Definition
Progressive destruction or the absence of all or part of the extrahepatic BILE DUCTS, resulting in the complete obstruction of BILE flow. Usually, biliary atresia is found in infants and accounts for one third of the neonatal cholestatic jaundice. Type 3 accounts for more than 90% of cases.
Epidemiology
Biliary atresia is a disorder unique to the neonatal period. It has an incidence of approximately 1/10000 live births worldwide. Different incidence rates are reported varying from 1.46/10000 live births in Taiwan, to 0.65 to 0.85/10000 live births in the United States, indicating that the incidence of BA is highest in Asia and the Pacific region. It has been noticed that females are affected slightly more often than males.
Tiao et al. (2008) reported a peak incidence of biliary atresia in Taiwan occurred in 2002 (1.90/10,000), contemporary to an epidemic tropical fever in the same year. These findings implicated viral infection outbreaks as a potential cause of biliary atresia.
Biliary Atresia: pathogenesis and treatment. 1998
Genomic alterations in BA. 2010
Epidemiological features in BA. 1996-2003
Clinical Features
After birth, the clinical triad of BA is:
- Jaundice (conjugated hyperbilirubinemia lasting beyond two weeks of life)
- Acholic (white) stools and dark urine
Failure to thrive is a late sign. It results from poor absorption of long-chain fats and the catabolic state, appearing with weight loss and irritability. Later signs (>3 months of age) include splenomegaly (suggesting portal hypertension), ascites and haemorrhage (which can be intracranial, gastrointestinal or from the umbilical stump) due to impaired absorption of vitamin K. Untreated, this condition leads to cirrhosis and death within the first years of life.
Diagnosis
Since early diagnosis appears essential for effective surgical treatment, every case of neonatal jaundice lasting more than two weeks should be investigated and biliary atresia actively excluded. Laboratory studies typically identify cholestatic liver function tests (table 1) [5]. Serum gamma-glutamyltransferase (GGT) is usually higher in biliary atresia than in other causes of neonatal cholestasis—especially when correlated with age [6]. Serum cholesterol might be raised but triglycerides are within the normal range.
| Typical concentration at presentation | Normal range |
| Bilirubin (μmol/L) | >100 | <20 |
| Alkaline phosphatase (IU/L) | >600 | <500 |
| γ-glutamyl transferase (IU/L) | >100 IU/L | 20–40 |
| Aspartate aminotransferase (U/L) | 80–200 | 15-40 |
| Alanine aminotransferase (U/L) | 80–200 | 10-55 |
| Albumin (g/L) | Normal at presentation | 37–56 |
| Prothrombin time (s) | Normal at presentation | 9–13 |
|
| Table 1: Biochemical variables in biliary atresia |
No single pre-operative investigation can diagnose BA with certainty. However, by using a combination of tests it is possible to be reasonably certain about the diagnosis in most cases. The following investigations are particularly helpful:
- Ultrasonography
Ultrasonography of the liver is performed after 12 hours of fasting (with an IV dextrose infusion). BA is suspected when the gallbladder is shrunk despite fasting, when the liver hilum appears hyperechogenic ("triangular cord sign") or when there is a cyst at the liver hilum. There should be no evidence of bile duct dilatation. Syndromic BA infants may show other features such as multiple spleens, preduodenal portal vein, absence of retrohepatic vena cava or abdominal situs inversus.
- Cholangiography
When the gallbladder seems normal on ultrasonography scans, cholangiography is needed to assess the morphology and patency of the biliary tree. A cholangiogram can be obtained percutaneously (puncture of the gallbladder), endoscopically (ERCP) or at operation.
- Liver biopsy
The main histological features suggestive of BA are bile plugs, ductular proliferation, portal oedema and/or fibrosis. As with any other cause of neonatal cholestasis, giant cell transformation may be observed.
- Others
Hepatobiliary scintigraphy (e.g. HIDA scans) demonstrates a failure of excretion of the radioisotope into the intestine, but this feature can also be observed in any severe neonatal cholestasis.
Orphanet.org/Diagnostic Methods
Biliary Atresia. 2009
Differential diagnosis of BA. 2008
Pathogenesis
Despite intensive interest and investigation, the cause of BA remains unknown. Two different forms are described:
1) In syndromic BA (also known as the embryonic type), there are associated congenital anomalies such as an interrupted inferior vena cava, preduodenal portal vein, intestinal malrotation, situs inversus, cardiac defects and polysplenia. In this variety, which accounts for about 10–20% of all cases, BA is likely to be due to a developmental insult occurring during differentiation of the hepatic diverticulum from the foregut of the embryo.
2) Non-syndromic BA (also known as the perinatal type) may have its origins later in gestation and run a different clinical course.
Some factors that might contribute to development are genetic, infective, inflammatory, and even toxic insult:
- Viral agents
Reovirus type 3 infection, rotavirus, cytomegalovirus, papillomavirus and Epstein–Barr virus have all been proposed as possible aetiologic agents but conclusive evidence is lacking.
- Genetic factors
Generally, BA is not considered to be an inherited disorder. However, genetic mutations that result in defective morphogenesis may be important in syndromic BA. Mutations of the CFC1 gene, which is involved in left–right axis determination in humans, have recently been identified in a few patients with syndromic BA.
- Abnormal ductal plate remodeling
Intrahepatic bile ducts are derived from primitive hepatocytes which form a sleeve (the ductal plate) around intrahepatic portal vein branches and associated mesenchyme in early gestation. Remodelling of the ductal plate in fetal life results in the formation of the intrahepatic biliary system. Non-syndromic BA might be caused by a failure of bile duct remodelling at the hepatic hilum, with persistence of fetal bile ducts poorly supported by mesenchyme.
- Immune-mediated mechanisms
Biliary obstruction in non-syndromic BA is progressive. A few such infants even have a history of pigmented stools at birth. Pathogenesis may involve an immune-mediated inflammatory destruction of intra- and extrahepatic bile ducts. Several studies have investigated the susceptibility of the bile duct epithelial cells to immune/inflammatory attack because of abnormal expression of human leukocyte antigens (HLA-B12, class II HLA-DR) or intercellular adhesion molecules on their surface (ICAM-1). Expression of ICAM-1 has been found to be correlated with disease severity.
Extrahepatic BA. 2003
Pathogenesis and Etiology of BA. 2005
Association between HLA and Extrahepatic BA. 1993
Therapy
The current management of BA patients involves two steps:
- Kasai operation or hepatoporto-enterostomy (in the neonatal period), which aims to restore bile flow. In this procedure the entire extrahepatic biliary tree is excised so that the porta hepatis is transected at the level of the liver capsule and the ductules that remain (typically microscopic) are exposed. A jejunal Roux loop is anastomosed to the cut surface, thus completing the reconstruction.
- Liver transplantation is reserved to children for whom the Kasai operation has failed in its primary aim or for whom complications of biliary cirrhosis have supervened.
Eating, Diet and Nutrition
Effective management includes also prevention and treatment of complications and provision of effective nutritional and family support. This can be achieved with an integrated multidisciplinary approach. All infants should have supplementation of nutrition and fat-soluble vitamins to prevent malnutrition, overcome fat malabsorption, and reduce the effects of excess catabolism. Supplementation is best achieved with a high-energy, high-protein feed that provides between 110–160% of the recommended daily amount. Steatorrhoea from fat malabsorption can be managed by provision of between 40% and 60% of fat in the feed as medium-chain triglycerides. Fat-soluble vitamins can be poorly absorbed, and thus supplementation should include vitamins A, D, E, and K. High-dose oral vitamins should meet nutrition requirements and serum concentrations should be monitored. In refractory cases parenteral vitamins might be needed.
Early use of nasogastric feeding is encouraged in order to cope with the high energy, restricted volume and need of specific nutrients like BCAA (branched chain amino acid).
The effect of poor nutrition on the outcome of liver disease has already been emphasized. PN is an accepted mode of delivery of calories and nutrients when the naso-gastric route cannot be used because of risk of esophageal variceal hemorrhage or the patient is intolerant to enteral nutrition through diarrhea with osmotic disturbance or fails to respond.
Current management of BA. 2007
Nutritional support in liver disease. 1993
Outcome
BA is a rare, complex disorder and demands expert multidisciplinary management. Despite progressive improvement in the results of treatment, the condition is extremely distressing for parents and families who not only face the anxieties of newborn surgery with an uncertain outcome, but also the possibility of eventual liver transplantation and its attendant risks.
Kasai portoenterostomy is a palliative procedure and does not cure biliary atresia. The disease progresses in 70% of children in whom bile drainage is established, with development of fibrosis, portal hypertension, and cirrhosis. The rate of progression varies, but progression is most likely when cholangitis is recurrent. Despite this fact, more than 80% of those who have had a successful procedure survive longer than 10 years with their native liver with good quality of life.
Transplantation in infants, which is often the most technically challenging, also has a good outcome and is associated with long-term catch-up growth, improved nutrition, and maintenance of healthy development. Data from the largest US follow-up study of 1976 transplanted children with biliary atresia show that 10-year actuarial graft survival is 73% and patient survival is 86%.
Biliary Atresia. 2009
