Supporting data for "Organoid systems to study the effect of steroids in modulating immune-mediated inflammation in billary atresia"

Biliary atresia (BA) is devastating congenital anomaly characterized by inflammatory fibrosclerosing changes of the extra- and intra-hepatic biliary systems. It is the most frequent cause of persistent neonatal cholestasis globally, with a higher incidence observed in the Asia-Pacific regions including Hong Kong. It is widely believed that most BA start with a series of abnormal immune interactions that trigger biliary inflammation as the common pathway. The critical role of inflammation in the pathogenesis of BA has been well established. The inflammatory damage to the cholangiocytes eventually results in biliary fibrosis and obstruction, ultimately leads to liver failure. A timely Kasai operation during the neonatal or early infantile period can potentially restore biliary drainage but the outcome is still far from optimal. A previous study by the PA revealed that long-term transplant-free survival could only be achieved in less than half of the patients and many of them suffer from major complications such as recurrent cholangitis or life-threatening portal hypertension. Although liver transplant is the salvage treatment, due to the scarcity of suitable liver grafts, patients could die before a liver graft is available. 

BA not only impairs the children’s well-being but also imposes a heavy burden on their families, carers, and society. It is estimated that mean health cost for each BA patient ranges from HK$0.2–3.3 million. BA thus represents a huge medico-societal problem and, clearly, surgery alone cannot be the sole treatment to this condition. New therapies that could enhance the curative rate of BA are needed urgently. 

Most of the previous and ongoing research focuses on the operative approach and adjuvant treatment, while there is little knowledge on pre-operative treatment. Unlike other congenital anomalies, which have been well-developed during the fetal period, the major pathobiology of BA takes place continuously throughout the peri-natal period. As the diagnosis of BA could be made in the early phase by liver biopsy and/or cholangiogram, there is thus a valuable window period for therapeutic intervention between diagnosis and operation with an attempt to slow down or even terminate the pathological process to enhance the surgical (Kasai operation) success rate. 

Steroids are drugs that are well-known for their anti-inflammatory action. However, almost all research on steroids focuses on post-operative usage, and their therapeutic value as a neo-adjuvant treatment to improve the surgical outcome remains undetermined. On the other hand, steroids are associated with potential side effects such as growth impairment and should be used cautiously with scientific evidence. Therefore, our objective is to investigate the effect of a steroid in pre-operative BA liver with attention on its anti-inflammatory mechanism via in-vitro and in-vivo experiments. In-vitro study will be conducted via organoid technology. This will be supplemented with an in-vivo animal study to provide additional data on phenotypical changes in an animal BA model.