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BILIARY ATRESIA
Defintion
Biliary atresia is the most common cause of neonatal cholestasis. It is defined as obstruction to the flow of bile in the extrahepatic bile ducts. In the majority of children the entire extrahepatic biliary tree is obliterated secondary to an inflammatory fibrosing cholangiopathy; a few infants have only part of the biliary tree involved. About 10% of infants have so-called fetal-embryonal biliary atresia associated with a family of stereo-typical laterality-type anomalies, about 10% have major anomalies noted at birth but not the stero-typical anomalies, and the majority, ~80%, have acquired biliary atresia that occurs in an otherwise healthy infant.
Etiology
The cause of biliary atresia is unknown. A number of etiologies have
been postulated, including viral, toxin-induced, vascular, morphogenetic
defect, and immune dysregulation (1). In support of the viral theory,
the livers of afflicted children exhibit many of the inflammatory responses
characteristic of viral infection including activated macrophages, CD4
and CD8 T cells, interferon gamma, cytokines such as tumor necrosis alpha,
and IgM and IgG antibodies. In addition there is time-space clustering
of cases consistent with an infectious etiology (a phenomen also
invoked in support of the toxin theory). There have been two animal models
of biliary atresia which utilize virus – the reovirus mouse model
and more recently the rotavirus mouse model. In addition there have
been isolated cases of human biliary atresia in which one of the following
viruses has been identified in liver biopsies , including reovirus, rotavirus,
CMV, HHV6, and human papillomavirus. In support of the vascular etiology
both hyperplasia and hypertrophy of the hepatic artery have been described
but these findings could be secondary to the characteristic hepatic fibrosis
and cirrhosis.
Support of the morphogenetic defect theory is provided by the infants
with so-called fetal –embryonal form of the disease (about 10% of
all infants with biliary atresia) which is associated with a stereotypical
collection of anomalies including preduodenal portal vein, annular pancreas,
situs inversus, cardiac abnormalities, and splenic malformation including
asplenia, polysplenia or double spleen. In addition some infants exhibit
ductal plate abnormalities in liver biopsies. There is an INV
mouse model of biliary obstruction and situs inversus. Some infants exhibit
polymorphisms in the Jag 1 gene. Mutations in the CFC1
gene (CRYPTIC protein) have also been described (2).
There is both human and animal data in support of some sort of immune
dysregulation. These data include increased expression of intercellular
adhesion molecules, increased frequency of the HLA-B12 allele, oligoclonal
expansion of lymphocytes, and prevention of experimental biliary atresia
in mice by loss of α2β1 integrin, interferon-γ, CD8+
cells, and NK cells (3)(4) It is entirely possible and perhaps most likely,
that biliary atresia is of diverse etiology – secondary to
dysmorphogenesis in the minority and one or more viral infections in an
immunologically susceptible host in the majority.
Pathogenesis
Both the rotavirus mouse model and observations in a few human newborns with the fetal-embryonal form of biliary atresia suggest that the inflammatory fibrosing process begins in the extra-hepatic biliary system (5). The current thinking is that the obstruction to the flow of bile results in intra-hepatic bile stasis and resultant luxuriant periportal inflammation, fibrosis and cirrhosis which may occur even in neonates. Biliary atresia is the most rapidly fibrosing liver disease in man and the precise reason for the rapidity and severity of the fibrosis is not clear. A recent report in the rotavirus mouse model suggested that up-regulation of hepatic αvβ6 integrin (known to activate transforming growth factor β and the resultant fibrogenic cascade) is an early event (6). Liver biopsies of human infants with the disease typically show bile duct proliferation and luminal plugging by inspissated bile in addition to abundant peri-portal fibrosis. There is often some hepatocyte injury and infants can even exhibit some degree of giant cell transformation.
Clinical Features
For infants with the acquired form of biliary atresia, appearance at birth is that of a well newborn with what is usually interpreted as physiologic jaundice. As the postnatal weeks go by, the infant remains jaundiced; acholic stools develop in the majority. Typically infants may present to the pediatrician at 5 -6 weeks of age. Hepatomegaly is usually found on physical examination but the infant otherwise appears well. Infants who have developed cirrhosis may exhibit splenomegaly as well. For infants with the fetal-embryonal form of the disease, the cardiac disease which is often associated, may dominate the clinical picture. Typical congenital heart disease associated with this form of biliary atresia includes ventricular septal defect and Tetralogy of Fallot. Total serum bilirubin is usually 6 - 8 mg/dl with the conjugated or direct fraction being at least 20% of the total. Serum aminotransferases are modestly elevated in the 100 - 200 U/L range and gamma glutamyl transpeptidase is markedly elevated.
Diagnosis
The gold standard for diagnosing biliary atresia is the operative cholangiogram; diagnosis is established when dye injected into the biliary remnant fails to pass into the intestine. In some cases, the biliary tract is obliterated and that finding is diagnostic of biliary atresia. However, when injvestigating an infant for biliary atresia, evaluation usually begins with a liver ultrasound to exclude a choledochal cyst. In biliary atresia, the ultrasound may be normal or may show a hypoplastic or even absent gallbladder. Hepatic scintigraphy (which is performed after 5 days of phenobarbitol to maximize bile flow) shows absence of isotope excretion into the intestinal tract. However this finding is not specific for biliary atresia and experts disagree as to whether or not the study should be included in the diagnostic algorithm. Liver biopsy is usually characteristic (see Pathogenesis). However ~5% of infants who exhibit clinical, radiologic and histologic findings characteristic of biliary atresia may exhibit a patent biliary system at laparotomy. In questionable cases, some experts recommend magnetic resonance cholangiopancreatography (MRCP) before proceeding to operative cholangiography and others recommend endoscopic retrograde cholangiopancreatography (ERCP). However since both of these studies require deep sedation or general anesthesia and may delay eventually laparotomy, there is considerable controversy as to the role of these diagnostic modalities in infants with possible biliary atresia.
Genetics
Biliary atresia occurs in 1, 800, 1:20,000 live births and only rarely occurs in families. It is clearly not a classical genetic disease, not autosomal dominant or autosomal recessive. It is not sex-linked. As noted above, there have been isolated cases with abnormalities of JAG 1, CFC1 as well as associations with HLA B12. With tremendous advances in molecular biology and in characterization of the human genome it seems likely that more underlying genetic abnormalities will be found which may help explain at least some cases of the disease.
Treatment
The treatment of biliary atresia is the Kasai hepatic portoenterostomy, which is performed during the same operation as the operative cholangiogram. Prior to the development of this procedure, biliary atresia was a uniformly fatal disease. The outcome of the procedure is clearly related to the age at which it is performed. The most dramatic data came from France where the best outcomes were obtained when infants were operated on before 30 days of age (7.) An important part of the treatment is excellent nutritional support. If the infant is not thriving on breast milk, elemental formulas are indicated as is supplementation with fat soluble vitamins. Antibiotic prophylaxis to prevent ascending cholangitis is also recommended and ursodeoxycholic acid is often used in an attempt to promote bile flow. Perhaps the area of greatest controversy is the question of the role of corticosteroids in improving outcome post Kasai. For this reason the ChiLDREN consortium is currently performing a large scale randomized placebo controlled trial of corticosteroids post Kasai.
Prognosis
As noted above, the prognosis of biliary atresia depends in large part on the age at which the Kasai was performed especially for those infants with "acquired" biliary atresia. For infants with the fetal-embryonal form the outcome is often influenced in a major way by the severity of the cardiac defect. For infants with either form of biliary atresia it is recommended that the procedure be performed before 45 days of age. However most authorities recommend proceeding with the Kasai whenever the infant presents unless there is decompensated liver disease, because the procedure has been successful in infants up to 100 days of age. Even with timely performance of the Kasai, about half of infants who undergo the procedure need liver transplantation by age two - three years and about 25% of infants who initially do well will eventually need liver transplantation by adolescence for slowly progressive cirrhosis and its complications. Nonetheless, outcome of liver transplantation for biliary atresia (the indication for about half of all liver transplants in childhood) is usually very good. In order to maximize the prognosis of children with this very serious liver disease, more research on the precise cause is needed so that rational specific therapies can be applied as early as possible.
References
- Santos JL, Choquette M, and Bezerra JA. Cholestatic Liver Disease in Children Curr Gastroenterol
Rep (2010) 12: 30-39 - Davit-Spraul A, Baussan C, Hermeziu B, et al.: CFC1 gene involvement in biliary atresia with polysplenia syndrome. J Pediatr Gastroenterol Nutr 2008, 46:111–112.
- Jafri M, Donnelly B, Allen S et al Cholangiocyte expression of alpha2beta1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia Am J Physiol Gastrointest Liver Physiol 2008, 295;G16-G26.
- Shivakumar P, Sabla GE, Whitington P et al Neonatal NK cells target the mouse duct epithelium via Nkg2d and drive tissue-specific injury in experimental biliary atresia. J Clin Invest 2009, 119:2281-2290.
- Makin E, Quaglia A, Kvist N et al. Congenital biliary atresia liver injury begins at birth. J Pediatr Surg 2009, 44:630-633
- Nadler EP, Patterson D, Violette S, Weinreb, Lewis M, Magid MS, Greco MA. Integrin αv, β6 and Mediators of Extracellular Matrix Deposition Are Up-Regulated in Experimental Biliary Atresia. J Surg Res 2009;154:21-9.
- Serinet MO, Wildhaber BE, Broue P et al. Impact of age at Kasai operation on its results in late childhood and adolescence: a rational basis for biliary atresia screening. Pediatrics 2009, 123:1280-1286.
For information on studies about ChiLDREN diseases, click here.
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