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Doença de Wilson: abordagem terapêutica
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O cobre é um oligoelemento essencial para o funcionamento do organismo humano. É um metal imprescindível para a atividade de várias enzimas envolvidas em diversos processos fisiológicos importantes, atuando como cofator catalítico.
A incorporação de cobre no organismo é feita maioritariamente por via oral, através da alimentação. No intestino, a absorção do cobre é realizada por uma ATPase, a ATP7A, localizada na membrana dos enterócitos. Após entrar na circulação portal, o cobre chega rapidamente ao fígado, que é o principal órgão responsável pela sua metabolização. Nos hepatócitos, a proteína ATP7B é responsável por incorporar o cobre na ceruloplasmina, e está envolvida no processo de excreção biliar de cobre. Assim, a inativação de ATP7B resulta num distúrbio grave da homeostase do cobre e na inativação de enzimas dependentes deste metal, manifestando-se clinicamente como a Doença de Wilson.
Esta doença caracteriza-se por uma mutação rara no cromossoma 13 que codifica para a proteína ATP7B, resultando numa acumulação de cobre em vários tecidos e órgãos, nomeadamente no fígado e no cérebro. Esta patologia apresenta uma ampla heterogeneidade de sintomas, pelo que as manifestações clínicas podem ser predominantemente hepáticas, neurológicas ou psiquiátricas. Uma das características, mais comuns, é o anel Kayser-Fleischer presente na maioria dos pacientes com sintomas neurológicos. O diagnóstico desta patologia é baseado numa ampla combinação de testes laboratoriais e características clínicas, como a análise da concentração hepática de cobre e da ceruloplasmina sérica. Antes do desenvolvimento de terapêuticas farmacológicas, a doença de Wilson era inevitavelmente uma doença fatal, contudo, atualmente o prognóstico dos pacientes é bastante favorável.
O tratamento farmacológico da Doença de Wilson fundamenta-se na remoção do excesso de cobre através da utilização de agentes quelantes, como a D-penicilamina e a trientina, e na diminuição da absorção de cobre com o auxílio de sais de zinco.
O tratamento farmacológico disponível geralmente é bastante eficaz, contudo as opções terapêuticas ainda são limitadas e possuem inúmeros efeitos secundários que não favorecem a sua adesão. Inúmeros avanços estão a ser feitos no sentido de desenvolver novos compostos e terapêuticas inovadoras. A terapia genética representa um futuro tratamento curativo para esta patologia.
Copper is an essential trace element for the functioning of the human organism. It is an indispensable metal for the activity of several enzymes involved in many important physiological processes, acting as a catalytic cofactor. The incorporation of copper in the body is mostly done orally, through feeding. In the intestine, the absorption of copper is performed by an ATPase, the ATP7A, located in the enterocyte membrane. After entering the portal circulation, copper quickly reaches the liver, which is the main organ responsible for copper metabolization. In the hepatocytes, the ATP7B protein is responsible for incorporating copper into the ceruloplasmin, and is involved in the process of bile excretion of copper. Therefore, the inactivation of ATP7B results in a severe disturbance of the homeostasis of copper and in the inactivation of enzymes dependent on this metal, manifesting itself clinically as Wilson's disease. This pathology presents a wide clinical heterogeneity, so the clinical manifestations can be predominantly hepatic, neurological or psychiatric. One of the most common features is the Kayser-Fleischer ring present in most patients with neurological symptoms. The diagnosis of this pathology is based on a wide combination of laboratory tests and clinical characteristics, such as the analysis of the hepatic concentration of copper and serum ceruloplasmin.Before the development of pharmacological therapies, Wilson's disease was inevitably a fatal disease, however, currently the patients' prognosis is very positive. The pharmacological treatment of Wilson's disease is based on the removal of excess copper using chelating agents such as D-penicillamine and trientine, and on reducing the absorption of copper with the use of zinc salts. The available pharmacological treatment is generally quite effective, however the therapeutic options are still limited and have numerous side effects that do not promote their compliance. Numerous advances are being made towards the development of new compounds and innovative therapies. Gene therapy represents a future curative treatment for this pathology.
Copper is an essential trace element for the functioning of the human organism. It is an indispensable metal for the activity of several enzymes involved in many important physiological processes, acting as a catalytic cofactor. The incorporation of copper in the body is mostly done orally, through feeding. In the intestine, the absorption of copper is performed by an ATPase, the ATP7A, located in the enterocyte membrane. After entering the portal circulation, copper quickly reaches the liver, which is the main organ responsible for copper metabolization. In the hepatocytes, the ATP7B protein is responsible for incorporating copper into the ceruloplasmin, and is involved in the process of bile excretion of copper. Therefore, the inactivation of ATP7B results in a severe disturbance of the homeostasis of copper and in the inactivation of enzymes dependent on this metal, manifesting itself clinically as Wilson's disease. This pathology presents a wide clinical heterogeneity, so the clinical manifestations can be predominantly hepatic, neurological or psychiatric. One of the most common features is the Kayser-Fleischer ring present in most patients with neurological symptoms. The diagnosis of this pathology is based on a wide combination of laboratory tests and clinical characteristics, such as the analysis of the hepatic concentration of copper and serum ceruloplasmin.Before the development of pharmacological therapies, Wilson's disease was inevitably a fatal disease, however, currently the patients' prognosis is very positive. The pharmacological treatment of Wilson's disease is based on the removal of excess copper using chelating agents such as D-penicillamine and trientine, and on reducing the absorption of copper with the use of zinc salts. The available pharmacological treatment is generally quite effective, however the therapeutic options are still limited and have numerous side effects that do not promote their compliance. Numerous advances are being made towards the development of new compounds and innovative therapies. Gene therapy represents a future curative treatment for this pathology.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Palavras-chave
Doença de Wilson Cobre ATP7B Terapêutica Mestrado integrado - 2020