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Advisor(s)
Abstract(s)
A doença hepática esteatótica associada à disfunção metabólica é cada vez mais
prevalente no mundo. Isto deve-se ao aumento da incidência de outras patologias como
diabetes, síndrome metabólica e dislipidémia, e associa-se a um estilo de vida sedentário, a par
de uma alimentação pouco saudável. Esta doença hepática caracteriza-se por acumulação de
gordura no fígado, a qual causa um quadro inflamatório e fibrótico que culmina na diminuição
de função do órgão. O excesso de gordura no fígado pode ter origem na desregulação da lipólise,
consequência da resistência à insulina, e no excesso de carboidratos, que favorecem a síntese
de ácidos gordos livres. A progressão patológica para esteatohepatite e carcinoma
hepatocelular, dependem de processos de inflamação e fibrose. O firsocostat e o clesacostat
inibem a acetil-CoA carboxilase, essencial à lipogénese de novo. Os agonistas do fator de
crescimento dos fibroblastos 21, como o pegbelferim, atuam no metabolismo glicolipídico e
permitem obter efeitos benéficos na doença hepática. Outros fármacos em estudo incluem o
ácido obeticólico, que atua nas células hepáticas, e a pioglitazona e o saroglitazar, que se ligam
aos recetores ativados por proliferadores do peroxissoma, também presentes nos hepatócitos.
Por outro lado, a lesão hepática ativa o sistema imunitário desencadeando um estado
inflamatório que acentua o dano hepático. Assim, as células imunitárias são também
consideradas alvos terapêuticos. A continuidade do ciclo de lesão celular contribui para a
diferenciação das células hepáticas estreladas, aumentando a deposição de matriz fibrótica no
fígado com diminuição das suas funções. A empagliflozina é um fármaco promissor, com
atuação no metabolismo das células estreladas. Uma vez que as estratégias farmacológicas são
escassas e muitas ainda se encontram em desenvolvimento, a cirurgia bariátrica e o transplante
hepático são frequentemente considerados como opção. Considerando que os primeiros
fármacos para a doença hepática esteatótica associada à disfunção metabólica estão só agora a
começar de ser aprovados, uma das formas mais eficazes de tratar essa condição parece ser uma
dieta regrada e o exercício físico, que devem integrar qualquer regime de tratamento. Apesar
dos progressos, é essencial estimular a investigação nesta área.
Metabolic dysfunction-associated steatotic liver disease is increasingly prevalent in the world, associated with the growing increased incidence of other pathologies such as diabetes, metabolic syndrome and dyslipidemia, along with a sedentary lifestyle and unhealthy diet. This liver disease is characterized by the accumulation of fat in the liver, which causes an inflammatory and fibrotic condition that culminates in decreased organ function. Excess fat in the liver can originate from the deregulation of lipolysis, a consequence of insulin resistance, and from excess carbohydrates, which favour the synthesis of free fatty acids. Steatohepatitis and hepatocellular carcinoma developed from processes of inflammation and fibrosis. Firsocostat and clesacostat inhibit acetyl-CoA carboxylase, which is essential for de novo lipogenesis. Fibroblast growth factor 21 agonists, such as pegbelferim, act on glycolipid metabolism and provide beneficial effects in liver disease. Other drugs being studied include obeticholic acid, which acts on liver cells, as well as pioglitazone and saroglitazar, which bind to peroxisome proliferator-activated receptors that are also present in hepatocytes. On the other hand, liver damage activates the immune system, triggering an inflammatory state that accentuates liver damage. Thus, immune cells are also considered therapeutic targets. The continuation of the cell damage cycle contributes to the differentiation of hepatic stellate cells, increasing the deposition of fibrotic matrix and significantly impacting on liver fibrosis with a decrease in its functions. By acting on the metabolism of these cells, empagliflozin is a promising drug. Pharmacologic strategies are scarce, and many are still under development. Bariatric surgery and liver transplantation are often deemed alternatives. Considering that the first drugs for metabolic dysfunction-associated steatotic liver disease are only now being approved, one of the most effective ways of treating this condition seems to be a rigorous diet and physical exercise, which should be part of any treatment regimen. Despite the progress, it is essential to stimulate research in this area.
Metabolic dysfunction-associated steatotic liver disease is increasingly prevalent in the world, associated with the growing increased incidence of other pathologies such as diabetes, metabolic syndrome and dyslipidemia, along with a sedentary lifestyle and unhealthy diet. This liver disease is characterized by the accumulation of fat in the liver, which causes an inflammatory and fibrotic condition that culminates in decreased organ function. Excess fat in the liver can originate from the deregulation of lipolysis, a consequence of insulin resistance, and from excess carbohydrates, which favour the synthesis of free fatty acids. Steatohepatitis and hepatocellular carcinoma developed from processes of inflammation and fibrosis. Firsocostat and clesacostat inhibit acetyl-CoA carboxylase, which is essential for de novo lipogenesis. Fibroblast growth factor 21 agonists, such as pegbelferim, act on glycolipid metabolism and provide beneficial effects in liver disease. Other drugs being studied include obeticholic acid, which acts on liver cells, as well as pioglitazone and saroglitazar, which bind to peroxisome proliferator-activated receptors that are also present in hepatocytes. On the other hand, liver damage activates the immune system, triggering an inflammatory state that accentuates liver damage. Thus, immune cells are also considered therapeutic targets. The continuation of the cell damage cycle contributes to the differentiation of hepatic stellate cells, increasing the deposition of fibrotic matrix and significantly impacting on liver fibrosis with a decrease in its functions. By acting on the metabolism of these cells, empagliflozin is a promising drug. Pharmacologic strategies are scarce, and many are still under development. Bariatric surgery and liver transplantation are often deemed alternatives. Considering that the first drugs for metabolic dysfunction-associated steatotic liver disease are only now being approved, one of the most effective ways of treating this condition seems to be a rigorous diet and physical exercise, which should be part of any treatment regimen. Despite the progress, it is essential to stimulate research in this area.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2024 Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Fígado Inflamação Fibrose Esteatose Doença hepática esteatótica associada à disfunção metabólica Mestrado Integrado - 2024