Biliary atresia is a rare gastrointestinal obstructive cholangiopathy disease of the intrahepatic or extrahepatic bile duct disorder characterized by the destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and promoting the absorption of fats and vitamins by the intestines. In biliary atresia, the absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (fibrosis). In some cases, additional abnormalities may be present, including heart defects and intestinal, spleen, and kidney malformations. The exact cause of biliary atresia is unknown.
Biliary atresia is a blockage in the tubes (ducts) that carry bile from the liver to the gallbladder. This congenital condition occurs when the bile ducts inside or outside the liver do not develop normally. It is not known why the biliary system fails to develop normally
Classifications
Biliary atresia is not a single disease that results from a specific etiology, but rather it is a phenotype that results from different etiologies. It is broadly classified as syndromic and non-syndromic isolated varieties. Davenport et al. grouped specific entities of biliary atresia based on the similarities they share.[rx]
Biliary Atresia Splenic Malformation Syndrome (BASM)
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. In this type, the malformation occurs early in embryogenesis and accounts for the other anomalies. Maternal diabetes seems to play a role, and there is a female predominance.
Cystic Biliary Atresia
In this type, there is the obliteration of the biliary system with cystic dilatation. The incidence is reported to be around 10%, and it carries a better prognosis.[rx]
Cytomegalovirus (CMV) IgM Positive Biliary Atresia
This type represents about 10% of the cases, and most of them are non-Whites. These children present with higher bilirubin and aspartate aminotransferase (AST) levels and more inflammatory infiltrates in the extrahepatic biliary apparatus on histology. This group has the worst prognosis.[rx]
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 common bile duct, hepatic duct, and cystic duct with no anastomose ducts at the porta hepatis; this is the most common variety.
Symptoms
The symptoms of biliary atresia usually appear by the age of two to six weeks and include a yellowish coloration of the skin and whites of the eyes (jaundice), abnormally pale stools, and dark urine. Infants may also have swollen (distended) stomach and/or abnormal enlargement of the liver (hepatomegaly). By the age of six to 10 weeks, additional symptoms may also develop including poor weight gain, irritability, and/or an increase in blood pressure within the veins that carry blood from the intestine to the liver (portal hypertension). Bile ducts inside the liver (intrahepatic bile ducts) are also involved. If left untreated, biliary atresia may result in permanent scarring of the liver (cirrhosis) and, eventually, liver (hepatic) failure.
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. Situs Inversus is a condition in which the internal organs are on the opposite side of the body from normal. Levocardia is a condition in which the heart is malpositioned. (For more information on ventricular septal defects sees the Related Disorders section below.)
Additional features may be associated with some cases of biliary atresia including the absence of the spleen (asplenia), the presence of more than one spleen (polysplenia), and/or other anatomical abnormalities.
Causes
The exact cause of biliary atresia is unknown, but several factors contribute to the development of the disorder, including immunologic, infectious/toxic, and genetic factors. Although the bile ducts may be normal at birth, one or more of these factors initiate epithelial damage (independently or with the help of an activated immune system) and trigger rapid production of fibrous tissue (sclerosis) obstructing bile ducts. Several viruses, including cytomegalovirus, reovirus type 3, and rotavirus infections are being studied as possible causative agents.
A minority of cases may be caused by defects during the development (morphogenesis) of the liver and biliary tree during pregnancy. Some of these cases may be diagnosed during gestation by a prenatal ultrasound that shows a cyst in the biliary system. Biliary atresia is not an inherited disease; rare genetic variants are being reported in children who also have non-liver defects (see above).
Diagnosis
The diagnosis of biliary atresia requires a direct examination of the bile ducts by abdominal surgery (laparotomy) and the microscopic examination of tissue from the liver (liver biopsy). During the surgery, special contrast dye is injected into the gallbladder, and x-ray films are taken to outline how the dye fills the major bile ducts (intraoperative cholangiogram). These films show the movement (or lack of movement) of the dye through bile ducts and into the small intestine. The physician/surgeon is then able to evaluate the structure of the bile ducts and determine the site of the blockage (proximal or distal). Blood tests may demonstrate elevated levels of liver enzymes, gamma-glutamyl transpeptidase, and bilirubin and detect viral agents; high blood levels of matrix metalloproteinase-7 have been discovered to be highly specific for biliary atresia. Ultrasound of the liver may show the absence of the gall bladder.
To diagnose biliary atresia, a doctor will ask about your infant’s medical and family history, perform a physical exam, and order a series of tests. Experts recommend testing for biliary atresia and other health problems in infants who still have jaundice 3 weeks after birth.
If test results suggest that an infant is likely to have biliary atresia, the next step is surgery to confirm the diagnosis.
Doctors may refer children with suspected biliary atresia to specialists, such as pediatric gastroenterologists, pediatric hepatologists, or pediatric surgeons.
Family and Medical history
The doctor will ask about your infant’s family and medical history. The doctor will also ask about symptoms such as jaundice and changes in stool color.
Physical exam
During a physical exam, the doctor may
- examine the infant’s body for signs of jaundice
- examine the infant’s body for other birth defects that sometimes occur along with biliary atresia
- feel the infant’s abdomen to check for an enlarged liver or spleen, which may be signs of biliary atresia
- check the color of the infant’s stool and urine. During a physical exam, the doctor may examine the infant’s body for signs of jaundice.
Doctors may order some or all of the following tests to diagnose biliary atresia and rule out other health problems. Doctors may perform several tests because many other diseases can cause signs that are like the signs of biliary atresia.
Laboratory Studies
In biliary atresia, the direct and indirect bilirubin levels are both elevated with the conjugated portion being more elevated. As alkaline phosphatase levels are elevated in children due to bone remodeling, the liver-specific alkaline phosphatase fraction 5′ nucleotidase level should be measured. Gamma-glutamyl transpeptidase (GGTP) is present in the canalicular bile membrane and is increased in cases of biliary obstruction. GGTP provides a diagnostic accuracy of 50% to 60% in biliary atresia.[rx][rx] Serum transaminase levels are mildly elevated.
Blood tests
A health care professional may take a blood sample from the infant and send the sample to a lab. Doctors may use blood tests to measure bilirubin levels and to check for signs of liver disease.
Ultrasound
Ultrasound NIH external link uses a device called a transducer, which bounces safe, painless sound waves off organs to create images of their structure. Using ultrasound, doctors can rule out other health problems and look for signs that suggest an infant may have biliary atresia. However, an ultrasound cannot confirm a diagnosis of biliary atresia.
Hepatobiliary scan
A hepatobiliary scan is an imaging test that uses a small amount of safe radioactive material to create an image of the liver and bile ducts. The test can show if and where bile flow is blocked.
Liver Test
During a liver biopsy, a doctor will take pieces of tissue from the liver. A pathologist will examine the tissue under a microscope to look for signs of damage or disease. A liver biopsy can show whether an infant is likely to have biliary atresia. A biopsy can also help rule out or identify other liver problems.
Hepatobiliary Scintigraphy
This study uses a technetium labeled compound diisopropyl iminodiacetic acid (INDIA).[rx] The presence of isotope in the intestine excludes biliary atresia. The reliability of this test decreases in the presence of high levels of conjugated bilirubin. It also carries a 10% false-positive or false-negative rate.
Endoscopic Retrograde Cholangiopancreatography
This test is not widely done due to the limited availability of neonatal scopes equipped with a side view. With an increase in expertise and availability, this modality will probably be used in situations where other tests have failed to confirm the diagnosis.[rx]
Duodenal Intubation
Aspiration of bile-stained fluid from the duodenum will rule out biliary atresia. This test is not widely performed as it is invasive and unreliable.[rx]
Magnetic Resonance Imaging (MRI) and Magnetic Resonance Cholangiopancreatography (MRCP)
These tests provide greater accuracy but are not readily performed due to the expense and requirement of sedation and limited resolution at this young age.
Liver Biopsy
Liver biopsy can differentiate biliary atresia from other causes of cholestatic jaundice with a high level of accuracy. Features suggestive of biliary atresia include bile duct proliferation, bile plugging, multinucleated giant cells, focal necrosis of liver parenchyma, extramedullary hemopoiesis, and inflammatory cell infiltrate. Among these features, bile ductular proliferation is considered the most sensitive and specific feature.[rx]
Treatment
No cure exists for biliary atresia, but the timely diagnosis and surgical intervention improve short- and long-term outcomes in most patients. Special attention to nutritional needs and diet is essential for children with this disorder. Special supplements, formulas, and dietary restrictions may be necessary for affected infants.
Peri-Operative Cholangiogram
Peri-operative cholangiogram will definitively diagnose biliary atresia by the failure of passage of dye into the intrahepatic and extrahepatic biliary system.[rx][rx]
Porto-Enterostomy
The standard surgical technique is the creation of a Roux-en-Y hepatic Porto-enterostomy (Kasai procedure) in which excision of the fibrotic biliary remnant, transaction of the fibrous portal plate with dissection extending up to the bifurcation of the portal vein is done. The Roux-en-Y loop reestablishes biliary-enteric continuity and allows bile drainage.
In rare instances where the gallbladder and common bile duct are patents, a surgeon might consider a Porto-cholecystostomy.[rx] However, the anastomosis is not as flexible as a standard Roux-en loop, and revisions for repeated biliary obstruction have been described with a poorer long-term outcome. It has a lower incidence of cholangitis. In some cases with type I biliary atresia, hepaticojejunostomy has been described, but the results are inferior to the standard Kasai procedure.
Some drugs are used as adjuncts after surgery to promote biliary drainage, among them, steroids and ursodeoxycholic acid have been extensively described.[rx][rx] Steroids decrease the inflammatory response and promote bile clearance.[rx] A single prospective, randomized, placebo-controlled trial used a low dose of prednisolone (2 mg/kg/day) and showed a significantly increased rate of jaundice clearance in the steroid group but did not provide any survival benefit.[rx] Another trial, START (Steroids in Biliary Atresia Randomized Trial) showed no benefit of high dose steroid therapy on biliary clearance at six months post-surgery and had an earlier onset of adverse effects related to steroids.[rx] Ursodeoxycholic acid is a hydrophilic bile acid and is normally present in about 1% to 4% of the total bile acid pool. It is known to promote bile clearance and is frequently prescribed postoperatively.
Liver Transplantation
Liver transplantation is an option offered if liver cirrhosis is far advanced or if a Kasai Porto-enterostomy has failed.
Surgery must be performed to remove the obstruction and allow bile to flow into the bile ducts and small intestine (also known as “Kasai hepatoportoenterostomy”). In this procedure, the extrahepatic bile ducts are removed and replaced with a portion of the affected infant’s small intestine thereby forming a conduit to allow for bile drainage. The exact surgical procedure may vary according to the location and nature of the obstruction. In the majority of cases, bile drainage can be established with this surgical procedure. However, some children may experience variable degrees of liver dysfunction even after successful surgery. The Kasai procedure may also be used as an early intermediate procedure to support the child’s growth. Despite the Kasai procedure, liver transplantation may ultimately become necessary in many cases. Antibiotics may be used to treat infections of the bile ducts (cholangitis).
Genetic counseling may be of benefit for people with biliary atresia and their families. Another treatment is symptomatic and supportive.
Nutrition and Biliary Atresia
Children with liver disease have more metabolic needs than healthy children. This means that children with biliary atresia may need more calories.
A child with biliary atresia and jaundice cannot properly digest fats. This is because not enough bile gets to the intestine. Due to liver damage, there may also be a loss of vitamins and protein.
Guidelines from your doctor for your child’s nutrition may include:
- Special formula and baby diet during the first year of life. For older children, a well-balanced diet consists of three meals a day plus small snacks in between meals.
- Vitamin supplements (specifically Vitamins A, D, E, and K as these are absorbed in fat, and children with biliary atresia cannot absorb these well).
- Adding medium-chain triglyceride (MCT) oil to foods and liquids or infant formulas. MCT adds extra calories that will help your child grow.
- High-calorie liquid feedings may be recommended if your child is too ill to eat normally. Feedings are given through a special tube (nasogastric tube) that is placed in the nose and guided down the esophagus and into the stomach.
Although digestion may return to normal after surgery, extra vitamins or MCT oil may be needed.
What Are the Complications of Biliary Atresia and What Can Be Done for Them?
Complications right after surgery are low. Most problems that develop are due to progression of the liver disease.
- After the Kasai procedure, it is common to get an infection in the bile ducts. This is treated with intravenous antibiotics. Treatment may continue with antibiotics taken by mouth.
- Jaundice or itching may occur. These can often be treated successfully with medications such as ursodeoxycholic acid.
- Many patients with cirrhosis have changes in blood flow through the liver and intestines. These changes may cause problems such as easy bruising of the skin, nosebleeds, retention of body fluid, and enlarged veins (varices) in the stomach and esophagus.
Increased pressure in these veins can cause a sudden and large amount of bleeding in the stomach and intestines. This can be a serious complication. With quick and experienced medical care, bleeding can usually be stopped. Sometimes treatment needs specialized procedures in which a hardening (sclerosing) agent is injected into the abnormal vessels.
- If retention of body fluid occurs, it can be treated with diuretics (medicine that helps remove excess water from the body).
As the disease gets worse, other complications of cirrhosis may also occur.
Liver Transplant for Biliary Artesia
If bile flow is not restored, liver transplantation will be necessary. A liver transplant operation removes the damaged liver and replaces it with a new liver from a donor.
Cincinnati Children’s has one of the largest and oldest pediatric liver transplant programs in the United States. The team offers an improved survival rate above the national average. With greater access to organs, the time children spend on the waiting list has decreased substantially at Cincinnati Children’s. Patients experience shorter average times on the transplant waitlist.
- The median wait time for a new liver at Cincinnati Children’s is 3.7 months, compared to the national median wait time of 8.7 months.
- 66.2% of our patients receive a transplant within one year of waitlisting, compared to 49.3% nationally.
After a transplant, ongoing lifelong care is required. Frequent contact with doctors and other members of the transplant team is also necessary.
What is the Long-Term Outlook After the Kasai?
It is very possible to have success and long-term survival after the Kasai procedure. Historically, nearly half of all infants who have had a Kasai procedure require liver transplantation before age 5. Hepatologists and surgeons at Cincinnati Children’s are developing protocols to improve long-term survival and decrease the need for liver transplantation. Older children may continue to have good bile drainage and no jaundice.
Some children may develop portal hypertension and have gastrointestinal bleeding, collection of fluid in the abdomen (ascites), and enlargement of the spleen (hypersplenism).
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