Understanding How Inflammation Causes Biliary Atresia
Faculty Profile: Jorge Bezerra, Gastroenterology, Hepatology and Nutrition
From infants to animal models -- and eventually back to infants -- researchers at Cincinnati Children's are pursuing the inflammatory response that destroys the bile ducts in infants with biliary atresia, the most common reason for chronic liver disease in children.
Healthy infants are born with an open bile duct that connects the liver and gallbladder to the intestines. In those with biliary atresia, the duct closes from the buildup of inflammation and scar tissue during the first or second months after birth, and the baby becomes jaundiced. More than half of all indications for liver transplantation in the United States and around the world are due to biliary atresia.
Although it was first identified as a threat to child health in the 1800s, little progress has been made in understanding its biological basis. In 2002, Jorge Bezerra, MD, and colleagues in the Cincinnati Children's Division of Gastroenterology, Hepatology and Nutrition published research showing that an inflammatory response in the liver appeared to trigger the biliary atresia disease process. Using gene chip studies of liver biopsy samples from babies diagnosed with biliary atresia, they found a unique genetic profile in these babies' livers. Most of the genes in this profile regulate inflammatory processes.
Since then, Dr. Bezerra has established an experimental mouse model that mimics the disease process in babies. Studies using gene chips proved that biliary atresia's molecular signature in mice is similar to that in humans. Specific biological processes can be targeted, with potential therapies to be tested in mice before going to human clinical trials. One of the particularly promising processes is the same inflammatory pathway present in the gene chip studies of infants with biliary atresia.
In October, Dr. Bezerra presented additional findings showing that when the inflammatory pathway is inhibited in the laboratory and researchers try to induce biliary atresia, the mice do not get the disease. This result further supports the theory that dysfunctions of inflammatory pathways may be an important cause of biliary atresia. Dr. Bezerra will continue to study inflammation in this laboratory model and in samples of patients with biliary atresia to determine if this pathway is valid, and hopes to use the results to design new treatments to rescue babies' livers.
Continuation of similar groundbreaking studies at Cincinnati Children's will be facilitated by the newly created Center for Biliary Atresia. Cincinnati Children's is one of nine institutions nationwide to receive National Institutes of Health funding to develop a center focused on following patients with the disease prospectively. Data on treatment and diagnosis collected at all nine centers will yield rich sources for researchers to fully understand how the disease develops and to devise new treatment methods.
