Journal of Pediatric Surgery Lecture
Biliary atresia: From Australia to the zebrafish

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Abstract

This review is based upon an invited lecture for the 52nd Annual Meeting of the British Association of Paediatric Surgeons, July 2015.

The aetiology of biliary atresia (BA) is at best obscure, but it is probable that a number of causes or pathophysiological mechanisms may be involved leading to the final common phenotype we recognise clinically.

By way of illustration, similar conditions to human BA are described, including biliary agenesis, which is the normal state and peculiar final pattern of bile duct development in the jawless fish, the lamprey. Furthermore, there have been remarkable outbreaks in the Australian outback of BA in newborn lambs whose mothers were exposed to and grazed upon a particular plant species (Dysphania glomulifera) during gestation. More recent work using a zebrafish model has isolated a toxic isoflavonoid, now named Biliatresone, thought to be responsible for these outbreaks.

Normal development of the bile ducts is reviewed and parallels drawn with two clinical variants thought to definitively have their origins in intrauterine life: Biliary Atresia Splenic Malformation syndrome (BASM) and Cystic Biliary Atresia (CBA). For both variants there is sufficient clinical evidence, including associated anomalies and antenatal detection, respectively, to warrant their aetiological attribution as developmental BA. CMV IgM + ve associated BA is a further variant that appears separate with distinct clinical, histological, and immunohistochemical features. In these it seems possible that this involves perinatal obliteration of a normally formed duct system. Although still circumstantial, this evidence appears convincing enough to perhaps warrant a different treatment strategy. This then still leaves the most common (more than 60% in Western series) variant, now termed Isolated BA, whereby origins can only be alluded to.

Section snippets

Development of the extrahepatic biliary system and BASM

The biliary system is derived in two distinct ways with different time schedules — the extrahepatic bile duct being the first to form and is derived directly from the foregut endoderm whilst the intrahepatic ducts are derived later from hepatoblasts forming within the liver primordium.

The extrahepatic duct itself appears at about day 20 as an outpouching from distal foregut and develops into a funnel-shaped structure with a lumen and a gallbladder by day 45. It is lined by cholangiocytes

Development of the intrahepatic biliary system

By 28 days, the embryonic liver is populated by hepatoblasts, derived directly from endoderm and haematopoietic cells initially derived from yolk sac. The former are arranged in plates, initially 3–4 cells thick, which line the vascular sinusoidal network. Hepatoblasts will give rise to both hepatocytes and ductal cells with Notch signalling promoting ductal cell development and inhibiting hepatocyte formation. The nascent intrahepatic bile ducts only appear as a distinct entity from about seven

Cystic biliary atresia

There is another variant of BA which definitely has its origins in the maternal uterus: Cystic biliary atresia. The evidence for this is that those with a sufficiently large cyst can be picked up on maternal ultrasound screening, typically from about 18 to 20 weeks’ gestation [20]. Postnatally the cyst neither increases nor decreases in size and in about 30% retains enough of a connection with the intrahepatic duct to fill with bile. These are the ones where we can appreciate cholangiography of

Natural animal models of biliary atresia

We do have a natural model of BA as normal variation in the peculiar development of the liver in the lamprey (Petromyzon marinus) [23]. Most educated people of course know this eel-like parasitic fish from a historical reference — King Henry I of England died from eating a “surfeit of lampreys”. Well lampreys themselves like nothing better than fastening their teeth into the skin of passing fish and sucking their blood. Despite what must be a haemoglobin-rich diet they manage to thrive quite

Secondary obliterative cholangiopathy

There is an inflammatory reaction evident in some infants at the time of Kasai within the liver and bile ducts. Our original immunohistochemical study [30] looked at 28 infants for various markers of the inflammatory process, current in the late 1990s, such as expression of cellular adhesion molecules (ICAM-1, VCAM-1 and e-selectin), and the nature of the inflammatory mononuclear cell infiltrate. We found that broadly 50% showed abnormal ICAM-1 expression on biliary and vascular endothelium,

Summary

Fig. 5 illustrates our current concept of the possible mechanistic explanations for the phenotype we recognised clinically as BA and is an example of aetiological heterogeneity. What is clear from the preceding discussion is not only our prevailing sense of ignorance on what actually is going on in this fundamental condition.

It is common when ending invited lectures to try and gaze into the future. However, according to Neils Bohr the famous nuclear physicist, prediction is very difficult

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