Gene Activity Signature Predicts Survival in Young Children with Biliary Atresia

Researchers identified a unique signature of gene activity levels at diagnosis that predicts survival in young children with biliary atresia—knowledge that could help determine disease progression and inform new treatment approaches. Biliary atresia is a rare and serious liver disease that occurs during the first few months of life in which bile ducts that drain from the liver to deliver bile acids to the intestine become inflamed and scarred, leading to a back-up of bile into the liver. Children with this disease must be treated with a surgery to restore bile drainage called hepatoportoenterostomy, or HPE, but even after this surgery, the liver can develop progressive damage requiring a liver transplant. Because the clinical course of biliary atresia is variable, it would be extremely valuable to have biological markers that predict disease progression, to inform the development of new and personalized treatment approaches.

Toward this goal, researchers studied liver biopsy tissue from girls and boys with biliary atresia, including those enrolled in NIDDK’s Childhood Liver Disease Research Network (ChiLDReN). By comparing the gene activity patterns of children who survived until age 2 after the HPE surgery without the need for a liver transplant to those who did not, they identified a set of 14 genes with activity levels at diagnosis that predicted transplant-free survival at 2 years of age. Further experiments suggested that the 14-gene activity pattern coupled with total bilirubin level (a major component of bile) measured 3 months after surgery was an even better predictor of 2-year survival without a liver transplant than the gene activity signature alone. Researchers next explored differences in overall gene activity in the children and how those differences may contribute to disease progression, finding increased activity of genes associated with liver injury and scarring in the children with lower transplant-free survival. They also found increased activity of genes involved in metabolism of glutathione (an antioxidant produced in the liver) in the children who survived without a transplant, suggesting that restoration of cellular glutathione may help protect against biliary atresia-associated liver damage. Investigating this concept further, studies of mouse models of biliary atresia showed reduced bile duct obstruction and improved survival when the animals were treated with N-acetylcysteine (NAC), a drug that restores cellular glutathione and was shown to treat acute liver failure in children and adults by other NIDDK-sponsored studies.

This study suggests that the newly identified 14-gene activity signature could be a useful biological marker to predict how biliary atresia will progress in young children after surgery. It also shows that restoring cellular glutathione may be a possible approach to decrease progressive liver damage caused by the disease. Further research could help determine if using NAC or another approach to increase cellular glutathione in children with biliary atresia could halt liver damage and improve overall health.