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Abstract(s)
A atresia biliar é a causa mais comum de colangiopatia obstrutiva infantil e a indicação mais
frequente para transplante hepático na população pediátrica. É uma patologia que se inicia
exclusivamente na infância e que se caracteriza por uma obstrução de parte ou da totalidade
das vias biliares extra-hepáticas. A portoenterostomia é um procedimento paliativo que visa
corrigir o fluxo biliar de bebés diagnosticados com atresia biliar, de modo a possibilitar
maior sobrevivência do fígado nativo até à realização, na maioria dos casos, da cirurgia
definitiva, o transplante hepático.
Os aspetos que influenciam o prognóstico pós-portoenterostomia (sobrevida do fígado
nativo) incluem fatores corrigíveis e não-corrigíveis. Entre os não-corrigíveis são
considerados relevantes os níveis de bilirrubinas aquando da portoenterostomia, a extensão
de fibrose e de reação ductular e a forma clínica de apresentação enquanto entre os
corrigíveis incluem-se a idade por ocasião do procedimento e a experiência dos centros que
investigam e tratam pacientes com a doença. O objetivo desta investigação prendeu-se em
estudar e compreender melhor alguns dos fatores acima citados e compreender como estes
influenciam a sobrevivência do fígado nativo e em que medida os resultados pós-operativos
podem ser otimizados. Para isso, fizemos uma análise retrospetiva, histórica, com registos
do acompanhamento clínico até ao fim do estudo descrito nesta tese de um banco de dados
histórico recolhido no Hospital de Clínicas de Porto Alegre, Brasil, na Unidade de
Gastroenterologia e Hepatologia Pediátricas entre 2006 e 2015. Todos os dados foram,
aquando da recolha, registados informaticamente com recurso ao software IBM SPSS
versão 27, para Windows®. As amostras de fígado foram obtidas e analisadas usando
anticorpo monoclonal de camundongo anti-citoqueratina para análise de intensidade da
reação ductular, e picrossírius para estudo da extensão da fibrose hepática, bem como a
expressão génica de citoqueratina 19 no caso das amostras ultracongeladas.
Os resultados do estudo, que constou apenas de uma análise subjetiva qualitativa devido ao
pequeno número de amostras, demonstraram que as características da reação ductular em
tecido marcado por imunohistoquímica com anticorpo anti-CK19 e a expressão génica desta
mesma molécula, acompanharam a ampliação da área de fibrose hepática no fígado
marcado com picrossírus. Ainda assim, não apresentaram diferenças estatísticas
significativas nem em relação ao PCK19 nem à expressão génica de CK19. A idade aquando
da portoenterostomia também não revelou diferenças significativas no que toca à expressão
de CK19.
Em relação à idade aquando da portoenterostomia, quando dividida em faixas etárias,
foram encontradas diferenças estatísticas significativas para procedimentos realizados entre 60-90dias e >90dias. A análise dos dados permitiu concluir que uma
portoenterostomia mais precoce aumenta a chance de sobrevivência do fígado nativo.
No momento da portoenterostomia, a medição da bilirrubina total e de reação direta
permitiu concluir que pacientes que apresentaram valores mais elevados de bilirrubinas
aquando da portoenterostomia tiveram um pior prognóstico no que toca à sobrevivência do
fígado nativo. Os pacientes que não conseguiram uma sobrevivência de fígado nativo
apresentaram médias de bilirrubina total e direta superiores aos que o conseguiram. Os
valores de bilirrubina total e direta decorridos 3 meses da portoenterostomia influenciaram
a sobrevivência do fígado nativo, sendo que indivíduos que apresentam valores superiores,
tiveram pior prognóstico. Para o nosso estudo, o valor de bilirrubina total influenciou mais
o prognóstico do fígado nativo que o valor de bilirrubina direta. Quando avaliamos a
bilirrubina total em regressão multivariada, a sua expressão no desfecho do fígado nativo
ganhou ainda mais impacto.
Os valores medidos de bilirrubina decorridos 3 meses da portoenterostomia foram o fator
prognóstico estudado que mais influenciou a sobrevivência do fígado nativo, e o mais fiável
para a sua avaliação.
Biliary atresia is the most common cause of obstructive cholangiopathy in children and the most frequent indication for liver transplantation in the pediatric population. It is a pathology that begins exclusively in childhood and is characterized by complete obstruction of part or all of the extrahepatic bile ducts. Portoenterostomy is a palliative procedure that aims to correct the bile flow in infants diagnosed with biliary atresia, in order to allow a greater survival of the native liver until the definitive surgery, liver transplantation, is performed in most cases. The aspects that influence post-portoenterostomy prognosis (native liver survival) include both correctable and non-correctable factors. Among the non-correctable factors, bilirubin levels at the time of portoenterostomy, the extent of fibrosis and ductular reaction, and the clinical form of presentation are considered relevant, while correctable ones include age at the time of the procedure and the experience of the centers investigating and treating patients with the disease. The aim of this investigation was to study and better understand some of the above factors and to understand how they influence native liver survival and to what extent post-operative outcomes can be optimized. To do this, we performed a retrospective, historical analysis with records from clinical follow-up to the end of the study described in this thesis of a historical database collected at the Hospital de Clínicas de Porto Alegre, Brazil, in the Pediatric Gastroenterology and Hepatology service between 2006 and 2015. All data was, at the time of collection, recorded informatically using IBM SPSS version 27, for Windows®. Liver samples were obtained and analyzed using mouse anti-cytokeratin monoclonal antibody to analyze the intensity of the ductular reaction and picrosirius to study the extent of liver fibrosis, as well as the expression of citokeratin in the ultrafrozen samples. The results of the study, which consisted only of a subjective qualitative analysis due to the small number of samples, showed that the characteristics of the ductular reaction in tissue marked by immunohistochemistry with anti-CK19 antibody and the gene expression of this same molecule, accompanied the enlargement of the area of liver fibrosis in the liver marked with picrosirius. Yet, it showed no statistically significant differences in either PCK19 or CK19 gene expression. Age at portenterostomy also showed no significant differences with respect to CK19 expression. Regarding age at portoenterostomy, when divided into age groups, statistically significant differences were found for procedures performed between 60-90days and >90days. Data analysis allowed the conclusion that earlier portoenterostomy increases the chance of native liver survival. At the time of portoenterostomy, measurement of total and direct reaction bilirubin allowed the conclusion that patients who have higher bilirubin values at the time of portoenterostomy have a worse prognosis regarding native liver survival. Patients who did not achieve native liver survival had higher mean total and direct bilirubin values than those who did. Total and direct bilirubin values 3 months after portoenterostomy influenced native liver survival, with individuals with higher measured values having a worse prognosis. For our study, the total bilirubin value influenced the prognosis of the native liver more than the direct bilirubin value. When we evaluated total bilirubin in multivariate regression, its expression on the outcome of native liver gained even more impact. Measured bilirubin values 3 months after portoenterostomy were the prognostic factor studied that most influenced native liver survival, and the most reliable for its evaluation.
Biliary atresia is the most common cause of obstructive cholangiopathy in children and the most frequent indication for liver transplantation in the pediatric population. It is a pathology that begins exclusively in childhood and is characterized by complete obstruction of part or all of the extrahepatic bile ducts. Portoenterostomy is a palliative procedure that aims to correct the bile flow in infants diagnosed with biliary atresia, in order to allow a greater survival of the native liver until the definitive surgery, liver transplantation, is performed in most cases. The aspects that influence post-portoenterostomy prognosis (native liver survival) include both correctable and non-correctable factors. Among the non-correctable factors, bilirubin levels at the time of portoenterostomy, the extent of fibrosis and ductular reaction, and the clinical form of presentation are considered relevant, while correctable ones include age at the time of the procedure and the experience of the centers investigating and treating patients with the disease. The aim of this investigation was to study and better understand some of the above factors and to understand how they influence native liver survival and to what extent post-operative outcomes can be optimized. To do this, we performed a retrospective, historical analysis with records from clinical follow-up to the end of the study described in this thesis of a historical database collected at the Hospital de Clínicas de Porto Alegre, Brazil, in the Pediatric Gastroenterology and Hepatology service between 2006 and 2015. All data was, at the time of collection, recorded informatically using IBM SPSS version 27, for Windows®. Liver samples were obtained and analyzed using mouse anti-cytokeratin monoclonal antibody to analyze the intensity of the ductular reaction and picrosirius to study the extent of liver fibrosis, as well as the expression of citokeratin in the ultrafrozen samples. The results of the study, which consisted only of a subjective qualitative analysis due to the small number of samples, showed that the characteristics of the ductular reaction in tissue marked by immunohistochemistry with anti-CK19 antibody and the gene expression of this same molecule, accompanied the enlargement of the area of liver fibrosis in the liver marked with picrosirius. Yet, it showed no statistically significant differences in either PCK19 or CK19 gene expression. Age at portenterostomy also showed no significant differences with respect to CK19 expression. Regarding age at portoenterostomy, when divided into age groups, statistically significant differences were found for procedures performed between 60-90days and >90days. Data analysis allowed the conclusion that earlier portoenterostomy increases the chance of native liver survival. At the time of portoenterostomy, measurement of total and direct reaction bilirubin allowed the conclusion that patients who have higher bilirubin values at the time of portoenterostomy have a worse prognosis regarding native liver survival. Patients who did not achieve native liver survival had higher mean total and direct bilirubin values than those who did. Total and direct bilirubin values 3 months after portoenterostomy influenced native liver survival, with individuals with higher measured values having a worse prognosis. For our study, the total bilirubin value influenced the prognosis of the native liver more than the direct bilirubin value. When we evaluated total bilirubin in multivariate regression, its expression on the outcome of native liver gained even more impact. Measured bilirubin values 3 months after portoenterostomy were the prognostic factor studied that most influenced native liver survival, and the most reliable for its evaluation.
Description
Keywords
Atresia Biliar Colestase Neonatal Fatores Prognósticos Histopatologia Idade Na Portoenterostomia