The team of scientists also found that N-acetyl-cysteine, an antioxidant, decreased liver injury and fibrosis in mice with biliary atresia, resulting in increased survival times.
Biliary atresia is a rare disease of the liver and bile ducts. It occurs in infants and is the most common diagnosis that leads to liver transplants in children.
Researchers at Cincinnati Children’s Hospital Medical Center identified 14 genes that at the time of diagnosis predict two-year, transplant-free survival in children with the disease.
The team of scientists also found that N-acetyl-cysteine (NAC), an antioxidant, decreased liver injury and fibrosis in mice with biliary atresia, resulting in increased survival times.
Liver cells produce bile, which helps to digest fat and carries waste products from the liver to the intestines, where it is then excreted. The channels and ducts that make up the network is called the biliary system. When it works properly, the bile drains from the liver into the intestines. But in biliary atresia, the flow of bile from the liver to the gallbladder is blocked, causing bile to be trapped inside the liver. This causes damage and scarring, known as cirrhosis, of the liver cells, leading to eventual liver failure.
“The relationship between a 14-gene signature at diagnosis and two-year survival provides insight into staging of liver disease and the development of new therapies,” states Jorge Bezerra, director of Gastroenterology, Hepatology and Nutrition at Cincinnati Children’s.
He added, “A particularly appealing possibility is the design of a clinical trial designed to activate the glutathione pathway—a molecule highly expressed in infants with biliary atresia. The activation of the pathway by the antioxidant NAC has the potential to improve bile flow and block fibrosis development.”
Bezerra and his group collected liver biopsies and clinical health data from babies with cholestasis, which is a decrease or stoppage of bile flow. The infants were enrolled in a prospective study of the Childhood Liver Disease Research Network, which is funded by the National Institutes of Health (NIH). The babies were evaluated at Cincinnati Children’s, and liver biopsies were performed at the time of biliary atresia diagnosis.
The researchers then performed RNA sequencing and developed a prognostic algorithm.
In related research, the researchers dosed neonatal mice that had biliary atresia and fibrosis with NAC. This resulted in decreased bilirubin and decreased liver fibrosis in the laboratory animals.
Bilirubin is created during the normal degradation of red blood cells. It passes through the liver and eventually is excreted from the body. But high levels of bilirubin can indicate liver problems.
“We don’t yet know if NAC is safe and effective in young babies with biliary atresia,” stated Bezerra. “Future clinical trials are needed before us in clinical practice.”
Although there are no drug therapies approved yet for biliary atresia, at least one company, Boston-based Albireo Pharma, is working on a drug for it. On June 7, the company presented clinical data from a Phase II trial of its lead product candidate odevixibat in biliary atresia, Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC). It made the presentation at the 2019 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Annual Meeting held in Glasgow, Scotland.
The drug is a bile acid modulator. In pediatric cholestatis, the drug showed marked decreases in serum bile acids (sBA) in the majority of Alagille patients, with as high as 92%. The majority of patients receiving the drug also showed improvement in pruritus. The drug also showed significant sBA decreases of 57.6% and 50.8% in two biliary atresia patients with high baseline bile acids and demonstrated improvement in pruritus.
