Pathogenetic and diagnostic aspects in pediatric hepatology and emerging complications of liver transplantation
CAROPRESO, MARIA (2009) Pathogenetic and diagnostic aspects in pediatric hepatology and emerging complications of liver transplantation. [Tesi di dottorato] (Inedito)
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The last decade has seen an explosion of activity in the clinical and research aspects of pediatric hepatology. The increased use of ultrasounds techniques and routine laboratory evaluation has drawn attention to several previously undiagnosed condition in childhood. The discipline has grown from a cataloguing of the many unique disorders that can occur during infancy and childhood to a more profound understanding of the genetic, biochemical, and virologic basis for many pediatric liver diseases. Nowadays hepatopathies still represent a significant cause of morbidity and mortality worldwide. However advances in diagnosis and treatment, particularly the successful development of transplantation, have dramatically improved the outcome for infants and children with liver disease, so that many of them can now expect to grow into adult life. Sophisticated molecular genetic techniques have not only identified new genes and categorized rare defects, but have also given us an insight into pathophysiology and potential therapy. National and international collaboration through clinical database has helped us refine diagnosis and treatment of several pediatric hepatic diseases. Differently from adults, the signs and symptoms of liver disease are often non specific and can vary greatly from child to child among the different liver diseases. This is one reason for which it can be hard to diagnose. As a result, liver disease may frequently be overlooked. Because most childhood hepatic diseases are progressive and life threatening, diagnosis failure can have devastating consequences. At present for most childhood liver diseases the cause is still unknown and is poorly satisfactory. The recognition of the pathogenesis of liver disease, the implications of innovative diagnostic techniques and therapies, the investigations of new clinical aspects during long-term follow-up, and the necessity for multidisciplinary working are as important for general paediatricians as for pediatric gastroenterologists, surgeons and hepatologists. The gratifying survival of increasing numbers of young people with liver disease into adult life means that it is essential also for adult practitioners with expertise in pediatric liver disease. Therefore, our research starts from the assumption that only knowledge of unexplored aspects can be an important tool for advancing into the management of hepatic disorders in children. It should be a contribute to both provide a framework to understand pathophisiology of some hepatobiliary disorders and offer analyses of their clinical-laboratory manifestations and the strategies for managing them. This project might be also useful to create specific competences related to a integrated and multidisciplinary approach, as required in pediatric liver disease. Our study concerns three areas that still present several either pathogenetic or diagnostic uncertainties, focusing on the following aspects: 1. Pathogenetic aspects of pediatric portal hypertension - Do genetic prothrombotic risk factors play a role in pediatric portal vein thrombosis ? If so are they harmful also for other districts ? 2. Diagnostic aspects of pediatric hypertransaminasemia and unconjugated hyperbilirubinemia - Which are the characteristcs of macro-aspartate aminotransferasemia (macro-AST) in pediatric age? Are current screening tests effective? Is this a “benign” condition? - Is electrophisiological evaluation of Crigler Najjar syndrome an helpful tool to detect Neurotoxic complications of chronic hyperbilirubinemia ? 3. Emerging complications of pediatric liver transplantation - Is erythrocytosis a possible post-transplant complication also in liver recipients ? - Does it exist a psychopatological risk in liver transplantated children ? AIM The aim of our project has been triggered by limited existing scientific evidences vs. the increasing observation of children with these problems which in clinical practice lead to frequent requests for specialist advices. In particular, the etiology of portal vein thrombosis in children affected by portal hypertension is unknown. In this thesis, we aimed to demonstrate the possible role of genetic predisposing factors, which are still not clear in childhood. This in the perspective of individuating patients at higher risk for thrombotic events also in other disctricts. Isolated increase of serum AST levels is a relatively frequent laboratoristic feature in absence of clinical symptoms. This often leads to unexpensive, time-consuming and sometimes invasive procedures. Therefore, we aimed to characterize a large series of children with cryptogenic AST levels to demonstrate the dimension and nature of macro-AST condition, and the accuracy of a simple screening test. The long term follow up was investigated as well to understand whether our previous observation that this is a benign condition is correct. Previous studies have investigated neurological aspects of genetic chronic non hemolytic hperbilirubinemia only in patients with severe forms of Crigler –Najjar Syndrome (type I). We aimed to assess the usefulness of neuroelectrophysiological studies also in patients with severe hyperbilirubinemia due to intermediate phenotype I/II Crigler-Najjar. This could be important to detect an early neurotoxic bilirubin effect without overt neurological damage, and to contribute for the appropriate timing of liver transplant. The purpose of the last two projects is to study two still poorly explored aspect of pediatric liver transplantation: the investigation and characterization of erythrocytosis, a post-transplant complication which has hitherto described only in kidney recipients, and of the psycopathological risk. We believe that to increase knowledges in the management of children undergoing liver transplantation may be extremely important because they will ultimately lead to a better quality of life. In fact it is now becoming clear that liver transplant outcome needs to be judged using a measure incorporating not only survival rates but also other features including psychological and social well being as well.
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