Gastroenterol Clin N Am 32 (2003) 891911

Biliary atresia
Barbara Anne Haber, MDa, Pierre Russo, MDb,*
a

Division of Gastroenterology and Nutrition, The Childrens Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA b Pathology Department, The Childrens Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104, USA

Biliary atresia (BA) is a progressive, idiopathic, necroinammatory process initially involving a segment or all of the extrahepatic biliary tree. As the disease progresses, the extrahepatic bile duct lumen is obliterated and bile ow is obstructed, resulting in cholestasis and chronic liver damage. With time, the intrahepatic biliary system becomes involved. BA occurs with an estimated frequency of 1 in 8 to 15,000 live births, which results in 250 to 400 new cases per year in the United States [1]. It is the most common cause of neonatal jaundice for which surgery is indicated; it is also the most common indication for liver transplantation in children. If not corrected, BA is uniformly fatal within the rst 2 years of life [2,3]. More than a century has passed since the rst descriptions of congenital obliteration of the bile ducts by Thompson [4] yet a clear understanding of this diseases etiology and pathogenesis remains lacking. Successful treatment also remains elusive. The rst surgical repair was introduced in 1916 by Holmes [5], who discussed a bilioenteric anastomosis and introduced the clinical classication of correctable and noncorrectable types. In 1928, the rst surgery was reported in which the patient survived [6]. The next signicant therapeutic advance occurred in 1959, when Morito Kasai introduced the hepatoportoenterostomy (a similar surgery is performed today). The only other new therapy introduced has been liver transplantation. For those patients who do not achieve drainage from hepatoportoenterostomy, liver transplantation is performed. Transplantation is also performed in those who develop complications of progressive liver disease such as growth failure, cirrhosis, or refractory cholangitis. Optimal timing of hepatoportoenterostomy is crucial in determining outcome after the rst surgery. It is believed that a window of opportunity occurs at approximately 4 to 8 weeks of age, because surgical and nonsurgical
* Corresponding author. E-mail address: russo@email.chop.edu (P. Russo). 0889-8553/03/$ - see front matter 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8553(03)00049-9

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entities are more easily distinguished at this age. The waiting period permits nonsurgical etiologies of neonatal jaundice to be suciently eliminated from the dierential diagnosis while still allowing for the option of surgical intervention before a point of desperate illness. BA is clearly a progressive disease, and despite hepatoportoenterostomy at an appropriate age two thirds of children in the United States still require liver transplantation.

Etiology At least two dierent forms of BA are recognized. However, it is possible that the BA phenotype represents the nal common pathway of several etiologies [2,3,7]. The more common of the two forms is the perinatal or postnatal form, which accounts for the majority of all cases. These children typically appear healthy at birth; their weights are average and they have pigmented stools. Jaundice develops at some variable interval postnatally; typical timing is between 2 to 6 weeks of age. Because of the frequency of breast milk jaundice, the diagnosis can be me missed unless a fractionated bilirubin is obtained. The less common presentation is the embryonic or fetal form, which occurs in 10% to 35% of cases [7]. These children are cholestatic at birth; 10% to 20% have associated congenital anomalies. Neither of the two forms is thought to be inherited, because HLA identical twins discordant for BA have been described and recurrence within the same family is exceedingly rare [8,9]. The pathogenesis of BA remains a mystery. The relative infrequency of the disease in any one center makes investigation of large numbers of cases dicult. Most of the causal theories and research to date can be divided into ve areas: (1) defects resulting from a viral infection or toxin exposure; (2) defects in morphogenesis; (3) genetic predisposition; (4) defects in prenatal circulation; and (5) immune or autoimmune dysregulation.

Viral/toxin An acquired viral infection or toxin exposure has been the most-pursued theory of BA etiology. The demonstration of timespace clusteringcombined with the fact that the disease appears to be acquired postnatally most frequentlyhas led researchers to look for events that might occur after birth, such as virus or toxin exposure. Initial reports described a higher incidence of BA in rural rather than urban areas, as well as a seasonal variation in which the winter months were predominating [10,11]. This epidemiologic information has been called into question by a more recent study in France that found no seasonal variation [12]. In animals, strong evidence comes from reported outbreaks of an epidemic of BA among lambs in 1964 and 1988 by Harper et al [13]. In each time period there was

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a correlation with a drought and a change of grazing patterns by pregnant ewes. In 1964, 60 of a ock of 400 died, and 300 lambs died in 1988. Autopsies revealed an enlarged, rm, dark liver with a shrunken brotic gallbladder. No specic infectious or toxic agent was identied, however. During the past 20 years, numerous studies exploring a viral etiology were published, though none have been fully substantiated. The common hepatotropic viruses A, B and C have all been investigated and none have been implicated in BA [14,15]. Rubella has been examined, but there have been no increases in BA during epidemics. Drut et al [16] found evidence of human papilloma virus types 6 and 18 by nested polymerase chain reaction in archived tissue from patients with BA and with neonatal hepatitis, though these ndings could not be duplicated by others [17]. This is just the beginning of a long list of unsuccessful endeavors. The most promising candidate viruses have been reovirus, rotavirus, and cytomegalovirus. Of these three, the evidence for a role by infection with reovirus type 3, a double-stranded RNA virus, has been the most compelling. A relatively high prevalence of reovirus type 3 antibodies has been detected in infants with BA [18] and neonatal hepatitis [19]. Reovirus particles have been reported in bile duct remnants by immunohistochemistry and electron microscopy [20,21], though this nding has been disputed [22]. Similarities between a weanling mouse model of infection and human disease have been proposed [23,24], and reovirus particles were found in the biliary tract of a rhesus monkey that developed BA [25]. Recently, Tyler et al [26] have demonstrated the presence of reovirus RNA by polymerase chain reaction in 55% of frozen tissues of patients with BA (except, interestingly, those with associated polysplenia), as well as in 78% of specimens from patients with choledochal cysts (versus 21% of specimens from other hepatobiliary diseases). A similar search using archived paranembedded material was negative [27]. Much of the diculty in interpreting ndings is attributable to the amount of contradictory results, which is most likely due to dierences in experimental design. Riepenho-Talty et al [28] found evidence of rotavirus type C in liver tissues of patients with BA. They also reported the development of extrahepatic biliary obstruction in mice inoculated with group A rotavirus, and immunization of the newborn pups appeared to be protective [29]. However, a separate study by Bobo et al [30] could nd no evidence for rotavirus A, B, or C in hepatobiliary samples. Studies by Fischler et al [31] have implicated infection with cytomegalovirus in the pathogenesis of BA and other neonatal cholestatic disorders, as had earlier studies by Tarr [32] and Hart [33]. Other investigators, however, have reported no evidence of the virus in hepatobiliary samples [34,35]. As stated above, the diculties in the interpretation of this data is in part due to dierent techniques, sample size, the frequent occurrence of many of these infections in neonates, and the likelihood that BA may represent the nal common path of several dierent types of injuries.

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Defective morphogenesis The hypothesis that BA represents a defect in morphogeneis is especially appealing for cases of the embryonic form, in which there is a high frequency of associated congenital anomalies. These children are thought to have a dierent disease than those who have the postnatal form. Some authors have reported a poorer overall prognosis for these patients [3638], although this is not well substantiated [39,40]. In the series reported by Davenport et al [37], children with associated anomalies had a lower birth weight and a higher incidence of maternal diabetes compared with nonsyndromic cases. The most frequently reported association is with polysplenia syndrome, which is noted in 5% to 20% of patients with BA [39,4143]. Polysplenia syndrome is a disorder of laterality development [44]. The reported anomalies are numerous and include polysplenia, double spleen, asplenia, portal vein anomalies, situs inversus, malrotation, cardiac anomalies, annular pancreas, immotile cilia syndrome, doudenal atresia, esophageal atresia, polycystic kidney, cleft palate and jejunal atresia. Some authors have observed a histologic appearance suggestive of ductal plate malformation and segmental agenesis of bile ducts in the livers of infants with the fetal form [40]. This nding raises the possibility that in some instances the defect in BA may result from abnormal interactions of a growth factor at a particular time of development [45]. Recently, a mouse model has been described that results in a similar constellation of defects. The inversin mouse (Inv) has either a deletion or a recessive insertional mutation in the proximal region of chromosome 4, resulting in anomalous development of the hepatobiliary system, as well as anomalies of visceral organ symmetry [46,47]. The mice experienced complete situs inversus, severe jaundice, and death in the rst weeks of life. The human inversin gene has been mapped to chromosome 9q, although no mutation of that gene was detected in a series of cases with BA and laterality disorders [48]. Further support of the theory that BA is a defect in morphogenesis is its relationship to choledochal cysts. Landing [49] proposed that biliary atresia, choledochal cysts, and neonatal hepatitis formed a continuum that he termed infantile cholangiopathies. He viewed the relationship as dierent degrees of response to an inammatory process. Injury to the bile duct epithelial cells that in turn led to obliteration would result in biliary atresia; if the injury only caused weakening of the bile duct wall, a choledochal cyst would develop. Further supportive evidence has included cystic dilatation of a segment of the extrahepatic biliary tree observed by preoperative ultrasound in patients with BA [50,51] and antenatal ultrasound demonstrating cystic dilitation similar to that seen with choledochal cyst, in patients found to have BA [52,53]. Lastly, evolution from an apparent choledochal cyst to BA has been also been reported [54].

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Genetic BA is not thought to be a heritable disorder, but it is likely that genetics is a factor. Potential gene candidates include those genes implicated in laterality such as inversin and CFC; Jagged 1, which is responsible for bile duct paucity in Alagille syndrome; and background genes, such as the HLA genes. In the fetal form, the associated anomalies and the similarities with Inv mouse suggest that a large gene defect or alteration in gene expression at a critical time of development accounts for the anomalies. A recent study demonstrated an increased frequency of Jagged 1 mutations in cases of BA [55]; the mutations reported are identical to those found in Alagille syndrome. This work raises the possibility that the Jagged 1 gene may be involved at dierent stages of biliary development. In the other instances, as with many diseases, a specic genetic background may be necessary for the manifestation or acquisition of disease. The increased association with certain HLA loci and its early onset suggests a genetic susceptibility to an acquired insult [5658]. Reports of the occurrence of BA with other cholestatic diseases within families lends further credence to the possibility of shared etiologic features among these entities, possibly modulated by the timing and severity of the insult. BA and neonatal hepatitis have been reported in siblings [33], as has BA and intrahepatic paucity of bile ducts [59]. Familial associations of BA with dilatation of the biliary tree and malformation of the pancreaticobiliary junction [60], sclerosing cholangitis [61], and with North American Indian cirrhosis [62] have also been reported. Vascular etiology There is a frequent association in BA between abnormalities of the portal vein and hepatic artery. This association has raised the question of an ischemic insult to the biliary tree in utero. The bile ducts receive their blood supply exclusively from the hepatic arterial circulation. Interruptions of this ow account for bile duct damage in liver transplantation in humans as well as in a fetal sheep model [63,64]. In animal models, the lesion resembles the less common correctable variant of BA. Immunologic/autoimmune dysfunction Many studies support a role for immune dysfunction in BA. The central concept is that after a particular insult (eg, a viral or toxin exposure) the biliary epithelium expresses inappropriate antigens on the surface of the bile duct epithelia, which in the proper genetic milieu are recognized by circulating T lymphocytes. These cells then elicit a cellular immune injury, resulting in inammation and brosis of the bile duct epithelium. Like a number of autoimmune diseases, there appears to be a female

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predominance in BA and aberrant HLA expression in bile duct epithelium. It has been proposed that some insult to the fetus or neonate leads to abnormal expression of antigens in bile duct epithelium [1]. Support for such a theory comes from T cell subset ratios that are more suggestive of an immune or metabolic pathogenesis than an infectious one. For example, the subsets are more akin to a1-antitrypsin deciency than hepatitis B-related inammation of the liver [65]. At present, there is evidence supporting a number of aspects of the immune cascade, including antigen expression and presentation, T cell activation, Kuper cell activation, cytokine release, and apoptosis. A number of HLA associations have been reported. Silveira et al [66] reported an association with the HLA-B12 allele and the haplotypes A9-B5 and A28B35. The increase in HLA-B12 occurred most frequently in those without other anomalies. In a dierent ethnic group, Kobayashi et al [67] reported associations with A33, B44, and DR6. Further support of an immune mechanism is the nding of abnormal expression of HLA-DR, a class II antigen, in biliary epithelium in patients with BA. Normally only major histocombatibility complex class I antigens are expressed by bile duct epithelium. When aberrant expression is present, it is possible that the biliary epithelium is behaving as an antigen-presenting cell in the immune pathway and thus directly activates T lymphocytes. The activation of T cells requires adhesion to the antigen-presenting cell through intercellular adhesion molecules (ICAMs). ICAM expression by biliary epithelium in BA has been reported both by Broome et al [68] and Dillon et al [69]. Lastly, Davenport et al [70] have demonstrated that activated and proliferating helper T cells and natural killer cells are present in the liver and in bile ducts in BA. Taken together, there is evidence of abnormal antigen expression in the livers of children with BA, as well as evidence that T cell activation and cytotoxicity play some role in causing injury. The damage may also be mediated through Kuper cells. Recent histologic studies have demonstrated increased numbers and size of Kuper cells in liver tissue of BA patients [71], and Davenport et al [70] have reported a poorer prognosis in children with increased CD68+ cells (Kuper cells) in the biliary remnant. Expression of FAS ligand in bile duct epithium in BA patients has also been reported and may play a role in apoptotic injury [72]. Anatomy and histopathology The destructive inammatory process that underlies BA may involve a short segment of a duct, an entire duct, or the entire system. There is obliteration or discontinuity of the hepatic or common bile ducts for any length between the porta hepatis to the duodenum. Many dierent classications of BA have been proposed over the years. All essentially recognize three broad types of lesions. The most comprehensive classication

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is that used in the Japanese Biliary Atresia Registry (reviewed by Ohi and Masaki [72]), which includes the following main types: type I, atresia of the common bile duct (10% of patients); type II, atresia of the hepatic ducts (2% of patients); and type III, atresia at the porta hepatis (88% of patients). The rst two are sometimes referred to as correctable, whereas the latter corresponds to the noncorrectable type of atresia and accounts for the majority of patients. However, with current hepatoportoenterostomy techniques, most patients achieve drainage; thus the correctable versus noncorrectable distinction is rarely used. True biliary agenesiswhich likely results from primary agenesis of the hepatic diverticulumis rare, and patients with this disorder present early after birth and require hepatic transplantation without an intervening portoenterostomy [73]. Serial sectioning of the extrahepatic remnant usually reveals at least focal complete obliteration of a segment, while biliary structures of various sizes with inammation are seen in the remaining segments. These remnants have been classied into various types according to dierent authors [7476]. One type corresponds to a brous cord with concentrically arranged collagen bers around an obliterated lumen. Another corresponds to multiple small ducts (generally \ 50 lm) set in a bro-inammatory matrix. A third type represents a biliary structure with a recognizable central lumen, characterized by extensive degenerative changes and injury to the epithelium, with inammation and brosis of the surrounding wall. The most active site of inammation is usually the porta hepatis, with brous obliteration of the distal biliary tree. The gallbladder is often absent or shows epithelial degeneration with brosis and inammation of the wall. Numerous studies have attempted to correlate the size of bile duct remnants at the porta hepatis with the outcome of the portoenterostomy. Chandra and Altman [75] found that optimal biliary drainage was achieved with a diameter of the proximal biliary remnant greater than 150 lm. Matsuo et al [77] found that the sum of the areas of the dierent bile duct lumens in a section of the porta hepatis was perhaps a better indicator than the largest diameter. A more recent study by Langenburg [78] showed no correlation with bile duct size. The diculty in obtaining constant and reproducible sections permitting accurate measurements is a major methodological problem inherent with most of these studies, and prognostication based on the size of the remnants now appears to have little practical value. In most centers, age at operation (with increased success when the patient is less than 60 days of age) [3], degree of liver damage [79], and experience of the operating team [80] appear to be the most important determinants of success. Evaluation of the child with suspected BA All children with persistent conjugated jaundice over the age of 14 days should be evaluated to ensure timely diagnosis of BA [81]. Typically these

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children are healthy and thriving, so pediatricians can easily be misled. Diagnosis is made by pursuing a series of serologic, urine, and imaging studies. When suspicion becomes high, a liver biopsy or intraoperative cholangiogram is recommended. Box 1 shows that a broad dierential needs to be considered in the evaluation of a child with neonatal cholestasis. Because the timing of surgery is crucial, the diagnostic approach is often to proceed with the evaluation, even if all the tests have not returned. Attempts have been made to develop easy tests that reliably predict BA. Recently, the triangular cord sign seen on ultrasound has been reported to have a positive predictive value of 95% [82]. If the reliability and reproducibility of this test is established, it will likely become a standard in the evaluation. At this point, if suspicion is high, more invasive tests are recommended. The choices are liver biopsy, endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiogram, or operative cholangiogram. The liver biopsy is used to discriminate between intra- and extrahepatic causes of cholestasis and to determine the appropriateness of surgical exploration. Liver biopsy In experienced hands, the accuracy rate of interpretation of liver biopsies in neonatal cholestasis is high (probably > 90%) [83]. The accuracy rate of interpretation of needle and open liver biopsies is roughly the same, assuming the needle biopsy is adequate [84]. The main purpose of the biopsy is to distinguish obstructive from nonobstructive causes of cholestasis. Histology alone cannot discriminate between biliary atresia and other causes of obstruction, such as a choledochal cyst. However, a diagnosis of obstruction mandates surgical exploration, and biliary atresia is by far the most frequent cause of obstructive jaundice in the neonate. As in any area of diagnostic pathology, close collaboration with the clinical team is essential to diagnosis. Diagnostic changes for BA noted on biopsy include expansion of the portal spaces with proliferation of bile ductules and interlobular bile ducts with bilirubinostasis, which is the presence of bilirubin pigment in bile plugs (Fig. 1). Bile duct proliferation with bile plugs is the most specic nding for biliary obstruction and is the nding with the strongest discriminating value [83]. Edema and some brosis are present in the portal tracts, accompanied by an inammatory inltrate, which frequently represents myelopoiesis. Variable degrees of extramedullary hematopoiesis, canalicular and hepatocellular cholestasis, ballooning, and giant cell transformation of hepatocytes may also be observed in the lobule. A major pitfall in the interpretation of these biopsies is overreading milder degrees of bile duct and ductular proliferation [85]. Lesser degrees of bile duct proliferation, even with bile stasis, may occur in other

Box 1. Differential diagnosis of neonatal and infantile cholestasis Neonatal hepatitis  Idiopathic NH  Viral NH CMV Herpes Rubella Reovirus Adenovirus Enteroviruses Parvovirus B19 Paramyxovirus Hepatitis B HIV  Bacterial and parasitic Bacterial sepsis UTI Syphilis Listeriosis Toxoplasmosis Tuberculosis Malaria Bile duct obstruction  Cholangiopathies Biliary atresia Choledochal cysts Nonsyndromic paucity Alagille syndrome Sclerosing cholangitis Spontaneous duct perforation Caroli disease Congenital hepatic brosis Bile duct stenosis  Other Inspissated bile/mucus Cholelithiasis Tumors Masses Cholestatic syndromes  PFIC Type 1 Byler P-type ATPase Type 2 Canalicular bile acid Tx Type 3 MDR3 deciency  Aagenaes cholestasis lymphedema  N. Am. Indian cholestasis (continued on next page)

   

Nielsen Greenland Eskimo cholestasis Benign recurrent intrahepatic cholestasis DubinJohnson MRP2 cMOAT deciency Rotor syndrome

Metabolic disorders  a1-antitrypsin deciency  Cystic brosis  Neonatal iron storage disease  Endocrinopathies Hypopituitarism Hypothyroidism  Amino acid disorders Tyrosinemia Hypermethionemia Mevalonate kinase deciency  Lipid disorders Niemann-Pick A, B Niemann-Pick C Gaucher Wolman Cholesterol ester storage ds  Urea cycle disorders Arginase deciency  Carbohydrate disorders Galactosemia Fructosemia Glycogen storage IV  Mitochondrial disorders Oxidative phosphorylation  Peroxisomal disorders Zellweger Infantile refsum Other enzymopathies  Bile acid synthetic disorders 3b-hydroxysteroid dehydrogenase/i D4-3-oxosteroid 5b-reductase Oxosterol 7a-hydroxylase Toxic  Drugs  Parenteral alimentation  Aluminum Miscellaneous associations  Shock/hypoperfusion  Histiocytosis X  Neonatal lupus erythematosus  Indian childhood cirrhosis  Autosomal trisomies 17, 18, 21  Graft v host disease

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Fig. 1. Typical ndings of biliary atresia on a liver biopsy from a 7-week-old patient with cholestasis. There is portal tract expansion, with characteristic bile duct and ductular proliferation with the presence of bile plugs in the lumen of biliary structures (arrows). Some brosis and inammation is also noted. Hepatocytes in the lobule are variably ballooned, with retention of bile pigment, and some multinucleated forms may be observed, but generally less than in non-specic neonatal giant cell hepatitis. Extramedullary hematopoiesis in liver sinusoids is a frequent concomitant nding.

nonobstructive disorders (eg, cytomegalovirus infection [86]; a1-antitrypsin deciency [87]; early Alagille syndrome [88]; total parenteral nutrition [89,90]; cystic brosis, especially in young infants [91,92]; and sepsis [93]). Furthermore, the earliest histologic changes associated with BA may be relatively nonspecic, and biopsies too early in the course of the disease may result in a falsely negative diagnosis [94]. In any instance when a strong clinical suspicion of obstruction exists, early biopsies with nonspecic changes should be followed by a repeat biopsy. Endoscopic retrograde cholangiopancreatography and magnetic resonance cholagiogram Endoscopic retrograde cholangiopancreatography has been advocated as a relatively noninvasive method (compared with surgical exploration) to determine biliary obstruction. However, the technical diculties of this procedureas well as the fact that few institutions possess appropriately

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sized equipmenthas made this an infrequent choice. Even in skilled centers the failure rate is 3% to 14% and the morbidity ranges from 0.8% to 7% [95]. Magnetic resonance cholangiogram has also been suggested as an alternative to intraoperative cholangiogram. The sensitivity has been reported to be 90%, specicity 77%, and accuracy 82% [96], yet most centers are still not skilled at this test in this age group. It remains for the present that if the biopsy is suggestive of obstruction, most physicians then proceed with an intraoperative cholangiogram. Box 1 lists the massive dierential that is considered in the evaluation of neonatal cholestasis. Fig. 2 shows the algorithm for diagnosis. As stated previously, evaluation often proceeds despite the fact that more sophisticated laboratory tests have yet to be completed. It is of utmost importance that a rapid diagnosis of BA is made so that a hepatoportoenterostomy is performed in a timely manner if needed. If a cholangiogram is consistent with BA, a surgical hepatoportenterostomy is recommended. Initially, the two most important prognostic factors in determining surgical outcome are the age at operation and the surgeons experience [97]. All in the eld agree that children who have initial surgery after 100 days of age have a worse outcome; what is less clear is whether or not there are advantages to operating earlier than 40 to 60 days of age. A Kings College study examined the outcomes of children who had their initial surgery at less than 40 days of age, between 41 and 60 days of age, between 61 and 99 days of age, and 100 days or more [98]. The study measured survival with native liver at 1 year of age and yielded a 90% success rate for all groups under 100 days and a 60% success rate for the 100 days or later group.

Management after portoenterostomy After surgery, the management of a child with BA is aimed at optimizing nutrition, promoting choleresis, and preventing inammation. Children are given antibiotics immediately postoperatively, and when bowel sounds return a diet that is easily digested is given.

Nutrition and vitamins Malnutrition and growth retardation result from a combination of factors including fat malabsorption from decreased intestinal bile salts, organomegaly or ascites. The child might not be able to meet the increased metabolic demands of a liver with chronic inammation. Typically a formula high in medium chain triglycerides (MCT) is chosen to overcome some of the fat malabsorption. Previously used formulas with more than 80% MCT were decient in long chain fatty acids, especially linoleic acid. The more recently developed formulas contain approximately 60% MCT and provide

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Fig. 2. Algorithm for evaluation of neonatal jaundice.

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essential fatty acids. This choice will allow dietary fat to be absorbed without a substantial need for micelle formation, which may be impaired. If a child does not sustain adequate growth, supplementation is achieved by increasing the caloric density of the formula; if necessary, nasogastric feedings are implemented to guarantee intake. Infants may have caloric requirements in excess of 150 kcal/kg/day. Growth is usually monitored by following length and weight and head circumference. However, there is good evidence that this may underrecognize nutritional issues because of the issues of organomegaly and uid retention. Midarm circumference and triceps skinfold measured by a technician trained in anthropometry may be a better way to detect true lean body and fat mass [99]. Protein is typically not restricted in a childs diet unless encephalopathy is present. Protein intake aids in achieving positive nitrogen balance, and the type of caseine protein typical of most infant formulas is well tolerated. Monitoring of proteins such as albumin, retinol binding protein, and PT provides an index of protein balance and hepatic synthetic function. Fat soluble vitamins are closely monitored and supplemented as needed [100]. Some institutions routinely provide supplements for vitamins A, D, E, and K until the total bilirubin is below 2 mg/dL; however, no unied standard has been adopted. Vitamin A deciency is rare, but its toxicity when administered inappropriately has made it the most commonly monitored vitamin, and it is only supplemented when decient. The goal of therapy is low normal serum levels of 400 to 500 lm/mL. Vitamin D is normally ingested in the diet, but is highly dependent on bile salt solubilization for absorption [101,102]. Dietary vitamin D is hydroxylated at the 25 position in the liver, followed by hydroxylation at the 1 position by the kidney to form the active hormone. Usual supplementation is with 25OHD, which is the most common form found in the circulation. Because there is no impairment of the hydroxylation in the kidney, this is the preferred and safer form. However, if rickets is present, the active hormone 1,25-(OH)2D is administered with close monitoring of calcium and phosphorous levels [101]. Vitamin E deciency is found in BA, and supplementation can be successfully achieved with d-alpha-tocopherol polyethylene glycol [103105]. Lastly, Vitamin K is critical for activation of clotting factors II, VII, IX, and X. Two naturally occurring forms of vitamin K exist. K1 is of dietary origin, and K2 is synthesized by intestinal bacteria. Monitoring PT is standard and is an easy method of assessing vitamin K status [100,106]. Other nutrients that may need to be monitored include iron, zinc, and cholesterol. Iron may become decient because of inadequate dietary content, chronic inammation with poor iron use, and gastrointestinal blood loss. Zinc is sometimes depleted in malabsorptive states and has been associated with poor linear growth. Cholesterol is often elevated in chronic cholestasis, with some patients developing cutaneous deposits in the form of xanthomas.

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Choleresis and decreasing inammation: steroids, antibiotics, and ursodeoxycholic acid In the initial postoperative period, the major objective is to prevent postoperative cholangitis. Administration of a combination of antibiotics and possibly steroids is recommended. The use of steroids has been adopted from the Japanese, who use steroids routinely. Prednisolone is given intravenously for 4 days, followed by oral administration until the total bilirubin is less than 2.0 mg/dL. Some centers in the United States have adopted this practice, but there has yet to be a well-designed controlled study. In one study, 25 infants were studied retrospectively after a 6-week course of steroids. The measured outcome was survival with native liver. At a mean follow-up of 50 months, 88% still had their native liver [107]. Progression of liver disease is also thought to be related to repeated bouts of cholangitis; therefore, one clinical approach is to aggressively treat cholangitis. Cholangitis typically occurs in the rst year of life [108]. Reports from the 1980s suggest that the incidence of cholangitis ranges from 50% to more than 90%. Our more recent experience is signicantly less (unpublished data). Some hospitals routinely use antibiotic prophylaxis for the rst year of life; however, some argue that the risk of developing resistant intestinal ora outweighs any proven benets. The diagnosis is made by percutaneous liver biopsy and conrmed by blood culture. The suspicion should be raised in any child with fever, irritability, leukocytsosis, or an unexplained change in liver enzymes. Unfortunately, the diagnosis is complicated by the frequency of childhood febrile diseases (eg, otitis media, viral illnesses). When no specic source is identied and clinical suspicion exists, broad spectrum antibiotics should be used to cover enteric organisms. Ursodeoxycholic acid is routinely given to promote choleresis and to prevent scarring [109]. There is no documented ecacy in BA; however, it is considered a well-tolerated medicine with potential benet. Its use stems from the literature regarding PBC, AIH, and rat models of brosis. Ursodeoxycholic acid is a naturally occurring dihydroxy bile acid with known choleretic properties. It undergoes extensive enterohepatic recycling. Following conjugation and biliary secretion, the drug is hydrolyzed to active ursodiol. Several large, well-designed studies in adults with primary biliary cirrhosis have demonstrated its usefulness and tolerability. Ursodeoxycholic acid signicantly lowers serum levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase at a dose of 13 to 15 mg/ kg/day in adults with PBC [110112]. With this chemical improvement, there has also been documented reduction in disease progression based on histology and mortality [113]. Few subjects in these studies have had to discontinue drug administration because of adverse events. The literature regarding the ecacy of ursodeoxycholic acid in preventing brosis is edgling, although a bile duct-ligated rat model of brosis has demonstrated benet [114].

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Summary BA is a rare disease of unclear etiology; nevertheless, its impact in the eld of pediatric hepatology is signicant. It is the most common surgically correctable cause of neonatal cholestasis and is the most common pediatric disease referred for liver transplantation. Little progress has been made with regard to improving outcome or understanding its pathogenesis in the past decade. Fortunately, however, a national, government-sponsored collaborative endeavor has begun that will hopefully make a signicant impact upon the progress of designing new treatments for BA and develop a better understanding of its pathogenesis.

References
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