Genetic discovery could dramatically reduce need for liver transplants in children

07/28/04

CINCINNATI — A new study published in the Journal of Clinical Investigation opens the door to the possibility of new treatments for children who suffer from biliary atresia, a deadly disease of infancy and the most common reason for liver transplantation in children. The new treatments could dramatically reduce the number of liver transplants performed on children every year.

Jorge Bezerra, M.D., a physician/researcher in the Division of Gastroenterology, Hepatology and Nutrition at Cincinnati Children's Hospital Medical Center, and research colleagues at Cincinnati Children's, discovered that in the early phases of biliary atresia, inflammatory genes are activated and control the obstruction of bile ducts in mice. The discovery "substantiates our initial observation in humans and opens the door for the future development of agents to control inflammation and progression of disease," Dr. Bezerra said.

Biliary atresia occurs in infants and usually becomes evident two to eight weeks after birth. Its cause has been unknown. Symptoms include unexplained jaundice, dark urine, clay-colored stools and weight loss. The disease destroys bile ducts in the liver, trapping bile, rapidly causing damage to liver cells and severe scarring.

Biliary atresia accounts for up to 50 percent of children who undergo liver transplantation. Although a surgical procedure is successful in many infants, three of every four children who have biliary atresia need a liver transplant before the age of 20. The total annual cost, including transplant care, of treating all infants with biliary atresia is estimated to be $65 million.

In a previous study published in The Lancet, Dr. Bezerra obtained biopsies of livers of 14 infants with biliary atresia. Using gene chip technology, he and the Cincinnati Children's research team discovered that in the early phases of biliary atresia, inflammatory genes are activated and immunoglobulin genes are suppressed, pointing to a potential role of cytokines (proteins that control inflammation) secreted by disease-fighting blood cells in the origin and development of the disease.

In other words, infants with biliary atresia are prone to develop an inflammatory response against themselves, according to Dr. Bezerra. The study suggests that these inflammatory cells see the biliary system as a foreign target. Proof of this concept, however, requires additional studies.

To determine how inflammatory cells obstructed bile flow from the liver, Dr. Bezerra worked with a unique mouse model of biliary atresia in which one gene produced by inflammatory cells was inactivated. He found that by blocking in mice the same inflammatory signal that is highly expressed in the livers of children with biliary atresia, "obstruction of bile ducts in mice was completely prevented, jaundice was improved and long-term survival increased."

In addition to continuing patient-based studies, Dr. Bezerra will be using the mouse model to develop new treatments to ultimately block obstruction of bile ducts in children who have biliary atresia. "The long-term goal is to stop progression of disease at the time of diagnosis and increase the chances of long-term survival with the native liver," he said.

Source: Eurekalert & others

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