Biliary atresia - El Blog de la Dra. Salgado · Biliary atresia (BA) is a progressive, idiopathic,...

Gastroenterol Clin N Am

32 (2003) 891–911

Biliary atresia

Barbara Anne Haber, MDa, Pierre Russo, MDb,*aDivision of Gastroenterology and Nutrition, The Children’s Hospital of Philadelphia,

34th and Civic Center Boulevard, Philadelphia, PA 19104, USAbPathology Department, The Children’s Hospital of Philadelphia,

34th and Civic Center Boulevard, Philadelphia, PA 19104, USA

Biliary atresia (BA) is a progressive, idiopathic, necroinflammatoryprocess initially involving a segment or all of the extrahepatic biliary tree. Asthe disease progresses, the extrahepatic bile duct lumen is obliterated andbile flow is obstructed, resulting in cholestasis and chronic liver damage.With time, the intrahepatic biliary system becomes involved. BA occurs withan estimated frequency of 1 in 8 to 15,000 live births, which results in 250 to400 new cases per year in the United States [1]. It is the most common causeof neonatal jaundice for which surgery is indicated; it is also the mostcommon indication for liver transplantation in children.

If not corrected, BA is uniformly fatal within the first 2 years of life [2,3].More than a century has passed since the first descriptions of congenitalobliteration of the bile ducts by Thompson [4] yet a clear understanding of thisdisease’s etiology and pathogenesis remains lacking. Successful treatmentalso remains elusive. The first surgical repair was introduced in 1916 byHolmes [5], who discussed a bilioenteric anastomosis and introduced theclinical classification of ‘‘correctable’’ and ‘‘noncorrectable’’ types. In 1928,the first surgery was reported in which the patient survived [6]. The nextsignificant therapeutic advance occurred in 1959, when Morito Kasaiintroduced the hepatoportoenterostomy (a similar surgery is performedtoday). The only other new therapy introduced has been liver transplantation.For those patients who do not achieve drainage from hepatoportoenter-ostomy, liver transplantation is performed. Transplantation is also performedin those who develop complications of progressive liver disease such asgrowth failure, cirrhosis, or refractory cholangitis.

Optimal timing of hepatoportoenterostomy is crucial in determiningoutcome after the first surgery. It is believed that a window of opportunityoccurs at approximately 4 to 8 weeks of age, because surgical and nonsurgical

* Corresponding author.

E-mail address: [email protected] (P. Russo).

0889-8553/03/$ - see front matter � 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0889-8553(03)00049-9

mailto:[email protected]

892 B.A. Haber, P. Russo / Gastroenterol Clin N Am 32 (2003) 891–911

entities are more easily distinguished at this age. The waiting period permitsnonsurgical etiologies of neonatal jaundice to be sufficiently eliminated fromthe differential diagnosis while still allowing for the option of surgicalintervention before a point of desperate illness. BA is clearly a progressivedisease, and despite hepatoportoenterostomy at an ‘‘appropriate age’’ twothirds of children in the United States still require liver transplantation.

Etiology

At least two different forms of BA are recognized. However, it is possiblethat the BA phenotype represents the final common pathway of severaletiologies [2,3,7]. The more common of the two forms is the perinatal orpostnatal form, which accounts for the majority of all cases. These childrentypically appear healthy at birth; their weights are average and they havepigmented stools. Jaundice develops at some variable interval postnatally;typical timing is between 2 to 6 weeks of age. Because of the frequency ofbreast milk jaundice, the diagnosis can be me missed unless a fractionatedbilirubin is obtained. The less common presentation is the embryonic orfetal form, which occurs in 10% to 35% of cases [7]. These children arecholestatic at birth; 10% to 20% have associated congenital anomalies.Neither of the two forms is thought to be inherited, because HLA identicaltwins discordant for BA have been described and recurrence within the samefamily is exceedingly rare [8,9].

The pathogenesis of BA remains a mystery. The relative infrequency ofthe disease in any one center makes investigation of large numbers of casesdifficult. Most of the causal theories and research to date can be divided intofive areas: (1) defects resulting from a viral infection or toxin exposure; (2)defects in morphogenesis; (3) genetic predisposition; (4) defects in prenatalcirculation; and (5) immune or autoimmune dysregulation.

Viral/toxin

An acquired viral infection or toxin exposure has been the most-pursuedtheory of BA etiology. The demonstration of time–space clustering—com-bined with the fact that the disease appears to be acquired postnatally mostfrequently—has led researchers to look for events that might occur afterbirth, such as virus or toxin exposure. Initial reports described a higherincidence of BA in rural rather than urban areas, as well as a seasonalvariation in which the winter months were predominating [10,11]. Thisepidemiologic information has been called into question by a more recentstudy in France that found no seasonal variation [12]. In animals, strongevidence comes from reported outbreaks of an epidemic of BA among lambsin 1964 and 1988 by Harper et al [13]. In each time period there was

893B.A. Haber, P. Russo / Gastroenterol Clin N Am 32 (2003) 891–911

a correlation with a drought and a change of grazing patterns by pregnantewes. In 1964, 60 of a flock of 400 died, and 300 lambs died in 1988.Autopsies revealed an enlarged, firm, dark liver with a shrunken fibroticgallbladder. No specific infectious or toxic agent was identified, however.

During the past 20 years, numerous studies exploring a viral etiologywere published, though none have been fully substantiated. The commonhepatotropic viruses A, B and C have all been investigated and none havebeen implicated in BA [14,15]. Rubella has been examined, but there havebeen no increases in BA during epidemics. Drut et al [16] found evidence ofhuman papilloma virus types 6 and 18 by nested polymerase chain reactionin archived tissue from patients with BA and with neonatal hepatitis, thoughthese findings could not be duplicated by others [17]. This is just thebeginning of a long list of unsuccessful endeavors.

The most promising candidate viruses have been reovirus, rotavirus, andcytomegalovirus. Of these three, the evidence for a role by infection withreovirus type 3, a double-stranded RNA virus, has been the mostcompelling. A relatively high prevalence of reovirus type 3 antibodies hasbeen detected in infants with BA [18] and neonatal hepatitis [19]. Reovirusparticles have been reported in bile duct remnants by immunohistochemistryand electron microscopy [20,21], though this finding has been disputed [22].Similarities between a weanling mouse model of infection and humandisease have been proposed [23,24], and reovirus particles were found in thebiliary tract of a rhesus monkey that developed BA [25]. Recently, Tyler etal [26] have demonstrated the presence of reovirus RNA by polymerasechain reaction in 55% of frozen tissues of patients with BA (except,interestingly, those with associated polysplenia), as well as in 78% ofspecimens from patients with choledochal cysts (versus 21% of specimensfrom other hepatobiliary diseases). A similar search using archived paraffin-embedded material was negative [27].

Much of the difficulty in interpreting findings is attributable to theamount of contradictory results, which is most likely due to differences inexperimental design. Riepenhoff-Talty et al [28] found evidence of rotavirustype C in liver tissues of patients with BA. They also reported thedevelopment of extrahepatic biliary obstruction in mice inoculated withgroup A rotavirus, and immunization of the newborn pups appeared to beprotective [29]. However, a separate study by Bobo et al [30] could find noevidence for rotavirus A, B, or C in hepatobiliary samples. Studies byFischler et al [31] have implicated infection with cytomegalovirus in thepathogenesis of BA and other neonatal cholestatic disorders, as had earlierstudies by Tarr [32] and Hart [33]. Other investigators, however, havereported no evidence of the virus in hepatobiliary samples [34,35].

As stated above, the difficulties in the interpretation of this data is in partdue to different techniques, sample size, the frequent occurrence of many ofthese infections in neonates, and the likelihood that BA may represent thefinal common path of several different types of injuries.


Defective morphogenesis

The hypothesis that BA represents a defect in morphogeneis isespecially appealing for cases of the embryonic form, in which there isa high frequency of associated congenital anomalies. These children arethought to have a different disease than those who have the postnatalform. Some authors have reported a poorer overall prognosis for thesepatients [36–38], although this is not well substantiated [39,40]. In theseries reported by Davenport et al [37], children with associated anomalieshad a lower birth weight and a higher incidence of maternal diabetescompared with nonsyndromic cases. The most frequently reported associa-tion is with polysplenia syndrome, which is noted in 5% to 20% of patientswith BA [39,41–43]. Polysplenia syndrome is a disorder of lateralitydevelopment [44]. The reported anomalies are numerous and includepolysplenia, double spleen, asplenia, portal vein anomalies, situs inversus,malrotation, cardiac anomalies, annular pancreas, immotile cilia syn-drome, doudenal atresia, esophageal atresia, polycystic kidney, cleft palateand jejunal atresia. Some authors have observed a histologic appearancesuggestive of ‘‘ductal plate malformation’’ and segmental agenesis of bileducts in the livers of infants with the fetal form [40]. This finding raises thepossibility that in some instances the defect in BA may result from ab-normal interactions of a growth factor at a particular time of development[45].

Recently, a mouse model has been described that results in a similarconstellation of defects. The inversin mouse (Inv) has either a deletion ora recessive insertional mutation in the proximal region of chromosome 4,resulting in anomalous development of the hepatobiliary system, as well asanomalies of visceral organ symmetry [46,47]. The mice experienced com-plete situs inversus, severe jaundice, and death in the first weeks of life. Thehuman inversin gene has been mapped to chromosome 9q, although nomutation of that gene was detected in a series of cases with BA and lateralitydisorders [48].

Further support of the theory that BA is a defect in morphogenesis is itsrelationship to choledochal cysts. Landing [49] proposed that biliary atresia,choledochal cysts, and neonatal hepatitis formed a continuum that hetermed ‘‘infantile cholangiopathies.’’ He viewed the relationship as differentdegrees of response to an inflammatory process. Injury to the bile ductepithelial 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 cystwould develop. Further supportive evidence has included cystic dilatationof a segment of the extrahepatic biliary tree observed by preoperativeultrasound in patients with BA [50,51] and antenatal ultrasound demon-strating cystic dilitation similar to that seen with choledochal cyst, inpatients found to have BA [52,53]. Lastly, evolution from an apparentcholedochal cyst to BA has been also been reported [54].


Genetic

BA is not thought to be a heritable disorder, but it is likely that genetics isa factor. Potential gene candidates include those genes implicated inlaterality such as inversin and CFC; Jagged 1, which is responsible for bileduct paucity in Alagille syndrome; and ‘‘background’’ genes, such as theHLA genes. In the fetal form, the associated anomalies and the similaritieswith Inv mouse suggest that a large gene defect or alteration in geneexpression at a critical time of development accounts for the anomalies. Arecent study demonstrated an increased frequency of Jagged 1 mutations incases of BA [55]; the mutations reported are identical to those found inAlagille syndrome. This work raises the possibility that the Jagged 1 genemay be involved at different stages of biliary development. In the otherinstances, as with many diseases, a specific genetic background may benecessary for the manifestation or acquisition of disease. The increasedassociation with certain HLA loci and its early onset suggests a geneticsusceptibility to an acquired insult [56–58]. Reports of the occurrence of BAwith other cholestatic diseases within families lends further credence to thepossibility of shared etiologic features among these entities, possiblymodulated by the timing and severity of the insult. BA and neonatalhepatitis have been reported in siblings [33], as has BA and intrahepaticpaucity of bile ducts [59]. Familial associations of BA with dilatation of thebiliary 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 portalvein and hepatic artery. This association has raised the question of anischemic insult to the biliary tree in utero. The bile ducts receive their bloodsupply exclusively from the hepatic arterial circulation. Interruptions of thisflow account for bile duct damage in liver transplantation in humans as wellas in a fetal sheep model [63,64]. In animal models, the lesion resembles theless common correctable variant of BA.

Immunologic/autoimmune dysfunction

Many studies support a role for immune dysfunction in BA. The centralconcept is that after a particular insult (eg, a viral or toxin exposure) thebiliary epithelium expresses inappropriate antigens on the surface of thebile duct epithelia, which in the proper genetic milieu are recognizedby circulating T lymphocytes. These cells then elicit a cellular immuneinjury, resulting in inflammation and fibrosis of the bile duct epithelium.Like a number of autoimmune diseases, there appears to be a female


predominance in BA and aberrant HLA expression in bile duct epithelium.It has been proposed that some insult to the fetus or neonate leads toabnormal expression of antigens in bile duct epithelium [1]. Support for sucha theory comes from T cell subset ratios that are more suggestive of animmune or metabolic pathogenesis than an infectious one. For example, thesubsets are more akin to a1-antitrypsin deficiency than hepatitis B-relatedinflammation of the liver [65].

At present, there is evidence supporting a number of aspects of theimmune cascade, including antigen expression and presentation, T cellactivation, Kupffer cell activation, cytokine release, and apoptosis. Anumber of HLA associations have been reported. Silveira et al [66] reportedan association with the HLA-B12 allele and the haplotypes A9-B5 and A28-B35. The increase in HLA-B12 occurred most frequently in those withoutother anomalies. In a different ethnic group, Kobayashi et al [67] reportedassociations with A33, B44, and DR6. Further support of an immunemechanism is the finding of abnormal expression of HLA-DR, a class IIantigen, in biliary epithelium in patients with BA. Normally only majorhistocombatibility complex class I antigens are expressed by bile ductepithelium. When aberrant expression is present, it is possible that thebiliary epithelium is behaving as an antigen-presenting cell in the immunepathway and thus directly activates T lymphocytes. The activation of T cellsrequires adhesion to the antigen-presenting cell through intercellularadhesion molecules (ICAMs). ICAM expression by biliary epithelium inBA has been reported both by Broome et al [68] and Dillon et al [69]. Lastly,Davenport et al [70] have demonstrated that activated and proliferatinghelper T cells and natural killer cells are present in the liver and in bile ductsin BA.

Taken together, there is evidence of abnormal antigen expression in thelivers of children with BA, as well as evidence that T cell activation andcytotoxicity play some role in causing injury. The damage may also be medi-ated through Kupffer cells. Recent histologic studies have demonstratedincreased numbers and size of Kupffer cells in liver tissue of BA patients[71], and Davenport et al [70] have reported a poorer prognosis in childrenwith increased CD68+ cells (Kupffer cells) in the biliary remnant.Expression of FAS ligand in bile duct epithium in BA patients has alsobeen reported and may play a role in apoptotic injury [72].

Anatomy and histopathology

The destructive inflammatory process that underlies BA may involvea short segment of a duct, an entire duct, or the entire system. There isobliteration or discontinuity of the hepatic or common bile ducts for anylength between the porta hepatis to the duodenum. Many different classi-fications of BA have been proposed over the years. All essentially rec-ognize three broad types of lesions. The most comprehensive classification


is that used in the Japanese Biliary Atresia Registry (reviewed by Ohi andMasaki [72]), which includes the following main types: type I, atresia of thecommon 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 first two are sometimes referred to as correctable, whereas the lattercorresponds to the noncorrectable type of atresia and accounts for themajority of patients. However, with current hepatoportoenterostomy tech-niques, most patients achieve drainage; thus the correctable versus noncor-rectable distinction is rarely used. True biliary agenesis—which likely resultsfrom primary agenesis of the hepatic diverticulum—is rare, and patientswith this disorder present early after birth and require hepatic trans-plantation without an intervening portoenterostomy [73]. Serial sectioningof the extrahepatic remnant usually reveals at least focal complete oblitera-tion of a segment, while biliary structures of various sizes with inflammationare seen in the remaining segments. These remnants have been classified intovarious types according to different authors [74–76]. One type correspondsto a fibrous cord with concentrically arranged collagen fibers aroundan obliterated lumen. Another corresponds to multiple small ducts (gen-erally\ 50 lm) set in a fibro-inflammatory matrix. A third type representsa biliary structure with a recognizable central lumen, characterized byextensive degenerative changes and injury to the epithelium, with in-flammation and fibrosis of the surrounding wall. The most active site ofinflammation is usually the porta hepatis, with fibrous obliteration of thedistal biliary tree. The gallbladder is often absent or shows epithelialdegeneration with fibrosis and inflammation of the wall.

Numerous studies have attempted to correlate the size of bile ductremnants at the porta hepatis with the outcome of the portoenterostomy.Chandra and Altman [75] found that optimal biliary drainage was achievedwith a diameter of the proximal biliary remnant greater than 150 lm.Matsuo et al [77] found that the sum of the areas of the different bile ductlumens in a section of the porta hepatis was perhaps a better indicatorthan the largest diameter. A more recent study by Langenburg [78] showedno correlation with bile duct size. The difficulty in obtaining constant andreproducible sections permitting accurate measurements is a major metho-dological problem inherent with most of these studies, and prognosticationbased on the size of the remnants now appears to have little practicalvalue. In most centers, age at operation (with increased success when thepatient is less than 60 days of age) [3], degree of liver damage [79], andexperience of the operating team [80] appear to be the most importantdeterminants of success.

Evaluation of the child with suspected BA

All children with persistent conjugated jaundice over the age of 14 daysshould be evaluated to ensure timely diagnosis of BA [81]. Typically these


children are healthy and thriving, so pediatricians can easily be misled.Diagnosis is made by pursuing a series of serologic, urine, and imagingstudies. When suspicion becomes high, a liver biopsy or intraoperativecholangiogram is recommended.

Box 1 shows that a broad differential needs to be considered in theevaluation of a child with neonatal cholestasis. Because the timing ofsurgery is crucial, the diagnostic approach is often to proceed with theevaluation, even if all the tests have not returned. Attempts have been madeto develop easy tests that reliably predict BA. Recently, the ‘‘triangular cordsign’’ seen on ultrasound has been reported to have a positive predictivevalue of 95% [82]. If the reliability and reproducibility of this test isestablished, 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 cholangiopancreatog-raphy, magnetic resonance cholangiogram, or operative cholangiogram.The liver biopsy is used to discriminate between intra- and extrahepaticcauses of cholestasis and to determine the appropriateness of surgicalexploration.

Liver biopsy

In experienced hands, the accuracy rate of interpretation of liver biopsiesin neonatal cholestasis is high (probably > 90%) [83]. The accuracy rateof interpretation of needle and open liver biopsies is roughly the same,assuming the needle biopsy is adequate [84]. The main purpose of the biopsyis to distinguish obstructive from nonobstructive causes of cholestasis.Histology alone cannot discriminate between biliary atresia and other causesof obstruction, such as a choledochal cyst. However, a diagnosis ofobstruction mandates surgical exploration, and biliary atresia is by far themost frequent cause of obstructive jaundice in the neonate. As in any area ofdiagnostic pathology, close collaboration with the clinical team is essentialto diagnosis.

Diagnostic changes for BA noted on biopsy include expansion of theportal spaces with proliferation of bile ductules and interlobular bile ductswith bilirubinostasis, which is the presence of bilirubin pigment in bile plugs(Fig. 1). Bile duct proliferation with bile plugs is the most specific finding forbiliary obstruction and is the finding with the strongest discriminating value[83]. Edema and some fibrosis are present in the portal tracts, accompaniedby an inflammatory infiltrate, which frequently represents myelopoiesis.Variable degrees of extramedullary hematopoiesis, canalicular and hepato-cellular cholestasis, ballooning, and giant cell transformation of hepatocytesmay 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 degreesof bile duct proliferation, even with bile stasis, may occur in other

Box 1. Differential diagnosis of neonatal and infantilecholestasis

Neonatal hepatitis� Idiopathic NH� Viral NH

CMVHerpesRubellaReovirusAdenovirusEnterovirusesParvovirus B19ParamyxovirusHepatitis BHIV

� Bacterial and parasiticBacterial sepsisUTISyphilisListeriosisToxoplasmosisTuberculosisMalaria

Bile duct obstruction� Cholangiopathies

Biliary atresiaCholedochal cystsNonsyndromic paucityAlagille syndromeSclerosing cholangitisSpontaneous duct perforationCaroli diseaseCongenital hepatic fibrosisBile duct stenosis

� OtherInspissated bile/mucusCholelithiasisTumorsMasses

Cholestatic syndromes� PFIC

Type 1 Byler P-type ATPaseType 2 Canalicular bile acid TxType 3 MDR3 deficiency

� Aagenaes cholestasis lymphedema� N. Am. Indian cholestasis

(continued on next page)

� Nielsen Greenland Eskimo cholestasis� Benign recurrent intrahepatic cholestasis� Dubin–Johnson MRP2 cMOAT deficiency� Rotor syndrome

Metabolic disorders� a1-antitrypsin deficiency� Cystic fibrosis� Neonatal iron storage disease� Endocrinopathies

HypopituitarismHypothyroidism

� Amino acid disordersTyrosinemiaHypermethionemiaMevalonate kinase deficiency

� Lipid disordersNiemann-Pick A, BNiemann-Pick CGaucherWolmanCholesterol ester storage ds

� Urea cycle disordersArginase deficiency

� Carbohydrate disordersGalactosemiaFructosemiaGlycogen storage IV

� Mitochondrial disordersOxidative phosphorylation

� Peroxisomal disordersZellwegerInfantile refsumOther enzymopathies

� Bile acid synthetic disorders3b-hydroxysteroid dehydrogenase/iD4-3-oxosteroid 5b-reductaseOxosterol 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


nonobstructive disorders (eg, cytomegalovirus infection [86]; a1-antitrypsindeficiency [87]; early Alagille syndrome [88]; total parenteral nutrition[89,90]; cystic fibrosis, especially in young infants [91,92]; and sepsis [93]).

Furthermore, the earliest histologic changes associated with BA may berelatively nonspecific, and biopsies too early in the course of the disease mayresult in a falsely negative diagnosis [94]. In any instance when a strongclinical suspicion of obstruction exists, early biopsies with nonspecificchanges should be followed by a repeat biopsy.

Endoscopic retrograde cholangiopancreatography and magneticresonance cholagiogram

Endoscopic retrograde cholangiopancreatography has been advocated asa relatively noninvasive method (compared with surgical exploration) todetermine biliary obstruction. However, the technical difficulties of thisprocedure—as well as the fact that few institutions possess appropriately

Fig. 1. Typical findings 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

fibrosis and inflammation 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-specific neonatal ‘‘giant cell hepatitis.’’ Extramedullary hematopoiesis in liver

sinusoids is a frequent concomitant finding.


sized equipment—has made this an infrequent choice. Even in skilled centersthe failure rate is 3% to 14% and the morbidity ranges from 0.8% to 7%[95]. Magnetic resonance cholangiogram has also been suggested as analternative to intraoperative cholangiogram. The sensitivity has beenreported to be 90%, specificity 77%, and accuracy 82% [96], yet mostcenters 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 differential that is considered in the evaluation ofneonatal cholestasis. Fig. 2 shows the algorithm for diagnosis. As statedpreviously, evaluation often proceeds despite the fact that more sophisti-cated laboratory tests have yet to be completed. It is of utmost importancethat a rapid diagnosis of BA is made so that a hepatoportoenterostomy isperformed in a timely manner if needed.

If a cholangiogram is consistent with BA, a surgical hepatoportenter-ostomy is recommended. Initially, the two most important prognosticfactors in determining surgical outcome are the age at operation and thesurgeon’s experience [97]. All in the field agree that children who have initialsurgery after 100 days of age have a worse outcome; what is less clear iswhether or not there are advantages to operating earlier than 40 to 60 daysof age. A King’s College study examined the outcomes of children who hadtheir initial surgery at less than 40 days of age, between 41 and 60 days ofage, between 61 and 99 days of age, and 100 days or more [98]. The studymeasured 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 100days or later group.

Management after portoenterostomy

After surgery, the management of a child with BA is aimed at optimizingnutrition, promoting choleresis, and preventing inflammation. Children aregiven antibiotics immediately postoperatively, and when bowel soundsreturn a diet that is easily digested is given.

Nutrition and vitamins

Malnutrition and growth retardation result from a combination offactors including fat malabsorption from decreased intestinal bile salts,organomegaly or ascites. The child might not be able to meet the increasedmetabolic demands of a liver with chronic inflammation. Typically a formulahigh in medium chain triglycerides (MCT) is chosen to overcome some ofthe fat malabsorption. Previously used formulas with more than 80% MCTwere deficient in long chain fatty acids, especially linoleic acid. The morerecently developed formulas contain approximately 60% MCT and provide


Fig.2.Algorithm

forevaluationofneonataljaundice.


essential fatty acids. This choice will allow dietary fat to be absorbedwithout a substantial need for micelle formation, which may be impaired. Ifa child does not sustain adequate growth, supplementation is achieved byincreasing the caloric density of the formula; if necessary, nasogastricfeedings are implemented to guarantee intake. Infants may have caloricrequirements in excess of 150 kcal/kg/day. Growth is usually monitored byfollowing length and weight and head circumference. However, there isgood evidence that this may underrecognize nutritional issues because of theissues of organomegaly and fluid retention. Midarm circumference andtriceps skinfold measured by a technician trained in anthropometry may bea better way to detect true lean body and fat mass [99].

Protein is typically not restricted in a child’s diet unless encephalopa-thy is present. Protein intake aids in achieving positive nitrogen balance,and the type of caseine protein typical of most infant formulas is welltolerated. Monitoring of proteins such as albumin, retinol bindingprotein, and PT provides an index of protein balance and hepatic syntheticfunction.

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 unifiedstandard has been adopted. Vitamin A deficiency is rare, but its toxicitywhen administered inappropriately has made it the most commonlymonitored vitamin, and it is only supplemented when deficient. The goalof therapy is low normal serum levels of 400 to 500 lm/mL. Vitamin D isnormally ingested in the diet, but is highly dependent on bile saltsolubilization for absorption [101,102]. Dietary vitamin D is hydroxylatedat the 25 position in the liver, followed by hydroxylation at the 1 position bythe kidney to form the active hormone. Usual supplementation is with 25-OHD, which is the most common form found in the circulation. Becausethere is no impairment of the hydroxylation in the kidney, this is thepreferred and safer form. However, if rickets is present, the active hormone1,25-(OH)2D is administered with close monitoring of calcium andphosphorous levels [101]. Vitamin E deficiency is found in BA, andsupplementation can be successfully achieved with d-alpha-tocopherol poly-ethylene glycol [103–105]. Lastly, Vitamin K is critical for activation ofclotting factors II, VII, IX, and X. Two naturally occurring forms of vitaminK 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 Kstatus [100,106]. Other nutrients that may need to be monitored includeiron, zinc, and cholesterol. Iron may become deficient because of inadequatedietary content, chronic inflammation with poor iron use, and gastrointes-tinal blood loss. Zinc is sometimes depleted in malabsorptive states and hasbeen associated with poor linear growth. Cholesterol is often elevated inchronic cholestasis, with some patients developing cutaneous deposits in theform of xanthomas.


Choleresis and decreasing inflammation: steroids, antibiotics,and ursodeoxycholic acid

In the initial postoperative period, the major objective is to preventpostoperative cholangitis. Administration of a combination of antibioticsand possibly steroids is recommended. The use of steroids has been adoptedfrom the Japanese, who use steroids routinely. Prednisolone is given in-travenously for 4 days, followed by oral administration until the totalbilirubin is less than 2.0 mg/dL. Some centers in the United States haveadopted this practice, but there has yet to be a well-designed controlledstudy. In one study, 25 infants were studied retrospectively after a 6-weekcourse of steroids. The measured outcome was survival with native liver. Ata 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 boutsof cholangitis; therefore, one clinical approach is to aggressively treatcholangitis. Cholangitis typically occurs in the first year of life [108]. Reportsfrom the 1980s suggest that the incidence of cholangitis ranges from 50% tomore than 90%. Our more recent experience is significantly less (un-published data). Some hospitals routinely use antibiotic prophylaxis for thefirst year of life; however, some argue that the risk of developing resistantintestinal flora outweighs any proven benefits. The diagnosis is made bypercutaneous liver biopsy and confirmed by blood culture. The suspicionshould be raised in any child with fever, irritability, leukocytsosis, or anunexplained change in liver enzymes. Unfortunately, the diagnosis iscomplicated by the frequency of childhood febrile diseases (eg, otitis media,viral illnesses). When no specific source is identified and clinical suspicionexists, broad spectrum antibiotics should be used to cover enteric organisms.

Ursodeoxycholic acid is routinely given to promote choleresis and toprevent scarring [109]. There is no documented efficacy in BA; however, it isconsidered a well-tolerated medicine with potential benefit. Its use stemsfrom the literature regarding PBC, AIH, and rat models of fibrosis.Ursodeoxycholic acid is a naturally occurring dihydroxy bile acid withknown choleretic properties. It undergoes extensive enterohepatic recycling.Following conjugation and biliary secretion, the drug is hydrolyzed to activeursodiol. Several large, well-designed studies in adults with primary biliarycirrhosis have demonstrated its usefulness and tolerability. Ursodeoxycholicacid significantly lowers serum levels of alkaline phosphatase, alanineaminotransferase, and aspartate aminotransferase at a dose of 13 to 15 mg/kg/day in adults with PBC [110–112]. With this chemical improvement,there has also been documented reduction in disease progression based onhistology and mortality [113]. Few subjects in these studies have had todiscontinue drug administration because of adverse events. The literatureregarding the efficacy of ursodeoxycholic acid in preventing fibrosis isfledgling, although a bile duct-ligated rat model of fibrosis has demonstratedbenefit [114].


Summary

BA is a rare disease of unclear etiology; nevertheless, its impact in thefield of pediatric hepatology is significant. It is the most common surgicallycorrectable cause of neonatal cholestasis and is the most common pediatricdisease referred for liver transplantation. Little progress has been made withregard to improving outcome or understanding its pathogenesis in the pastdecade. Fortunately, however, a national, government-sponsored collabo-rative endeavor has begun that will hopefully make a significant impactupon the progress of designing new treatments for BA and develop a betterunderstanding of its pathogenesis.

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