Pediatric liver disease has significant morbidity and mortality. Biliary atresia accounts for more than half of pediatric liver transplants. Genetic causes of neonatal cholestasis include Alagille's syndrome, alpha-1- antitrypsin deficiency, Progressive Familial Intrahepatic Cholestasis (PFIC), bile acid synthetic defects, mitochondrial hepatopathies, and cystic fibrosis. All of these diseases can progress to cirrhosis and end stage liver disease. In order to study the diagnosis, progression, and treatment of these rare disorders, we propose to continue participation in the CHILDREN Research Network, contributing and studying children with the above diseases. The goals of the network are to follow large numbers of these subjects longitudinally to allow accumulation of clinical data and biospecimens for studies that can help diagnose, prognosticate for, and treat these diseases. Identification of biomarkers to use for diagnosis and to ascertain disease progression is a particular goal. Translational research founded on this remarkable CHILDREN database and biorepository can result in new insights regarding pathogenesis, disease modifiers, and ultimately treatment. Our center will recruit patients with CHILDREN diseases aggressively, retain them for longitudinal follow-up, and contribute to ongoing studies. The Cystic fibrosis study will continue to evaluate the role of ultrasound in predicting the development of cirrhosis i children with CF and to study the progression of cirrhosis in this disease. Our center will activel participate in clinical trials planned to 1)study the effect of an intestinal bile-acid transport inhibitor on pruritus, one of the most disabling symptoms of cholestasis, and 2) study a novel vitamin supplement targeted to optimally supplement fat-soluble vitamin deficiency in cholestasis. The ultimate goal of the network is to learn more about natural history and pathogenesis in order to inform therapy and clinical management of cholestatic diseases of children. The scientific project proposed by the IU center is a proteomic study of cystic fibrosis-related liver disease. While most patients with CF have some degree of liver involvement, only 5-10% develop advanced cirrhosis. The goals of the study are to identify plasma proteins that are associated with the development of CF cirrhosis and can track progression of that disease. Identification of biomarkers of advanced CF liver disease would allow early identification and the opportunity to select these children for clinical trials of novel therapeutic agents which might improve bile flow and change the course of the disease.
Pediatric liver disease, associated with chronic illness, malnutrition, and the need for liver transplantation, has significant public health impact. There i a knowledge gap regarding physiology, diagnosis, natural history, risk factors and treatment. Because these diseases are rare, multicenter collaborations like the CHILDREN network are crucial for studying these children and improving medical management and outcomes.
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