Growth failure and malnutrition are common clinical features in Alagille Syndrome (AS), the pathobiology of which is poorly understood. The role that pancreatic insufficiency may play, as a contributory factor to energy imbalance and malabsorption is not known. In AS there is diminished bile salt excretion and low intraluminal bile salt concentration, resulting in ineffective solubilization and absorption of dietary lipid, essential fatty acids and fat-soluble vitamins. This fat malabsorption leads in part to the malnourished state that is characteristic of children with AS. Absorption of fats and fat-soluble vitamins depends on not only the solubilization by bile acids into mixed micelles, but also requires pancreatic and intestinal esterases for hydrolysis before traversing the aqueous water layer in the intestinal lumen into the enterocyte. Therefore, pancreatic function is essential for adequate absorption of dietary lipids and fatty acids. Most of these children have steatorrhea which could be a major contributory factor to secondary growth failure and failure to thrive. No previous data support any role of the intestine or its pathobiology in contributing to fat malabsorption. The role of pancreatic insufficiency has not been systematically explored in a cohort of children with AS. If pancreatic insufficiency is present in AS patients, therapy is available which may dramatically improve growth and nutrition.
The specific aims of this proposal are: to determine the prevalence of exocrine pancreatic sufficiency by assessing direct and indirect pancreatic function in children with AS; and to assess baseline and prospective nutritional measures, including anthropometrics and bone density in children with AS and either pancreatic sufficiency or insufficiency. This study will be the first to identify the role of several clinical variables, including pancreatic function, in the contribution to malnutrition and growth failure in children with AS.
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