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|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 be congenital or acquired. As a birth defect in newborn infants, it has an incidence of one in 10,000–15,000 live births in the United States, and a prevalence of one in 16,700 in the British Isles. Biliary atresia is most common in East Asia, with a frequency of one in 5,000.
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 a result of an autoimmune inflammatory response, possibly due to a viral infection of the liver soon after birth. The only effective treatments are surgeries such as the Kasai procedure and liver transplantation.
Signs and symptoms
Initially, the symptoms of biliary atresia are indistinguishable from those of neonatal jaundice, a usually harmless condition commonly seen in infants. Distinctive symptoms of biliary atresia 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. When the liver is unable to excrete bilirubin through the bile ducts in the form of bile, bilirubin begins to accumulate in the blood, causing symptoms. These symptoms include yellowing of the skin, itchiness, poor absorption of nutrients (causing delays in growth), pale stools, dark urine, and a swollen abdomen. Eventually, cirrhosis with portal hypertension will develop. If 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. This is because in biliary atresia, the liver, although diseased, is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood–brain barrier.
The cause of biliary atresia is unknown. Many possible causes have been proposed, such as reovirus 3 infection, congenital malformation, congenital cytomegalovirus infection, and autoimmunity. However, experimental evidence is insufficient to confirm any of these theories.
There have been extensive studies of the pathogenesis and proper management of progressive cirrhosis. When the biliary tract cannot transport bile to the duodenum, bile is retained in the liver (a condition known as cholestasis), which results in cirrhosis of the liver. Small bile ductules proliferate, and peribiliary fibroblasts are activated. These "reactive" biliary epithelial cells produce and secrete 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 pro-fibrogenic cytokine that can be seen in progressive cirrhosis. During the chronic activation of biliary epithelium and progressive cirrhosis, patients eventually show signs and symptoms of portal hypertension, such as esophagogastric varix bleeding, hypersplenism, hepatorenal syndrome, and hepatopulmonary syndrome. The latter two syndromes are essentially caused by systemic mediators that maintain the body in a hyperdynamic state.
There are three main types of extra-hepatic biliary atresia:
- Type I: Atresia is restricted to the common bile duct.
- Type II: Atresia of the common hepatic duct.
- Type III: Atresia of the right and left hepatic duct.
An association between biliary atresia and the ADD3 gene was first detected in Chinese populations through a Genome-wide association study, and was confirmed in Thai 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) and is involved in the regulation of inflammation and the Hedgehog gene.
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 is a link between human cases of biliary atresia and toxins such as biliatresone. There are some indications that a metabolite of certain human gut bacteria may be similar to biliatresone.
Diagnosis is made by an assessment of symptoms, physical exam, and medical history, in conjunction with blood tests, a liver biopsy, and imaging. Diagnosis is often made following investigation of prolonged jaundice that is resistant to phototherapy and/or exchange transfusions, with abnormalities in liver enzyme tests. Ultrasound or other forms of imaging can confirm the diagnosis. Further testing may include 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 through an operation known as the Kasai procedure (after Morio Kasai, the Japanese surgeon who developed the surgery) or hepatoportoenterostomy. This procedure is not usually curative, but may temporarily alleviate symptoms until the child is fully grown and can undergo liver transplantation. Many individuals are known to have undergone the Kasai procedure and lived for more than a few years without requiring additional surgeries.
If the atresia is complete, liver transplantation is the only option. Timely Kasai portoenterostomy (< 60 postnatal days) has shown better outcomes. Nevertheless, a considerable number of patients undergo liver transplantation within a couple years of the Kasai procedure, even if that procedure was successful.
Recent large-scale studies by Davenport et al. (Annals of Surgery, 2008) show that the age of the patient is not an absolute clinical factor affecting prognosis. The influence of age differs according to the disease etiology—i.e., whether biliary atresia is isolated, cystic (CBA), or accompanied by splenic malformation (BASM).
It is widely accepted that corticosteroid treatment after a Kasai operation, with or without choleretics and antibiotics, has a beneficial effect on postoperative bile flow and can clear jaundice, but the dosing and duration of the ideal steroid protocol are controversial. Furthermore, it has been observed in many retrospective longitudinal studies that corticosteroid treatment 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 had no effect on the mid- or long-term prognosis of biliary atresia patients.
Biliary atresia seems to affect females slightly more often than males, and Asians and African Americans more often than Caucasians. It is common for only one child in a pair of twins or within the same family to have the condition. There seems to be no link to medications or immunizations given immediately before or during pregnancy.
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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