The association between preoperative chemotherapy and the prevalence of hepatic steatosis in hepatectomy for metastatic colorectal cancer / Associação da quimioterapia pré-operatória e a prevalência de esteatose hepática em hepatectomias por metástase de câncer colorretal

BACKGROUND: Some studies have suggested that preoperative chemotherapy for hepatic colorectal metastases may cause hepatic injury and increase perioperative morbidity and mortality. AIM: To evaluate the prevalence of hepatic steatosis in patients undergoing preoperative chemotherapy for metastatic colorectal cancer. METHODS: Observational retrospective cohort study in which 166 patients underwent 185 hepatectomies for metastatic colorectal cancer with or without associated preoperative chemotherapy from 2004 to 2011. The data were obtained from a review of the medical records and an analysis of the anatomopathological report on the non-tumor portion of the surgical specimen. The study sample was divided into two groups: those who were exposed and those who were unexposed to chemotherapy. RESULTS: From the hepatectomies, 136 cases (73.5%) underwent preoperative chemotherapy, with most (62.5%) using a regimen of 5-fluorouracil + leucovorin. A 40% greater risk of cell damage was detected in 62% of the exposed group. The predominant histological pattern of the cell damage was steatosis, which was detected in 51% of the exposed cases. Exposure to chemotherapy increased the risk of steatosis by 2.2 fold. However, when the risk factors were controlled, only the presence of risk of hepatopathy was associated with steatosis, with a relative risk of 4 (2.7-5.9). CONCLUSION: Patients exposed to chemotherapy have 2.2 times the risk of developing hepatic steatosis, and its occurrence is associated with the presence of predisposing factors such as diabetes mellitus and hepatopathy. .

RACIONAL: Alguns estudos sugerem que a quimioterapia pré-operatória para metástases hepáticas do câncer colorretal pode causar dano celular e aumentar morbidade e mortalidade. OBJETIVO: Analisar a prevalência de esteatose hepática em fígados de pacientes expostos à quimioterapia pré-operatória por metástase de câncer colorretal. MÉTODOS: O delineamento do estudo foi observacional de coorte retrospectivo, no qual 166 pacientes foram submetidos a 185 hepactectomias por metástase de câncer colorretal, com e sem quimioterapia pré-operatória, no período de 2004 a 2011. Os dados foram extraídos da revisão dos prontuários e da análise do laudo anatomopatológico da parte não tumoral da peça cirúrgica. A amostra foi dividida em grupo exposto e não-exposto à quimioterapia. Os dados foram analisados por programa estatístico Stata 11.2, e aplicado o teste exato de Fischer para análise bivariada, e a regressão de Poisson, para análise multivariada; valores p< 0,05 foram considerados como significativos. RESULTADOS: Das hepatectomias, 136 casos (73,5%) receberam quimioterapia pré-operatória, e o regime mais utilizado (62,5%) foi 5-fluorouracila+leucovorin. No grupo exposto, a lesão hepatocelular esteve presente em 62% dos casos e correspondeu a risco de 40% em relação ao grupo não-exposto. O padrão histológico da lesão hepatocelular predominante foi a esteatose, em 51% de casos do grupo exposto. A exposição à quimioterapia aumentou em 2,2 vezes a possibilidade de esteatose. Entretanto, quando foram controlados os fatores de risco, somente a hepatopatia prévia esteve associada à presença de esteatose após quimioterapia com risco relativo de 4 (2,7-5,9). CONCLUSÕES: Pacientes expostos ...

Preventive effect of omega-3 fatty acids on ethinyl estradiol induced hepatosteatosis in female wistar rat

Hepatic steatosis due to estrogen therapy increases the activity of inflammatory markers, particularly the activity of TNF alpha -which in turn induces more lipogenesis. Omega-3 fatty acids are among the negative regulators of hepatic lipogenesis. In this research, the preventive effect of omega-3 fatty acids on estrogen-induced steatosis in rats was evaluated. 2 mg/kg. BW/SC of 17 alpha-ethiny-lestrasdiol were injected into 25 female wistar rats in 5 equal groups [excluding the control group] over 10 consecutive days. Simultaneously, 3 of estradiol-treated groups were orally given 250, 500, and 1000 mg/kg. BW omega-3 fatty acids, respectively. At the end of the experiment, plasma ALT, AST, and TNF alpha level were determined. Histopathological changes in the liver were also identified by the evaluation of samples stained with H and E and Oil Red O. The histological findings revealed hepatic microvesicular steatosis and fat deposit in ethinylestradiol and, to a lesser extent, in the 250 mg/kg BW omega-3 fatty acids groups. The plasma levels of AST, ALT, and TNF alpha -significantly increased in the ethinylestradiol group compared to the control [p<0.05] and 1000 mg/kg. B.W omega-3 group. Omega-3 fatty acids reduced these parameters in comparison to the estradiol group [p<0.05]. It was concluded that 1000mg/kg.BW of omega-3 protects the liver against steatotic injuries

A reduced grade of liver fibros-steatosis after raltegravir, maraviroc and fosamprenavir in an HIV/HCV co-infected patient with chronic hepatitis, cardiomyopathy, intolerance to nelfinavir and a marked increase of serum creatine phosphokinase levels probably related to integrase inhibitor use / Grado reducido de fibroesteatosis tras la administración de raltegravir, maraviroc y fosamprenavir en un paciente co-infectado de VIH/VHC con hepatitis crónica, cardiomiopatía, intolerancia al nelfinavir y un aumento pronunciado de los niveles de creatina fosfoquinasa sérica probablemente debido al uso del inhibidor de la integrasa

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.

Effect of silybin on high-fat-induced fatty liver in rats

Silybin, a natural antioxidant, has been traditionally used against a variety of liver ailments. To investigate its effect and the underlying mechanisms of action on non-alcoholic fatty liver in rats, we used 60 4-6-week-old male Sprague-Dawley rats to establish fatty liver models by feeding a high-fat diet for 6 weeks. Hepatic enzyme, serum lipid levels, oxidative production, mitochondrial membrane fluidity, homeostasis model assessment-insulin resistance index (HOMA-IR), gene and protein expression of adiponectin, and resistin were evaluated by biochemical, reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. Compared with the model group, silybin treatment (26.25 mg·kg-1·day-1, started at the beginning of the protocol) significantly protected against high-fat-induced fatty liver by stabilizing mitochondrial membrane fluidity, reducing serum content of alanine aminotransferase (ALT) from 450 to 304 U/L, decreasing hepatic malondialdehyde (MDA) from 1.24 to 0.93 nmol/mg protein, but increasing superoxide dismutase (SOD) and glutathione (GSH) levels from 8.03 to 9.31 U/mg protein and from 3.65 to 4.52 nmol/mg protein, respectively. Moreover, silybin enhanced the gene and protein expression of adiponectin from 215.95 to 552.40, but inhibited that of resistin from 0.118 to 0.018. Compared to rosiglitazone (0.5 mg·kg-1·day-1, started at the beginning of the protocol), silybin was effective in stabilizing mitochondrial membrane fluidity, reducing SOD as well as ALT, and regulating gene and protein expression of adiponectin (P < 0.05). These results suggest that mitochondrial membrane stabilization, oxidative stress inhibition, as well as improved insulin resistance, may be the essential mechanisms for the hepatoprotective effect of silybin on non-alcoholic fatty liver disease in rats. Silybin was more effective than rosiglitazone in terms of maintaining mitochondrial membrane fluidity and reducing oxidative stress.

Experimental induction of steatosis in different tissues after the ingestion of a carbohydrate-rich diet: effect on the liver, on the heart and on indicators of oxidation / Esteatose experimental em diferentes tecidos induzida pela ingestão de dieta rica em carboidratos: efeito sobre o fígado, coração e indicadores do estresse oxidativo

CONTEXT: The western dietary pattern is characterized by a high calorie intake with a high proportion of simple sugars. This diet is associated with comorbidities such as hepatic fat deposition and is possibly related to non-alcoholic fatty liver disease. OBJECTIVE: To evaluate the capacity of a hyperglucidic diet to induce steatosis in adult male Wistar rats. After the administration of a carbohydrate-rich diet, we also evaluated the presence of hepatic and cardiac steatosis and the levels of intrinsic antioxidants in the liver. METHODS: Forty-six eutrophic adult male Wistar rats were used and 10 of them were chosen, at random, to serve as controls, while the remaining ones formed the experimental group. Control animals received the standard ration offered by the animal house and the experimental group received the hyperglucidic diet. The diets were offered for 21 days and, at the end of this period, tissue samples were collected for analysis of indicators of oxidative stress (malondialdehyde, and reduced glutathione) and of vitamin E. The animals were then sacrificed by decapitation and their viscera were removed for analysis of liver and heart fat. RESULTS: The hyperglucidic diet used induced hepatic fat deposition, with lipid vacuoles being detected in 83 percent of the livers analyzed by histology. No lipid vacuoles were observed in the heart. Malondialdehyde and reduced glutathione levels remained unchanged when the animals were submitted to the hyperglucidic diet, probably because there was no liver development of fibrosis or inflammation. In contrast, the levels of vitamin E (antioxidant) were reduced, as confirmed in the literature for steatotic animals. CONCLUSION: The hyperglucidic diet induced hepatic steatosis. In the heart there was an increase in fat content, although no histological changes were observed. These alterations cannot be explained by the presence of malondialdehyde or reduced glutathione (indicators of oxidation), since the values were similar in the groups studied. However, a significant reduction of vitamin E was observed in the experimental group.

CONTEXTO: O padrão alimentar ocidental é caracterizado pela ingestão de dieta rica em açúcares simples. Esta alimentação é associada com comorbidades como, por exemplo, deposição de gordura no fígado e possivelmente relacionada com a esteatose hepática não-alcoólica. OBJETIVO: Avaliar a capacidade de uma alimentação hiperglicídica induzir esteatose em ratos Wistar adultos. Após administração de uma dieta rica em hidratos de carbono, foi avaliada a presença de esteatose hepática cardíaca e a presença de antioxidantes no fígado. MÉTODOS: Quarenta e seis ratos Wistar adultos eutróficos foram utilizados no experimento. Destes, 10 animais escolhidos por meio de sorteio simples (ao acaso) foram considerados controles e os demais pertencentes ao grupo experimental. Os animais controles receberam, durante todo experimento dieta usual do biotério. Os animais do grupo experimental, durante 21 dias, receberam dieta com 70 por cento de sacarose. Ao final os animais foram sacrificados por decapitação e suas vísceras (fígado e coração) analisada quanto ao teor de gordura. As amostras de tecido hepático foram também analisadas quanto ao teor de antioxidantes (malondialdehido e glutationa reduzida) e vitamina E. RESULTADOS: A dieta hiperglicídica induziu a deposição de gordura no fígado, sendo os vacúolos lipídicos detectados em 83 por cento das amostras no fígado (histologia). No coração foi detectado bioquimicamente aumento do percentual de gordura, sem a detecção de vacúolos lipídico por histologia. Os teores de malondialdehido e glutationa reduzida não foram diferentes entre os animais dos grupos controle e experimental. Por outro lado, os valores de vitamina E, no grupo experimental, foram significativamente inferiores ao do grupo controle. CONCLUSÃO: A dieta hiperglicídica induziu ao esteatose hepática. No coração houve maior deposição de lípides, embora a histologia não tenha mostrado alterações. Esta deposição, tanto no coração como no fígado, não pode ser explicada pelos indicadores de oxidação utilizados. No entanto, foram observados baixos níveis de vitamina E, que pode estar associada a esta indução de esteatose, principalmente, hepática.

El propóleos reduce la esteatosis hepática inducida por dieta en ratones / Propolis decrease diet-induced hepatic steatosis in mice

El hígado graso no alcohólico (HGNA), comprende un amplio espectro de lesiones, que van desde esteatosis hepática, hasta cirrosis y carcinoma hepatocelular, siendo sus principales factores de riesgo los desordenes asociados a síndrome metabólico (SM). El propóleos, sustancias resinosa elaborada por Apis mellifera para la protección de la colmena, ha demostrado un efecto hepatoprotector, así el objetivo de esta investigación fue evaluar el efecto de un propóleos chileno sobre el desarrollo de esteatosis hepática no alcohólica en ratones C57BL/6J sometidos a una dieta aterogénica tipo Paigen. Veintiocho ratones (C57BL/6J), divididos en: 1, dieta balanceada (CH); 2, dieta hipercolesterolémica (HC); 3, dieta HC + 10 mg/kg/día de propóleos (BP); 4, dieta HC + 40 mg/kg/día de propóleos (AP). Después de 16 semanas, se determinó la concentración de glucosa, colesterol total, triglicéridos y los niveles de alanina aminotransferasa (ALAT). El tejido hepático fue fijado en una solución de formalina tamponada al 10 por ciento para, posteriormente, ser incluido en paraplast y teñido con Hematoxilina-Eosina y fragmanetos congelados a -30C fijados en formalina teñidos con tinción Oil red O. No existieron diferencias en la concentración de glucosa ni triglicéridos, a diferencia del colesterol total, entre el grupo alimentado con dieta balanceada (CH) y los alimentados con la dieta aterogénica D12336 (HC, BP y AP). De la misma forma se observó que existen diferencias en los niveles de actividad de ALAT entre los grupos estudiados, destacando su reducción en los grupos suplementados con propóleos (BP y AP). De forma concordante, la histoarquitectura del grupo HC, mostró esteatosis simple y focos de infiltrado leucocitario en el lobulillo hepático, observándose una disminución gradual de las alteraciones en los grupos de BP y AP. En conclusión, el propóleos chileno estudiado disminuye la esteatosis hepática inducida por la dieta aterogénica tipo Paigen en ratones C57BL/6J, sin embargo, los mecanismos implicados en esta actividad hepatoprotectora tienen que ser identificados.

Nonalcoholic fatty liver disease (NAFLD) covers a wide spectrum of injuries ranging from simple steatosis to cirrhosis and hepatocellular carcinoma. Its main risk factors are disorders associated with metabolic syndrome (MS). Propolis, a resinous substance produced by Apis mellifera to protect is hive, has demonstrated a hepatoprotective effect. Thus, the aim of this study was to evaluate the effect of Chilean propolis on development of nonalcoholic hepatic steatosis in C57BL/6J mice exposed to Paigen atherogenic diet. Twenty eight mice C57BL/6J were divided four groups: 1, balanced diet (CH); 2, hypercholesterolemic diet (HD); 3, HD diet supplemented with 10 mg/kg/day of propolis (LP); 4, HD diet supplemented with 40 mg/kg/day of propolis (HP). After 16 weeks of treatment was determined glucose, total cholesterol and triglycerides concentrations and alanine aminotransferase (ALT) activity. The liver tissue was fixed in 10 percent buffered formalin solution, embedded in paraplast and stained with hematoxylin-eosin. No differences was detected in glucose and triglycerides concentrations, contrasting with total cholesterol levels between group fed with a balanced diet (CH) and feed with atherogenic diet D12336 (HD, LP and HP). In the same way, it was noted differences in ALT activity between groups, standing out the reduction in propolis supplemented groups (LP and HP). Likewise the histoarchitecture of HD group, showed simple steatosis, inflammatory cell infiltration and inflammatory foci in hepatic lobule. This characteristics show a gradual decrease in LP and HP groups. In conclusion, the Chilean propolis analyzed decreases hepatic steatosis induced by atherogenic diet in C57BL/6J mice. However, the involved mechanisms in this hepatoprotective activity must be identified.

Steatohepatitis due to antiretroviral therapy / Esteatohepatitis debido a la terapia antiretroviral

Jamaica has recorded the largest increase in the rate of HIV/AIDS infection in the English-speaking Caribbean since 1985. Treatment has significantly improved recently with approximately 50% availability of antiretrovirals (ARVs) to patients. The incidence of drug induced hepatotoxicity is not well known for most ARV drugs and few studies have assessed adverse drug effects in clinical practice. A patient with HIV on highly active antiretroviral therapy (HAART) presented with a one year history of progressive abdominal distension. Abdominal examination revealed a 17 cm, smooth, non-tender liver with a rounded edge; 12 cm of which was below the right costal margin. Liver enzymes were grossly abnormal. The liver biopsy revealed parenchymal distortion by fibrosis with macrovesicular fatty change and Mallory's hyaline in keeping with steatohepatitis. Follow-up studies after discontinuation of stavudine revealed that the liver enzymes improved within four months. Physicians should be mindful of the hepatotoxic potential of ARVs and monitor liver enzymes in HIV-infected patients on therapy.

Jamaica ha registrado el mayor aumento de la tasa de infección de VIH/SIDA en el Caribe anglófono desde 1985. El tratamiento ha mejorado recientemente de manera significativa, con una disponibilidad de 50% de antiretrovirales (ARVs) para pacientes. La incidencia de la hepatotoxicidad inducida por medicamentos no es conocida para la mayoría de los medicamentos ARV y pocos estudios han evaluado los efectos adversos de esos medicamentos en la práctica clínica. Un paciente con VIH, sometido a una terapia antiretroviral altamente activa, se presentó con una historia de distensión abdominal progresiva de un año. El examen abdominal reveló un hígado de 17 cm, liso, no blando, y de bordes redondeados, 12 cm del cual se hallaban por debajo del margen del costado derecho. Las enzimas del hígado eran evidentemente anormales. La biopsia del hígado reveló una distorsión parenquimatosa por fibrosis con cambio graso macrovesicular y formación de hialina de Mallory en correspondencia con la esteatohepatitis. Los estudios de seguimiento tras la discontinuación de la estavudina, revelaron que las enzimas del hígado mejoraron en cuatro meses. Los médicos deben tomar conciencia del potencial hepatotóxico de los ARVs y monitorear las enzimas del hígado en pacientes infectados con el VIH que se hallen bajo terapia.

Somatic, Biochemical and Hepatic Alterations in Wild Type Mice Chronically Fed High Fat Diet / Alteraciones Somáticas Bioquímicas y hepáticas en un Tipo de Ratas Alimentadas Crónicamente con Dieta Alta en Grasas

This study evaluated whether a high fat diet (HFC group) induces overweight, hepatic steatosis and plasma lipoproteins level alteration compared to standard chow diet (SC group). Female mice were submitted to each diet over 6 months. Body mass and food intake were evaluated weekly throughout the experiment. Total cholesterol, TG, LDL-c, HDL-c and VLDL-c were analyzed. Mice were sacrificed to remove liver, spleen, heart and intestine. The volume of the organs was determined according to the submersion method. Fixed livers were embedded in paraffin and stained with hematoxylin and eosin and Masson's trichrome. The analysis used a video microscope system and a test-system with 42 test-points. The volume density was estimated for hepatocytes, steatosis and sinusoids. Animals fed HFC had smaller chow intake than SC group. HFC group presented body mass greater than SC. Animals fed HFC showed heavier liver and spleen and lighter intestine than SC (p<0.05), heart mass was not significant between groups. Plasma lipoproteins differed between groups (p<0.05) except VLDL-c and TG fractions. The liver structure was without major alteration in SC group however, HFC mice group showed different degrees of fatty degeneration with micro- and macrovesicular steatosis dispersed in all liver with typical peri-cellular/peri-sinusoidal fibrosis. The quantitative study showed significant (p<0.05) volume density reduction for hepatocytes and sinusoids. In conclusion, our results clearly show that hepatic steatosis can be induced in mouse by such a fat-rich diet without any toxin ingestion, alimentary deficiency and genes depletion.

Este estudio evaluó cómo una dieta de alta densidad energética (grupo ADE) induce sobrepeso, esteatosis hepática y altera los niveles de las lipoproteínas plasmáticas cuando son comparados con la dieta patrón (grupo SC). Hembras de camundongos fueron sometidas a cada una de las dietas durante 6 meses. La masa corporal y la ingestión de alimento fueron evaluadas semanalmente durante el experimento. Además fueron medidos el colesterol total, TG, LDL-c, HDL-c e VLDL-c. Los animales fueron sacrificados y el hígado, bazo, corazón e intestinos fueron removidos para estudio. El volumen de los órganos fue medido por el método de la sumersión. Fragmentos de hígado fueron preparados para el estudio en microscopía de luz, teñidos con hematoxilina-eosina y tricrómico de Masson. El análisis fue realizado con video microscopía y sistema test M42. La densidad de volumen fue estimada para hepatocitos, esteatosis y sinusoides. Los animales alimentados con dieta ADE presentaron menor ingestión de alimento y tuvieron masa corporal mayor que los animales con dieta patrón. Animales ADE mostraron también hígado y bazo más pesados e intestino más liviano que animales SC (p<0.05). Para la masa del corazón no hubo diferencia significativa entre los dos grupos. Las lipoproteínas plasmáticas fueron diferentes entre los grupos (p<0.05) excepto VLDL-c y fracciones de TG. La estructura hepática no presentó grandes alteraciones en el grupo SC; sin embargo, animales del grupo ADE presentaron diferentes grados de degeneración adiposa con esteatosis macro y microvesicular dispersas en todo el hígado con típica fibrosis pericelular y perisinusoidal, y significativa reducción de la densidad de volumen de hepatocitos y sinosoides. En conclusión, los resultados muestran que la esteatosis hepática puede ser inducida experimentalmente en camundongos, a través de dieta ADE, sin ingestión de cualquier toxina, deficiencia alimentaria o depleción genética.