Biliary atresia

Synonyms

2

Overview

Biliary atresia (extrahepatic ductopenia, 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 incidence 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.

Symptoms

Initially, the symptoms of biliary atresia are indistinguishable from neonatal jaundice, a usually harmless condition commonly seen in infants after birth. 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. 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.

Causes

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.

In approximately 10% of cases, anomalies associated with biliary atresia include heart lesions, polysplenia, situs inversus, absent venae cavae, and a preduodenal portal vein.

Genetics

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.

Toxins

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

Diagnosis is made by assessing an individual's 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 and abnormalities in liver enzymes tests are present. Ultrasound investigation or other forms of imaging can confirm the diagnosis. Further testing includes radioactive scans of the liver and a liver biopsy.

Prognosis

Early surgery will improve the survival of more than a third of babies with this condition. The long-term benefit of liver transplant is not yet known, but is expected to improve survival.

Treatment

If the intrahepatic biliary tree is unaffected, surgical reconstruction of the extrahepatic biliary tract is possible through an operation known as 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.