Treatment regimens of antituberculosis with correct dosage, time and proper use and full adherence to treatment are the basics to achieve healing. The association of anti-TB drugs causes numerous adverse drugs reactions (ADRs). ADRs are classified as minor or major adverse reactions. Objective: To estimate the frequency of occurrence and the factors associated with ADRs to antituberculosis drugs, in the city of Dourados/MS. Methods: It's a prospective epidemiological study of descriptive and analytical character. The frequency and time of occurrence of adverse drugs reactions in the group of indigenous and non-indigenous patients were analyzed by a questionnaire with on self-reported questions about symptoms and assessment of liver function tests, collected at four different times during the treatment (0-15 days, 30 days, 60 days; 180 days). The analysis of changes in liver function tests were performed by transaminases AST and ALT. The causality assessment of adverse drugs reactions was performed using the Naranjo algorithm. The CAGE instrument was administered to investigate alcohol abuse among patients. Data were analyzed using frequency distribution, χ2 test and univariate and bivariate logistic regression. Results: Of the 117 patients treated for active TB, 66.7 percent were male, 35.3 percent were indigenous...

Riesgos de la herbolaria: reporte de un caso de hepatitis por cardo santo (Argemone mexicana L) / Risks of herbalism: a case report of Mexican poppy (Argemone mexicana L) induced liver toxicity

El consumo cada vez mayor de productos de la medicina alternativa y complementaria ha permitido reconocer con más frecuencia los efectos deletéreos asociados y las interacciones que estos productos pueden ocasionar. Así en la literatura médica encontramos casos reportados de toxicidad hepática con Aloe (sábila), Camellia sinensis (té verde), Rhammus purshianus (cáscara sangrada), Aesculus hippocastanum (castaño de indias) y Valeriana officinalis (valeriana), entre otros. El presente caso trata sobre una paciente femenina que consumió en dos ocasiones cardo santo (Argemone mexicana L), con intervalo de un año entre un evento y otro. En ambas oportunidades desarrolló un cuadro de diarrea, ictericia y ataque al estado general con alteración en las pruebas de función hepática. Se excluyeron otras causas de hepatopatía. Se utilizaron escalas para evaluar efectos adversos en el hígado relacionados con medicamentos. Se recabó la información del expediente clínico de la paciente y se revisó la bibliografía relacionada con el tema. Se concluyó que existe la posibilidad de lesión hepática relacionada con el consumo de Argemone mexicana L, al menos en esta paciente.

The increasing consumption of alternative medicines has lead to a greater awareness about the deleterious effects and interactions that these products can induce. Consequently, medical literature reports liver toxicity from Aloe, Camellia sinensis (green tea), Rhammus purshianus, Aesculus hippocastanum (buckeye) and Valeriana officinalis (valerian), among others. This article reports a female patient who twice consumed Mexican poppy (Argemone mexicana L) with a one-year interval between ingestions. Both times she developed diarrhea, jaundice and general malaise with impaired liver function tests. Other causes of liver disease were ruled out. Questionnaires were used to assess the possibility of drug-induced liver damage. Clinical information was collected from the patient's medical record and the literature on the subject was reviewed. We conclude that, at least in this case, the most likely cause of liver toxicity was Argemone mexicana L consumption.

Efeitos do consumo agudo e crônico de etanol sobre as funções mitocondriais: estudos em ratos Wistar (Rattus novergicus) / Effects of short and long-term ethanol consumption on mitochondrial functions: studies in Wistar rats (Rattus novergicus)

O número de indivíduos que sofrem com patologias associadas ao consumo abusivo de etanol tem aumentado significativamente no último século. Como consequência desse fato, os custos associados ao tratamento do alcoolismo, bem como das doenças associadas a ele também têm aumentado, onerando o sistema de saúde e se tornando um problema de saúde pública de grande relevância atualmente. Os mecanismos moleculares que desencadeiam muitas dessas doenças não estão completamente esclarecidos. O tecido hepático é o mais afetado pelo etanol e as mitocôndrias têm sido apontadas como alvos cruciais na toxicidade hepática induzida pelo álcool. Logo, o objetivo desse trabalho foi investigar como o consumo de etanol afeta o estado redox e o metabolismo mitocondriais no fígado. Ratos Wistar machos adultos jovens e de meia-idade receberam ad libitum solução alcoólica 25% (v/v) como única fonte de líquido. Os grupos controle receberam somente água. Ambos os grupos receberam ração ad libitum. Mitocôndrias hepáticas foram isoladas usando técnicas padrão. O consumo de ração e de líquidos foi significativamente menor em animais que ingeriram álcool, resultando em menor ganho de massa corpórea nos protocolos utilizados. As mitocôndrias dos animais que consumiram etanol apresentaram menores níveis de respiração em condição basal e quando energizadas com substratos respiratórios. A atividade e os níveis protéicos de citocromo c oxidase foi menor nos grupos tratados com etanol. Independente da duração do período de tratamento, mitocôndrias hepáticas de animais que ingeriram álcool foram menos susceptíveis à transição de permeabilidade mitocondrial induzida por cálcio, quando comparadas às mitocôndrias dos animais do grupo controle...

The number of people suffering from alcoholism has increased significantly over the last century. As a result, costs associated with treating the addiction itself as well as the associated pathologies have also increased, such that this is considered as public health issue. Furthermore, the molecular events leading to several of these diseases are not yet clearly understood. Hepatic tissue is the most affected by alcohol, and mitochondria have been suggested to be a crucial target in alcohol-induced liver toxicity. Thus, the aim of our study was to investigate how ethanol consumption affects the redox state and mitochondrial metabolism in the liver. Young adult and middle-aged male Wistar rats were given a 25 % (v/v) ethanol solution as the only source of drinking water. Control groups received water only. Liver mitochondria were isolated using standard techniques. Food and water intake was significantly lower in alcohol-drinking rats, resulting in lower weight gain during the treatment regimes. Mitochondria from the alcohol-drinking group had lower respiration under levels in basal condition, when energized by substrates feeding electrons into complexes I and IV. Cytochrome c oxidase activity and protein levels were lower in the alcohol group as well. Additionally, regardless of the length of the treatment, liver mitochondria from the alcohol-treated animals were more resistant to Ca2+-induced mitochondrial permeability transition (MPT), when compared to mitochondria from control animals. This effect was abrogated by oxidizing agents of pyridine nucleotides (acetoacetate, diamide or tert butylhydroperoxide) or in uncoupled mitochondria. We also found that liver mitochondria from the alcohol-drinking rats had a more reduced pyridine nucleotide pool and higher NAD(P)H/NAD(P)+ ratios. In addition, Nampt (an enzyme of the NAD+ synthetic pathway) protein levels did not differ after alcohol consumption. ..

Eficacia del ácido ursodesoxicólico en el tratamiento de la enfermedad hepática grasa no alcohólica / Efficacy of ursodeoxycholic acid in the treatment of nonalcoholic fatty liver disease

Introducción: La enfermedad hepática grasa no alcohólica (EHGNA), tiene una prevalencia del 10 % al 24 % en la población general, con una historia natural poco conocida para poder establecer sus opciones terapéuticas. El ácido ursodosoxicólico (AUDC) es una droga utilizada en enfermedades hepáticas colestásicas, la cual tiene un efecto citoprotector en la EHGNA, en donde el estrés oxidativo es uno de los mecanismos fisiopatológicos. Objetivos: evaluar la eficacia del AUDC para mejorar los valores de aminotransferasas (ALT) en un tiempo determinado. Pacientes y métodos: se realizó un estudio prospectivo, experimental, incluyendo aquellos sujetos con aumento de ALT que acudieron a la consulta de centro privado entre enero 2009 - diciembre 2011, se les indicó AUDC a 13 mg/Kg/día por 12 semanas. Para el análisis estadístico se utilizó la prueba de Kolmogorov- Smirnov con un nivel de significancia del 99 % y Chi2 con un nivel de significancia del 95 %. Resultados: del total de los casos n=53, 55 % (n=29) perteneció al sexo femenino con una media de edad de 47,1 años (DS ±13,7 años). Al comparar los promedios de ALT antes y después del tratamiento del total de la muestra, se obtuvo una media 122,3 U/L y 64,7 U/L respectivamente, siendo estas diferencias significativas (p<0,001). Al comparar según sexo, hubo diferencias significativas tanto para el femenino en los promedios ALT antes y después del tratamiento: 110,9 U/L y 53,13 U/L, como en el sexo masculino 136 U/L y 78,7 U/L respectivamente, p<0,001. Existe una relación entre las variables y tiempo de tratamiento, observándose diferencias significativas al comparar los valores de ALT a las 4,8 y 12 semanas con 34,8 %, 30 % y 80 % respectivamente, siendo mayor a las 12 semanas, p<0,05. Conclusión: en nuestro estudio se pudo determinar que el AUDC en un tiempo establecido, mostro ser eficaz para la reducción de los niveles de ALT.

The history natural is poorly unknown for focused therapeutic options. Ursodeoxycholic Acid (UDCA) has long been used in the chronic cholestatic liver diseases, in NALFD believed to have cytoprotective properties and may help to reduce oxidative stress. Objetive: to know the efficacy of UDCA for improvement the serum aminotransferase levels (ALT). Patients and Methods: a prospective, experimental study was performed between january 2009 and december 2011 all patients with elevated ALT were included received UDCA 13 mg/kg/daily for 12 weeks. Analyses were conducted using Kolmogorov-Smirnov and chi-squared test with p<0,001 and p<0,05 was considered as the level of significance respectively. Results: a total of 53 patients, 55 % were female with a mean of 47,1 years old (DS±13,7 years). To compare the mean of ALT among the patients underwent starting treatment before and after was 122,3 U/L y 64,7 U/L respectively and statistically significant p<0,001 and the mean of ALT female gender was rate of response showed difference in patients 110,9 U/L y 53,13 U/L and male gender was 136 U/L y 78,7 U/L before and after UDCA was statistically significant p<0,001. Rate of response did differ in patients treated with UDCA 4, 8 and 12 weeks was 34,8 %, 30 % y 80 % respectively being statistically significant p<0,05 % at 12 weeks. Conclusion: at the present study we determined that UDCA was effective, in a given time, for improvement the serum aminotransferase levels.

Hepatite aguda: como avaliar? / Acute hepatitis: how to evaluate?

Hepatite aguda define lesão hepática com inflamação do fígado com padrão histológico bem definido. Esses pacientes apresentam sintomas inespecíficos, como mal-estar, náuseas, vômitos e anorexia, com ou sem icterícia. Na maioria dos pacientes com elevação predominante de transaminases uma história clínica cuidadosa e um pequeno número de exames laboratoriais podem identificar a etiologia e definir tratamento específico subsequente, incluindo especialmente a investigação de hepatites virais, hepatotoxicidade induzida por drogas, hepatite autoimune e hepatite aguda alcoólica.

The acute hepatitis defines liver injury with inflammation of the liver histological pattern well defined. Such patients present with nonspecific symptoms such as malaise, nausea, vomiting, and anorexia, with or without jaundice. In most patients with the amino-transferase-predominant picture, careful history and examination and a small number of laboratory tests can identify the etiology and define subsequent management including in particular the investigation of viral hepatitis, drug-induced hepatoxicity, autoimmune hepatitis and acute alcoholic liver disease.

Osteodistrofia hepática / Hepatic osteodystrophy

Osteodistrofia hepática é distúrbio de mineralização óssea associada à doença hepática crônica, sendo a osteoporose, e mais raramente a osteomalácia, sua forma de apresentação clínica. Apesar de pouco diagnosticada e com prevalência de grande variação na literatura, na maioria das vezes, apresenta-se de forma assintomática e, quando não identificada, aumenta consideravelmente o risco de fratura e sequelas permanentes. Seu diagnóstico, portanto, requer alta suspeição e faz-se, na prática clínica, por meio da avaliação da densitometria óssea. De fisiopatogenia multifatorial, envolve fatores genético, ambiental e do próprio estado clínico-nutricional do paciente. Uma atenção maior deve ser despendida a hepatopatas desnutridos, com cirrose hepática avançada, doença colestática crônica e transplantados pelo maior risco de desmineralização óssea. Nesta revisão, será discorrido sobre o metabolismo fisiológico da síntese óssea e a fisiopatologia do distúrbio de mineralização óssea, desde mecanismos fisiopatogênicos na doença hepática crônica, seu diagnóstico e revisão da terapêutica atual empregada.

Hepatic osteodystrophy is a disorder of bone mineralization associated to liver disease, clinically manifested by osteoporosis and more rarely osteomalacia. Although seldomly diagnosed and varying greatly in literature, most of the time, it presents asymptomatically and, when it is not recognized, it enhances considerably the risk of fracture and permanent sequelae. Indeed it requires a high grade of suspicion and it is confirmed by means of bone densitometry evaluation in clinical practice. Presenting with a multifactorial physiopathology, it involves factors, such as genetical, environmental, and patient clinical-nutritional status. A greater attention must be spent on patients with liver disease, especially those malnourished, with advanced cirrhosis, chronic cholestatic disease, and transplanted, because of a higher risk of bone demineralization. In this data, it will be reviewed the bone synthesis metabolism and the physiopathology of bone mineralization disorder ? since fisiopatogenic mechanisms in chronic liver disease, diagnosis and recent therapeutic review employed.

Lesão hepática grave induzida por fármacos anticonvulsivantes: relato de casos / Serious liver injury induced by anticonvulsants drugs: case reports

JUSTIFICATIVA E OBJETIVOS: Inúmeros medicamentos empregados rotineiramente na prática médica podem apresentar como efeito adverso significativo a agressão hepática, manifestando-se, por vezes, com lesões graves irreversíveis, sendo possível causa de óbito em determinadas situações. O objetivo deste estudo foi relatar dois casos de pacientes que apresentaram hepatotoxicidade por fármacos anticonvulsivantes, suas consequências e possível prevenção. RELATO DOS CASOS: Caso 1: Paciente do sexo feminino, 12 anos, com história de epilepsia, em uso de carbamazepina (CBZ), haloperidol, clorpromazina e clobazan. Ao exame clínico apresentava-se sonolenta e confusa, com exames laboratoriais contendo dosagem de CBZ elevada e enzimas hepáticas alteradas. Apresentou piora progressiva com surgimento de icterícia, elevação de enzimas hepáticas e diminuição do nível de consciência. A paciente evoluiu com broncopneumonia, hemorragia pulmonar, insuficiência respiratória e óbito. Caso 2: Paciente do sexo masculino, 4 anos, em uso contínuo de depakene, foi encaminhado com quadro de sonolência, icterícia, diminuição do nível de consciência, náuseas e dor abdominal. Houve agravamento do quadro hemodinâmico, com abalos mioclônicos, choque hipovolêmico e óbito. Durante a internação apresentou elevação de enzimas hepáticas e, assim como no primeiro caso, as sorologias virais eram negativas e a tomografia de crânio não apresentava anormalidades. CONCLUSÃO: Nos últimos anos, lesões hepáticas induzidas por diferentes agentes têm sido cada vez mais observadas. E, progressivamente, a importância dada a esse fenômeno tem aumentado de maneira significativa. Sendo o fígado o principal órgão metabolizador corporal, é esperado um comprometimento proporcionalmente extenso à medida que um número crescente de substâncias farmacológicas é utilizado. Diante do exposto, destaca-se a importância do uso racional de interações medicamentosas, na tentativa de prevenir lesões possivelmente evitáveis.

BACKGROUND AND OBJECTIVES: Countless medicines employees routinely in medical practice can present as significant adverse effect the hepatic aggression, manifesting, sometimes, with serious irreversible injuries, being a possible cause of death in determined situations. The objective of this study was reported two cases of patients who presented hepatotoxicity by anticonvulsants, its consequences and possible prevention. CASE REPORTS: Case 1: Female patient, 12 years, with a history of epilepsy, in use of carbamazepine (CBZ), haloperidol, chlorpromazine and clobazam. On clinical examination the patient was drowsy and confused, with laboratory containing elevation of CBZ dosage and liver enzymes changed. There was progressive worsening, with appearance of jaundice, elevation of liver enzymes and decreased level of consciousness. The patient evolved with bronchopneumonia, pulmonary hemorrhage, respiratory failure and death.Case 2: Male patient, 4 years, in continuous use of depakene, was directed with drowsiness, jaundice, decreased level of consciousness, nausea and abdominal pain. There was aggravation of hemodynamic status, with myoclonic tremors, hypovolemic shock and death. During hospitalization in our department, presented liver enzymes elevated and, as in the first case, viral serology was negative and tomography of skull showed no abnormalities. CONCLUSION: In recent years, liver injury induced by different agents has been increasingly observed. And gradually, the importance given to this phenomenon has increased significantly. Being the liver the main metabolizing organ body is expected a proportionally extensive involvement as a growing number of pharmacological substances is used. Given the above, highlights the importance of rational use of drug interactions in an attempt to prevent possibly avoidable injuries.

Análisis del resultado de pruebas hepáticas en pacientes psoriáticos tratados con metotrexato: Estudio retrospectivo / Serum liver tests in patients treated with methotrexate: A retrospective analysis

Background: Methotrexate is one of the best systemic treatments for psoriasis. However it has significant adverse effects such as myelotoxicity and hepatotoxicity. Aim: To evaluate serum liver test in psoríatic patients treated with methotrexate. Material and Methods: Retrospective review of medical records of psoríatic patients treated with methotrexate between the years 2000 and 2005. All patients received a minimum of 7.5 mg weekly of methotrexate, for at íeast 4 weeks. Results: Sixty three patients were included. Mean cumulative dose of methotrexate was 576 mg. Thirty two percent had alterations in liver tests, but only 9 percent had values that duplicated the upper limit of normal range of aminotransferases or alkaline phosphatases or a serum bilirubin over 2 mg/dl. We did not find a direct relationship between the dose of methotrexate and the magnitude of liver test alterations. Only one patient exceeded 1.5 g as cumulative dose. A liver biopsy performed to him, did not show signs of fibrosis. Conclusions: This retrospective study does not show a direct relationship between weekly doses, cumulated dose and length of treatment with methotrexate, and the degree of alteration of serum liver tests.

Primeira injeção de drogas e hepatite C: achados preliminares / The first drug injection and hepatitis C: preliminary findings

Investigou-se o contexto da primeira injeção de drogas e sua possível associação com a infecção pelo vírus da hepatite C (HCV). Usuários de drogas injetáveis (UDI) – N=606 – foram recrutados em “cenas de uso” no Rio de Janeiro, Brasil. Os voluntários foram entrevistados e testados para a presença de anti-HCV. A utilização anterior, não injetável, da mesma droga injetada (basicamente cocaína) foi relatada por 92,0% dos UDI (último mês), administrada semanal/diariamente (86,2%). O primeiro injetador foi um amigo próximo (51,7%), utilizando uma seringa/agulha usada (51,5%), e as drogas foram obtidas como “presente” em 40,0% dos casos. Cerca de 68,0% dos UDI introduziram novos usuários: 88,1% iniciaram um a cinco outros indivíduos. A prevalência de anti-HCV foi menor entre injetadores que iniciaram o uso de drogas após 1980. Visando controlar a infecção pelo HCV nessa população, as estratégias voltadas à prevenção/redução de danos deveriam considerar distintos cenários e gerações de usuários, desde a primeira injeção...