Biliary Atresia Research Consortium (BARC)

Biliary atresia is a severe disease of newborns in which there is fibrotic obliteration of the intrahepatic and extrahepatic bile ducts resulting in progressively worsening bile retention and cholestatic liver injury. Untreated, biliary atresia invariably leads to death from end-stage liver disease in early infancy. Portoenterostomy (the Kasai Procedure), if performed within the first few months of life, can restore bile flow and prevent further liver injury, allowing for the possibility of normal health and development. However, even with portoenterostomy, a high proportion of children with biliary atresia develop worsening chronic cholestasis and liver dysfunction ultimately requiring liver transplantation during childhood. Biliary atresia affects approximately 1 in 10,000 newborns. It is the single most common reason for liver transplantation in children accounting for at least 40% of cases in the United States. The cause of biliary atresia is unknown. The disease typically presents shortly after birth; yet it does not appear to be an inherited disease. Family clustering of cases is rare, and identical twins discordant for biliary atresia have been described. Some cases of biliary atresia are associated with other congenital abnormalities, particularly those of laterality (situs inversus, polysplenia). For these reasons, multiple environmental, infectious, immunological, and epigenetic causes for biliary atresia have been proposed. Yet to date, pursuit of these hypotheses has been slow and difficult. Epidemiological studies have failed to identify possible environmental or toxic exposures that might explain biliary atresia. Studies of viruses, other infectious agents and immunological factors have been contradictory or inconclusive. Epigenetic causes of biliary atresia have yet to be adequately investigated. In an assessment of the NIH grant portfolio on biliary atresia conducted in 2000, virtually no grants focusing on the pathogenesis of this disease were identified. The difficulty in studying biliary atresia appeared to be due to the lack of clear and testable hypotheses for its etiology, the absence of reliable animal models, and the relative rarity of the disease, which is sufficiently uncommon that no single center can accrue enough cases for prospective clinical and epidemiological analysis. Similar shortcomings have hampered clinical research on biliary atresia and pursuit of improved means of early diagnosis and management. In light of these difficulties and to promote progress in research on biliary atresia, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Biliary Atresia Research Consortium (BARC). BARC consists of a central data coordinating center and nine United States medical centers with expertise in the clinical and laboratory investigation of neonatal liver disease. Jorge Bezerra, M.D.: Children's Hospital Medical Center, Cincinnati, OH; Barbara Haber, M.D.: Children's Hospital of Philadelphia, PA; David Perlmutter, M.D., Children's Hospital, Pittsburgh, PA; Philip Rosenthal, M.D., University of California, San Francisco, CA; Kathleen Schwarz, M.D., Johns Hopkins School of Medicine, Baltimore, MD; Ross Shepherd, M.D., Washington University School of Medicine, St Louis, MO; Benjamin Shneider, M.D., Mount Sinai Medical Center, New York, NY; Ronald Sokol, M.D., Children's Hospital of Denver, CO; Peter Whitington, M.D, Children's Memorial Hospital, Chicago, IL. Morton B. Brown, Ph.D. University of Michigan, Ann Arbor, MI. Patricia Robuck, Ph.D., M.P.H., NIDDK, Bethesda, MD. Additional financial support for BARC is provided by Office for Rare Diseases, NIH. BARC was established in September 2002. The specific aims are to investigate and identify (1) the etiology of biliary atresia, (2) practical means for diagnosis, (3) the natural history of the disease, (4) risk factors for progression of disease and its complications, and (5) better medical and surgical interventions. The BARC steering committee has developed both retrospective and prospective patient databases that will allow for standardized collection of clinical information as well as serum, plasma, DNA, and tissue samples from well-characterized cases and controls. Patient accrual will begin in early 2004. The consortium has also designed a prospective, randomized, double-blind controlled trial comparing high doses of corticosteroids with placebo therapy at the time of the Kasai procedure. BARC has initiated plans for ancillary studies based upon patient samples and directed at the pathogenesis, diagnosis, and management of biliary atresia. The steering committee has also developed a procedure for collaboration with outside investigators interested in the data and specimens available through BARC. Further information about BARC is available at http://www.med.umich.edu/borc/barc.