This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This longitudinal observational study will investigate the nat plain f3 fs18 ural history and progression of four genetic causes of intrahepatic cholestasis of childhood, including alpha-1 antitrypsin deficiency ( 'e11-AT), Alagille syndrome (AGS), progressive familial intrahepatic cholestasis (PFIC), and bile acid synthesis defects ( plain f3 fs18 BAD). This study will be conducted as part of the Cholestatic Liver Disease Consortium (CLiC), an NIH-funded multi-centered Rare Disease Clinical Research Consortium. In this study, we will collect defined data elements in a uniform fashion at fixed intervals for five years over a relatively large number of patients with these rare disorders. In addition, a biobank of patient specimens and DNA samples will be established for use in ancillary studies to be performed in addition to this study. By comparing outcome measures between the four liver diseases (i.e., using each disorder as a disease-control for the other disorders), the full impact of each disorder can best be determined in comparison to the other liver diseases. Using the longitudinal database in this fashion, this study will provide an improved understanding of the effects of the cholestatic liver during childhood irrespective of the underlying etiology as well as to the pathophysiology, outcome, and complications of each of the disorders. This initial characterization will allow calculation of sample sizes for future therapeutic intervention clinical trials and provide the baseline to which interventions should be compared. HYPOTHESIS 1. Each of the four intrahepatic cholestatic diseases will have unique phenotypic features and a characteristic natural history. 2. Genotypic differences in participants with each of the cholestatic diseases may influence the disease phenotype and progression. 3. Poor growth and decreased bone mineral density in patients with cholestatic liver diseases is variably dependent on the degree of cholestasis, body composition, and/or the severity of liver synthetic dysfunction. 4. Early biomarkers will be predictive of outcome in cholestatic liver diseases. To determine the clinical phenotype and natural history of each of the four liver diseases during childhood and early adulthood.
Specific Aim 2 : To determine the frequency of poor growth and decreased bone mineral density and its predictors in all four diseases.
Specific Aim 3 : To develop a repository of serum, urine, tissue, and DNA specimens, that will be used in future ancillary studies to determine circulating biomarkers that predict disease progression and outcomes, and to identify modifier genes that influence the incidence, severity and progression of liver disease among genetically affected individuals.
Specific Aim 4 : To determine genotype-phenotype relationships in Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) disorders.
Specific Aim 5 : To determine if the natural history and progression of liver disease in alpha-1 antitrypsin deficiency is consistent in a given family with multiply affected children (""""""""breeds true"""""""")
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