Landmark SickKids-led study offers new understanding of outcomes for children and youth with Alagille syndrome
In the largest study of its kind, researchers at The Hospital for Sick Children (SickKids) have described an international cohort of children with Alagille syndrome (ALGS), offering a more complete picture of how this rare liver disease progresses in childhood. The research team also identified a novel biomarker that could be used to potentially predict which patients may need a liver transplant.
ALGS is a rare, genetic disorder in which a patient has an inadequate number of bile ducts, which usually drain bile from the liver into the intestine. The bile then builds up and causes liver damage. ALGS is estimated to affect between one in 30,000 to one in 50,000 individuals and is caused by mutations in one of two genes, JAGGED1 (JAG1) or NOTCH2. It is also associated with a range of other features, such heart and kidney issues and facial and skeletal abnormalities, often appearing in the first year of life. ALGS also accounts for about four per cent of all paediatric liver transplants in North America.
While the disorder can be confirmed through genetic screening, the symptoms and severity of the disease varies, which means early detection and diagnosis can be a challenge.
International collaboration opens new doors for future ALGS research
SickKids researchers Shannon Vandriel and Dr. Binita Kamath established the Global Alagille Alliance (GALA) Study in 2018, an initiative to create an international database of clinical, genetic and laboratory data in children and young adults with ALGS.
In a recent study published in Hepatology, the researchers reviewed medical records of 1,433 children with ALGS from 67 paediatric centres in 29 countries through GALA. They found that 40.3 per cent of children reach adulthood with their original liver and 59.7 per cent receive a liver transplant by age 18, with almost three-quarters of all transplants occurring in the first five years.
“Prior to this study, the largest cohort of ALGS patients described was roughly 300 patients and much of the data was from tertiary referral centres. Through our international collaboration, we had access to data on patients that have never been reported on and in places that may not have the resources to conduct research. Through this study, we’ve given those patients a voice,” says Vandriel, lead author and Program Manager in the Division of Gastroenterology, Hepatology and Nutrition at SickKids.
“Prior to this, native liver survival was reported at 24 per cent among paediatric patients with ALGS. This landmark study offers a better understanding of the true rate of liver transplants for patients with ALGS, using the largest cohort of children with ALGS ever described,” says Vandriel.
“Given that transplants are one of the major clinical decisions families of children with ALGS face, these findings could one day be used to support family counselling and decision-making around when a patient should receive a transplant.”
Biomarker could help doctors predict risk of transplant
The research team also identified a potential biomarker, or a measurable piece of evidence in the blood, to help clinicians assess whether a patient might eventually require a liver transplant.
Bilirubin is a pigment found in bile, typically released when the liver breaks down red blood cells. Since bilirubin typically passes out of the body as bile, high levels of total bilirubin (TB) could indicate that the liver is not functioning correctly.
The team found that TB levels of less than 5.0mg/dL between the ages of 6 to 12 months old were associated with better native liver survival outcomes, and those patients with levels between 5.0mg/dL and 10.0 mg/dL had an almost five-fold increased risk of needing a liver transplant.
“Rare disease like ALGS can be incredibly challenging to study as researchers and clinicians simply don’t have access to large enough patient cohorts, especially outside North America. With our findings, total bilirubin levels can act as an objective prognostic threshold that any liver team around the world could use to help make individualized decisions for their patients,” says Kamath, Staff Physician, Division of Gastroenterology, Hepatology and Nutrition, Senior Associate Scientist, Developmental & Stem Cell Biology, and Principal Investigator and senior author of the study.
Knowing more about how patients survive into adulthood can also help guide clinical management as patients transition into adult care.
“With 88 per cent of children with ALGS surviving to adulthood, adult hepatologists need to be aware of ALGS and its complex manifestations,” adds Kamath, who is also the Director of the Hepatology Program at SickKids.
Looking beyond the liver to learn more about ALGS
While the study focused on liver outcomes, the GALA database also aims to help researchers increase understanding of non-liver features associated with the rare disease, including heart and kidney anomalies.
Kamath adds: “This syndrome was first described by hepatologists but there’s much more to uncover, including looking beyond the liver. As we learn more about Alagille syndrome and build up our understanding of it through the GALA study, we can hopefully help reduce stress and worry for patients and families managing this rare disease.”
Funding for this study was provided by grants from The Alagille Syndrome Alliance, Mirum Pharmaceuticals and Albireo Pharma to SickKids Foundation.