Biliary atresia and other cholestatic childhood diseases: Advances and future challenges

Abstract

Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

Biliary Atresia: Clinical and Research Challenges for the Twenty‐First Century

“…Recent reports indicate that those who develop bile flow (defined as a serum total bilirubin level <2 mg/dL) within 3 months of HPE have a >80% chance to be in the group of BA patients surviving with the native liver at 2 years of age . More importantly, although these patients are considered “successful” responders to Kasai HPE, at least 75% will develop ongoing fibrosis, portal hypertension, and cirrhosis, with significant risks of hepatic complications, death, and transplant from childhood through young adulthood . These BA patients are candidates for trials of an array of therapeutic agents as they have the potential to respond and stand to benefit significantly.…”

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

“…Biliary atresia (BA) is a severe neonatal cholangiopathy characterized by progressive fibroinflammatory obliteration of both extrahepatic and intrahepatic bile ducts, generally leading to cholestasis, portal fibrosis, and, ultimately, biliary cirrhosis. Among children, BA is the most common cause of end‐stage liver disease worldwide and the primary indication for liver transplantation, yet its etiology (or etiologies) remains unknown . Hypotheses regarding the pathogenesis of BA include perinatal viral infections or toxins targeting cholangiocytes, chronic inflammatory or autoimmune‐mediated bile duct injury, and mutations in specific genes that regulate hepatobiliary development .…”

Cytokine‐Producing B Cells Promote Immune‐Mediated Bile Duct Injury in Murine Biliary Atresia

“…Biliary atresia (BA) is a progressive inflammatory biliary disease resulting in fibrosis of the extrahepatic and intrahepatic bile ducts early in life . Despite surgical intervention with hepatic portoenterostomy at diagnosis, approximately 80% of BA patients eventually require liver transplantation .…”

“…In order to study immune‐mediated mechanisms of biliary disease, the group A rhesus rotavirus (RRV)–induced mouse model of BA (“murine BA”) is used. This model mimics the biochemical, immunological, and histological abnormalities found early in the human disease …”