Esteatose hepática altera acúmulo celular em tilápias do Nilo durante aerocistite infecciosa / Hepatic steatosis alters cellular recruitment during induced aerocystitis in Nile tilapia

O presente estudo avaliou a hepatotoxicidade induzida pelo CCl4 durante o efeito glicocorticoide da dexametasona (DEX) na fisiopatologia da reação inflamatória aguda em tilápias do Nilo, Oreochromis niloticus, correlacionando a funcionalidade hepática à cinética de acúmulo celular em aerocistite infecciosa. Para tal, utilizou-se 84 tilápias do Nilo distribuídas em 4 tratamentos: controle, CCl4, DEX e CCl4+DEX. Sendo amostrados 7 animais por tratamento em três períodos, isto é: seis, 24 e 48h após indução de inflamação. Utilizou-se CCl4 em dose única de 0,5mL/kg, via intraperitoneal para causar o transtorno hepático. Para indução da aerocistite utilizou-se inóculo de Aeromonas hydrophila. A dexametasona foi administrada via intramuscular na dose de 2 mg/kg de peso vivo. Os resultados revelaram que quanto maior foi à atividade sérica de aspartato aminotransferase (AST) maior foi a alteração somática do fígado, sendo estes achados inversamente proporcionais ao acúmulo celular no foco inflamatório, demonstrando menor número de células inflamatórias nos animais acometidos com maior grau de distúrbios hepáticos induzidos pelo CCl4. O estudo histopatológico revelou alterações degenerativas transitórias na fase mais aguda, pois os fígados das tilápias revelaram o acúmulo lipídeos nos hepatócitos 6h após administração de CCl4, sendo esta degeneração gordurosa não mais observada nos tempos de 24 e 48h. Contudo, a administração de CCl4 em tilápias do Nilo resultou em degeneração hepática aguda e transitória, caracterizada pelo acúmulo de gordura nos hepatócitos, aumento de AST no sangue e hepatomegalia. Com a disfunção hepática houve comprometimento do recrutamento celular em aerocistite infecciosa, indicando que há participação do fígado na resposta imune inata em peixes.(AU)

The study evaluated the hepatotoxicity induced by CCl4 during the glucocorticoid effect of dexamethasone (DEX) on the pathophysiology of the acute inflammatory reaction in Nile tilapia, Oreochromis niloticus, correlating hepatic functionality with cellular accumulation kinetics in infectious aerocystitis. Eighty- four Nile tilapia were distributed into four treatments: control, CCl4, DEX and CCl4 + DEX. Seven tilapia were sampled per treatment in three periods: 6, 24 and 48h after induction of inflammation. CCl4 was used in a single dose of 0.5mL/kg intraperitoneally to cause hepatic disorder. Aeromonas hydrophila inoculum was used to induce aerocystitis. Dexamethasone was administered intramuscularly at the dose of 2mg/kg b. w. The results revealed a higher serum aspartate transaminase (AST) activity associated with greater somatic liver alteration, being these findings inversely proportional to the cellular accumulation in the inflammatory focus, demonstrating a lower number of inflammatory cells in the animals affected with a higher degree of hepatic disorders induced by CCl4. The histopathological study revealed transient degenerative changes in the most acute phase, as livers of tilapia showed accumulation of lipids in hepatocytes 6 hours after administration of CCl4, and this fatty degeneration was no longer observed in 24 and 48h. However, administration of CCl4 in Nile tilapia resulted in acute and transient liver degeneration, characterized by accumulation of fat in hepatocytes, increased AST in the blood and hepatomegaly. With liver dysfunction there was compromise of cellular recruitment in infectious aerocystitis, indicating that there is liver involvement in the innate immune response in tilapia.(AU)

Duodenal-jejunal bypass normalizes pancreatic islet proliferation rate and function but not hepatic steatosis in hypothalamic obese rats

Modifications in life-style and/or pharmacotherapies contribute to weight loss and ameliorate the metabolic profile of diet-induced obese humans and rodents. Since these strategies fail to treat hypothalamic obesity, we have assessed the possible mechanisms by which duodenal-jejunal bypass (DJB) surgery regulates hepatic lipid metabolism and the morphophysiology of pancreatic islets, in hypothalamic obese (HyO) rats. During the first 5 days of life, male Wistar rats received subcutaneous injections of monosodium glutamate (4 g/kg body weight, HyO group), or saline (CTL). At 90 days of age, HyO rats were randomly subjected to DJB (HyO DJB group) or sham surgery (HyO Sham group). HyO Sham rats were morbidly obese, insulin resistant, hypertriglyceridemic and displayed higher serum concentrations of non-esterified fatty acids (NEFA) and hepatic triglyceride (TG). These effects were associated with higher expressions of the lipogenic genes and fatty acid synthase (FASN) protein content in the liver. Furthermore, hepatic genes involved in β-oxidation and TG export were down-regulated in HyO rats. In addition, these rats exhibited hyperinsulinemia, β-cell hypersecretion, a higher percentage of islets and β-cell area/pancreas section, and enhanced nuclear content of Ki67 protein in islet-cells. At 2 months after DJB surgery, serum concentrations of TG and NEFA, but not hepatic TG accumulation and gene and protein expressions, were normalized in HyO rats. Insulin release and Ki67 positive cells were also normalized in HyO DJB islets. In conclusion, DJB decreased islet-cell proliferation, normalized insulinemia, and ameliorated insulin sensitivity and plasma lipid profile, independently of changes in hepatic metabolism.

Microbiota e hígado graso: potencial terapéutico / Microbiota and fatty liver: therapeutic potencial

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, characterized by accumulation of fat on the liver parenchyma with a heterogeneous clinical presentation. In recent years its prevalence and incidence has been increasing in association with the rise in obesity and its comorbidities, becoming one of the main causes of cirrhosis. The cause of NAFLD is multifactorial, and currently the role of intestinal microbiota and its interaction with the metabolic syndrome and NAFLD has become of interest. Different pathophysiological phenomena have emerged, the main being intestinal dysbiosis, loss of intestinal barrier, bacterial translocation, with activation of inflammation and oxidative stress, and production of active metabolites, such as ethanol. The management of this factor seems promising and adds to the classic approach of changes in lifestyle. Probiotics are the most studied tool and show evidence of effectiveness, however further studies are needed.

La enfermedad por hígado graso no alcohólico (EHGNA) es la manifestación hepática del síndrome metabólico,caracterizándose por acumulación de grasa a nivel del parénquima con una heterogénea presentación clínica. En los últimos años su prevalencia e incidencia ha ido en aumento, en asociación al aumento de la obesidad y sus comorbilidades, transformándose en una de las principales etiologías de cirrosis hepática. La causa de la EHGNA es multifactorial, siendo de interés en la actualidad el rol de la microbiota intestinal y su interacción con el síndrome metabólico y la EHGNA. Distintos fenómenos fisiopatológicos se han planteado, siendo los principales la disbiosis intestinal, la pérdida de la barrera intestinal, la translocación bacteriana con activación de la cascada de la inflamación y estrés oxidativo y la producción de metabolitos activos como el etanol. El manejo de este factor parece promisorio y se agrega al clásico enfrentamiento de cambios en estilo de vida. Los probióticos son la herramienta más estudiada y disponen de evidencia de efectividad, pero con necesidad de mayores estudios.

ASSOCIATION OF THE NUTRITIONAL PROFILE WITH HISTOLOGICAL FINDINGS OF PATIENTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION

Background - Different factors are responsible for the progression of hepatic fibrosis in chronic infection with hepatitis C virus, but the role of nutritional factors in the progression of the disease is not clearly defined. This study aimed to evaluate the nutritional status and dietary profile among patients with chronic hepatitis C who were candidates for treatment and its association with histopathological features. Methods - A crossectional study was conducted on treatment-naïve patients with chronic hepatitis C genotype 1, between 2011 and 2013. The following assessments were performed before treatment: liver biopsy, anthropometric measurements and qualitative/quantitative analysis of food intake. Results - Seventy patients were studied. The majority of patients was classified as obese (34%) or overweight (20%) according to body mass index [BMI] and as at risk for cardiovascular diseases by waist circumference (79%). Unhealthy food intake was presented by 59% according to qualitative parameters and several patients showed an insufficient intake of calories (59%), excessive intake of protein (36%) and of saturated fat (63%), according to quantitative analysis. With respect to histology, 68% presented activity grade ≥2, 65% had steatosis and 25% exhibited fibrosis stage >2. Comparative analysis between anthropometric parameters and histological features showed that elevated waist circumference was the only variable associated to hepatic steatosis ( P =0.05). There was no association between qualitative and quantitative food intake parameters with histological findings. Conclusion - In this study, most of the patients with hepatitis C presented inadequate qualitative food intake and excessive consumption of saturated fat; in addition, excess of abdominal fat was associated to hepatic steatosis. Therefore, nutritional guidance should be implemented prior to treatment in patients with chronic hepatitis C, in order to avoid nutritional disorders and negative impact on the management of patients.

Contexto - Diferentes fatores são responsáveis pela progressão da fibrose na infecção crônica pelo vírus da hepatite C, mas o papel dos fatores nutricionais na progressão da doença não está definido. Este estudo teve como objetivo avaliar o estado nutricional e o perfil dietético de pacientes com hepatite C crônica candidatos a tratamento e sua associação com achados histopatológicos. Métodos - Foi conduzido um estudo transversal em pacientes com hepatite C crônica genótipo 1 virgens de tratamento, entre 2011 e 2013. Foram analisados, antes do tratamento, os seguintes aspectos: biópsia hepática, medidas antropométricas e análise qualitativa e quantitativa do consumo alimentar. Resultados - Setenta pacientes foram estudados. A maioria dos pacientes apresentava obesidade (34%) ou sobrepeso (20%) de acordo com índice de massa corporal e risco para doenças cardiovasculares de acordo com a circunferência da cintura elevada (79%). Na análise qualitativa do consumo alimentar, 59% apresentavam uma dieta inadequada. Conforme análise quantitativa, 59% tinham consumo insuficiente de calorias, 36% consumo excessivo de proteínas e 63% consumo excessivo de gorduras saturadas. Com relação à histologia, 68% apresentavam grau de atividade inflamatória ≥2, 65% mostraram esteatose hepática e 25% possuíam grau de fibrose >2. Na análise comparativa entre as medidas antropométricas e achados histológicos, somente a circunferência da cintura elevada mostrou associação com esteatose hepática ( P =0,05). Não houve associação entre consumo alimentar qualitativo e quantitativo com parâmetros histológicos. Conclusão - A maioria dos pacientes apresentava consumo alimentar inadequado de acordo com parâmetros qualitativos e consumo excessivo de gordura saturada, além de excesso de gordura abdominal, que esteve associada à esteatose hepática. Portanto, aconselhamento nutricional deveria ser implementado em pacientes candidatos a tratamento para hepatite C crônica visando evitar distúrbios nutricionais que podem impactar negativamente no manejo dos pacientes.

Physical training at sub-threshold intensity reduces the prevalence of hepatic steatosis after high-fat diet in rats

The purpose of the present study was to evaluate the effects of swimming physical training with sub-threshold load on the prevalence of hepatic steatosis in Wistar rats fed high-fat diets (cafeteria or baru). After 2 months of cafeteria diet administration, the rats were separated into 6 groups: Sedentary or Trained Baru diet; Sedentary or Trained Cafeteria diet; Sedentary or Trained standard diet. The trained groups were subjected to swimming exercise at sub-threshold intensity (2% of body weight) during 8 weeks, 5x/week, 1h/day. The body weight and hepatohistological changes were analyzed. Sedentary groups fed high-fat diets presented higher body weight gain when compared to control trained group. The swimming training at the proposed intensity was able to prevent the hepatic steatosis in rats fed high-fat diets.

O objetivo do presente estudo foi avaliar os efeitos do treinamento físico de natação com carga sub-limiar sobre a prevalência de esteatose hepática em ratos Wistar alimentados com dietas hiperlipidícas (cafeteria ou baru). Após dois meses de dieta cafeteria, os ratos foram separados em 6 grupos: Baru treinado ou sedentário; Cafeteria treinado ou sedentário; Controle treinado ou sedentário. Os grupos treinados foram submetidos ao exercício de natação em intensidade sub-limiar, durante 8 semanas, 5x/semana, 1h/dia. As alterações de peso corporal e histopatológicas foram analisadas. Os grupos sedentários alimentados com dietas hiperlipídicas apresentaram maior ganho de peso corporal se comparados ao grupo controle treinado. O treinamento de natação na intensidade proposta diminuiu a prevalência de esteatose hepática induzida por dietas hiperlipídicas.

El objetivo de este estudio fue evaluar los efectos de la natación de entrenamiento físico con la carga por debajo del umbral de la prevalencia de la esteatosis hepática en ratas alimentadas con dietas con hiperlipidemia (cafetería o baru). Después de dos meses de dieta de cafetería, las ratas se dividieron en 6 grupos: entrenados o sedentarios Baru, entrenados o Cafeteria sedentaria; Control entrenados o sedentario. Los grupos formados fueron sometidos a nadar ejercicio de intensidad por debajo del umbral durante 8 semanas, y 1 hora al día 5x/week. Se analizó el peso y la histopatología. Grupos sedentarios alimentados con una dieta alta en grasas aumentó más de peso en comparación con el grupo de control entrenado. El entrenamiento de natación disminuyó la prevalencia de la esteatosis hepática inducida por la dieta alta en grasas.

Imunoexpressão hepática de marcadores inflamatórios e de resistência insulínica na esteato-hepatite não alcóolica / Immunohistochemistry pattern of hepatic inflammatory and insulin resistance markers in experimental model of nonalcoholic steatohepatitis

Introduction: The pathophysiology of nonalcoholic steatohepatitis (NAS) includes, basically, insulin resistance, inflammation and oxidative stress. Thus, a study of immunostaining for liver insulin, adiponectin, tumor necrosis factor alpha (TNF-α), and inducible nitric oxide synthase (iNOS) receptors was conducted. Objective: To expand the knowledge about the pathophysiological and molecular mechanisms underlying the experimental model of steatohepatitis in rats fed a high-fat diet. Method: Twenty Wistar rats were divided into two groups: G1 (control, fed a standard diet), and G2 (fed a high-fat diet containing 58% of energy derived from fat, 18% from protein and 24% from carbohydrate). After eight weeks the animals were sacrificed. Blood glucose, insulin, total cholesterol, high-density lipoprotein (HDL), the very low-density lipoproteins (VLDL), triglycerides, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were determined. The liver tissue was submitted to histopathological analysis, using a NAS score. In immunohistochemistry, we studied the expression of the insulin receptor, adiponectin, TNF-α and iNOS by tissue microarray method. Results and conclusion: There was marked cytoplasmic immunostaining for TNF-α and iNOS mediators in the group on a fat diet. Regarding insulin and adiponectin molecular markers, a reduction of cytoplasmic immunoreactivity of these antigens was observed in the group on a fat diet, reflecting, respectively, the state of hepatocellular inflammation (steatohepatitis) and insulin resistance in this experimental model of fat liver disease...

Introdução: Os mecanismos fisiopatológicos da esteato-hepatite não alcoólica incluem basicamente resistência insulínica, processo inflamatório e estresse oxidativo. Desta forma, um estudo sobre o padrão de imunoexpressão hepática para receptores de insulina, adiponectina, fator de necrose tumoral alfa (TNF-α) e sintase indutível do óxido nítrico (iNOS) foi conduzido. Objetivo: Ampliar os conhecimentos sobre os mecanismos moleculares subjacentes, em modelo experimental de esteato-hepatite. Método: Vinte ratos Wistar com dois meses de idade, pesando de 250 a 300 mg foram subdivididos em dois grupos: G1 (controle normal, submetido à dieta padrão) e G2 (grupo-controle, submetido à dieta hiperlipídica contendo 58% de energia derivada de gorduras, 18% de proteínas e 24% de carboidratos). Após oito semanas, os animais foram sacrificados; o sangue, submetido à análise bioquímica; e o fígado, removido e fixado em formalina tamponada e emblocado em parafina para estudo histopatológico. Para estudo imuno-histoquímico, foi utilizada a técnica de microarranjo de tecido. As lâminas obtidas foram submetidas à incubação com os anticorpos contra adiponectina, receptor de insulina, TNF-α e iNOS. Resultados e conclusão: Observou-se marcada imunoexpressão citoplasmática para os mediadores TNF-α e iNOS no grupo submetido à dieta hiperlipídica. No que diz respeito aos marcadores moleculares insulina e adiponectina, observou-se uma redução da imunoexpressão citoplasmática desses anticorpos no grupo submetido à dieta hiperlipídica, traduzindo, respectivamente, o estado de inflamação hepatocelular (esteato-hepatite) e resistência insulínica, desenvolvidos nesse modelo experimental de doença hepática gordurosa...

Sistema endocanabinoide y desarrollo de esteatosis hepática / A role for the endocannabinoid system in hepatic steatosis

The endocannabinoid system (SEC) is an important modulator of several metabolic functions. This system is composed by cannabinoid receptors type 1 and 2 (RCB1 and RCB2), their endogenous ligands, known as endocannabinoids, and the enzymes involved in their synthesis and degradation. A deregulated SEC originates metabolic alterations in several tissues, resulting in the typical manifestations of the metabolic syndrome. Liver steatosis of different origins constitutes a physiopathological condition where an altered hepatic SEC is observed. In this condition, there is an increased expression of RCB1 and/or higher endocannabinoid levels in different hepatic cells, which may exert an autocrine/paracrine hyperstimulation of RCB1/RCB2. Activation of RCB1 stimulate the expression of several hepatocyte lipogenic factors, thus leading to increased de novo fatty acids synthesis and consequently to an abnormal accumulation of triglycerides. The effect of RCB2 activity on hepatic function is still controversial because, on one side its stimulation has an interesting protective effect on alcoholic liver disease while, on the other, it may enhance the development of hepatic steatosis in experimental models of diet-induced obesity. In this review we discuss the proposed mechanisms by which SEC is involved in the etiology of hepatic steatosis, as well as the therapeutic possibilities involving peripheral RCB1/RCB2 antagonism/agonism, for the treatment of this condition.

Hígado graso no alcohólico en pediatría / Pediatric nonalcoholic fatty liver

La obesidad es un síndrome o trastorno nutricional multifactorial complejo con causas genéticas, conductuales y ambientales, es la forma más común de malnutrición en los países desarrollados y en muchos en vías de desarrollo. El HGNA se define como una entidad anátomo-patológica con la acumulación macrovesicular de grasa (triglicéridos) superior al 5 por ciento de los hepatocitos. El espectro de esta enfermedad incluye la esteatosis simple, la esteatohepatitis no alcohólica, que puede acompañarse de varios grados de fibrosis, y en su etapa final la cirrosis. El objetivo de esta revisión resumir en forma monográfica los aspectos más esenciales de esta afección en pediatría para el uso de cualquier especialista médico...

Obesity is a complex multifactor nutritional syndrome or disease with genetic, behavioral and environmental causes, and it is also the most common form of malnutrition in developed and in many developing countries. The NAFL is defined as an anatomical-pathological disease showing over 5 percent macrovesicular accumulation of adiposity (triglycerides) in hepatocytes. The spectrum of this disease includes simple steatosis, non-alcoholic steatohepatitis that may be accompanied by several levels of fibrosis, and finally cirrhosis in the final stage. The objective of this review was to summarize in a monographic way the most essential aspects of this disease at pediatric ages so that this information may be used by any medical expert...

Hematoma subdural agudo espontâneo e hemorragia intracerebral em paciente com microangiopatia trombótica gestacional / Spontaneous acute subdural hematoma and intracerebral hemorrhage in a patient with thrombotic microangiopathy during pregnancy

Pré-eclâmpsia, síndrome HELLP (hemólise, elevação de enzimas hepáticas e plaquetopenia) e fígado gorduroso agudo da gestação são as principais causas de microangiopatia trombótica e disfunção hepática grave durante a gestação, representando um spectrum do mesmo processo patológico. Relatou-se aqui o caso de uma gestante com 35 semanas internada em unidade de terapia intensiva no pós-operatório imediato de cesariana por morte fetal, com náuseas, vômitos e icterícia. Diagnosticaram-se pré-eclâmpsia pós-parto e fígado gorduroso agudo da gestação. Houve evolução tardia com hematoma subdural agudo e hemorragia intracerebral, sendo realizado tratamento neurocirúrgico. A paciente foi a óbito por anemia hemolítica refratária, com sangramento espontâneo em múltiplos órgãos. Pré-eclâmpsia, síndrome HELLP e fígado gorduroso agudo da gestação são processos patológicos que podem se sobrepor e se associar a complicações potencialmente fatais, como a hemorragia intracraniana aqui descrita. Sua detecção e diagnóstico precoces são fundamentais para a instituição de manejo adequado e sucesso do tratamento.

Preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, and low-platelet count), and acute fatty liver of pregnancy are the main causes of thrombotic microangiopathy and evere liver dysfunction during pregnancy and represent different manifestations of the same pathological continuum. The case of a 35-week pregnant woman who was admitted to an intensive care unit immediately after a Cesarean section due to fetal death and the presence of nausea, vomiting, and jaundice is reported. Postpartum preeclampsia and acute fatty liver of pregnancy were diagnosed. The patient developed an acute subdural hematoma and an intracerebral hemorrhage, which were subjected to neurosurgical treatment. The patient died from refractory hemolytic anemia and spontaneous bleeding of multiple organs. Preeclampsia HELLP syndrome, and acute fatty liver of pregnancy might overlap and be associated with potentially fatal complications, including intracranial hemorrhage, as in the present case. Early detection and diagnosis are crucial to ensure management and treatment success.

Prevention of liver steatosis through fish oil supplementation: correlation of oxidative stress with insulin resistance and liver fatty acid content / Prevención de la esteatosis hepática mediante suplementación con aceite de pescado: correlación de los niveles hepáticos de ácidos grasos poliinsaturados con el estrés oxidativo y la resistencia a la insulina

Non-alcoholic fatty liver disease (NAFLD) is triggered by a nutritional-metabolic alteration characterized by triacylglicerides acumulation, insulin resistance (IR), oxidative stress and depletion of polyunsaturated fatty acid (PUFA). The n-3 PUFA, such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, would be hepatoprotective against the development of NAFLD by stimulating lipolysis and inhibit lipogenesis. So, fish oil supplementation (EPA + DHA) prevents HFDinduced NAFLD. In this context, the aim of this study is to evaluate the correlation between liver oxidative stress with IR and levels of PUFA in supplemented mice. Male mice C57BL/6J (n=9) were fed for 12th week: a) control diet (20% protein, 70% carbohydrate, 10% lipids), b) control diet and fish oil supplementation (200 mg EPA+DHA/kg/day), c) high fat diet (20% protein, 20% carbohydrate, 60% lipids), and d) high fat diet and fish oil supplementation. Liver steatosis (histology), insulin resistance (HOMA), liver oxidative stress (GSH/GSSG, carbonyl protein and 8-isoprostanes) and liver fatty acid content were evaluated. The significant decrease in liver oxidative stress parameters (p<0.05, ANOVA followed by Newman Keuls test) were correlated (Pearson test) with HOMA and levels of PUFA, along with the hepatoprotection observed. It concludes that prevention of NAFLD by supplementation with fish oil (EPA+DHA) is dependent of the prevention of liver oxidative stress, IR and PUFA depletion.

La enfermedad por hígado graso no alcohólica (EHGNA) está provocada por una alteración metabólico- nutricional caracterizada por la acumulación de triacilglicéridos, resistencia a la insulina, estrés oxidativo y disminución de ácidos grasos poliinsaturados (AGPI). Los AGPI ω-3, como los ácidos eicosapentaenoico (EPA) y docosahexaenoico (DHA), serían hepatoprotectores contra la EHGNA al estimular la lipolisis e inhibir la lipogénesis hepática. La suplementación con aceite de pescado (EPA + DHA) previene la esteatosis hepática inducida por una dieta alta en grasas. En este contexto, el objetivo de este estudio es evaluar la correlación entre el estrés oxidativo hepático, la resistencia a la insulina y los niveles de AGPI ω-3 en ratones suplementados. Ratones machos C57BL/6J (n=9) alimentados durante 12 semanas con: a) dieta control (20% proteína, 70% hidratos de carbono, 10% lípidos), b) dieta control y suplementación con 200 mg de EPA+DHA/kg/día, c) dieta alta en grasa (20% proteína, 20% hidratos de carbono, 60% lípidos), y d) dieta alta en grasas más EPA+DHA. Se evaluaron la esteatosis hepática (histología), resistencia a la insulina (HOMA), estrés oxidativo hepático (GSH/GSSG, proteínas carboniladas y 8-isoprostanos) y el contenido de ácidos grasos hepáticos. La disminución significativa en los parámetros hepáticos de estrés oxidativo (p <0,05, ANOVA seguido de Newman-Keuls) se correlacionó positivamente (test de Pearson) con el HOMA y los niveles de AGPI ω-3, junto con la hepatoprotección observada. Se concluye que la prevención de EHGNA por suplementación con EPA+DHA, se acompaña de una correlación inversa entre el estrés oxidativo y la resistencia a la insulina y la disminución de AGPI ω-3 hepáticos.

Enfermedad hepática por depósitos grasos. Una perspectiva actual / [Nonalcoholic fatty liver disease. A current perspective].

A review about nonalcoholic fatty liver disease is presented, considering the updated aspects related to pathophysiology, diagnosis and management of this medical condition.

Novedades en esteatohepatitis no alcohólica / Advances in non–alcoholic steatohepatitis

The non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the western countries. A subset of patients with this problem may progress to cirrhosis and liver cancer. The development of nonalcoholic steatohepatitis (NASH) and fibrosis identifies patients with an increased risk of cirrhosis. Although the exact pathological mechanism is unknown. Several hypotheses suggest that the liver damage is multifactorial. Lipototoxicity, oxidative stress, and cytokines may each play a role in transition of steatosis into NASH. Despite a number of clinical trials on the treatment, there is still no approved therapy. The most important treatment for this disease is to motivate affected persons to adopt a healthier lifestyle. In this article, the recent overall evidence on pathogenesis, treatment and potential lines of future research of nonalcoholic fatty liver disease are reviewed.

La enfermedad hepática grasa no alcohólica es la causa más prevalente de enfermedad hepática crónica en el mundo occidental. Una parte de estos pacientes desarrollará cirrosis y hepatocarcinoma. Obesidad, diabetes mellitus II e insulino resistencia son los principales factores de riesgo. La presencia de esteatohepatitis y fibrosis se relaciona directamente con progresión a cirrosis y sus complicaciones. A pesar de los avances en el conocimiento sobre la enfermedad, su patogénesis aún no está dilucidada; la mayoría de las hipótesis apuntan a un daño multifactorial. Lipotoxicidad, estrés oxidativo, citoquinas inflamatorias y predisposición genética juegan un importante rol en la progresión de la enfermedad. Numerosos estudios se han efectuado para validar las opciones de tratamiento, sin embargo, están limitados por el número pequeño de pacientes enrolados, la corta duración y el seguimiento inadecuado. Se requieren ensayos randomizados, controlados y doble-ciego para evaluar la eficacia y seguridad de estas drogas. Como aún no existe una droga eficaz y segura para el tratamiento, nuestros esfuerzos deben dirigirse a modificar los estilos de vida, promoviendo la baja de peso y el aumento de la actividad física. En este artículo se revisan las novedades en el diagnóstico, patogénesis, tratamiento y futuras líneas de investigación.

Alteración de la función secretora biliar en esteatosis hepática experimental / Altered bile secretory function in experimental non-alcoholic fatty liver disease

Non-alcoholic fatty liver (NAFLD) is a clinical entity whose importance has been increasing, because of its potential progression to chronic liver disease. The alteration of bile secretory function may be a relevant factor of hepatic injury in NAFLD. Objectives: To assess basal bile secretory function and protein mass of three major hepatobiliary transporters in an experimental NAFLD model. Materials and Methods: The bile secretory function was determined by conventional techniques in Sprague-Dawley control rats fed with a choline-deficient diet (CDD) for 8 weeks. Protein mass of Ntcp, Bsep and Mrp2 was measured by western blot. Results: An impaired bile secretory function was observed in rats fed with DDC (reduction of bile flow and secretion of bile acids and organic anions). In addition, DDC fed rats showed higher levels of serum aminotransferases. Ntcp protein mass decreased in rats with DDC, while Bsep and Mrp2 did not show quantitative variations in this experimental model. Conclusions: In this experimental model of NAFLD an impaired bile secretory function was observed, determining a cholestatic pattern. The decrease in Ntcp protein mass with unaltered Bsep and Mrp2 protein mass, associated with a significant decrease in bile secretion suggests a functional impairment of these transporters in rats fed with DDC diet.

El hígado graso no alcohólico (HGNA) es una entidad clínica de importancia creciente por su potencial progresión a daño hepático crónico. La alteración de la función secretora biliar puede ser un factor relevante en el daño o lesión hepática asociada al HGNA. Objetivos: Evaluar la función secretora biliar basal y los niveles de expresión proteica de tres de los principales transportadores hepatobiliares en un modelo de HGNA experimental. Materiales y Métodos: La función secretora biliar fue determinada por técnicas convencionales en ratas Sprague-Dawley control y alimentadas con una dieta deficiente en colina (DDC) durante 8 semanas. Los niveles de expresión proteica de Ntcp, Bsep y Mrp2 fueron cuantificados por western blot. Resultados: Se observó un deterioro de la función secretora biliar en las ratas alimentadas con DDC (reducción del flujo biliar y de secreción de ácidos biliares y aniones orgánicos). Además, las ratas con DDC presentaron niveles más altos de transaminasas séricas. Los niveles de expresión proteica de Ntcp disminuyeron en las ratas con DDC, mientras que Bsep y Mrp2 no presentaron variaciones cuantitativas en este modelo experimental. Conclusiones: En este modelo de HGNA experimental se observó una función secretora biliar alterada, determinando un patrón colestásico. La disminución de los niveles de expresión proteica de Ntcp junto con la mantención de Bsep y Mrp2, asociados a una disminución significativa de la secreción biliar, sugiere un deterioro funcional de estos transportadores en ratas alimentadas con dieta DDC.

Dopplerfluxometria da veia hepática em pacientes com esteatose não alcoólica / Hepatic vein Doppler flowmetry in patients with nonalcoholic steatosis

OBJETIVO: Avaliar a correlação entre a dopplerfluxometria da veia hepática direita e o grau de esteatose, inflamação e fibrose à biópsia na doença hepática gordurosa não alcoólica. MATERIAIS E MÉTODOS: Foi realizada ultrassonografia com Doppler em 80 pacientes, sendo 40 portadores de doença hepática gordurosa não alcoólica, também submetidos à biópsia. Quarenta controles normais saudáveis, sem fatores risco para doença hepática gordurosa não alcoólica foram submetidos a ultrassonografia com Doppler. O padrão ao Doppler da veia hepática direita foi classificado em trifásico, bifásico e monofásico. Os espécimes de biópsia foram classificados conforme o grau de esteatose, inflamação e fibrose. RESULTADOS: O fluxo foi trifásico em 38 (95 por cento) dos controles e em 9 (56,3 por cento) dos pacientes com esteatose discreta, enquanto nos com esteatose acentuada o padrão foi monofásico em 60 por cento. Encontrou-se diferença significante na distribuição dos padrões ao Doppler (p < 0,01). Houve correlação negativa e significante entre o padrão ao Doppler da veia hepática direita e grau de esteatose (r = -0,57; p < 0,01). CONCLUSÃO: A alteração do padrão ao Doppler da veia hepática direita em pacientes com doença hepática gordurosa não alcoólica pode sugerir redução da complacência vascular consequente a infiltração gordurosa.

OBJECTIVE: To evaluate the correlation between right hepatic vein Doppler flowmetry and degree of steatosis, inflammation and fibrosis at biopsy in nonalcoholic fatty liver disease. MATERIALS AND METHODS: Doppler ultrasonography was performed in 80 patients divided into two groups as follows: 40 patients diagnosed with nonalcoholic fatty liver disease and also submitted to biopsy, and a control group including 40 healthy adults with no risk factor for nonalcoholic fatty liver disease. The Doppler waveform patterns of right hepatic vein were classified into triphasic, biphasic and monophasic. Biopsy specimens were classified according to the degree of steatosis, inflammation and fibrosis. RESULTS: Triphasic flow was observed in 38 (95 percent) patients of the control group and in nine (56 percent) patients with mild steatosis, whereas in patients with severe steatosis, the pattern was monophasic in 60 percent. A statistically significant difference was observed in the distribution of Doppler patterns (p < 0.01). A significant negative correlation between the Doppler waveform pattern of right hepatic vein and steatosis degree was observed (r = 0.57; p < 0.01). CONCLUSION: An abnormal Doppler waveform pattern of right hepatic vein in patients with nonalcoholic fatty liver disease may suggest the presence of decreased vascular compliance caused by fatty infiltration.

Evaluation of Portal Venous Velocity with Doppler Ultrasound in Patients with Nonalcoholic Fatty Liver Disease

PURPOSE: We examined the relationship between portal venous velocity and hepatic-abdominal fat in patients with nonalcoholic fatty liver disease (NAFLD), using spectral Doppler ultrasonography (US) and magnetic resonance imaging (MRI). MATERIALS AND METHODS: In this prospective study, 35 patients with NAFLD and 29 normal healthy adults (control group) underwent portal Doppler US. The severity of hepatic steatosis in patients with NAFLD was assessed by MRI through chemical shift imaging, using a modification of the Dixon method. Abdominal (intra-abdominal and subcutaneous) fat was measured by MRI. RESULTS: The difference in portal venous velocity between the patients with NAFLD and the control group was significant (p 0.05). There were strong correlations between the hepatic fat fraction and subcutaneous adiposity (p < 0.0001), intraperitoneal fat accumulation (p = 0.017), and retroperitoneal fat accumulation (p < 0.0001). CONCLUSION: Our findings suggest that patients with NAFLD have lower portal venous velocities than normal healthy subjects.

Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals / Índice de resistência insulínica (HOMA-IR) na diferenciação entre pacientes com doença hepática gordurosa não-alcoólica e indivíduos saudáveis

CONTEXT: Due to its good correlation to glycemic clamp, HOMA-IR has been widely utilized as insulin resistance index in clinical and epidemiological studies involving non-alcoholic fatty liver disease carriers. However, values used for this parameter have shown large variability. OBJECTIVE: To identify the HOMA-IR cut value that best distinguishes non-diabetic non-alcoholic fatty liver disease patients from a control group. METHODS: One hundred sixteen non-alcoholic fatty liver disease patients were studied, diagnosed by clinical, biochemical, and liver image or biopsy criteria, and 88 healthy individuals, without any liver disease and testing for oral glucose tolerance within normality. These groups did not differ in age and gender. All were submitted to oral glucose tolerance test and blood samples were collected for glucose and insulin measurements by immunofluorometric method. HOMA-IR was calculated according to the formula: fasting insulin (µU/L) x fasting glucose (nmol/L)/22.5. RESULTS: NAFLD patients showed higher insulin, glycemia, and HOMA-IR values than control group, even when excluding glucose intolerant and diabetes mellitus patients by their glycemic curves. HOMA-IR 75th percentile for control group was 1.78 and the best area under the curve index was obtained for HOMA-IR values of 2.0 [AUC= 0.840 (0.781-0.899 CI 95 percent), sensitivity (Se): 85 percent, specificity (Sp): 83 percent] while value 2.5 showed best specificity without important loss in sensitivity [AUC=0,831 (0.773-0.888) Se = 72 percent, Sp = 94 percent]. CONCLUSION: HOMA-IR values above or equal to 2.0 or 2.5 show enhanced diagnostic value in distinguishing non-alcoholic fatty liver disease carriers from control group individuals.

CONTEXTO: Pela sua boa correlação com o "clamp" glicêmico, o HOMA-IR tem sido largamente utilizado como índice de resistência insulínica em estudos clínicos e epidemiológicos em pacientes com doença hepática gordurosa não-alcoólica. Porém os valores utilizados para esse parâmetro têm sido muito variáveis. OBJETIVO: Identificar o valor de corte do HOMA-IR que melhor diferencie pacientes com doença hepática gordurosa não-alcoólica não-diabéticos, de um grupo controle. MÉTODOS: Foram estudados 116 pacientes com doença hepática gordurosa não-alcoólica, diagnosticados por critérios clínicos, bioquímicos e de imagem ou biopsia hepática e 88 indivíduos saudáveis, sem doença hepática e com teste de tolerância oral à glicose dentro da normalidade. Esses grupos não diferiam quanto à idade e gênero. Todos foram submetidos ao teste de tolerância oral à glicose e coletadas amostras de sangue para dosagem de glicemia e de insulina através de método imunofluorimétrico. Foi feito o cálculo do HOMA-IR de acordo com fórmula = insulina de jejum (µU/L) x glicemia de jejum (nmol/L)/22.5. RESULTADOS: Os pacientes com doença hepática gordurosa não-alcoólica apresentaram valores mais elevados de insulina, glicemia e HOMA-IR que o grupo controle, mesmo quando excluídos os pacientes com diagnóstico de intolerância à glicose ou de diabetes mellitus pela curva glicêmica. O percentil 75 para HOMA-IR no grupo controle foi de 1.78 e o melhor índice de área sob a curva foi obtido para os valores de HOMA-IR de 2,0 [ASC = 0,840 (0,781-0,899 IC95 por cento), sensibilidade: 85 por cento, especificidade: 83 por cento] enquanto o valor de 2,5 foi o que apresentou melhor especificidade, sem perda importante de sensibilidade [ASC = 0,831 (0.773-0.888) sensibilidade: 72 por cento, especificidade: 94 por cento] . CONCLUSÃO: Valores de HOMA-IR acima ou iguais a 2.0 ou 2.5 mostram elevado valor diagnóstico na distinção entre os doentes com doença hepática gordurosa não-alcoólica...

Hepatic artery resistance in children with obesity and fatty liver.

Objective. To assess correlation between hepatic artery resistive index (HARI) and increase of body mass index and hepatosteatosis grading in children with non-alcoholic fatty liver disease (NAFLD). Methods. Thirty three healthy children [body mass index(BMI): mean± standart deviation(SD), min-max: 20.1±1.14(18.5-23.7), 33 overweight [BMI:25.1±2.2 (18.5-23.7)] and 66 obese [BMI:31.1±2(25.6-40)] adolescents were enrolled into the study. To search the relation of HARI with fatty liver degree, study subjects subdivided into groups according to their degree of fatty liver at ultrasonography(US). Results. Increase of HARI was correlated with increase in BMI (p<0.0001, r=0.533). Increase of HARI was well correlated with increase in degree of fatty liver (p<0.0001, r=0.630). Conclusion. The present study results suggest that there are positive correlations of HARI with BMI and hepatoseatosis grade in obese children with NAFLD. HARI may be a candidate parameter to determine early alarming hemodynamic changes in hepatic tissue of obese children with fatty liver before development of severe stages NAFLD.

Dieta hiperlipídica materna e pós-natal promove remodelamento adverso do fígado, pâncreas e tecido adiposo na prole / Maternal and postnatal high-fat diet and promotes adverse remodeling of the liver, pancreas and adipose tissue in offspring

A dieta hiperlipídica (high-fat, HF) materna durante a gestação e/ou lactação aumenta a susceptibilidade da prole para o desenvolvimento de doenças crônicas na fase adulta. Verificar a hipótese que a ingestão materna de dieta HF nos períodos críticos de desenvolvimento (gestação e/ou lactação) predispõe à doença não alcoólica do fígado gorduroso e alterações pancreáticas e no tecido adiposo de camundongos machos adultos. Camundongos C57BL/6 fêmeas receberam durante a gestação e/ou lactação dieta padrão (standard chow, SC) ou HF. Filhotes machos foram divididos em cinco grupos: SC - provenientes de mães SC; G - provenientes de mães HF durante a gestação; L - provenientes de mães HF durante a lactação; GL/HF - provenientes de mães HF durante a gestação/lactação, mantendo a mesma dieta HF no período pós-natal (do desmame aos 3 meses de idade); GL - provenientes de mães HF durante a gestação/lactação trocando a dieta para SC no período pós-natal (do desmame aos 3 meses de idade). Foi analisada ao longo do experimento a massa corporal da prole. No sacrifício (3 meses), o fígado, o pâncreas e a gordura epididimária foram removidos, pesados e processados e o sangue foi coletado para análise bioquímica. Ao nascimento e ao desmame, filhotes GL/HF foram mais pesados (+6% e +44%, p<0,05, respectivamente) que os filhotes SC. Os filhotes G apresentaram resistência à insulina e menor expressão do transportador de glicose no fígado (GLUT-2). A esteatose hepática foi observada nos grupos G, L, GL e principalmente nos filhotes do grupo GL/HF. A expressão hepática da proteína ligante de elementos regulatórios de esteróis (SREBP-1c) estava aumentada nos filhotes G, GL e GL/HF. Os filhotes G, GL e GL/HF apresentaram hipertrofia da ilhota pancreática e dos adipócitos quando comparados com o grupo SC. O consumo de dieta HF durante a gestação mostra-se ser o período mais prejudicial para os filhotes adultos de camundongos. A programação metabólica por dieta HF ...

Maternal high-fat diet (HF) during gestation and/or lactation period increases the susceptibility to development of chronic disease in offspring adult life. This work aimed to verify the hypothesis that maternal intake of high-fat diet in critical periods of pregnancy and/or suckling period predisposes to non alcoholic fatty liver disease, pancreatic and adipose tissue alterations in adulthood mice offspring. C57BL/6 female mice were fed, during gestation and/or lactation phases, with standard chow (SC) of HF diet. Male pups were divided into 5 groups: SC - from SC fed dam; G - from HF fed dam during gestation period; L - from HF fed dam during lactation period; GL - from HF fed dam during gestation and lactation periods and GL/HF - from HF fed dam during gestation and lactation, maintaining HF diet from post-weaning to adulthood. We analyzed body mass in all experiment, and at the euthanasia (3 mo-old), liver, pancreas and adipose tissue were removed, weighted and embedded. Blood was collected to biochemical analyses. At birth and at weaning, GL/HF pups were heavier than SC pups (+6% and +44%, p<0.05, respectively). G offspring showed insulin resistance and lower glucose transporter-2 expression (GLUT-2). Hepatic steatosis was present in G, L, GL and mainly in GL/HF offspring. Sterol regulatory element-binding protein-1c (SREBP-1c) expression was higher in G, GL and GL/HF offspring. It is important to mention that pancreatic islet hyperthophy and adipocyte hypertrophy were affected in G, GL and GL/HF offspring in comparison to SC. HF diet administration during gestation period is worse than lactation period. Furthermore, this type of programming by HF predisposes to adverse remodeling in liver, pancreas and adipose tissue in adult mice offspring

Protective roles of adiponectin in obesity-related fatty liver diseases: mechanisms and therapeutic implications: [review] / Adiponectina e seu papel na proteção contra a doença hepática gordurosa na obesidade: mecanismos e implicações terapêuticas: [revisão]

Adiponectin is an insulin-sensitizing adipokine possessing multiple beneficial effects on obesity-related medical complications. This adipokine is secreted from adipocytes into the circulation as three oligomeric isoforms, including trimer, hexamer and the high molecular weight (HMW) oligomeric complex. Each oligomeric isoform of adiponectin possesses distinct biological properties and activates different signaling pathways in various target tissues. The hepato-protective activities have been demonstrated by many clinical and experimental studies. The decreased level of serum adiponectin represents an independent risk factor for nonalcoholic fatty liver disease (NAFLD) and liver dysfunctions in humans. In animals, elevation of circulating adiponectin by either pharmacological or genetic approaches leads to a significant alleviation of hepatomegaly, steatosis and necro-inflammation associated with various liver diseases. In adiponectin knockout mice, there is a pre-existing condition of hepatic steatosis and mitochondria dysfunction, which might contribute to the increased vulnerabilities of these mice to the secondary liver injuries induced by obesity and other conditions. This review aims to summarize recent advances on delination of the structural, molecular and cellular mechanisms underlying the hepato-protective properties of adiponectin.

A adiponectina é uma adipocitocina com ação insulino-sensibilizadora com múltiplos efeitos benéficos sobre as complicações clínicas da obesidade. Essa adipocitocina é secretada pelos adipócitos na circulação sistêmica em três isoformas oligoméricas, incluindo as formas em trímeros, hexâmeros e complexas de alto peso molecular (HMW). Cada forma oligomérica da adiponectina apresenta propriedades biológicas distintas e ativam diferentes vias de sinalização celular em diversos tecidos. Suas atividades hepatoprotetoras têm sido descritas em vários estudos clínicos e experimentais. Em humanos, os níveis reduzidos da adiponectina sérica, características da obesidade, representam um fator de risco independente para a doença hepática gordurosa não-alcoólica (NAFLD), incluindo variados graus de disfunções hepáticas. Em animais, a elevação dos níveis circulantes de adiponectina, por manipulações genéticas ou farmacológicas, conduz a uma atenuação da hepatomegalia, da esteatose e da necroinflamação usualmente associadas a várias doenças hepáticas. No animal sem o gene da adiponectina (knockout), existe uma condição preexistente de esteatose e disfunção mitocondrial que contribui para a vulnerabilidade desses animais aos processos de lesões teciduais hepáticos induzidos pela obesidade e outras condições. Esta revisão sumariza os recentes avanços na compreensão e caracterização dos mecanismos celulares, moleculares e estruturais das ações hepatoprotetoras da adiponectina.