Approaches to Biliary Atresia Care at Cincinnati Children's - Aki Asai, MD, PhD - Recent discoveries on pathogenesis of biliary atresia

Biliary atresia is a severe cholangiopathy of early infancy that destroys the extrahepatic bile ducts and disrupts bile flow, progressing to end-stage cirrhosis if not treated timely.

Cincinnati is the birthplace of disease modeling of BA, led by Doctor Tiao and Doctor Bizarro, with the traditional mouse model being the only well-established animal model of BA.

The traditional mouse model using rhesus rotavirus (RRV) has highlighted that abnormal perinatal immune response to viral infection triggers the BA phenotype.

Biliatrizone, a toxin associated with biliary atresia, was discovered through high-throughput zebrafish studies and causes cholangiocyte injury via disruption of the redox system and accumulation of reactive oxygen species.

Environmental toxin screening using human biliary organoids revealed that microcystin-RR can prompt a biliary atresia phenotype by disrupting redox balance, impairing bile duct development, and leading to ductal obliteration.

The lack of gene PKD1L1 was found to cause epithelial cell defect by the loss of cilia in syndromic BA.

Mesenchymal cells surrounding peribiliary glands provide mechanical support through cell-cell interaction and paracrine signals to maintain and develop the glands.

Genetic variants in GLE1 or SOX17 can cause mesenchymal cell defects leading to a BA phenotype in mouse models.

Abnormal perfusion of bile ducts induces ischemic injury and subsequently develops BA phenotypes through abnormalities in the peribiliary plexus consisting of vascular endothelial cells.

Some BA patients develop severe portal hypertension, ascites, and variceal bleeding even with draining Kasai without jaundice, representing a distinct clinical pattern requiring earlier liver transplant.

Cystic variant BA patients have a distinctive response to hepaticoportoenterostomy with favorable clinical outcomes.

A distinctive BA patient pattern develops multiple bile lakes and hepatopulmonary syndrome in early disease state.

Ciliopathy is a genetic defect causing loss of cellular polarity on epithelial cells, probably causing the distinct clinical pattern of hepatopulmonary syndrome with multiple bile lakes.

The strategy for the next 5-10 years should be identifying very rare but distinct patient populations with different clinical outcomes and developing different approaches for each.

There is new evidence of cytomegalovirus (CMV) as a modifier in BA, though it is not thought to be the cause; there is evidence of active CMV effects emerging in the past two years.

Small series have identified viruses including human papillomavirus, reovirus, rotavirus, and CMV in explants of BA patients, but establishing causation is complicated.

In the mouse model, the virus is cleared typically by a couple of weeks after injection, making it uncertain to claim definitive viral causation.

CMV may be a direct target for therapy with emerging evidence that it is not only a remote insult but may warrant treatment at the time of Kasai if detected.

BA patients with CMV have been excluded from certain clinical trials in the past.

Ciliopathy in BA cases with unusual presentation can cause hypoxemia and multiple bile lakes, changing clinical approach.

Ciliopathy manifestations in BA may not become apparent until later in the disease course, affecting longer-term follow-up rather than initial Kasai treatment paradigm.

Cincinnati Children's is developing a gene panel of 1700 genes including cholestasis panel and ciliopathic genes for BA evaluation, almost ready to launch.