Biliary atresia (BA) is a rare disease characterized by a biliary obstruction of unknown origin that presents in the neonatal period. It is the most important surgical cause of cholestatic jaundice in this age-group. The common histopathological picture is one of inflammatory damage to the intra- and extrahepatic bile ducts with sclerosis and narrowing or even obliteration of the biliary tree. Untreated, this condition leads to cirrhosis and death within the first years of life. Surgical treatment usually involves an initial attempt to restore bile flow: the Kasai portoenterostomy which is performed as soon after diagnosis as possible. Later, liver transplantation may be need for failure of the Kasai operation or because of complications of cirrhosis. BA remains the commonest indication for paediatric liver transplantation throughout the world.
Biliary Atresia Epidemiology
The reported incidence of BA varies from 5 / 100,000 live births in The Netherlands, 5.1 / 100,000 in France, 6 / 100,000 in the British Isles, 6.5 / 100,000 in Texas, 7 / 100,000 in Victoria Australia 7.4 / 100,000 in Atlanta USA and in Japan, 10.6 / 100,000 in Hawaii, to 32 / 100,000 in French Polynesia. Although some studies of time- and space-time distribution of BA cases have at times suggested seasonal variation and clustering of cases, this has not been confirmed in larger studies.
Biliary Atresia Anatomy
Two different forms of BA are identified:
Syndromic BA (~10%), in which biliary atresia is associated with various congenital anomalies such as polysplenia, asplenia, cardiac or intra abdominal defects (situs inversus, pre-duodenal portal vein, absence of retro-hepatic inferior vena cava, intestinal malrotation).
Non-syndromic BA (~90%), in which biliary atresia is an isolated anomaly. Several surgical classifications of BA cases have been proposed. The French classification is based on the anatomical pattern of the extrahepatic biliary tract remnant.
Biliary Atresia Aetiology
The aetiology of BA remains unknown. Some cases seem to be related to abnormal morphogenesis of bile ducts occurring early in gestation, while others appear to arise as a result of later perinatal damage to normal developed bile ducts.
There are several strands of evidence to suggest that even in non-syndromic BA, the onset is early in gestation. It is possible to detect those forms of BA showing cystic change using antenatal ultrasonography. In a series of 10 infants detected antenatally, most were non-syndromic and the first abnormal scans occurred at about 20 weeks gestation. In one study on serial digestive enzyme sampling in amniotic fluid, gamma glutamyl transpeptidase levels were found to be low as early as 18 weeks gestation in non-syndromic infants born with BA – strong evidence of biliary obstruction at this gestation.
Human embryo studies have also shown similarities between the appearance of the developing bile ducts during the first trimester of pregnancy, and the residual ductules at the level of the porta hepatis in BA patients, suggesting that some cases may be the result of an alteration of the remodeling process of the bile ducts originating from the ductal plate membrane. The persistence of primitive foetal-type bile ducts, functionally leaking bile into surrounding tissues and inducing a secondary inflammatory reaction in–utero has also been suggested. Recent studies have focused on normal and altered bile duct morphogenesis and the initiation of hepatic fibrosis.
The role of viruses has been extensively studied. An association of BA with cytomegalovirus, respiratory syncitial virus, Epstein-Barr virus, and human papilloma virus has been reported, and alternatively, no association has been found with hepatitis A, B and C viruses has been found. Reovirus type 3 can cause cholangitis resembling BA in mice and may be associated with spontaneous BA in the rhesus monkey. In human neonates, the association of reovirus type 3 and BA has been suggested in several studies but not supported in others. Rotavirus type A can cause biliary obstruction in newborn mice, again mimicking BA, and deleterious effects of rotavirus infection in mice can be prevented by interferon alpha. In humans, the role of rotavirus type C in the aetiology of BA remains controversial.
Several observations support a genetic component in the pathogenesis of BA although this is probably unlikely in isolation. Thus, familial cases of BA have been reported although discordant sets of monozygotic twins have also been observed. There are consistent variations in the incidence of BA among different races such as in Hawaii and Atlanta, USA. The incidence of HLA B12 and haplotypes A9-B5 and A28-B35 was found to be higher in infants with BA compared to a control group in one UK study.
Biliary Atresia Diagnosis:
Since early diagnosis appears essential for effective surgical treatment every case of conjugated jaundice lasting more than two weeks should be investigated, and biliary atresia actively excluded.
Prenatal diagnosis of BA remains exceptional. Types 1 and 2 of BA, which are rare, can be suspected on prenatal US scans if a cystic structure is detected in the liver hilum. The post-natal examination has to distinguish the cystic form of BA, which requires urgent surgery from a choledocal cyst, where the surgery can usually be delayed.
After birth, the clinical triad of BA is:
Jaundice (conjugated, and beyond two weeks of life).
Acholic (white) stools and dark urine
The general condition of the child is usually good and at least early on there is no failure to thrive. Later signs include splenomegaly (suggesting portal hypertension), ascites and haemorrhage (which can be intracranial, gastrointestinal or from the umbilical stump and is due to impaired absorption of vitamin K).
Ultrasonography of the liver is performed after a 12 hours fast (with an IV fluid infusion). BA is suspected if the gallbladder is shrunken despite fasting, if the liver hilum appears hyperechogenic (“triangular cord sign”), or if 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 multiples spleens, a preduodenal portal vein, absence of the retrohepatic vena cava etc.
In the cases where the gallbladder seems normal on US scans, cholangiography is needed to assess the morphology and patency of the biliary tree. The cholangiogram can be percutaneous (puncture of the gallbladder), endoscopic (ERCP) or operative.
The main features suggesting BA are bile plugs, ductular proliferation, portal oedema and/or fibrosis. As in any other cause of neonatal cholestasis, giant cell transformation may be observed.
Biochemical liver function tests show cholestasis (with elevated cholesterol and gamma GTs). Hepatobiliary scintigraphy (e.g. HIDA scans) demonstrates a failure of excretion of the radioisotope into the intestine, but can also be observed in any severe neonatal cholestasis. Moreover, scintigraphy can be falsely reassuring in the early stage of BA.
Absence of medical causes of neonatal cholestasis:
Medical causes of neonatal cholestasis need to be excluded. The most common differential diagnosis is: Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC), alpha-1-antitrypsin deficiency, and cystic fibrosis. The diagnosis of BA can be strongly suspected in most cases having considered clinical features, US scans, and having excluded the main medical causes of neonatal cholestasis. Cholangiography and/or liver biopsy are indicated only in cases where the diagnosis remains uncertain, especially when the gallbladder seems normal on US scans.
Biliary Atresia Treatment
The current management of BA patients involves two steps:
- Kasai operation (in the neonatal period), which aims to restore bile flow.
- Liver transplantation in those where the Kasai operation has failed in its primary aim or complications of biliary cirrhosis have supervened.
The Kasai operation: hepatoporto-enterostomy:
Transverse supra-umbilical incision and laparotomy. The diagnosis of biliary atresia is confirmed by inspection of the liver and biliary tract. In most cases (type 4: complete extrahepatic biliary atresia), the diagnosis is obvious with a cholestatic or fibrotic liver and a shrunken, fibrotic gallbladder. If the gallbladder is still patent, or if there is a cyst of the liver hilum, the colour of its content is noticed, and cholangiography is performed. Features of the polysplenia syndrome, as well as any other intra-abdominal anomaly, are noted. The portal pressure can be measured through a small catheter introduced via the umbilical vein. After section of the falciform, left and right triangular ligaments, the liver is exteriorised out of the abdominal cavity. The entire extrahepatic biliary tree is excised together with the fibrous tissue situated inside the bifurcation of the portal vein at the level of the porta hepatis. A 45 cm Roux en Y loop is prepared and passed through the mesocolon to the liver hilum. An anastomosis is fashioned between the cut edge of the transsected tissue in the porta hepatis and the antimesenteric side of the Roux loop. A liver biopsy is performed.
Many technical variants are possible, according to the anatomical pattern of the biliary remnant:
Type 1 BA: cholecysto-enterostomy, or hepatico-enterostomy.
Type 2 BA: cysto-enterostomy. This operation can be performed only if the hilar cyst communicates with the dystrophic intra-hepatic bile ducts (cholangiography).
Type 3 BA: hepatoporto-cholecystostomy. The patent galbladder, cystic duct and common bile duct are preserved. The gallbladder is mobilised with preservation of its pedicle. An anastomosis is performed between the gallbladder and the transsected tissue in the porta hepatis. Since there is no direct contact between the porta hepatis and the intestine, this operation reduces the risk of post operative cholangitis. Its specific complications are however, bile leaks and post-operative biliary ascites due to kinking and obstruction of cystic duct and common bile duct.
Biliary Atresia Post Operative Course
Post-operatively, different drugs have been proposed either to reduce the inflammatory process at the liver hilum, which might lead to granulation and fibrous scar obstructing the biliary ductules, or to increase the biliary flow. Although recommended by several surgeons, the use of corticosteroids remains controversial since a long-term benefit has not been proven and there is a theoretical risk of exacerbating cholangitis.
Outcome after successful Kasai Operation
If the Kasai operation succeeds in restoring bile flow, the stools become coloured, and jaundice fades. This process may last several weeks or months. The evolution of the biliary cirrhosis is stopped or at least delayed, and survival with the native liver has been reported up to adulthood.
Several Complications may occur after the Kasai Operation:
Cholangitis: Direct communication of the intestine to the dystrophic intrahepatic bile ducts, with poor bile flow, can cause an ascending cholangitis. This occurs particularly in the first weeks or months after the Kasai procedure in 30-60% of cases. This infection may be severe and sometimes fulminant. There are signs of sepsis (fever, hypothermia, impaired haemodynamic status), recurrent jaundice, acholic stools and perhaps abdominal pain. The diagnosis can be confirmed by cultures of blood and/or liver biopsies. The treatment requires IV antibiotics, and effective intravenous resuscitation. In those cases of recurrent and/or late cholangitis, obstruction of the Roux en Y loop or persistent colonisation of an intrabiliary cyst should be sought. Recurrent cholangitis without a “surgical” cause may require continuous antibiotic prophylaxis.
Portal hypertension: Portal hypertension occurs in at least two-thirds of the children after portoenterostomy, even in those with complete restoration of the bile flow. The most common site of varices are in the oesophagus, stomach, at the site of the Roux loop anastomosis and the anorectum. If the Kasai operation has clearly failed with poor biochemical liver function and persisting jaundice then liver transplantation is indicated. However variceal sclerotherapy or band ligation before liver replacement may be necessary. In those cases with good liver function and an absence of jaundice, endoscopic therapy may be the only treatment necessary. Transjugular intrahepatic portosystemic shunts (TIPS) are rarely used in this indication due to the young age of these patients, the frequently observed hypoplasia of the portal vein, and the possible development of intrahepatic biliary cavities. Surgical porto-systemic shunts are nowadays rarely indicated, certainly when transplantation is available, but should be considered if there is normal liver function, non-progression of the liver disease, and life-threatening varices. Severe hypersplenism may require splenic artery embolisation.
Hepatopulmonary syndrome and pulmonary hypertension: As in patients with other causes of spontaneous (cirrhosis or prehepatic portal hypertension) or acquired (surgical) portosystemic shunts, pulmonary arteriovenous shunts may occur even after complete clearance of jaundice (hepatopulmonary syndrome). This may arise as gut-derived vasoactive substances are not cleared by the liver due to the porto-systemic shunt. Typically this causes hypoxia, cyanosis, dyspnoea and digital clubbing, the diagnosis being confirmed by confirmed by pulmonary scintigraphy. Alternatively, pulmonary hypertension can occur in cirrhotic children and be a cause of malaise and even sudden death. The diagnosis in these cases is suggested by echocardiography. Liver transplantation reverses pulmonary shunts, and can reverse pulmonary hypertension at its early stage.
Intrahepatic biliary cavities: Large intrahepatic biliary cysts may develop several months to years after the Kasai operation, even in patients with complete clearance of jaundice. These cavities may become infected and/or compress portal vein, requiring external drainage. Cystoenterostomy or liver transplantation may eventually be required.
Malignancies: Hepatocarcinomas, hepatoblastomas and cholangiocarcinomas have been described in the cirrhotic livers of patients with BA, in childhood or adulthood. Screening for malignancy has to be performed regularly in the follow-up of patients with successful Kasai operations.
Outcome after unsuccessful Kasai Operation
Biliary cirrhosis is progressive if the Kasai operation fails to restore the bile flow, and should lead to liver transplantation. This is usually performed in the second year of life, but may be necessary earlier (from 6 months of life) in case of rapid deterioration in the liver disease. Biliary atresia represents more than half of the indications for liver transplantation in childhood. It may also be required in those cases where there is an initially successful outcome after the Kasai operation usually due to recurrence of jaundice (secondary failure of the Kasai operation), or to various complications of cirrhosis (e.g. hepatopulmonary syndrome).
There are two sources for a liver graft :
- Cadaveric Donor:
This is rarely a full size liver graft taken from a size-matched paediatric donor and is more often a left lobe (segments 2+3) or left liver (2+3+4) obtained after reduction or splitting of an adult liver graft.
- Living–related Donation:
This is usually from one of the parents of the child.
Five and 10 year survival after liver transplantation for BA nowadays exceeds 80%. In most cases, the quality of life of the transplanted patient is close to normal, with attainment of a normal somatic growth pattern and physical, sexual and intellectual maturity.
Overall Outcome of BA Patients
The overall prognosis of BA patients has improved since the early days of paediatric liver transplantation, and nowadays about 90% of BA patients may hope to survive.
Several prognostic factors of BA have been identified. Some of them are related to characteristics of the disease (and cannot be altered): existence of a polysplenia syndrome, anatomical pattern of the extra-hepatic biliary remnant, histological lesions of the biliary remnant, degree of liver fibrosis at time of the Kasai operation. Other prognostic factors are related to the management of BA patients, and are therefore improvable: age at Kasai operation, accessibility to LT, experience of the centre managing the BA patient. This later point led the British health authorities to centralize all BA patients from England and Wales in three paediatric liver units.