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Operative view of complete extrahepatic biliary atresia.
|Classification and external resources|
Biliary atresia, also known as "extrahepatic ductopenia" and "progressive obliterative cholangiopathy", is a congenital or acquired disease of the liver and one of the principal forms of chronic rejection of a transplanted liver allograft. As a birth defect in newborn infants, it has an occurrence of 1/10,000 to 1/15,000 cases in live births in the United States. In the congenital form, the common bile duct between the liver and the small intestine is either blocked or absent. The acquired type most often occurs in the setting of autoimmune disease, and is one of the principal forms of chronic rejection of a transplanted liver allograft.
Infants and children with biliary atresia have progressive cholestasis with all the usual concomitant features: jaundice, pruritus, malabsorption with growth retardation, fat-soluble vitamin deficiencies, hyperlipidemia, and eventually cirrhosis with portal hypertension. If unrecognized, the condition leads to liver failure—but not kernicterus, as the liver is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood–brain barrier. The cause of the condition is unknown. 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.
Symptoms and diagnosis
Initially, the symptoms are indistinguishable from neonatal jaundice, a common phenomenon. Symptoms are usually evident between one and six weeks after birth. Besides jaundice, other symptoms include pale stools, dark urine, swollen abdominal region and large hardened liver (which may or may not be observable by the naked eye). Prolonged jaundice that is resistant to photo therapy and/or exchange transfusions should prompt 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.
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.
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There is no known cause of biliary atresia. There have been many theories about etiopathogenesis such as Reovirus 3 infection, congenital malformation, congenital CMV infection, and autoimmune theory. This means that the etiology and pathogenesis of biliary atresia are largely unknown.
However, there have been extensive studies about the pathogenesis and proper management of progressive liver fibrosis, which is arguably one of the most important aspects of biliary atresia patients. As the biliary tract cannot transport bile to the intestine, bile is retained in the liver (known as stasis) and results in cirrhosis of the liver. 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, cardiac lesions, polysplenia, situs inversus, absent vena cava, and a preduodenal portal vein.
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.
A possible association with 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. In addition to the association of mutations in the gene and the abnormally low levels of this protein in human cases, knock out mutants in zebra fish develop similar lesions in the liver. Hedgehog inhibitors ameliorate the features in the mutated fish and the addition of hedgehog to normal fish produce lesions.
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.
- Sleisenger, MH; Feldman M, Friedman, LS (2006). Sleisenger and Fordtran's gastrointestinal and liver disease: pathophysiology, diagnosis, management (8th Edition ed.). Philadelphia: Saunders.
- Cui S, Leyva-Vega M, Tsai EA, Eauclaire SF, Glessner JT, Hakonarson H, Devoto M, Haber BA, Spinner NB, Matthews RP (2013) Evidence from human and zebrafish that GPC1 is a biliary atresia susceptibility gene. Gastroenterology doi:10.1053/j.gastro.2013.01.02200
- Information from the European Biliary Atresia Registry
- Biliary Atresia Research Consortium (U.S.)
- Children's Liver Disease Foundation (U.K.)
- Choledochal cyst associated with extrahepatic bile duct atresia
- How Inflammation Causes Biliary Atresia by Jorge Bezerra, MD at Cincinnati Children's Hospital Medical Center