Clinical trial NCT03273049: Mapping Disease Pathways for Biliary Atresia
Official title: Coordinating Center- Mapping Disease Pathways for Biliary Atresia
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Biliary Atresia
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2017-09-06
Enrollment: 1100
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals who have had a liver transplantation due to a diagnosis of biliary atresia.

Brief summary: This project will primarily evaluate the developmental/genetic basis of biliary atresia, the most common cause of liver failure at birth, and which accounts of half of all liver transplants performed worldwide in children.

Detailed description: Characterized by failure to drain bile from the liver due to atretic extrahepatic bile ducts, BA is corrected in less than half of all affected children with surgical reconstruction. The remainder progress to cirrhosis and require liver transplantation. Because bile duct loss can be accompanied by other birth defects such as laterality defects of the gut and cardiovascular systems, the disease has been categorized into the more common 'isolated' variety presumably due to a perinatal viral cholangitis, and the 'syndromic' variety, due to genetic factors. Mechanistic differences implied by this categorization have not been demonstrated conclusively. In contrast, three susceptibility genes identified in predominantly 'isolated" BA cases, and the presence of abnormal cilia which are known to predispose to laterality defects, in both isolated and syndromic forms of BA suggest that in addition to environmental influences, genetic susceptibility is important in both forms of BA. This view is reinforced by our preliminary work which shows that knockdown of a novel BA susceptibility gene causes both biliary dysgenesis and laterality defects in animal models. This finding also suggests that common birth defects affecting the liver and other organs may originate from defects in the same genes. The project will combine candidate gene identification and replication with human DNA samples from 1100 BA subjects and their biological parents or siblings, if available, with validation using corresponding human BA liver tissue and zebrafish knockdown models.

The project outcome will consist of pathways comprising multiple susceptibility genes involved in morphogenesis of the liver and other organs, which explain the complex phenotype of BA. The project will use the experimental and bioinformatics capabilities of the Universities of Pittsburgh and California (at San Diego) to analyze data and study human samples from the participating centers. Four of the world's largest pediatric liver transplant centers, the Children's Hospitals of Pittsburgh (CHP), King's College Hospital (KCH), London, UK, Birmingham Children's Hospital, UK (BCH), and the Hospital Sirio Libanes (HSL), Sao Paulo, Brazil will enroll biliary atresia subjects and their biological parents and/or siblings, if available.

Information developed in this project will be the basis for designing novel management strategies to reduce the societal impact of this rare childhood disease.

Eligibility criteria: Inclusion Criteria:

* living individuals who were diagnosed with Biliary Atresia and received or are about to receive a liver transplant from multiple participating centers (Children's Hospital of Pittsburgh, Kings College Hospital, Children's Hospital of Birmingham, and Hospital Sírio-Libanês).

Exclusion Criteria:

* No child participant in the care of the state will be enrolled, nor will patients in the care of temporary or informal guardians be enrolled

Primary outcomes:
measure: Genomic pathways of BA
timeFrame: up to two years
Secondary outcomes:
measure: Predisposition of BA
timeFrame: upwards of four years to achieve this outcome measure
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
Study officials:
References: