BackgroundNon-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, which includes a spectrum of hepatic pathology such as simple steatosis, steatohepatitis, fibrosis and cirrhosis. The increased serum levels of homocysteine (Hcy) may be associated with hepatic fat accumulation. Genetic mutations in the folate route may only mildly impair Hcy metabolism. The aim of this study was to investigate the relation between liver steatosis with plasma homocysteine level and MTHFR C677T and A1298C polymorphisms in Brazilian patients with NAFLD.MethodsThirty-five patients diagnosed with NAFLD by liver biopsy and forty-five healthy controls neither age nor sex matched were genotyped for C677T and A1298C MTHFR polymorphisms using PCR-RFLP and PCR-ASA, respectively, and Hcy was determined by HPLC. All patients were negative for markers of Wilson’s, hemochromatosis and autoimmune diseases. Their daily alcohol intake was less than 100 g/week. A set of metabolic and serum lipid markers were also measured at the time of liver biopsies.ResultsThe plasma Hcy level was higher in NAFLD patients compared to the control group (p = 0.0341). No statistical difference for genotypes 677C/T (p = 0.110) and 1298A/C (p = 0.343) in patients with NAFLD and control subjects was observed. The genotypes distribution was in Hardy-Weinberg equilibrium (677C/T p = 0.694 and 1298 A/C p = 0.188). The group of patients and controls showed a statistically significant difference (p < 0.001) for BMI and HOMA_IR, similarly to HDL cholesterol levels (p < 0,006), AST, ALT, γGT, AP and triglycerides levels (p < 0.001). A negative correlation was observed between levels of vitamin B12 and Hcy concentration (p = 0.005).ConclusionOur results indicate that plasma Hcy was higher in NAFLD than controls. The MTHFR C677T and A1298C polymorphisms did not differ significantly between groups, despite the 677TT homozygous frequency was higher in patients (17.14%) than in controls (677TT = 4.44%) (p > 0.05). The suggested genetic susceptibility to the MTHFR C677T and A1298C should be confirmed in large population based studies.
The folate pathway is involved in hepatic carcinogenesis and angiogenesis. Polymorphisms in genes related to such processes, including methylene tetrahydrofolate reductase (MTHFR) and vascular endothelial growth factor (VEGF)] may play an important role in the development of hepatocellular carcinoma (HCC). The objective of this study was to evaluate MTHFR and VEGF polymorphisms in Brazilian patients with hepatitis C virus (HCV)-related HCC. METHODS: A total of 119 patients diagnosed with confirmed HCC and HCV were included in the study. SNP genotyping assays were performed using real-time PCR. VEGFA (rs2010963, rs3025039, and rs833061) and MTHFRC677T (rs1801133, rs1801131) polymorphisms were evaluated. RESULTS: The C alleles of MTHFR (rs1801131) and VEGF (rs2010963) were associated with protection against the development of multinodular HCC, while the T allele of MTHFR (rs1801133) was associated with a higher risk of multinodular presentation [p=0. ]. Multivariate analysis revealed that the GG/GC genotypes of VEGF rs2010963 were independently associated with multinodular tumors at diagnosis (p=0.013; OR 4.78 ]. CONCLUSION: Our results suggest that these polymorphisms may increase the risk of rapid tumor progression in patients with HCV infection. This subgroup of patients with HCC and who present polymorphism is more likely to be diagnosed with multinodular disease and not be amenable to receiving curative treatments. These data must be validated in larger cohorts, and the screening intervals can be customized based on genetic history.
AGRADECIMENTOS"Gratidão é o ato de reconhecimento de uma pessoa por alguém que lhe prestou um auxílio...em um sentido mais amplo abrange situações e dávidas que a vida lhe proporcionou e ainda proporciona." (Wikipédia) É chegada a hora de agradecer! Agradecer a todos que de alguma forma estiveram ligados a esta missão. Agradeço a Deus, Pai de todas as Dávidas desta vida. Foi a Fé que sempre me impulsionou até aqui. Agradeço aos meus pais e irmãos, base de minha educação, de minha personalidade e exemplos profissional. Agradeço a Aldo Cezar companheiro de minha jornada e aos meus filhos, pelo incentivo, compreensão, amor e atenção aos detalhes que fazem a diferença. Agradeço a meu orientador Dr Flair Carrilho e a minha co-orientadora Dra. Claúdia Oliveira. Pela confiança depositada e serem o meu ponto de apoio nesta missão. Agradeço ao grupo de nódulos do IFP nas pessoas de Dra. Leila Beltrão e Dra. Dayse, por acima de tudo compartilhar e incentivar. Agradeço a todos os colegas de trabalho por estarem juntos a mim neste processo, do início ao fim. Um agradecimento especial aos diretores do Hospital Universitário Oswaldo Cruz, Professora Doutora Izabel Avelar e do Hospital da Restauração de Pernambuco, Professor Doutor Miguel Arcanjo, pelo estímulo para o crescimento profissional. Agradeço ao grupo de trabalho do laboratório de cirurgia Experimental LIM-37-setor de biologia molecular da FMUSP pelo cuidado e atenção em realizar o trabalho. Agradeço a Vilma Libério secretária de pós-graduação em Ciências em gastroenterologia/ FMUSP, por toda atenção e responsabilidade com seu trabalho, e todo carinho dedicado. E por último, de forma especial, agradeço aos amigos queridos, Luydson Vasconcelos, Fábio Moura, Clarissa Rocha e Gabriela Foinquinos que estiveram ao meu lado, incentivando, escutando, compartilhando, colaborando. Este grupo define amor. Obrigada a todos sem exceção... NORMALIZAÇÃO Esta tese está de acordo com as seguintes normas, em vigor no momento desta publicação.
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