Biliary atresia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:Saud Khan M.D.

Biliary atresia can be classified into several subtypes, since it does not arise from a specific cause. As such, it is broadly classified according to syndromic and non-syndromic expression. Biliary atresia can be classified by:

Biliary Atresia Splenic Malformation Syndrome (BASM)

In this type, malformation occurs early in embryogenesis also giving rise to other anomalies. Biliary atresia is associated with polysplenia, vascular anomalies including a pre-duodenal portal vein, interrupted vena cava, azygous continuation, cardiac malformation, malrotation, and situs inversus. Maternal diabetes may be associated, and there is a female predominance.

Cystic Biliary Atresia

In this type, the biliary system gets destroyed with subsequent cystic dilatation. The incidence is reported to be around 10%, and it carries a better prognosis.

Cytomegalovirus (CMV) IgM Positive Biliary Atresia

This type is associated with CMV infections, and present with higher bilirubin and aspartate aminotransferase (AST) levels and more inflammatory infiltrates in the extrahepatic biliary ducts on histology. It represents about 10% of the cases, and has the worst prognosis. Most of these patients are non-Whites.

Isolated Biliary Atresia

This represents the largest group, but the etiology is unknown.

Morphological Classification

Morphological classification is based on the level at which the biliary lumen is obliterated. The Japanese Association Of Pediatric Surgeons has classified it as:

• Type I: Obliteration of the common bile duct
• Type II a: Obliteration of the common hepatic duct
• Type II b: Obliteration of the common bile duct, hepatic duct, cystic duct with no abnormality of the gallbladder, and cystic dilatation at the porta hepatis
• Type III: Obliteration of the most proximal part of the common bile duct, hepatic duct, and cystic duct with no anastomosable ducts at the porta hepatis (Most common). ^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saud Khan M.D.

Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice.

• 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.

• At 20 days of gestation the extrahepatic bile ducts appear as an out-pouching of the foregut, while the intrahepatic bile ducts become visible at 45 days, which arise from the primitive hepatocytes. The porta-hepatis is where the extra and intrahepatic bile ducts combine, and any flaw in this joining results in an obstructed biliary system. The isolated type of biliary atresia may be due to flawed assembly at the hepatic hilum. Similarities in the cytokeratin staining of the bile ducts in patients with biliary atresia and first-trimester fetal bile ducts supports the possibility that biliary atresia could occur due to the failure of the bile duct remodeling at the hepatic hilum with the persistence of fetal bile ducts.^[1]

• 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.^[2]

Biliary atresia is a progressive fibrosing obstructive cholangiopathy of the intrahepatic and extrahepatic biliary system, resulting in obstruction of bile flow and neonatal jaundice.

Histopathological findings in liver biopsies include the expansion of the portal tracts, with edematous fibroplasia and bile ductular proliferation, with bile plugs in duct lumen. Lobular morphological features may include variable multinucleate giant cells, bilirubinostasis and hemopoiesis.

Associated anomalies include, in about 20% cases,

• Cardiac lesions
• Polysplenia
• Situs inversus
• Absent vena cava
• A preduodenal portal vein

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There have been many theories about etiopathogenesis such as Reovirus 3 infection, congenital malformation, congenital CMV infection, autoimmune theory. This means that the etiology and pathogenesis of biliary atresia are largely unknown.

Biliary atresia does not have a clear identified cause. It was previously thought to be idiopathic, a destructive inflammatory process leaving fibrotic remnants at the porta hepatis. It is now thought it may be secondary to viral infections or an autoimmune-induced injury in some cases. The viruses thought to be involved are:

• Reovirus,
• Rotavirus,
• Cytomegalovirus (CMV)^[1][2]
  • The highest association of a viral infection with biliary atresia is with CMV. There may be an inability to identify the virus because of a short timeframe to detect it, which leads to uncertainty in association. The viral infection of cholangiocytes may predispose to an aberrant autoimmune response, cascading to progressive biliary injury and cirrhosis.

Through a genome-wide study, an association between biliary atresia and the ADD3 gene was detected in Chinese populations and confirmed in Thai populations. Anther possible association with the deletion of the GPC1 gene has been reported, which encodes a glypican 1-a heparan sulfate proteoglycan.^{[3] [4]}

Aflatoxin B1 exposure, and to a lesser extent aflatoxin B2 exposure during late pregnancy may cause biliary atresia. Maternal detoxification ability protects the fetus during intrauterine life, but it struggles with the aflatoxin in its blood and liver after birth, causing cholangitis in the baby. ^[5]

Biliary atresia must be differentiated from other diseases that present with symptoms typical of cholestasis in neonates, jaundice and acholic pale stools, which are main features of obstructive jaundice, associated with conjugated (direct) hyperbilirubinemia.

Biliary atresia must be differentiated from other diseases that cause cholestatic jaundice and hepatic fibrosis, such as:^[1]

• Alagille Syndrome
  • Presents with cholestatic jaundice, along with a variety of other manifestations such as renal, otic, skeletal, ocular and cardiovascular.

• Byler disease
  • Progressive Familial Intrahepatic cholestasis (PFIC), an inherited mutation in the ATP8b1 gene that results in the cells of the liver not being able to release bile. This leads to cholestasis and jaundice. Careful history taking can help in differentiating this disease from biliary atresia.

• Congenital biliary dilatation
• Choledochal Cysts
• Cholestasis
• Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)
• Idiopathic neonatal hepatitis
• Inborn errors of bile acid synthesis
• Neonatal Hemochromatosis
• Intrahepatic bile duct hypoplasia
• Lipid Storage Disorders
• Caroli Disease
  • Caroli disease is the dilatation of larger intrahepatic bile ducts, whereas Caroli syndrome is the combination of dilated small bile ducts and congenital hepatic fibrosis. These present in childhood usually, whereas biliary atresia presents in neonates.
• Cystic Fibrosis
• Bile plug syndrome
  • This is a rare form of extrahepatic mechanical obstruction in the major bile duct which is caused by viscous bile (sludge) within its lumen. It presents identically to biliary atresia, diagnosis is confirmed on ultrasound which shows sludge in the lumen of the common bile duct.
• Toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes simplex [TORCH]^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saud Khan M.D.

Biliary atresia is a very rare disorder. About one in 10,000 to 20,000 babies in the U.S are affected every year. About 400-600 new cases are described in the United States each year (according to rarediseases.org). Biliary atresia seems to affect girls slightly more often than boys. Within the same family, 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 does not appear to be any link to medications or immunizations given immediately before or during pregnancy.

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. Diabetes during pregnancy particularly during the first trimester seems to predispose to a number of distinct congenital abnormalities in the infant such as sacral agenesis, transposition of the great vessels and the syndromic form of biliary atresia.

• The incidence of biliary atresia is 1 in 10,000-15,000 newborn infants.

• Biliary atresia seems to affect Asians and African Americans more often than Caucasians.

• Gender bias remains controversial. Some studies suggest that biliary atresia affects females slightly more often than males, others report a clear male predilection.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Saud Khan M.D.

If left untreated, patients with biliary atresia may progress to develop cirrhosis and liver failure. No cure exists for biliary atresia, but the timely diagnosis and surgical intervention improves short- and long-term outcomes in most patients. Special attention to the nutritional needs and diet are essential for children with this disorder. Special supplements, formulas, and dietary restrictions may be necessary for affected infants.

The symptoms of biliary atresia usually appear by the age of two to six weeks and include jaundice, pale stools and dark urine. Infants may present with a distended abdomen and hepatomegaly. By the age of six to ten weeks, weight gain is usually very poor, the infant is usually irritability and may show signs of portal hypertension (G.I bleeding). If left untreated, biliary atresia may result in permanent scarring of the liver.

Some children with biliary atresia may have additional congenital abnormalities including malformations of the heart (e.g., situs inversus, levocardia, and ventricular septal defects) and/or kidneys.^[1]

If untreated, the condition leads to cirrhosis, portal hypertension, liver failure but not (as one might think) to kernicterus. This is because the liver is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood-brain barrier. Left untreated or with failure of the Kasai procedure, biliary atresia progresses towards biliary cirrhosis, end-stage liver failure and death by age 3.

Recent large volume studies from Davenport et al. (Ann Surg, 2008) show that 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). Performing the Kasai portoenterostomy early has very good prognosis, though some cases may ultimately need liver transplantation.^[1][2]