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

Abstract

Biliary atresia (BA) is a fibroinflammatory disease of the intra- and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a pre-natal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g. biliatresone) and of viruses (e.g. CMV) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate pro-inflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following an epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. This article is protected by copyright. All rights reserved.

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

“…). At the time of selection, 27% of participants were alive with native liver, similar to published series . Review of PROBE and BASIC case report forms indicated that the majority of BASM participants in this study exhibited at least two laterality features (Fig.…”

“…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 .…”

Clinical Consequences of Cardiomyopathy in Children With Biliary Atresia Requiring Liver Transplantation

“…Subsequent studies have found that CCM is present in approximately 50% of adult patients undergoing liver transplantation (LT) and, though reversible post‐LT, is associated with increased mortality, acute cardiac failure, intraoperative complications, graft rejection, dysrhythmia, hepatorenal syndrome, and multiorgan dysfunction (MOD) . Despite the potential for life‐threatening complications, no treatment currently exists for this disease outside of LT. CCM therefore continues to pose significant clinical challenges to the multidisciplinary team taking care of these patients, and further study is essential …”

60 Days in Biliary Atresia: A Historical Dogma Challenged

“…However, the predicament facing the pediatric hepatologist and/or surgeon is that the earlier the child is investigated, the more challenging it is to make a confident diagnosis, especially because there are, as yet, no unequivocal genetic or other laboratory biomarkers for BA. There is no clear‐cut solution to this dilemma except to maintain a high level of suspicion even though this is a rare disorder (1 in 8000‐18,000 live births) that the average pediatrician may see only a handful of times in a career …”

“…The problem with the 60‐day deadline is that it is relatively late in the early course of BA. A variety of lines of investigation suggest that BA often begins prenatally and manifests by cholestasis in the newborn period . A fascinating analysis of elastographic assessment of liver stiffness in infants who were subsequently diagnosed with BA revealed an alarming progression of disease in the first weeks of life (Fig.…”