Biliary atresia
Encyclopedia
Biliary atresia, also known as "extrahepatic ductopenia" and "progressive obliterative cholangiopathy" is a congenital or acquired disease of the liver and one of the principle forms of chronic rejection of a transplanted liver allograft. As a birth defect in newborn infants, it has an occurrence of 1/10,000 to 1/15,000 cases in live births in the United States. In the congenital form, the common bile duct
between the liver
and the small intestine
is blocked or absent. The acquired type most often occurs in the setting of autoimmune disease, and is one of the principle forms of chronic rejection of a transplanted liver allograft.
Infants and children with biliary atresia have progressive cholestasis with all the usual concomitant features: pruritus, malabsorption with growth retardation, fat-soluble vitamin deficiencies, hyperlipidemia, and eventually cirrrhosis with portal hypertension. If unrecognized, the condition leads to liver failure
-- but not kernicterus
, as the liver is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood-brain barrier. The cause of the condition is unknown. The only effective treatments are certain surgeries such as the kasai procedure, or liver transplantation.
s should prompt a search for secondary causes. By this time, liver enzymes are generally measured, and these tend to be grossly deranged, hyperbilirubinaemia is conjugated and therefore does not lead to kernicterus
. Ultrasound
investigation or other forms of imaging can confirm the diagnosis. Further testing includes radioactive scans of the liver and a liver biopsy
.
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.
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.
There are three main types of extrahepatic biliary atresia:-
Type I: atresia restricted to the common bile duct.
Type II: atresia of the common hepatic duct.
Type III: atresia of the right and left hepatic duct.
Associated anomalies include, in about 20% cases, cardiac lesions, polysplenia, situs inversus, absent vena cava and a preduodenal portal vein.
. 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 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 at 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.
Bile duct
A bile duct is any of a number of long tube-like structures that carry bile.Bile, required for the digestion of food, is excreted by the liver into passages that carry bile toward the hepatic duct, which joins with the cystic duct to form the common bile duct, which opens into the intestine.The...
between the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
is blocked or absent. The acquired type most often occurs in the setting of autoimmune disease, and is one of the principle forms of chronic rejection of a transplanted liver allograft.
Infants and children with biliary atresia have progressive cholestasis with all the usual concomitant features: pruritus, malabsorption with growth retardation, fat-soluble vitamin deficiencies, hyperlipidemia, and eventually cirrrhosis with portal hypertension. If unrecognized, the condition leads to liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
-- but not kernicterus
Kernicterus
Kernicterus is damage to the brain centers of infants caused by increased levels of unconjugated bilirubin. This may be due to several underlying pathologic processes. Newborn babies are often polycythemic. When they break down the erythrocytes, one of the byproducts is bilirubin, which circulates...
, as the liver is still able to conjugate bilirubin, and conjugated bilirubin is unable to cross the blood-brain barrier. The cause of the condition is unknown. The only effective treatments are certain surgeries such as the kasai procedure, or liver transplantation.
Symptoms and diagnosis
Initially, the symptoms are indistinguishable from neonatal jaundice, a common phenomenon. Symptoms are usually evident between one and six weeks after birth. Besides jaundice, other symptoms include clay colored stools, dark urine, swollen abdominal region and large hardened liver (which may or may not be observable by the naked eye). Prolonged jaundice that is resistant to photo therapy and/or exchange transfusionExchange transfusion
An exchange transfusion is a medical treatment in which apheresis is used to remove one person's red blood cells or platelets and replace them with transfused blood products...
s should prompt a search for secondary causes. By this time, liver enzymes are generally measured, and these tend to be grossly deranged, hyperbilirubinaemia is conjugated and therefore does not lead to kernicterus
Kernicterus
Kernicterus is damage to the brain centers of infants caused by increased levels of unconjugated bilirubin. This may be due to several underlying pathologic processes. Newborn babies are often polycythemic. When they break down the erythrocytes, one of the byproducts is bilirubin, which circulates...
. Ultrasound
Medical ultrasonography
Diagnostic sonography is an ultrasound-based diagnostic imaging technique used for visualizing subcutaneous body structures including tendons, muscles, joints, vessels and internal organs for possible pathology or lesions...
investigation or other forms of imaging can confirm the diagnosis. Further testing includes radioactive scans of the liver and a liver biopsy
Liver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
.
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.
Pathophysiology
There is no known cause of biliary atresia. There have been many theories about ethiopathogenesis 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. 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, bileBile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
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
CCL2
For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.Chemokine ligand 2 also known as monocyte chemotactic protein-1 or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC...
, Tumor necrosis factor (TNF)
Tumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
, Interleukin-6 (IL-6), TGF-beta, Endothelin (ET)
Endothelin
Endothelins are proteins that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure and heart disease....
, and nitric oxide (NO)
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
. 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.
There are three main types of extrahepatic biliary atresia:-
Type I: atresia restricted to the common bile duct.
Type II: atresia of the common hepatic duct.
Type III: atresia of the right and left hepatic duct.
Associated anomalies include, in about 20% cases, cardiac lesions, polysplenia, situs inversus, absent vena cava and a preduodenal portal vein.
Treatment
If the intrahepatic biliary tree is unaffected, surgical reconstruction of the extrahepatic biliary tract is possible. This surgery is called a Kasai procedure (after the Japanese surgeon who developed the surgery, Dr. Morio Kasai) or hepatoportoenterostomyHepatoportoenterostomy
A hepatoportoenterostomy, or Kasai portoenterostomy is a surgical treatment performed on infants with biliary atresia to allow for bile drainage...
. 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
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
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 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 at 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.
External links
- Information from the European Biliary Atresia Registry
- Biliary Atresia Research Consortium (U.S.)
- Children's Liver Disease Foundation (U.K.)
- Choledochal cyst associated with extrahepatic bile duct atresia
- How Inflammation Causes Biliary Atresia by Jorge Bezerra, MD at Cincinnati Children's Hospital Medical CenterCincinnati Children's Hospital Medical CenterCincinnati Children's Hospital Medical Center is a 523-bed pediatric hospital located in Cincinnati, Ohio. It is currently ranked the third-best pediatric medical center in the United States by US News and World Report...