A study led by physicians and scientists at Texas Children’s Hospital and Baylor College of Medicine has developed a new screening approach for early diagnosis of biliary atresia, a serious pediatric liver disease that is the leading cause of liver transplantation among children. The study published in the Journal of American Medical Association reports elevated serum levels of direct or conjugated bilirubin can quickly and accurately identify newborns with this condition within two weeks of birth.
Early surgical intervention is critical to avoid or delay liver transplants in children with biliary atresia. However, early detection of this condition in infants has proved to be very challenging. The breakthrough approach developed by a team of researchers led by Dr. Sanjiv Harpavat, pediatric hepatologist at Texas Children’s Hospital and assistant professor at Baylor College of Medicine, offers a novel solution that can be used as a universal newborn screening protocol that can reduce the enormous burden of liver transplant and improve clinical outcomes for these infants.
Under normal conditions, the liver produces a yellow liquid called bile that is transported via bile ducts to the small intestine where it helps to digest the food we eat. However, in patients with biliary atresia, the bile ducts are blocked, hampering the flow of bile from the liver to the intestine. The trapped bile damages the liver - within three months of birth if bile can’t flow, newborn livers are irreparably damaged and these infants need a new liver to survive.
Biliary atresia cannot be treated with medication. Currently, the only way to slow down liver damage and delay or avoid liver transplant, is by a surgical procedure – the ‘Kasai portoenterostomy’- in which blocked bile ducts are removed and the liver is directly connected to the intestine to re-establish bile flow.
“The Kasai operation has mixed results – it works really well for some patients but not so well for others. Pediatric hepatologists have been trying hard to find ways to make this surgery work better, so we can avoid or delay liver transplants in infants with biliary atresia,” said Harpavat, the corresponding author of the study.
One of the major factors crucial for the success of the Kasai procedure is the age of the infant when they undergo this procedure. Studies have shown that this surgery must be performed before the liver undergoes significant damage, which occurs rapidly within the first few months of life. By the time infants with biliary atresia are three months old, the surgery is unlikely to be helpful and the infants need liver transplants. Early detection and Kasai surgical intervention - ideally within 30 to 45d of life - offers the best chance of delaying or preventing liver transplants in these patients.
“In the United States, however, the Kasai surgery often takes place more than two months after birth. This is because it is very difficult to identify newborns with biliary atresia early on. Despite ongoing severe damage to the liver internally; outwardly, there are no dramatic clinical symptoms in the first weeks of life. These babies look similar to other infants, making biliary atresia very difficult to catch early on with just physical exams,” Harpavat said.
The narrow window available for clinical intervention underscores the urgent need for a simple and cost-effective diagnostic test can detect biliary atresia early on.
“Previously, our team found that babies with biliary atresia have elevated levels of direct or conjugated bilirubin at birth,” Harpavat said. Bilirubin is a yellow-orange pigment that is released when the red blood cells break down and is excreted out via bile and urine. The conjugated form is transported from the liver to the intestine and its levels in the blood increase when the liver cannot clear the bilirubin efficiently, which occurs when there is a block in the ducts. “Within a day or two of birth, many hospitals in the US, already perform a blood test to measure total bilirubin levels to determine if the newborns may need phototherapy for newborn jaundice. Although direct or conjugated bilirubin values are also measured and reported as part of this test, the significance of the result was not previously known. We were incredibly excited at the prospect of being able to use this test result as a solution for early detection of biliary atresia”.
The team developed a 2-step screening protocol to assess the levels of direct or conjugated bilirubin in the blood - the first measurement was obtained within a few days of birth and those who had high levels were tested again after two weeks. This 2-step protocol was conducted in more than 124,000 infants born in 14 south Texas hospitals between January 2015 and June 2018.
Infants who had consistently high levels of direct or conjugated bilirubin in both the steps were considered positive and followed up with other tests to determine the cause of the elevated bilirubin levels. The authors found this approach was highly sensitive, yielding a true positive rate of 100% and was able to identify biliary atresia patients very early in life with high accuracy.
In the second part of the study, they compared the association between participation in this screening protocol and the average age of infants receiving the Kasai procedure. They found infants treated at Texas Children’s Hospital during the screening period underwent the Kasai procedure at around 36 days after birth, which was roughly 20 days earlier than the usual age of the infants who undergo this procedure. Moreover, after the operation, the levels of conjugated bilirubin, a marker of success of the Kasai procedure, returned to normal earlier in infants who underwent the screening and received early intervention.
“While further research in larger populations is needed to obtain precise estimates of the diagnostic yield and to validate the cost-effectiveness of this approach, the initial findings are very exciting. We think these promising results could help inform decision-making about using this approach as a universal newborn screening metric for early detection of biliary atresia in the US,” Harpavat concluded.
“There are a number of remarkable things about this study. First it took advantage of an existing test and leveraged unappreciated aspects of the data in the test to dramatically change the outcome of infants with biliary atresia. Interestingly, this screening approach also permitted the early identification and treatment of other serious newborn liver disease,” said Dr. Benjamin Shneider, chief of Gastroenterology, Hepatology and Nutrition at the Texas Children’s Hospital, professor of pediatrics at Baylor College of Medicine and a senior co-author of the study. “In the process of developing this protocol, Dr. Harpavat spent countless hours explaining the rationale for the approach to pediatricians throughout South Texas. Those pediatricians learned the value of assessing newborn direct and conjugated bilirubin levels and went on to identify at risk infants on their own outside of the formality of Dr. Harpavat’s protocol. During the time of this study as many infants were identified outside the protocol as within it – all as a direct result of Dr. Harpavat’s incredible and tireless efforts. I have been involved in the care of children with liver disease for over three decades and this is the most dramatic change in clinical care that I have observed. The clinical picture of biliary atresia and other forms of neonatal cholestasis are dramatically different and better in Houston relative to anywhere else in the world. Dr. Harpavat’s next goal is to expand these advances to the rest of the world – given his track record, this seems eminently possible”.
For more information about biliary atresia, read this editorial article.