|Extrahepatic Biliary atresia|
Operative view of complete extrahepatic biliary atresia.
|Classification and external resources|
Biliary atresia, also known as "extrahepatic ductopenia" and "progressive obliterative cholangiopathy", is a childhood disease of the liver in which one or more bile ducts are abnormally narrow, blocked, or absent. It can occur as a birth defect or as an acquired disease. As a birth defect in newborn infants, it has an occurrence rate of one in 10,000 to 15,000 cases in live births in the United States, with the most accurate prevalence recorded at one in 16,700 in the British Isles. Biliary atresia is most common in east Asia, with a frequency of one in 5,000. In the congenital form, the common bile duct between the liver and the small intestine is either blocked or absent. The causes of biliary atresia are not well understood. Congenital biliary atresia has been associated with certain genes, while acquired biliary atresia is thought to be the result of an autoimmune inflammatory response, possibly to a viral infection of the liver soon after birth. The only effective treatments are certain surgeries such as the Kasai procedure and liver transplantation, both of which have proven effective in only a small number of historical cases.
Signs and symptoms
Initially, the symptoms of biliary atresia are indistinguishable from neonatal jaundice, a common phenomenon. Symptoms are usually evident between one and six weeks after birth. Infants and children with biliary atresia develop progressive cholestasis, a condition in which bile is unable to leave the liver and builds up inside of it. With the liver unable to excrete bilirubin through the bile ducts, bilirubin begins to accumulate in the blood, causing a constellation of other symptoms to appear. These include yellowing of the skin, itchiness, poor absorption of nutrients (causing delays in growth), fat-soluble vitamin deficiencies, abnormally high levels of lipids in the blood, pale stools, dark urine, swollen abdominal region, and large hardened liver (which may or may not be observable by the naked eye). Eventually cirrhosis with portal hypertension will develop. Left untreated, biliary atresia can lead to liver failure. Unlike other forms of liver failure, however, biliary atresia-related liver failure does not result in kernicterus, a form of brain damage resulting from liver dysfunction. The reason for this is that the liver, although diseased, is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood–brain barrier.
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There is no known cause of biliary atresia. Many theories were proposed about possible causes of biliary atresia such as reovirus 3 infection, congenital malformation, congenital cytomegalovirus infection, and autoimmune theory, and none is supported by enough evidence to be accepted as an aetiology of biliary atresia.
However, there have been extensive studies about the pathogenesis and proper management of progressive liver fibrosis. As the biliary tract cannot transport bile to the intestine, bile is retained in the liver (known as stasis) and results in liver cirrhosis. Proliferation of the small bile ductules occur, and peribiliary fibroblasts become activated. These "reactive" biliary epithelial cells in cholestasis, unlike normal condition, produce and secrete various cytokines such as CCL-2 or MCP-1, tumor necrosis factor (TNF), interleukin-6 (IL-6), TGF-beta, endothelin (ET), and nitric oxide (NO). Among these, TGF-beta is the most important profibrogenic cytokine that can be seen in liver fibrosis in chronic cholestasis. During the chronic activation of biliary epithelium and progressive fibrosis, afflicted patients eventually show signs and symptoms of portal hypertension (esophagogastric varix bleeding, hypersplenism, hepatorenal syndrome (HRS), hepatopulmonary syndrome (HPS)). The latter two syndromes are essentially caused by systemic mediators that maintain the body within the hyperdynamic states.
There are three main types of extrahepatic biliary atresia:
- Type I: atresia restricted to the common bile duct.
- Type II: atresia of the common hepatic duct.
- Type III: atresia of the right and left hepatic duct.
Associated anomalies include, in about 10% cases, heart lesions, polysplenia, situs inversus, absent vena cava, and a preduodenal portal vein.
Genetic association with the ADD3 gene was detected first in Chinese through a Genome-wide association study, and was confirmed later in Thailand Asians and Caucasians. A possible association with deletion of the gene GPC1 which encodes a glypican 1-a heparan sulfate proteoglycan has been reported. This gene is located on the long arm of chromosome 2 (2q37). This gene is involved in the regulation of the gene Hedgehog and also of inflammation.
Eating plants that contain a toxin called biliatresone has been implicated in outbreaks of a biliary atresia-like illness in lambs. Studies are ongoing to determine whether there may be a link to human cases of biliary atresia. There are some indications that a metabolite of certain human gut bacteria may be similar to biliatresone. 
Prolonged jaundice that is resistant to phototherapy and/or exchange transfusions often prompts a search for secondary causes. By this time, liver enzymes are generally measured, and these tend to be grossly deranged, hyperbilirubinemia is conjugated and therefore does not lead to kernicterus. Ultrasound investigation or other forms of imaging can confirm the diagnosis. Further testing includes radioactive scans of the liver and a liver biopsy.
If the intrahepatic biliary tree is unaffected, surgical reconstruction of the extrahepatic biliary tract is possible. This surgery is called a Kasai procedure (after the Japanese surgeon who developed the surgery, Morio Kasai) or hepatoportoenterostomy. This procedure is not usually curative, but ideally does buy time until the child can achieve growth and undergo liver transplantation.
If the atresia is complete, liver transplantation is the only option. Timely Kasai portoenterostomy (e.g. < 60 postnatal days) has shown better outcomes. Nevertheless, a considerable number of the patients, even if Kasai portoenterostomy has been successful, eventually undergo liver transplantation within a couple of years after Kasai portoenterostomy.
Recent large volume studies from Davenport et al. (Ann Surg, 2008) show that the age of the patient is not an absolute clinical factor affecting the prognosis. In the latter study, influence of age differs according to the disease etiology—i.e., whether isolated BA, BASM (BA with splenic malformation ), or CBA(cystic biliary atresia).
It is widely accepted that corticosteroid treatment after a Kasai operation, with or without choleretics and antibiotics, has a beneficial effect on the postoperative bile flow and can clear the jaundice; but the dosing and duration of the ideal steroid protocol have been controversial ("blast dose" vs. "high dose" vs. "low dose"). Furthermore, it has been observed in many retrospective longitudinal studies that steroid does not prolong survival of the native liver or transplant-free survival. Davenport et al. also showed (hepatology 2007) that short-term low-dose steroid therapy following a Kasai operation has no effect on the mid- and long-term prognosis of biliary atresia patients.
Biliary atresia seems to affect girls slightly more often than boys. It is common for only one child in a pair of twins or only one child within the same family to have it. Asians and African-Americans are affected more frequently than Caucasians. There seems to be no link to medications or immunizations given immediately before or during pregnancy.
As of 2013[update], numerous individuals are known to have undergone the Kasai procedure and lived for more than a few years without requiring additional surgeries. A group existing on Facebook as well as other social networking sites consist of patients and families who share both their success and hardship stories.
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- Information from the European Biliary Atresia Registry
- Biliary Atresia Research Consortium (U.S.)
- Children's Liver Disease Foundation (U.K.)
- Bhatnagar, V; Kumar, Arun; Gupta, AK (2005). "Choledochal cyst associated with extrahepatic bile duct atresia". Journal of Indian Association of Pediatric Surgeons 10 (1): 48–9. doi:10.4103/0971-9261.16077.
- How Inflammation Causes Biliary Atresia by Jorge Bezerra, MD at Cincinnati Children's Hospital Medical Center