Associação entre uso de clozapina e alterações hepáticas em portadores de esquizofrenia
Data
2023-11-27
Autores
Dias, Cíntia Lopes 
Orientadores
Noto, Cristiano de Souza
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Objetivo: Realizar uma revisão narrativa da literatura sobre os mecanismos fisiopatológicos de lesão hepática induzida por antipsicóticos, os protocolos e métodos de detecção e manejo do tratamento. Métodos: Realizou-se a busca na base de dados PUBMED usando os termos “antipsychotics” e “hepatotoxicity”, “hepatic injury”, “drug induced liver injury” ou “hepatits”. Além disto foram relatados dois casos que apresentaram sintomas e alterações laboratoriais indicativos de lesão hepática na introdução de Clozapina. Resultados: Os antipsicóticos promovem lesão hepática principalmente por via idiossincrática. Os três padrões envolvidos na etiologia deste fenômeno são o colestático, mas frequentemente associado às fenotiazidas, o hepatocelular, no qual o acúmulo de metabólitos da droga acumulados nos hepatócitos causam danos mitocondriais e desbalanço das vias de reparação celular através do aumento de estresse oxidativo pelo retículo endoplasmático, culminando em danos e morte celular por necrose e autofagia, além do padrão de esteatose, onde o acúmulo de gordura leva à morte do hepatócito mais a longo prazo. A doença hepática causada por antipsicóticos é mais frequente com a Clozapina, mesmo sendo um evento raro (0,001%). Ainda é importante diferenciar o aumento dos testes de função hepática transitória e assintomático, que ocorre mais frequentemente (60% dos casos em uso de Clozapina) e não implica em danos ou necessidade de retirada da droga por se resolver ao longo dos três primeiros meses de uso, da doença hepática induzida por antipsicóticos, a qual já indicaria suspensão do medicamento e cuidados clínicos. Deve-se suspeitar de doença hepática induzida por antipsicóticos quando houver um aumento da alanina aminotransferase acima de cinco vezes do limite superior, aumento da fosfatase alcalina acima de duas vezes o limite superior ou o aumento da alanina aminotransferase três vezes acima do limite superior em associação com aumento de bilirrubinas duas vezes acima do limite superior. Além disto, caso haja aumento de aminotransferases acima de três vezes o limite superior associado a algum sinal de hepatite como febre, eosinofilia, exantema ou icterícia. Embora a Food Drugs and Administration apresente diversos critérios específicos para a retirada de qualquer fármaco que induza doença hepática, no geral, para os antipsicóticos recomenda-se suspender a droga perante um aumento de alanina aminotransferase acima de três vezes o limite superior, fofatase alcalina duas vezes acima do limite superior ou qualquer alteração de testes de função hepática associados com sinais ou sintomas clínicos. Conclusão: Uma vez que os antipsicóticos muitas vezes são necessários para o tratamento de diversas doenças psiquiátricas, sendo que para alguns casos a Clozapina é o melhor tratamento disponível, precisamos definir com maior exatidão um protocolo para monitorização dos testes de função hepática, a fim de rastrear doença hepática induzida pela medicação, sem causas descontinuações desnecessárias. Não há um consenso na literatura sobre em qual período solicitar estes testes, mas sugere-se que, perante as alterações dos mesmos descritas acima, suspenda-se a medicação de imediato, encaminhando o indivíduo para o suporte clínico adequado.
Objective: To conduct a narrative review of the literature on the physiopathological mechanisms of liver injury induced by antipsychotic drugs, as well as the protocols and methods for detection and management of treatment. Methods: A search was performed on the PUBMED database using the terms "antipsychotics" and "hepatotoxicity," "hepatic injury," "drug-induced liver injury," or "hepatitis." Additionally, two cases were reported that presented symptoms and laboratory alterations indicative of liver injury upon the introduction of Clozapine. Results: Antipsychotic drugs mainly cause liver injury through an idiosyncratic pathway. The three patterns involved in the etiology of this phenomenon are cholestatic, often associated with phenothiazines; hepatocellular, in which the accumulation of drug metabolites in hepatocytes causes mitochondrial damage and imbalance in cellular repair pathways through increased oxidative stress by the endoplasmic reticulum, leading to damage and cell death by necrosis and autophagy; and steatosis pattern, where the accumulation of fat leads to hepatocyte death over the long term. Liver disease caused by antipsychotics is more common with Clozapine, even though it is a rare event (0.001%). It is important to differentiate transient and asymptomatic increases in liver function tests, which occur more frequently (60% of cases with Clozapine use) and do not imply damage or the need to discontinue the drug as they resolve within the first three months of use, from antipsychotic-induced liver disease, which would indicate drug withdrawal and clinical care. Antipsychotic- induced liver disease should be suspected when there is an increase in alanine aminotransferase above five times the upper limit, an increase in alkaline phosphatase above two times the upper limit, or an increase in alanine aminotransferase three times above the upper limit in association with an increase in bilirubin two times above the upper limit. In addition, if there is an increase in aminotransferases above three times the upper limit associated with any signs of hepatitis such as fever, eosinophilia, rash, or jaundice. Although the Food and Drug Administration provides various specific criteria for withdrawing any drug that induces liver disease, in general, for antipsychotics, it is recommended to discontinue the drug in the presence of an increase in alanine aminotransferase above three times the upper limit, alkaline phosphatase two times above the upper limit, or any alteration in liver function tests associated with clinical signs or symptoms. Conclusion: Since antipsychotic drugs are often necessary for the treatment of various psychiatric disorders, with Clozapine being the best available treatment for some cases, it is essential to define a more accurate protocol for monitoring liver function tests to screen for medication- induced liver disease without causing unnecessary discontinuations. There is no consensus in the literature on when to request these tests, but it is suggested that, in the presence of the above-mentioned changes, medication should be discontinued immediately, and the individual should be referred for appropriate clinical support.
Objective: To conduct a narrative review of the literature on the physiopathological mechanisms of liver injury induced by antipsychotic drugs, as well as the protocols and methods for detection and management of treatment. Methods: A search was performed on the PUBMED database using the terms "antipsychotics" and "hepatotoxicity," "hepatic injury," "drug-induced liver injury," or "hepatitis." Additionally, two cases were reported that presented symptoms and laboratory alterations indicative of liver injury upon the introduction of Clozapine. Results: Antipsychotic drugs mainly cause liver injury through an idiosyncratic pathway. The three patterns involved in the etiology of this phenomenon are cholestatic, often associated with phenothiazines; hepatocellular, in which the accumulation of drug metabolites in hepatocytes causes mitochondrial damage and imbalance in cellular repair pathways through increased oxidative stress by the endoplasmic reticulum, leading to damage and cell death by necrosis and autophagy; and steatosis pattern, where the accumulation of fat leads to hepatocyte death over the long term. Liver disease caused by antipsychotics is more common with Clozapine, even though it is a rare event (0.001%). It is important to differentiate transient and asymptomatic increases in liver function tests, which occur more frequently (60% of cases with Clozapine use) and do not imply damage or the need to discontinue the drug as they resolve within the first three months of use, from antipsychotic-induced liver disease, which would indicate drug withdrawal and clinical care. Antipsychotic- induced liver disease should be suspected when there is an increase in alanine aminotransferase above five times the upper limit, an increase in alkaline phosphatase above two times the upper limit, or an increase in alanine aminotransferase three times above the upper limit in association with an increase in bilirubin two times above the upper limit. In addition, if there is an increase in aminotransferases above three times the upper limit associated with any signs of hepatitis such as fever, eosinophilia, rash, or jaundice. Although the Food and Drug Administration provides various specific criteria for withdrawing any drug that induces liver disease, in general, for antipsychotics, it is recommended to discontinue the drug in the presence of an increase in alanine aminotransferase above three times the upper limit, alkaline phosphatase two times above the upper limit, or any alteration in liver function tests associated with clinical signs or symptoms. Conclusion: Since antipsychotic drugs are often necessary for the treatment of various psychiatric disorders, with Clozapine being the best available treatment for some cases, it is essential to define a more accurate protocol for monitoring liver function tests to screen for medication- induced liver disease without causing unnecessary discontinuations. There is no consensus in the literature on when to request these tests, but it is suggested that, in the presence of the above-mentioned changes, medication should be discontinued immediately, and the individual should be referred for appropriate clinical support.
Descrição
Citação
DIAS, Cíntia Lopes. Associação entre uso de clozapina e alterações hepáticas em portadores de esquizofrenia. 2023. 64 f. Dissertação (Mestrado em Psiquiatria e Psicologia Médica) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP). São Paulo, 2023.