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Master's Dissertation
DOI
10.11606/D.5.2012.tde-14012013-155052
Document
Author
Full name
Fabiana Cordeiro de Araujo
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2012
Supervisor
Committee
Cançado, Eduardo Luiz Rachid (President)
Kondo, Mario
Oliveira, Claudia Pinto Marques Souza de
Title in Portuguese
Doença de Wilson: a experiência de seis décadas no HC-FMUSP
Keywords in Portuguese
Diagnóstico
Doença de Wilson
Evolução clínica
Tratamento
Abstract in Portuguese
INTRODUÇÃO: A doença de Wilson é um distúrbio autossômico recessivo, decorrente de mutações no gene ATP7B, resultando em acúmulo tóxico de cobre no organismo. Devido a sua raridade, séries com grande casuística e longo seguimento são escassas na literatura. Nesse estudo relatamos a experiência do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) com os pacientes diagnosticados com doença de Wilson entre o período de 1946 a 2010. MÉTODOS: Realizamos análise retrospectiva de 262 casos, descrevendo as formas de apresentação clínica, os achados dos exames diagnósticos, os padrões de resposta terapêutica e a evolução clínica da doença. RESULTADOS: A idade média do início dos sintomas foi 17,4 anos (7-49 anos). Os pacientes foram acompanhados em média 9,6 anos (0-45 anos). As apresentações clínicas mais frequentes foram hepática (36,3%), neurológica (34,7%), assintomática (16,8%), neuro-psiquiátrica (8,3%) e hematológica (1,9%). Outras formas menos comuns foram renal, neuro-hepática, e osteoarticular. Disartria e manifestações clínicas de cirrose hepática descompensada foram as principais características neurológicas e hepáticas, respectivamente. Os parâmetros diagnósticos observados foram anéis de Kayser-Fleisher 78,3%, reduzidos níveis séricos de ceruloplasmina 98,3%, níveis elevados de cuprúria basal de 24 horas 73,0%, teste da D-penicilamina positivo em 54,0% e comprometimento nos dois alelos do gene ATP7B 84,4%. O exame de ressonância magnética encefálica mostrou alterações nos núcleos da base em 77,7% dos examinados. D-penicilamina foi prescrita inicialmente em 93,6% dos 245 casos tratados, e 53% relataram efeitos adversos. Houve necessidade de substituição em 50 indivíduos. Outras medicações utilizadas foram os sais de zinco e trientina. Não evidenciamos diferença significativa entre os resultados terapêuticos dessas três drogas (p=0,2). Os casos de má aderência à terapia evoluiram com pior desfecho quando comparados aos usuários regulares (p <0,0001). Nove pacientes realizaram transplante hepático. Durante o seguimento 82 casos faleceram. As principais causas dos óbitos foram descompensação hepática 41,5% (hemorragia digestiva, peritonite bacteriana espontânea, encefalopatia) e pneumonia 20,7%. Três pacientes cometeram suicídio. CONCLUSÕES: Não existe um exame padrão ouro ou achado patognomônico da doença. Todo paciente jovem com manifestações hepáticas, neurológicas, neuropsiquiátricas, hematológicas, renais ou osteoarticulares de causa indefinida deverá ser investigado para doença de Wilson. Além da farmacoterapia específica é necessária a avaliação psiquiátrica para detectar precocemente sintomas depressivos.
Title in English
Wilson's disease: the experience of six decades in the Hospital das Clínicas of Sao Paulo University School of Medicine
Keywords in English
Diagnosis
Outcomes
Treatment
Wilson's disease
Abstract in English
INTRODUCTION: Wilson's disease is an autosomal recessive disorder, caused by mutations in the gene ATP7B, leading to toxic copper accumulation in the body. Because it is a rare disease, large series with long-term follow-up are limited in literature. We reported the experience of Hospital das Clínicas of Sao Paulo University School of Medicine (HC-FMUSP) with Wilson's disease patients diagnosed between 1946 and 2010. METHODS: A retrospective analysis of 262 cases was performed describing the clinical presentation, the results of diagnostic tests, the patterns of treatment response and outcome. RESULTS: The mean age at the onset of symptoms was 17.4 years (7- 49 years). Patients were followed for a mean of 9.6 years (0-45 years). The most frequent clinical presentations were hepatic (36.3%), neurological (34.7%), asymptomatic (16.8%), neuro-psychiatric (8.3%) and hematologic (1.9%). Other less common forms were renal, neurological-hepatic, and musculoskeletal. Dysarthria and clinical manifestations of decompensated liver cirrhosis were the main neurological and liver features, respectively. The diagnostic parameters observed in this cohort of patients were Kayser-Fleischer rings in 78.3%, low serum ceruloplasmin in 98.3%, high 24-h urinary excretion of copper in 73.0%, positive challenge test with d-pencillamine in 54.0% and detection of two mutations of ATP7B gene in 84.4%. The magnetic resonance of brain showed abnormalities in the basal ganglia in 77.7% of those examined. D-penicillamine was prescribed in 93.6% of 245 cases as the first drug, and 53% reported adverse effects. It was need to replace it in 50 individuals. Other drugs used were salts of zinc and trientine. There was no significant difference between the therapeutic results of these three drugs (p = 0.2). The cases with poor adherence to therapy evolved with a worse outcome when compared to regular users (p <0.0001). Nine patients underwent liver transplantation. During the follow-up 82 patients died. The main causes of death were hepatic decompensation 41.5% (variceal hemorrhage, spontaneous bacterial peritonitis, encephalopathy) and pneumonia 20.7%. Three patients committed suicide. CONCLUSIONS: There is no gold standard or pathognomonic test for diagnosing this disease. Any young patient with hepatic, neurological, neuropsychiatric, hematologic, renal, or osteoarticular manifestations of unknown cause should be investigated for Wilson's disease. In addition to the classical pharmacotherapy, specific psychiatric evaluation is necessary to detect early symptoms of depression.
 
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Publishing Date
2013-01-14
 
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