Correlation between COVID-19 severity, body mass index and radiological hepatic morphology / Correlación entre la gravedad de COVID-19, el índice de masa corporal y la morfología hepática radiológica

SUMMARY: Obesity and fatty liver steatosis are already considered metabolic risk factors which may aggravate the severity of COVID-19. This study aims to investigate the correlation between COVID-19 severity, obesity, and liver steatosis and fibrosis. 230 consecutive patients with laboratory-confirmed COVID-19 aged between 15 and 84? years, admitted to a hospital devoted to COVID-19 patients, were enrolled in the study. COVID-19 severity was classified as severe versus non-severe based on admission to ICU. Obesity was assessed by Body Mass Index (BMI). CT-scan was used to check for the liver steatosis. Fibrosis-4 score was calculated. The study was conducted in March-May 2020. Obesity strongly and positively correlated with severe COVID-19 illness r: 0.760 (P<0.001). Hepatic steatosis had rather less of a correlation with COVID-19 severity r: 0.365 (P<0.001). Multivariable-adjusted association between hepatic steatosis or obesity, or both (as exposure) and COVID-19 severity (as the outcome) revealed increased risk of severe COVID-19 illness with obesity (Adjusted model I OR: 465.3, 95 % CI: 21.9-9873.3, P<0.001), with hepatic steatosis (Adjusted model I OR: 5.1, 95 % CI: 1.2-21.0, P<0.025), and with hepatic steatosis among obese patients (Adjusted model I OR: 132, 95 % CI: 10.3-1691.8, P<0.001). Obesity remained the most noticeable factor that strongly correlated with COVID-19 severity, more than liver steatosis. However, the risk to COVID-19 severity was greater in those with both factors: obesity and liver steatosis.

RESUMEN: La obesidad y la esteatosis del hígado graso ya se consideran factores de riesgo metabólico que pueden empeorar la gravedad de la COVID-19. Este estudio tiene como objetivo investigar la correlación entre la gravedad de COVID- 19, la obesidad y la esteatosis y fibrosis hepática. El estudio se realizó en 230 pacientes consecutivos entre 15 y 84 años con COVID-19 confirmado por laboratorio, ingresados en un hospital dedicado a pacientes con COVID-19. La gravedad de COVID-19 se clasificó como grave, versus no grave según el ingreso a la UCI. La obesidad se evaluó mediante el índice de masa corporal (IMC). Se utilizó una tomografía computarizada para verificar la esteatosis hepática. Se calculó la puntuación de Fibrosis-4. El estudio se realizó entre marzo-mayo de 2020. La obesidad se correlacionó fuerte y positivamente con la enfermedad grave de COVID-19 r: 0,760 (P <0,001). La esteatosis hepática tuvo una correlación bastante menor con la gravedad de COVID-19 r: 0.365 (P <0.001). La asociación ajustada multivariable entre la esteatosis hepática u obesidad, o ambas (como exposición) y la gravedad de COVID-19 (como resul- tado) reveló un mayor riesgo de enfermedad grave por COVID- 19 con obesidad (OR del modelo ajustado I: 465,3, IC del 95%: 21,9 -9873,3, P <0,001), con esteatosis hepática (OR del modelo I ajustado: 5,1, IC del 95 %: 1,2-21,0, P <0,025) y con esteatosis hepática entre los pacientes obesos (OR del modelo I ajustado: 132, IC del 95 % : 10,3-1691,8, P <0,001). La obesidad siguió siendo el factor más notable que se correlacionó significativamente con la gravedad de COVID-19, más que la esteatosis hepática. Sin embargo, el riesgo de gravedad de COVID-19 fue mayor en aquellos con ambos factores: la obesidad y esteatosis hepática.

Liver structural injury in leptin-deficient (ob/ob) mice: lipogenesis, fibrogenesis, inflammation, and apoptosis / Lesión estructural del hígado en ratones con deficiencia de leptina (ob/ob): lipogénesis, fibrogénesis, inflamación y apoptosis

SUMMARY: Nonalcoholic fatty liver disease (NAFLD) might progress the steatosis to nonalcoholic steatohepatitis (NASH), reaching a cirrhosis state and possibly hepatocellular carcinoma. The liver of three-month-old C57BL/6J mice (wild-type, WT group, n=10) and leptin- deficient obese mice (ob/ob group, n=10) were studied, focusing on the mechanisms associated with the activation of the hepatic stellate cells (HSCs) and pro-fibrogenesis. The obese ob/ob animals' liver showed steatosis, increased lipogenesis gene expressions, inflammation, increased pro-inflammatory gene expressions, inflammatory infiltrate, and potential apoptosis linked to a high Caspase 3 expression. In ob/ob mice, liver sections were labeled in the fibrotic zones by anti-alpha-smooth muscle actin (alpha-SMA) and anti-Reelin, but not in the WT mice. Moreover, the alpha-SMA gene expression was higher in the ob/ob group's liver than the WT group. The pro-fibrogenic gene expressions were parallel to anti- alpha-SMA and anti-Reelin immunofluorescence, suggesting HSCs activation. In the ob/ob animals, there were increased gene expressions involved with lipogenesis (Peroxisome proliferator-activated receptor-gamma, Cell death-inducing DFFA-like effector-c, Sterol regulatory element-binding protein-1c, and Fatty acid synthase), pro-fibrogenesis (Transforming growth factor beta1, Smad proteins- 3, Yes-associated protein-1, Protein platelet-derived growth factor receptor beta), pro-inflammation (Tumor necrosis factor-alpha, and Interleukin-6), and apoptosis (Caspase 3). In conclusion, the results in obese ob/ob animals provide a clue to the events in humans. In a translational view, controlling these targets can help mitigate the hepatic effects of human obesity and NAFLD progression to NASH.

RESUMEN: La enfermedad del hígado graso no alcohólico (HGNA) puede progresar de la esteatosis a esteatohepatitis no alcohólica (ENA), alcanzando un estado de cirrosis y posiblemente carcinoma hepatocelular. Se estudió el hígado de ratones C57BL / 6J de tres meses de edad (tipo salvaje, grupo WT, n = 10) y ratones obesos con deficiencia de leptina (grupo ob/ob, n = 10), centrándose en los mecanismos asociados con la activación de las células estrelladas hepáticas (HSC) y profibrogénesis. El hígado de los animales obesos ob/ob mostró esteatosis, aumento de la expresión génica de la lipogénesis, inflamación, aumento de la expresión génica proinflamatoria, infiltrado inflamatorio y posible apoptosis ligada a una alta expresión de Caspasa 3. En ratones ob/ob, las sec- ciones de hígado se marcaron en las zonas fibróticas con anti-alfa- actina de músculo liso (alfa-SMA) y anti-Reelin, pero no en los ratones WT. Además, la expresión del gen alfa-SMA fue mayor en el hígado del grupo ob/ob que en el grupo WT. Las expresiones génicas profibrogénicas fueron paralelas a la inmunofluorescencia anti-alfa-SMA y anti-Reelin, lo que sugiere la activación de las HSC. En los animales ob/ob, hubo un aumento de las expresiones génicas involucradas con la lipogénesis (receptor activado por proliferador de peroxisoma gamma, efector c similar a DFFA inductor de muerte celular, proteína de unión al elemento regulador de esterol-1c y sintasa de ácidos grasos), pro-fibrogénesis (factor de crecimiento transformante beta 1, proteínas Smad-3, proteína-1 asociada a Yes, receptor beta del factor de crecimiento derivado de plaquetas de proteínas), proinflamación (factor de necrosis tumoral alfa e interleucina-6) y apoptosis (caspasa 3). ). En conclusión, los resultados en animales obesos ob/ob proporcionan una pista de los eventos en humanos. Desde un punto de vista traslacional, el control de estos objetivos puede ayudar a mitigar los efectos hepáticos de la obesidad humana y la progresión de HGNA a ENA.

Sericin as treatment of obesity: morphophysiological effects in obese mice fed with high-fat diet / Sericina como tratamento da obesidade: efeitos morfofisiológicos de camundongos obesos por dieta hiperlipídica

ABSTRACT Objective To investigate the effects of sericin extracted from silkworm Bombyx mori cocoon on morphophysiological parameters in mice with obesity induced by high-fat diet. Methods Male C57Bl6 mice aged 9 weeks were allocated to one of two groups - Control and Obese, and fed a standard or high-fat diet for 10 weeks, respectively. Mice were then further subdivided into four groups with seven mice each, as follows: Control, Control-Sericin, Obese, and Obese-Sericin. The standard or high fat diet was given for 4 more weeks; sericin (1,000mg/kg body weight) was given orally to mice in the Control-Sericin and Obese-Sericin Groups during this period. Weight gain, food intake, fecal weight, fecal lipid content, gut motility and glucose tolerance were monitored. At the end of experimental period, plasma was collected for biochemical analysis. Samples of white adipose tissue, liver and jejunum were collected and processed for light microscopy analysis; liver fragments were used for lipid content determination. Results Obese mice experienced significantly greater weight gain and fat accumulation and had higher total cholesterol and glucose levels compared to controls. Retroperitoneal and periepididymal adipocyte hypertrophy, development of hepatic steatosis, increased cholesterol and triglyceride levels and morphometric changes in the jejunal wall were observed. Conclusion Physiological changes induced by obesity were not fully reverted by sericin; however, sericin treatment restored jejunal morphometry and increased lipid excretion in feces in obese mice, suggesting potential anti-obesity effects.

RESUMO Objetivo Investigar os efeitos da sericina extraída de casulos de Bombyx mori na morfofisiologia de camundongos com obesidade induzida por dieta hiperlipídica. Métodos Camundongos machos C57Bl6, com 9 semanas de idade, foram distribuídos em Grupos Controle e Obeso, que receberam ração padrão para roedores ou dieta hiperlipídica por 10 semanas, respectivamente. Posteriormente, os animais foram redistribuídos em quatro grupos, com sete animais cada: Controle, Controle-Sericina, Obeso e Obeso-Sericina. Os animais permaneceram recebendo ração padrão ou hiperlipídica por 4 semanas, período no qual a sericina foi administrada oralmente na dose de 1.000mg/kg de massa corporal aos Grupos Controle-Sericina e Obeso-Sericina. Parâmetros fisiológicos, como ganho de peso, consumo alimentar, peso das fezes em análise de lipídios fecais, motilidade intestinal e tolerância à glicose foram monitorados. Ao término do experimento, o plasma foi coletado para dosagens bioquímicas e fragmentos de tecido adiposo branco; fígado e jejuno foram processados para análises histológicas, e amostras hepáticas foram usadas para determinação lipídica. Resultados Camundongos obesos apresentaram ganho de peso e acúmulo de gordura significativamente maior que os controles, aumento do colesterol total e glicemia. Houve hipertrofia dos adipócitos retroperitoneais e periepididimais, instalação de esteatose e aumento do colesterol e triglicerídeos hepáticos, bem como alteração morfométrica da parede jejunal. Conclusão O tratamento com sericina não reverteu todas as alterações fisiológicas promovidas pela obesidade, mas restaurou a morfometria jejunal e aumentou a quantidade de lipídios eliminados nas fezes dos camundongos obesos, apresentando-se como potencial tratamento para a obesidade.

High-Lard and High-Cholesterol Diet, but not High-Lard Diet, Leads to Metabolic Disorders in a Modified Dyslipidemia Model / Dieta Rica em Banha e Colesterol, mas não Dieta Rica em Banha, Leva a Distúrbios Metabólicos em um Modelo Modificado de Dislipidemia

Abstract Background: In view of the increased global prevalence of cardiovascular and hepatic diseases, the diet lipid content and its relationship with the accumulation of fat in hepatocytes have been investigated as key factors in preventing these diseases. Objective: To evaluate the metabolic effects of a high-lard diet supplemented or not with cholesterol on a modified dyslipidemia model. Methods: We divided 24 adult male Wistar rats into three groups: standard diet (STD - 4% lipids), high-lard diet (HLD - 21% lard), and high-lard and high-cholesterol diet (HL/HCD - 20% lard, 1% cholesterol, 0.1% cholic acid). After six weeks of treatment, blood and liver were collected for biochemical (serum lipid profile and liver enzymes) and morphological analyses. Statistical analysis included one-way analysis of variance (ANOVA), followed by Tukey test for mean comparisons, and a 5% probability was considered statistically significant. Results: Animals fed HL/HCD showed increased total cholesterol, triacylglycerol, LDL-c, non-HDL-c, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) serum levels compared to those fed STD. In addition, the HL/HCD animals presented higher relative liver weight, with moderate macrovesicular hepatic steatosis and inflammatory infiltrate. Conclusion: A high-fat diet with lard (20%) and cholesterol (1%) triggered dyslipidemia with severe liver damage in rats in a shorter experimental time than the previously reported models. The high-lard diet without supplementation of cholesterol led to body weight gain, but not to dyslipidemia.

Resumo Fundamento: Tendo em vista o aumento da prevalência global de doenças cardiovasculares e hepáticas, o conteúdo lipídico da dieta e sua relação com o acúmulo de gordura nos hepatócitos têm sido investigados como fatores-chave na prevenção dessas doenças. Objetivo: Avaliar os efeitos metabólicos de uma dieta rica em banha suplementada com colesterol ou não, em um modelo modificado de dislipidemia. Métodos: Foram divididos 24 ratos Wistar machos adultos em três grupos: dieta padrão (DP - 4% de lipídios), dieta rica em banha (DRB - 21% de banha) e dieta rica em banha e colesterol (DRB/RC - 20% de banha, 1% de colesterol e 0,1% de ácido cólico). Após seis semanas de tratamento, o sangue e o fígado foram coletados para análises bioquímicas (perfil lipídico sérico e enzimas hepáticas) e morfológicas. A análise estatística incluiu análise de variância unidirecional (ANOVA), seguida do teste de Tukey para comparações de médias. Uma probabilidade de 5% foi considerada estatisticamente significativa. Resultados: Animais alimentados com DRB/RC apresentaram um aumento nos níveis séricos de colesterol total, triacilglicerol, LDL-c, não-HDL-c, alanina aminotransferase (ALT) e aspartato aminotransferase (AST) em comparação com aqueles alimentados com DP. Além disso, os animais tratados com DRB/RC apresentaram um peso relativo do fígado maior, com esteatose hepática macrovesicular moderada e infiltrado inflamatório. Conclusão: Uma dieta rica em gordura com banha (20%) e colesterol (1%) desencadeou dislipidemia com danos graves ao fígado em ratos em um tempo experimental menor do que os modelos previamente relatados. A dieta rica em banha sem suplementação de colesterol levou ao ganho de peso corporal, mas não à dislipidemia.

Resolution of fatty liver disease after growth hormone replacement in a pediatric survivor of thyroid cancer / Resolución de enfermedad hepática grasa posterior al reemplazo con hormona de crecimiento en un paciente pediátrico sobreviviente a cáncer de tiroides

Abstract Background A rare case of primary papillary thyroid cancer (PTC) and growth hormone (GH) deficiency in a pediatric patient is described. In addition, the patient developed fatty liver disease attributed to GH deficiency. Case report A 10-year-old male with a history of PTC with extension to the cervical nodes detected at 5 years of age was referred to the endocrinology consultation due to a low growth rate. On examination, GH deficiency was detected (height −3.51 standard deviations and low insulin-like growth factor-1 levels). This hormonal deficiency was not associated with thyroid cancer or treatment. Furthermore, elevated transaminases (~300 IU/ml), lipids, and fally liver disease by ultrasound were detected. These data suggested fatty liver disease, which was attributed to GH deficiency. Regardless of the risk of recurrence, somatotropin was administered due to liver dysfunction and very short stature of the patient. A considerable improvement in growth, transaminases, and lipid profile was observed. At present, at 14 years of age, resolution of hepatic steatosis and a considerable increase in his growth rate without recurrence of thyroid cancer 9 years after its diagnosis and 4 years after the initiation of GH treatment are confirmed. Conclusions GH therapy could be a good therapeutic option for pediatric cancer survivors to address impaired growth and fatty liver disease. However, additional medical evidence based on clinical trials is necessary to determine the benefits.

Resumen Introducción Se presenta el caso de un paciente pediátrico con una asociación de cáncer papilar de tiroides (CPT) y deficiencia de hormona de crecimiento (HC) que no ha sido descrita previamente. Además, presenta enfermedad hepática grasa atribuida a la deficiencia hormonal. Caso clínico Paciente de sexo masculino con antecedente de CPT con extensión a los ganglios cervicales diagnosticado a los 5 años de edad. Es referido a los 10 años por talla baja, sin datos de recurrencia del CPT. En el abordaje diagnóstico se detecta deficiencia de HC basándose en una estatura 3.51 desviaciones estándar por debajo de la media y niveles bajos de factor de crecimiento insulínico tipo 1. Adicionalmente, se detectó elevación de transaminasas (~300 IU/ml), dislipidemia y esteatosis hepática en el ultrasonido. Después de los estudios de extensión, la enfermedad hepática grasa se atribuyó a la deficiencia de HC. A pesar del riesgo de recurrencia del cáncer de tiroides, se decidió dar tratamiento con HC debido a la afectación hepática y de crecimiento. El paciente presentó una evolución satisfactoria y actualmente, a la edad de 14 años, la esteatosis hepática está resuelta, presenta una mejoría considerable en su estatura y no ha tenido recurrencia del cáncer de tiroides 9 años después del diagnóstico y 4 años después del inicio del tratamiento con HC. Conclusiones El tratamiento con HC puede ser una adecuada opción terapéutica para sobrevivientes de cáncer en la edad pediátrica con afectación en el crecimiento y esteatosis hepática. Sin embargo, se requieren estudios con mayor evidencia científica y seguimiento a largo plazo para apoyar esta afirmación.

¿Qué hay en común entre el hígado graso agudo del embarazo y la preeclampsia? Subdiagnóstico clínico de alta mortalidad / What is in Common Between Acute Fatty Liver of Pregnancy and Preeclampsia? Highly Mortal Clinical Sub-Diagnosis / O que tem em comum o fígado gorduroso agudo da gestação e a pré-eclâmpsia? Subdiagnóstico clínico de alta mortalidade

Resumen: El hígado graso agudo del embarazo es una de las alteraciones hepáticas con mayor mortalidad (cerca del 18%) presentes en la gestación, aunque es una patología poco frecuente: 1 de cada 7000 a 16.000 embarazos presenta muchas complicaciones y requiere un manejo inmediato para evitar la muerte de la gestante o del feto; sin embargo esta patología se puede enmascarar con la preeclampsia, que es otra patología hepática de mayor frecuencia, lo cual retrasa el manejo y aumenta el número de complicaciones. El objetivo de este artículo es realizar una búsqueda bibliográfica acerca del hígado graso agudo del embarazo e identificar los factores similares entre esta patología y la preeclampsia severa para lograr hacer un diagnóstico y manejo oportunos. Para ello se realizó una búsqueda sistemática en las bases de datos, PubMed, Science Direct, Medline, Embase, en junio de 2017; además, se seleccionaron artículos originales, reportes de casos y artículos de revisión, publicados en los últimos diez años.

Abstract: Acute fatty liver of pregnancy (AFLP) is one of the liver disorders with the highest mortality rate (about 18%) during pregnancy, although it is rare: 1 in 7,000 to 16,000 pregnancies has many complications and requires immediate treatment to avoid the death of the pregnant woman or the fetus. However, this pathology can be masked by preeclampsia, which is another more frequent liver disease. This delays treatment and increases the number of complications. The aim of this article is to conduct a bibliographic search about AFLP and identify similar factors between this pathology and severe preeclampsia to make a diagnosis and provide treatment in a timely manner. For this, a systematic search was carried out in databases (PubMed, Science Direct, Medline, Embase) in June 2017. In addition, original articles, case reports, and review articles published in the last ten years were selected.

Resumo: O fígado gorduroso agudo da gestação é uma das alterações hepáticas com mais mortalidade (cerca de 18 %) presentes na gravidez, embora seja uma patologia pouco frequente: 1 de cada 7.000 a 16.000 gestações apresenta muitas complicações e requer uma ação imediata para evitar a morte da gestante ou do feto. Contudo, essa patologia pode ser camuflada com a pré-eclâmpsia, que é outra patologia hepática de maior frequência, o que atrasa seu tratamento e aumenta o número de complicações. Nesse sentido, o objetivo deste estudo é realizar uma busca bibliográfica sobre o fígado gorduroso agudo da gestação e identificar os fatores semelhantes entre ele e a pré-eclâmpsia grave para poder fazer um diagnóstico e tratamento oportunos. Para isso, foi realizada uma busca sistemática nas bases de dados, PubMed, Science Direct, Medline, Embase, em junho de 2017, das quais foram selecionados artigos originais, relatos de caso e artigos de revisão, publicados nos últimos dez anos.

Steatosis and steatohepatitis found in adults after death due to non-burn trauma

OBJECTIVE: With the increasing prevalence of steatosis, the number of steatotic liver grafts from deceased donors is also increasing. Thus, determining the prevalence and the population risk factors of steatosis may assist in risk stratification. The aim of this study was to evaluate the prevalence and predictors of steatosis and steatohepatitis among livers from adults who died due to non-burn trauma. METHODS: Specimens were collected from 224 adults undergoing autopsy at a regional autopsy referral center from September 2011 to April 2013. Histopathological examination was performed on six samples obtained from different lobes of each liver. The outcomes of interest were the presence of steatosis, steatohepatitis, NASH inflammation and NASH fibrosis. The main predictors were body mass index, abdominal circumference, liver weight and volume, presence of cholelithiasis, and siderosis. Our modeling strategy made use of a series of generalized linear models with a binomial family. RESULTS: Our sample had a mean age of 40 years; steatosis was diagnosed in 48.2% of cases, and steatohepatitis was diagnosed in 2.7%. The presence of a high proportion of fatty changes was more prevalent among males and older individuals, with the most affected age group being 41-60 years. When evaluating the crude odds ratio for steatosis, the factors significantly associated with an increased risk of steatosis were greater abdominal circumference, BMI, and liver weight and the presence of siderosis. CONCLUSION: Our study reinforces the role of older age, obesity and hepatomegaly as predictors of fatty liver disease. These variables should be considered in the assessment of fatty changes in the livers of potential liver donors.

Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Liver biopsy may facilitate pancreatic graft evaluation: positive association between liver steatosis and pancreatic graft adipose infiltration

OBJECTIVES: The number of pancreatic transplants has decreased in recent years. Pancreatic grafts have been underutilized compared to other solid grafts. One cause of discard is the macroscopic appearance of the pancreas, especially the presence of fatty infiltration. The current research is aimed at understanding any graft-related association between fatty tissue infiltration of the pancreas and liver steatosis. METHODS: From August 2013 to August 2014, a prospective cross-sectional clinical study using data from 54 multiple deceased donor organs was performed. RESULTS: Micro- and macroscopic liver steatosis were significantly correlated with the donor body mass index ([BMI]; p=0.029 and p=0.006, respectively). Positive gamma associations between pancreatic and liver macroscopic and microscopic findings (0.98; confidence interval [CI]: 0.95-1 and 0.52; CI 0.04-1, respectively) were observed. Furthermore, comparisons of liver microscopy findings showed significant differences between severe versus absent (p<0.001), severe versus mild (p<0.001), and severe versus moderate classifications (p<0.001). The area under the receiver operating curve was 0.94 for the diagnosis of steatosis by BMI evaluation using a cut-off BMI of 27.5 kg/m2, which yielded 100% sensitivity, 87% specificity, and 100% negative predictive value. CONCLUSIONS: We observed a positive association of macroscopic and microscopic histopathological findings in steatotic livers with adipose infiltration of pancreatic grafts.

Differential therapeutic effects of Crataegus aronia and simvastatin on the hepatocyte ultrastructure in hepatic steatosis / Efectos terapéuticos diferenciales de Crataegus aronia y simvastatina sobre la estructura del hepatocito en la esteatosis hepática

Complications of fat accumulation in liver, hepatic steatosis such as liver cirrhosis and liver failure are among the common public health problems. We sought to investigate the damage to the hepatocyte ultrastructure induced by high fat diets (HFD) and compared the therapeutic effects at the cellular level of two antioxidant and lipid lowering agents; Crataegus aronia extracts and simvastatin on hepatic steatosis. Rats were either fed with HFD (model group) or low fat diets (LFD) (control group) for 15 weeks before being sacrificed and therapeutic groups started the treatment with these agents after week 11 until the sacrifice day. Harvested liver tissues were examined using transmission electron microscopy (TEM) and liver homogenates were assayed for markers of anti-oxidative stress that are known to be modulated in liver injury. TEM examinations of the model group showed a profound damage to the hepatocytes compared to the control group as demonstrated by steatosis, damaged mitochondria and vaculated cytoplasm, disrupted rough and smooth endoplasmic reticulum and nuclear membrane, dilated intercellular space between hepatocytes, and alterations in lysosomes. In addition, HFD ameliorated the anti-oxidant glutathione (GSH) and augmented the oxidative stress TBARS biomarkers. Both Crataegus aronia and simvastatin significantly reduced lipids and TBARS, and treated damage to hepatic cells, but hepatocyte structures were differentially responded to these agents. However, only Crataegus aronia induced GSH (p=0.001). We conclude that HFD-induced hepatic steatosis caused a substantial damage to the hepatocyte's ultrastructures, and Crataegus aronia and simvastatin treatments differentially reversed hepatic injuries.

Las complicaciones de la acumulación de grasa en el hígado, la esteatosis hepática como la cirrosis hepática y la insuficiencia hepática se encuentran entre los problemas comunes de salud pública. Se intentó investigar el daño a la ultraestructura de los hepatocitos inducido por la dieta alta en grasas (DAG) y se compararon los efectos terapéuticos a nivel celular de dos antioxidantes y agentes hipolipemiantes; Extracto de Crataegus aronia y simvastatina sobre esteatosis hepática. Las ratas fueron alimentadas con DAG (grupo modelo) o dieta baja en grasa (DBG) (grupo control) durante 15 semanas antes de sacrificarse y los grupos terapéuticos comenzaron el tratamiento con estos agentes después de la semana 11 hasta el día del sacrificio. Se examinaron los tejidos hepáticos usando microscopía electrónica de transmisión (MET) y se analizaron homogeneizados de hígado para marcadores de estrés anti-oxidativo, que se sabe están modulados en la lesión hepática. Los exámenes MET del grupo DAG mostraron un grave daño de los hepatocitos en comparación con el grupo control, demostrado por esteatosis, daño mitocondrial y citoplasma vacío, retículo endoplásmico rugoso y liso y membrana nuclear, el espacio intercelular dilatado entre hepatocitos y alteraciones en los lisosomas. Además, DAG mejoró el anti-oxidante glutatión (GSH) y aumentó el estrés oxidativo TBARS biomarcadores. Tanto Crataegus aronia como simvastatina redujeron significativamente los lípidos y TBARS, trataron el daño a las células hepáticas, pero las estructuras de hepatocitos respondieron diferencialmente a estos agentes. Sin embargo, sólo Crataegus aronia indujo GSH (p = 0,001). Concluimos que la esteatosis hepática inducida por HFD causó un daño sustancial a la ultraestructura del hepatocito y los tratamientos de Crataegus aronia y simvastatina diferenciaron las lesiones hepáticas.

Combined treatment with caffeic and ferulic acid from Baccharis uncinella C. DC. (Asteraceae) protects against metabolic syndrome in mice

Fractionation of the EtOH extract from aerial parts of Baccharis uncinella C. DC. (Asteraceae) led to isolation of caffeic and ferulic acids, which were identified from spectroscopic and spectrometric evidence. These compounds exhibit antioxidant and anti-inflammatory properties and have been shown to be effective in the prevention/treatment of metabolic syndrome. This study investigated whether the combined treatment of caffeic and ferulic acids exhibits a more significant beneficial effect in a mouse model with metabolic syndrome. The combination treatment with caffeic and ferulic acids was tested for 60 days in C57 mice kept on a high-fat (40%) diet. The data obtained indicated that treatment with caffeic and ferulic acids prevented gain in body weight induced by the high-fat diet and improved hyperglycemia, hypercholesterolemia and hypertriglyceridemia. The expression of a number of metabolically relevant genes was affected in the liver of these animals, showing that caffeic and ferulic acid treatment results in increased cholesterol uptake and reduced hepatic triglyceride synthesis in the liver, which is a likely explanation for the prevention of hepatic steatosis. In conclusion, the combined treatment of caffeic and ferulic acids displayed major positive effects towards prevention of multiple aspects of the metabolic syndrome and liver steatosis in an obese mouse model.

Both hepatic lipogenesis and beta-oxidation are altered in offspring of mothers fed a high-fat diet in the first two generations (F1 and F2) / La lipogénesis hepática y la beta-oxidación están alteradas en las crías de madres alimentadas con una dieta alta en grasas en las dos primeras generaciones (F1 y F2)

The high fat (HF) fed mothers may program susceptibility in offspring to chronic diseases and affect subsequent generations. The present study evaluated the liver structure in adulthood, focusing on the F1 and F2 generations. Females C57BL/6 (F0) were fed standard chow (SC) or HF diet (8 weeks) prior to mating and during the gestation and lactation to provide the F1 generation (SC-F1 and HF-F1). All other mothers and offspring fed SC. At 3 months old, F1 females were mated to produce the F2 generation (SC-F2 and HF-F2). The liver was kept in several fragments and prepared for histological analysis or frozen for biochemical and molecular analyzes. The F1 and F2 offspring were studied at 3 months old. HF-F1 had higher body mass (BM) compared to SC-F1 (P= 0.001), but not HF-F2 compared to SC-F2. HF-F1 had glucose intolerance when compared to SC-F1, but not HF-F2 compared to SC-F2. HF-F1 (P= 0.009) and HF-F2 (P= 0.03) showed hyperinsulinemia compared to their counterparts. Both groups HF-F1 and HF-F2 showed more steatosis than the SC counterparts (F1 and F2, P<0.0001). HF-F1 showed increased expression of PPAR-gamma and SREBP1-c compared to SC-F1 (P= 0.01). HF-F2 showed increased PPAR-gamma expression compared to SC-F2 (P= 0.04). In conclusion, HF-fed mother impairs both lipogenesis and beta-oxidation pathways in F1 through upregulation of PPAR-gamma and downregulation of PPAR-alpha. In F2, the only lipogenesis is enhanced, but it causes a disrupted PPAR balance, favoring the hepatic lipid accumulation and impaired metabolism in these animals that were not directly exposed to the maternal HF intake.

Los madres alimentadas con dieta rica en grasas (HF) pueden programar una susceptibilidad al desarrollo de enfermedades crónicas en su descendencia y de este modo afectar a las generaciones posteriores. El presente estudio evaluó la estructura del hígado en la edad adulta, centrándose en las generaciones F1 y F2. Las hembras C57BL/6 (F0) fueron alimentadas con dieta estándar (CS) o dieta HF (8 semanas) antes del apareamiento y durante la gestación y lactancia para producir la generación F1 (CS-F1 y HF-F1). Todas las demás madres y crías fueron alimentadas con CS. A los 3 meses de edad, las hembras F1 fueron apareadas para producir la generación F2 (CS-F2 y HF-F2). El hígado se conservó en varios fragmentos y se preparó, por un lado, para el análisis histológico, y por otro, se lo congeló para realizar análisis bioquímicos y moleculares. La descendencia F1 y F2 se estudió a los 3 meses de edad. HF-F1 tuvo una mayor masa corporal (BM) en comparación con CS-F1 (P= 0,001), pero no el grupo HF-F2 en comparación con CS-F2. HF-F1 tenía intolerancia a la glucosa en comparación con CS-F1, pero no el grupo HF-F2 en comparación con CS-F2. HF-F1 (P= 0,009) y HF-F2 (P= 0,03) mostraron hiperinsulinemia en comparación con sus homólogos. Ambos grupos HF-F1 y HF-F2 mostraron más esteatosis que las contrapartes CS (F1 y F2, P <0,0001). HF-F1 mostró una mayor expresión de PPAR-gamma y SREBP1-c en comparación con el grupo CS-F1 (P= 0,01). HF-F2 mostró aumento de la expresión de PPAR-gamma en comparación con CS-F2 (P= 0,04). En conclusión, la madre alimentada con HF presenta ambas vías afectadas, de lipogénesis y de la beta-oxidación, en la F1 a través de la regulación positiva de PPAR-gamma y con regulación a la baja de los PPAR-alfa. En F2, solo ha mejorado la vía de lipogénesis, pero causa un desbalance de PPAR, lo que favorece la acumulación de lípidos hepáticos y la alteración del metabolismo en estos animales que no estaban directamente expuestos a la ingesta materna de HF.

Effect of physical training on liver expression of activin A and follistatin in a nonalcoholic fatty liver disease model in rats

Nonalcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver and is associated with obesity and insulin resistance. Activin A is a member of the transforming growth factor beta (TGF)-β superfamily and inhibits hepatocyte growth. Follistatin antagonizes the biological actions of activin. Exercise is an important therapeutic strategy to reduce the metabolic effects of obesity. We evaluated the pattern of activin A and follistatin liver expression in obese rats subjected to swimming exercise. Control rats (C) and high-fat (HF) diet-fed rats were randomly assigned to a swimming training group (C-Swim and HF-Swim) or a sedentary group (C-Sed and HF-Sed). Activin βA subunit mRNA expression was significantly higher in HF-Swim than in HF-Sed rats. Follistatin mRNA expression was significantly lower in C-Swim and HF-Swim than in either C-Sed or HF-Sed animals. There was no evidence of steatosis or inflammation in C rats. In contrast, in HF animals the severity of steatosis ranged from grade 1 to grade 3. The extent of liver parenchyma damage was less in HF-Swim animals, with the severity of steatosis ranging from grade 0 to grade 1. These data showed that exercise may reduce the deleterious effects of a high-fat diet on the liver, suggesting that the local expression of activin-follistatin may be involved.

Esteatosis hepática, grasa visceral y alteraciones metabólicas, en individuos con sobrepeso/obesidad aparentemente sanos / Hepatic steatosis, visceral fat and metabolic alterations in apparently healthy overweight/obese individuals

La observación clínica indica que muchos obesos no presentan alteraciones metabólicas importantes, por lo que el objetivo del presente estudio fue comprobar si el sobrepeso/obesidad (SP/OB) simple, no asociado a otros factores de riesgo, se acompañaba de alteraciones metabólicas; o si estaba presente el fenómeno conocido como “paradoja de la obesidad”. A 30 individuos aparentemente sanos de Maracaibo, Venezuela, entre 20 y 59 años de edad, e índice de masa corporal (IMC) superior a 25 kg/m², y a un grupo control de 11 individuos con IMC inferior a 25 kg/m², se les realizó una historia clínica, medida de parámetros antropométricos, determinaciones basales de glicemia, insulina y lípidos, medición ultrasonográfica para esteatosis hepática y ultrasonografía e impedancia bioeléctrica para estimar la grasa visceral. El estudio demostró que solo en un tercio de los individuos con SP/OB, con elevado IMC y circunferencia de cintura (CC), se encontraron concentraciones elevadas de insulina, HOMA-IR y triglicéridos. A pesar de ello, la presencia de esteatosis hepática fue muy elevada (91%) en el grupo SP/OB, si se compara con 9% en el grupo control. La grasa visceral, en el grupo control, estuvo asociada a la CC y a la glicemia; sin embargo, no se relacionó con el IMC, insulina, HOMA-IR o HDLc; mientras que en el grupo SP/OB, aunque estadísticamente elevada en relación al grupo control, reveló una pérdida de estas asociaciones. Los resultados resaltan la importancia de investigar más la presencia de esteatosis hepática en los individuos con SP/OB, que la estimación de la grasa visceral, para identificar sujetos con alto riesgo cardiometabólico.

Clinical observation indicates that many obese individuals do not display important metabolic alterations. Consequently, the objective of this study was to establish whether simple obesity, non concurrent with other important risk factors, was associated with metabolic alterations; or if the phenomenon known as “obesity paradox” was present. A clinical history, measurements of anthropometric and metabolic parameters and estimation of hepatic steatosis and visceral fat, were determined in 30, apparently healthy, individuals from Maracaibo, Venezuela, between 20 and 59 years of age and a body mass index (BMI) above 25 kg/m²,and compared to a lean control group of 11 individuals with BMI less than 25 kg/m². The study demonstrated that only one third of overweight/obese individuals (OW/OB), with high body mass index (BMI) and waist circumference (WC), presented elevated values of insulin, HOMA-IR and triglycerides. Nevertheless, the presence of hepatic steatosis was elevated in the OW/OB group (91%) vs. 9% in the control group. The visceral fat in the lean control group was associated with both, WC and glycemia; however, it was not related to the BMI or insulin, HOMA-IR and HDLc. The visceral fat in the OW/OB group, although elevated in relation to the lean group, revealed a loss of these associations. In the OW/OB it was the BMI that was associated with insulin and HOMA-IR. The results emphasize the importance of investigating for the presence of hepatic steatosis, rather than visceral fat, in individuals with OW/OB, to identify subjects with high cardiometabolic risk.

Gallstone Disease Does Not Predict Liver Histology in Nonalcoholic Fatty Liver Disease

BACKGROUND/AIMS: We sought to examine whether the presence of gallstone disease (GD) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) is associated with liver fibrosis and histological nonalcoholic steatohepatitis (NASH) score. METHODS: We included 441 Turkish patients with biopsy-proven NAFLD. GD was diagnosed in the presence of sonographic evidence of gallstones, echogenic material within the gallbladder with constant shadowing and little or no visualization of the gallbladder or absence of gallbladder at ultrasonography, coupled with a history of cholecystectomy. RESULTS: Fifty-four patients (12.2%) had GD (GD+ subjects). Compared with the GD- subjects, GD+ patients were older, had a higher body mass index and were more likely to be female and have metabolic syndrome. However, GD+ patients did not have a higher risk of advanced fibrosis or definite NASH on histology. After adjustment for potential confounding variables, the prevalence of GD in NAFLD patients was not associated with significant fibrosis (> or =2) (odds ratio [OR], 1.06; 95% confidence interval [CI], 0.53 to 2.21; p=0.68) or definite NASH (OR, 1.03; 95% CI, 0.495 to 2.12; p=0.84). CONCLUSIONS: The presence of GD is not independently associated with advanced fibrosis and definite NASH in adult Turkish patients with biopsy-proven NAFLD.

Overview and recent trends of systematic reviews and meta-analyses in hepatology

A systematic review (SR) is a research methodology that involves a comprehensive search for and analysis of relevant studies on a specific topic. A strict and objective research process is conducted that comprises a systematic and comprehensive literature search in accordance with predetermined inclusion/exclusion criteria, and an assessment of the risk of bias of the selected literature. SRs require a multidisciplinary approach that necessitates cooperation with clinical experts, methodologists, other experts, and statisticians. A meta-analysis (MA) is a statistical method of quantitatively synthesizing data, where possible, from the primary literature selected for the SR. Review articles differ from SRs in that they lack a systematic methodology such as a literature search, selection of studies according to strict criteria, assessment of risk bias, and synthesis of the study results. The importance of evidence-based medicine (EBM) in the decision-making for public policy has recently been increasing thanks to the realization that it should be based on scientific research data. SRs and MAs are essential for EBM strategy and evidence-based clinical practice guidelines. This review addresses the current trends in SRs and MAs in the field of hepatology via a search of recently published articles in the Cochrane Library and Ovid-MEDLINE.

Nonalcoholic fatty liver disease in severe obese patients, subjected to bariatric surgery / Doenca hepatica gordurosa nao alcoolica em pacientes com obesidade morbida, submetidos a cirurgia bariatrica

Context Nonalcoholic fatty liver disease encompasses a spectrum of histopathological changes that range from simple steatosis to nonalcoholic steatohepatitis. Works suggest that iron (Fe) deposits in the liver are involved in the physiopathology of nonalcoholic steatohepatitis. Objective The aim of this study was to determine the prevalence of simple steatosis and nonalcoholic steatohepatitis in patients with morbid obesity, subjected to bariatric surgery and to establish a correlation of the anatomopathological findings with the presence of liver fibrosis. Methods A total of 250 liver biopsies were conducted in the transoperation of the surgeries. Results Steatosis was present in 226 (90.4%) of the samples, 76 (30.4%) being classified as mild; 71 (28.4%) as moderate and 79 (31.6%) as intense. Nonalcoholic steatohepatitis was diagnosed in 176 (70.4%) cases, where 120 (48.4%) were mild; 50 (20%) were moderate, and 6 (2.4%) cases were intense. Fibrosis was referred to in 108 (43.2%) biopsies, 95 of which (38%) were mild; 2 (0.8%) were moderate; 7 (2.8%) were intense, and cirrhosis was diagnosed in 4 (1.6%) cases. There was a correlation between the degree of steatosis and the level of inflammatory activity (rs = 0.460; P<0.001) and between the degree of this activity and the degree of fibrosis (rs = 0.583; P<0.001). Only 13 (5.2%) samples showed Fe deposits. Conclusion There is a high prevalence of nonalcoholic steatohepatitis in these patients and a positive correlation of the degrees of nonalcoholic steatohepatitis with the intensity of fibrosis. The low prevalence of Fe deposits found makes it questionable that the presence of this ion has any participation in the physiopathogeny of nonalcoholic fatty liver disease. .

Contexto A doença hepática gordurosa não alcoólica engloba um espectro de alterações histopatológicas que abrangem desde a esteatose simples até a esteato-hepatite não alcoólica. Trabalhos sugerem que depósitos de ferro (Fe) no fígado estão envolvidos na fisiopatologia da esteato-hepatite não alcoólica. Objetivo Determinar a prevalência de esteatose simples e de esteato-hepatite não alcoólica nos pacientes com obesidade mórbida, submetidos à cirurgia bariátrica e estabelecer uma correlação dos achados anatomopatológicos com a presença de fibrose hepática. Método Foram analisadas 250 biópsias hepáticas realizadas no transoperatório das cirurgias. Resultados A esteatose esteve presente em 226 (90,4%) das amostras, sendo 76 (30,4%) classificadas como leves; 71 (28,4%), como moderadas e, 79 (31,6%) como intensas. A esteato-hepatite não alcoólica esteato-hepatite não alcoólica foi diagnosticada em 176 (70,4%) dos casos, nos quais 120 (48,4%) eram de grau leve; 50 (20%) moderado e, 6 (2,4%) intenso. A fibrose foi referida em 108 (43,2%) biópsias, das quais 95 (38%) eram leves; 2 (0,8%), moderadas; 7 (2,8%) intensas e, em 4 (1,6%) casos, foi diagnosticado cirrose. Observou-se uma correlação entre o grau de esteatose e o nível de atividade inflamatória (rs = 0,460; P<0,001) e entre o grau dessa atividade com o de fibrose (rs = 0,583; P<0,001). Apenas 13 (5,2%) amostras apresentaram depósitos de Fe. Conclusão Existe uma prevalência elevada de esteato-hepatite não alcoólica nesses pacientes e uma correlação positiva dos graus de esteato-hepatite não alcoólica com a intensidade da fibrose. A baixa prevalência de depósitos de Fe encontrada torna questionável que a presença deste ...

The spectrum of non alcoholic fatty liver disease in morbidly obese patients: prevalence and associate risk factors

PURPOSE: To determine the prevalence of non alcoholic fatty liver disease (NAFLD) and non alcoholic steatohepatitis (NASH) in morbidly obese patients undergoing bariatric surgery and to identify risk factors associated with the disease spectrum. METHODS: Liver biopsy was performed in 60 patients who underwent bariatric surgery, after other causes of liver disease were excluded. Clinical, biochemical and histological features were evaluated. RESULTS: NAFLD was detected in fifty-seven patients (95%) of the sample and forty patients (66.7%) of the total sample met the criteria for NASH. Perisinusoidal fibrosis was only found in three (7.5%) patients with NASH. The γGT was an independent predictive factor associated with the degree of hepatic steatosis. The variables such as dyslipidemia and ALT were independently associated with the presence of Mallory's corpuscles with the following values, respectively, OR 0, 05, 95% CI 0.002 to 0.75, P = 0.031 and OR 10, 99, 95% CI 1.44 to 83.93, P = 0.021. CONCLUSIONS: Non alcoholic fatty liver disease seems to be an obese-related condition with approximately half of asymptomatic morbidly obese patients having histological NASH. The γGT was an independent predictor of the degree of steatosis.

Elevación de aminotransferasas y su relación con esteatosis hepática en pacientes obesos / Aminotransferases elevation and its relationship with hepatic steatosis in obese patients

NAFLD es la principal causa de enfermedad crónica del hígado siendo la causa más frecuente de alteración de aminotransferasas, en hasta un 66 a 90%. Determinar la elevación de aminotransferasas y su relación con esteatosis hepática en pacientes obesos. Se realizó un estudio descriptivo, prospectivo y transversal; el muestreo empleado fue intencional, no probabilístico desde Enero-Abril 2012. Se incluyeron 45 individuos obesos con edades entre 18 a 70 años, a los cuales se les practicó ultrasonido abdominal y química sanguínea. De los 45 pacientes incluidos el 73.3% (n=33) fueron del sexo femenino, con una edad promedio fue 47 ± 14 años; el IMC promedio fue 33,4 ± 5,5, la concentración media de AST fue 41 ± 15 UI/mL y de ALT fue 34 ± 14 UI/mL. La media de la concentración de colesterol total fue de 201 ± 39 mg y triglicéridos 171 ± 82 mg. Los pacientes con esteatosis hepática presentaron elevación de AST con respecto a los pacientes sin esteatosis, (p = 0,071); ALT se elevó más en pacientes con esteatosis que en los pacientes sin esteatosis, (p = 0,004), pudiendo inferir que la esteatosis hepática influye en su elevación. En cuanto al colesterol total y triglicéridos, no se encontró relación; aunque, el colesterol total estuvo más elevado en el grupo de pacientes con esteatosis que en los pacientes sin esteatosis. Se halló asociación entre los grados de obesidad y la presencia de esteatosis hepática (p = 0,001)

NAFLD is the leading cause of chronic liver disease being the most common cause of altered transaminases in up to 66 to 90%. Determine the elevation of aminotransferases and its relationship to hepatic steatosis in obese. We performed a descriptive, prospective and transversal study; the sample used was intentional, non-probability from January to April 2012. We included 45 obese persons aged 18 to 70 years old; we performed to all an abdominal ultrasound and blood chemistry. Of the 45 patients included 73.3% (n = 33) were female, mean age was 47 ± 14 years, mean BMI was 33.4 ± 5.5, the mean concentration of SAST was 41 ± 15 IU/mL and SALT was 34 ± 14 IU/mL. The mean total cholesterol concentration was 201 ± 39 mg and triglycerides 171 ± 82 mg. Patients with hepatic steatosis had elevation of AST compared to patients without steatosis, (p = 0.071), the value of ALT was higher in patients with steatosis than in patients without steatosis, (p = 0.004), we can infer that hepatic steatosis influences their elevation. As for total cholesterol and triglycerides, no relationship was found, although total cholesterol was higher in the group of patients with steatosis than in patients without steatosis. Association was found between the degree of obesity and the presence of hepatic steatosis (p = 0.001)