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Suscetibilidade genética para a progressão da doença hepática na Hepatite C crónica: eixo renina-angiotensina
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A infeção causada pelo vírus da hepatite C (HCV) é um problema de saúde global importante e que pode causar morbidade e mortalidade significativas e provocar hepatite aguda com alta propensão à infeção crónica. A infeção crónica pelo VHC pode evoluir para doença hepática grave, nomeadamente cirrose e carcinoma hepatocelular. Existem vários fatores de risco para a progressão da doença hepática: fatores do hospedeiro e fatores virais. A fibrose hepática, que se caracteriza por inflamação progressiva e deposição de componentes da matriz extracelular, é uma resposta comum à doença hepática crónica. Há cada vez mais evidências que indicam que os fatores genéticos influenciam a história natural das doenças hepáticas. A fibrose hepática pode ser vista como uma doença na qual múltiplos genes interagem com fatores ambientais. Contudo, nem todas as pessoas expostas a uma mesma causa desenvolvem a doença da mesma maneira. Um indivíduo pode não nascer com a doença, mas pode estar sujeito a um elevado risco de a adquirir. A isto chama-se predisposição ou suscetibilidade genética. Na última década, tornou-se claro que o papel da angiotensina II vai muito para além dos efeitos renais e cardiovasculares reconhecidos. A presença de um sistema renina-angiotensina (SRA) autólogo foi demonstrada em quase todos os tecidos do corpo. Vários estudos recentes demonstraram que o sistema renina-angiotensina desempenha um papel fundamental na fibrose hepática. O objetivo do presente estudo é determinar se os polimorfismos genéticos dos genes que codificam as proteínas do sistema renina-angiotensina influenciam a suscetibilidade à hepatite C crónica e podem levar à progressão da doença hepática (fibrose hepática). Os polimorfismos apresentados neste estudo e que foram testados são a enzima conversora de angiotensina (ECA), angiotensinogénio (AGT) e o recetor 1 de angiotensina II (AT1). Todos os polimorfismos genéticos estudados são funcionais porque alteram a função / atividade/quantidade de proteína para a qual o gene codifica. Essas alterações refletem-se em mudanças no ciclo renina-angiotensina, traduzindo-se numa variação nos níveis de angiotensina II. Níveis elevados dessa proteína podem estar associados ao desenvolvimento de fibrose hepática ou à progressão da doença para fases mais graves. Neste trabalho identificaram-se alguns marcadores intermediários, validados noutros estudos, que se podem relacionar com o desenvolvimento e progressão desta patogénese - plaquetas, fosfatase alcalina, AST, ALT, GGT, ferro, ferritina e glicémia. Verificou-se de igual modo que a atividade da ECA se pode relacionar com desenvolvimento e a progressão desta patogénese. Uma maior actividade da ECA na fibrose hepática, pode contribuir para a morbilidade dos doentes nesta situação. Os indivíduos portadores do genótipo DD poderão apresentar um maior risco de desenvolver doença hepática mais grave. Para que as pessoas possam fazer escolhas informadas é importante compreender a predisposição genética para a doença e ter conhecimento dos estilos de vida que podem aumentar ou diminuir o potencial para contrair a doença.
Hepatitis C virus (HCV) infection is a major global health problem, and that can result in significant morbidity and mortality and lead to acute hepatitis with a high propensity for chronic infection. Chronic HCV infection can progress to severe liver disease including cirrhosis and hepatocellular carcinoma. There are several risk factors for the progression of liver disease: host factors and viral factors. Hepatic fibrosis, which is characterized by progressive inflammation and deposition of extracellular matrix components, it is a common response to chronic liver disease. There is increasing evidence that genetic factors influence the natural history of liver disease. Hepatic fibrosis can be seen as a disease in which multiple gene interact with environmental factors. However, not all people expose to the same cause develop the disease in the same way. An individual may not be born with the disease but may be at high risk of acquiring it. This is called predisposition or genetic susceptibility. Over the last decade, it has become clear that the role of angiotensin II extends far beyond recognized renal and cardiovascular effects. The presence of an autologous renin-angiotensin system has been demonstrated in almost all tissues of the body. Several recent studies have demonstrated that the renin –angiotensin system (RAS) plays a key role in hepatic fibrosis. The aim of the present study is to determine whether genetic polymorphisms of genes encoding Renin-Angiotensin system proteins influence susceptibility to chronic hepatitis C and can lead to the progression of hepatic disease (liver fibrosis). The polymorphisms presented in this study which were tested are the angiotensin converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor 1 (AT1). All genetic polymorphisms studied are functional because they alter the function / activity / amount of protein for which the gene encodes. These changes are reflected in changes in the Renin-Angiotensin cycle, ultimately translating into a change in angiotensin II levels. Elevated levels of this protein may be associated either to the development of liver fibrosis or to the progression of the disease to more severe stages. In this work we have identified some intermediate markers, already validated in other studies, that can be related to the development and progression of this pathogenesis - platelets, alkaline phosphatase, AST, ALT, GGT, iron, ferritin and glycemia. It was also found that ACE activity may be related to the development and progression of this pathogenesis. Increased ACE activity in hepatic fibrosis may contribute to the morbidity of patients in this situation. Individuals with the DD genotype may be at increased risk of developing more severe liver disease. So that people can make informed choices it is important to understand the genetic predisposition to the disease and to be aware of lifestyles that may increase or decrease the potential to get the disease.
Hepatitis C virus (HCV) infection is a major global health problem, and that can result in significant morbidity and mortality and lead to acute hepatitis with a high propensity for chronic infection. Chronic HCV infection can progress to severe liver disease including cirrhosis and hepatocellular carcinoma. There are several risk factors for the progression of liver disease: host factors and viral factors. Hepatic fibrosis, which is characterized by progressive inflammation and deposition of extracellular matrix components, it is a common response to chronic liver disease. There is increasing evidence that genetic factors influence the natural history of liver disease. Hepatic fibrosis can be seen as a disease in which multiple gene interact with environmental factors. However, not all people expose to the same cause develop the disease in the same way. An individual may not be born with the disease but may be at high risk of acquiring it. This is called predisposition or genetic susceptibility. Over the last decade, it has become clear that the role of angiotensin II extends far beyond recognized renal and cardiovascular effects. The presence of an autologous renin-angiotensin system has been demonstrated in almost all tissues of the body. Several recent studies have demonstrated that the renin –angiotensin system (RAS) plays a key role in hepatic fibrosis. The aim of the present study is to determine whether genetic polymorphisms of genes encoding Renin-Angiotensin system proteins influence susceptibility to chronic hepatitis C and can lead to the progression of hepatic disease (liver fibrosis). The polymorphisms presented in this study which were tested are the angiotensin converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor 1 (AT1). All genetic polymorphisms studied are functional because they alter the function / activity / amount of protein for which the gene encodes. These changes are reflected in changes in the Renin-Angiotensin cycle, ultimately translating into a change in angiotensin II levels. Elevated levels of this protein may be associated either to the development of liver fibrosis or to the progression of the disease to more severe stages. In this work we have identified some intermediate markers, already validated in other studies, that can be related to the development and progression of this pathogenesis - platelets, alkaline phosphatase, AST, ALT, GGT, iron, ferritin and glycemia. It was also found that ACE activity may be related to the development and progression of this pathogenesis. Increased ACE activity in hepatic fibrosis may contribute to the morbidity of patients in this situation. Individuals with the DD genotype may be at increased risk of developing more severe liver disease. So that people can make informed choices it is important to understand the genetic predisposition to the disease and to be aware of lifestyles that may increase or decrease the potential to get the disease.
Descrição
Tese de mestrado em Biologia Humana e Ambiente, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, em 2018
Palavras-chave
Hepatite C crónica Fibrose hepática Suscetibilidade genética ECA/AGT/AT1 Teses de mestrado - 2018