Biliary atresia

Abstract

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.

Fig. 1 |. Global incidence of BA.

Incidences of BA reported in nationwide or multicentre studies. Overall, higher incidences were reported for East Asian than for Western countries/regions.

Fig. 2 |. Aetiological heterogeneity of BA.

Biliary atresia splenic malformation syndrome showing a pre-duodenal portal vein (part a, arrow) and left-sided polysplenia (part b, circled). Cystic biliary atresia with cholangiogram (part c) showing contrast retention in the cyst, absence of flow into the intestine, and abnormally fine, interconnecting etiolated intrahepatic bile ducts. Isolated biliary atresia (part d) showing (1) mobilized atrophic gallbladder, (2) umbilical vein and (3) sling around right hepatic artery. Cut surface of the porta hepatis before Roux loop reconstruction (part e). Photomicrograph of cut surface showing scattered biliary ductules within a fibroinflammatory stroma (vimentin-positive) (part f). Part f reproduced with permission from La Pergola E et al. (2021).

Fig. 3 |. BA as a combination of injury and maladaptive response.

Biliary atresia (BA) is viewed as the result of an injury, probably prenatal, and the response to that injury, probably occurring in both the prenatal and postnatal periods. Agents that may contribute to injury include genetic causes (most notably genetic alterations that lead to abnormal primary cilia), environmental agents and developmental susceptibilities of the immature extrahepatic bile duct (EHBD). Other factors, such as sex and ethnicity, can predispose to BA. Dysregulated immune and wound healing responses comprise the response to injury and facilitate progression of the disease. Clinically detectable outcomes of the disease progress to BA and, subsequently, liver dysfunction and liver fibrosis. The potential for recovery after injury by regenerative or reparative healing is unknown and remains speculative. CMV, cytomegalovirus; ECM, extracellular matrix.

Fig. 4 |. Hypothetical contribution of immune dysregulation to the pathogenesis of biliary atresia.

Injury by virus infection or toxins of altered cholangiocytes triggers a cascade of early innate (autoinflammatory) and subsequent adaptive (autoimmune) responses that proceed unchecked in the setting of regulatory T (T_reg) cell deficits. The chronic inflammation further damages cholangiocytes and activates stellate cells, resulting in progressive biliary fibrosis. EHBD, extrahepatic bile duct; IHBD, intrahepatic bile duct; ILC2, type 2 innate lymphoid cell; NET, neutrophil extracellular traps; NK, natural killer; ROS, reactive oxygen species.

Fig. 5 |. Kasai portoenterostomy.

The mobilized jejunum is transected, and its proximal end is anastomosed to the transected portal plate (portoenterostomy) to enable bile drainage from the intrahepatic biliary system into the intestine via remnant patent biliary ductules. The proximal limb of the small intestine (downstream of the duodenum) is anastomosed to the 30–40 cm retrocolic Roux loop (jejunojejunostomy).

Fig. 6 |. Potential regenerative strategies in biliary atresia treatment.

Pluripotent stem cells derived from reprogramming of primary somatic cells from patients or embryonic stem cells can be differentiated into various cell types useful for liver regeneration as cellular or tissue engineering therapies. Progenitors could also be used for mobilization of patients’ cells which can help regeneration through modulation of inflammation and fibrosis.

Fig. 7 |. Postoperative follow-up of native liver survivors.

For optimal timing of liver transplantation, native liver survivors should be monitored and managed by multidisciplinary teams in specialist centres throughout their life. Evaluation for liver transplantation should occur promptly after failed Kasai portoenterostomy (KPE), as most patients develop rapidly progressing end-stage liver disease within 1–2 years. Despite successful KPE, the underlying cholangiopathy advances variably increasing the proportion of transplanted patients over time. Successful transition of young patients to adult health services requires special cooperative efforts between paediatric and adult specialists and comprehensive patient education. BIL, bilirubin; LT, liver transplantation.

Fig. 8 |. Future research directions and effects on patient outlook.

Discovery of disease mechanisms and identification of gene sets for patient stratification could lead to early diagnosis and new interventions at several important time points to improve the outcomes in patients with biliary atresia (BA). Currently, patients undergo Kasai portoenterostomy (KPE) (85–95%) at ~2 months of age, or primary liver transplantation (LT) (5–15%) because of late diagnosis. Improved screening with new biomarkers would enable diagnosis of emerging BA in early infancy (7–60 days), providing the first preventative and/or therapeutic window for earlier KPE and avoidance of primary LT. Introduction of neoadjuvant therapies targeting the injury phase of BA, such as the antioxidant N-acetylcysteine in the expanded window before KPE, might improve clearance of jaundice rate and reduce early (at <1 year of age) LT incidence (currently 17–40%). After KPE, patients experience complications leading to progression of liver pathology requiring late (at >1 year of age) LT (currently 30–67%). During this second therapeutic window, disease mechanism-inspired novel drugs, targeting the dysregulated immune-inflammation and ECM response phase could reduce recalcitrant cholangitis and fibrosis responsible for late LT, and increase long-term native liver survival (NLS) (currently only 40%). For the remaining patients currently requiring LT, regenerative medicine might reduce or replace the need for LT.