Biliary Atresia and Its Complications*

A. S. K n is e l y , M.D.

Departments of Hematology and Pathology, University o f Utah School o f Medicine, Salt Lake City, UT 84132

ABSTRACT Infants with idiopathic perinatal fibroinflammatory obliteration of the lumen of the extrahepatic biliary tree (“biliary atresia”) invariably died of biliary cirrhosis before surgical techniques were devised to permit drain age of bile into the duodenum. Survival rates in operated patients now approach 75 percent at 10 years. While definitive diagnosis of biliary atre sia without the use of cholangiography at laparotomy is difficult, because other disorders have similar clinical features, early diagnosis is important. The earlier surgery is undertaken, the more successful it is. With delay, irreversible changes occur in the liver that produce portal hypertension. This and liver failure eventually make liver transplantation necessary even in some operated patients. Hepatic disease associated with biliary atresia is in part due to delay in diagnosis, but complications of surgical therapy, such as ascending cholangitis, also play a role. With prolonged survival and as numbers of liver transplant recipients rise, new therapy-related complications, such as those associated with immunosuppression, will become more important in surgically treated biliary atresia.

Introduction jaundice that has failed to clear within several weeks after birth.8 They are gen Extrahepatic bilary atresia (biliary erally well-nourished and well-devel- atresia) occurs in one of approximately oped otherwise,8 although associated 14,000 to 15,000 infants.8 44 The primary errors in morphogenesis and organogen anatomic lesion consists of inflammatory esis— cardiac defects, situs inversus, and fibrous obliteration of the lumen of abnormal topography of the spleen, por part or all of the extrahepatic biliary tal venous system, and gut— are present tree.14,15 If bile drainage is not reestab in as many as 25 percent.10,27’30 Biliary lished by surgery, the child with biliary atresia is almost never seen in premature atresia succumbs to cirrhosis and the or stillborn infants.3 Bile pigment may sequelae of portal hypertension at an be present in the stools early in postnatal average age of 19 m onths.16 life, only to disappear after several Infants with biliary atresia present as weeks.8 Clusters of affected infants seem well-appearing infants with “physiologic” to occur,8,44 but sets of twins have been reported in which only one had biliary * Supported in part by NIH Grant 5T32 DK07115. atresia,40 and recurrence of the disorder 113 0091-7370/90/0300-0113 $00.90 © Institute for Clinical Science, Inc. 11 4 KNISELY within a sibship is rare.7,26 These obser testing has ruled out infective or meta vations have led to the hypothesis that in bolic diseases, three principal entities most infants, particularly those without remain. These are biliary atresia, paucity associated cardiovascular lesions, biliary of intrahepatic bile ducts, and idiopathic atresia is not a heritable disorder, but neonatal hepatitis. In all three, cholesta instead is related to an exogenous peri sis and conjugated hyperbilirubinemia natal insult.27 may be present, and the duodenal con A murine model exists of reovirus- tents or stool may be acholic. associated hepatobiliary disease.2 Ele While laparotomy with cholangiogra vated serum titers of anti-reovirus anti phy can definitively distinguish among bodies have been observed in a higher these three disorders, much effort has proportion of infants with biliary atresia been directed toward establishing diag than of comparison infants,33 but others nostic criteria using less invasive tech have not been able to reproduce this niques. Sonographic assessment of finding.511 IgM-class antibodies have decreases in gallbladder size with feed been demonstrated at biliary-epithelium ing,18 measurement of serum concentra basement membranes in 44 of 128 tions of various bile acids29 and hepato excised specimens of the extrahepatic cellular enzymatic activities,42 imaging biliary tract, but without apparent corre for radioactive tracer substances lation to the presence of inflammation;15 excreted with bile,28 examination of duo characterization of the specificity of denal contents for bile,38 and endoscopic eluted antibodies has not been under retrograde choledochopancreatography47 taken. Prospective studies of biliary atre have been evaluated. Portal tract histol sia in large populations, attempting to ogy can be examined in percutaneous identify common agents in samples of needle biopsy specimens of the liver. blood or serum obtained from newborn Expansion of portal tracts by fibrous tis infants among whom some later manifest sue, with proliferation of bile ducts, is the disorder, have not been performed. characteristic of biliary atresia, and its The polymerase chain reaction may offer identification permits highly accurate a sensitive approach to screening body diagnosis in some hands.4 This combina fluids or surgically obtained tissues for tion of studies will spare some infants particular infective candidates.32 At from laparotomy. present, biliary atresia remains an idio Rapid and accurate diagnosis is urgent pathic disorder. in this setting because the prognoses in idiopathic neonatal hepatitis, paucity of Diagnosis intrahepatic bile ducts, and biliary atre sia differ so markedly. In idiopathic neo Evaluation of abnormally persistent natal hepatitis, although progression to conjugated hyperbilirubinemia in the cirrhosis may occur, spontaneous resolu newborn infant requires assessment for tion is the rule.9 In syndromic paucity of infections and various metabolic and ana intrahepatic bile ducts, the extrahepatic tomic disorders. The list of etiologies biliary tree may be patent but hypoplas other than biliary atresia that require tic;20 cholestasis in these children tends consideration is long, and can be found to resolve, although abnormalities on elsewhere.13 Very rarely, biliary atresia liver function testing may persist into and other metabolic disorders with simi adulthood.37 The prognosis in nonsyn- lar clinical manifestations may coexist,48 dromic paucity, the product of a nonspe but an exclusionary approach to the cific response of the intrahepatic biliary diagnosis is generally appropriate. After ducts to a variety of injurious agents, BILIARY ATRESIA AND ITS COMPLICATIONS 1 1 5 depends on the extent of damage done,21 have undergone hepatic portoenteros but is much more favorable than that in tomy and worsens their long-term prog untreated biliary atresia. nosis by nearly 50 percent.17 Efforts to Biliary atresia is surgically treated by promote bile flow with choluretics and any of several variants of hepatic por- orally administered bile-binding resins toenterostomy, a procedure in which the have not decreased the incidence of lumen of a segment of jejunum is cholangitis,49 nor has administration of sutured into apposition to the porta antibiotics.12 Increased susceptibility to hepatis at the site from which the atretic ascending cholangitis is perhaps the extrahepatic biliary tree has been most serious adverse effect of hepatic resected.22 This therapy is inappropriate portoenterostomy. in idiopathic neonatal hepatitis or pau It is difficult to separate the histologic city of intrahepatic bile ducts.19 Its effi sequelae of ascending cholangitis from cacy in biliary atresia decreases precipi the changes that are due to obstructive tously over both the short and long term cholestasis, but varying degrees of portal with advancing postnatal age. In one scarring, loss of interlobular bile ducts, series, resolution of jaundice occurred in and biliary cirrhosis are commonly seen 86 percent of infants who were operated in patients who have undergone hepatic on before eight weeks of age but in only portoenterostomy.6 While these findings 36 percent of infants who were operated are not associated with impaired absorp on after eight weeks of age.28 Over the tion of fat-soluble vitamins or abnormali long term, survival after 10 years was 75 ties in vitamin K-dependent clotting in percent for those under 60 days old at nonjaundiced patients,25 growth retarda surgery, and was 10 percent for those tion is usual.39 Portal hypertension, over 90 days old.23 Accordingly, if biliary accompanied by hypertrophy of smooth atresia cannot quickly be excluded from muscle in intrahepatic portal venules,34 the differential diagnosis of neonatal con is frequent even in patients without jugated hyperbilirubinemia, laparotomy, jaundice,35 and may already be present cholangiography, and, if indicated, at two months of age.24 The most severe hepatic portoenterostomy should be per complication of portal hypertension is formed without delay. hemorrhage from esophagogastric var ices; this can be effectively treated by Management Following endoscopic sclerotherapy.45 Hypersplen Hepatic Portoenterostomy ism and thrombocytopenia can be expected to assume greater significance While early hepatic portoenterostomy with increased long-term survival.39 is likely to establish bile drainage, it is Hepatocellular carcinoma is a known not invariably successful. Granulation complication of secondary biliary cirrho tissue at the porta hepatis or growth of sis that may be expected in some survi bowel epithelium onto the site of biliary vors of biliary atresia.19 tract resection may block bile outflow.36 Deteriorating liver function and portal Revision of the bowel loop with removal hypertension may eventually make it of obstructive material under direct necessary to consider liver transplanta vision can let bile drainage resume,46 as tion in either long-term survivors or can endoscopic curettage.36 infants in whom hepatic portoenteros With free passage out from the liver, tomy has failed to establish bile drain however, comes free passage up into the age. Three-year survival was calculated liver. Ascending cholangitis causes sub as 73 percent in one series of 80 children stantial morbidity among patients who who underwent liver transplantation at 1 1 6 KNISELY an average age of five years; 44 percent References had biliary atresia, and previous surgery in these children did not complicate 1. An d r e w s, W. S., W a n e k , E., F yock , B., G ray, transplantation.1 In another series of 36 S., and B en s e r , M.: Pediatric liver transplanta tion: A 3-year experience. J. Pediatr. Surg. children with biliary atresia who under 24:77-82, 1989. went liver transplantation at an average 2. B a n g a r u , B ., M o r e c k i, R., G la s e r , J. H., G artner, L. M ., and H o r w itz, M . S.: Compar age of 30 months, calculated three-year ative studies of biliary atresia in the human new survival was 75 percent. The rates of sur born and reovirus-induced cholangitis in weanl vival were 82 percent and 63 percent for ing mice. Lab. Invest. 43:456-462, 1980. patients who respectively had and had 3. Blanc, W. A.: Extrahepatic biliary atresia. Brent, R. L., ed. Persistent Jaundice in not previously undergone hepatic por- Infancy, p. 124. J. Pediatr. 61:111-144, 1962. toenterostomy; those who had were 4. Br o u g h , A. J. and B e r n s t e in , J.: Conjugated hyperbilirubinemia in early infancy: A reassess older (32 vs. 20 months) and larger (12.5 ment of liver biopsy. Hum. Pathol. 5:507-516, vs. 8 kg), and may have been better able 1974. to withstand surgery.31 5. Br o w n , W. R., So k o l , R. J., L e v in , M. J., Sil Morbidity after liver transplantation is v e r m a n , A ., T a m a r u , T ., L il ly , J. R., and C h en e y , M.: Lack of correlation between infec not specific to biliary atresia, and can be tion with reovirus 3 and extrahepatic biliary expected to be high; as defined by days atresia or neonatal hepatitis. J. Pediatr. hospitalized as a percentage of total 113:670-676, 1988. 6. 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