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Biliary atresia: clinical aspects
Seminars in Pediatric Surgery (2012) 21, 175-184
Biliary atresia: clinical aspects Mark Davenport, ChM, FRCS (Paeds) From the Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London, United Kingdom. KEYWORDS Biliary atresia; Clinical features; Cystic biliary atresia; BASM; Outcome
Biliary atresia (BA) remains an enigmatic disease with a degree of etiologic heterogeneity. A number of variants can be defined clinically, and these include the syndromic group (typically BA splenic malformation), cystic BA, and cytomegalovirus (CMV) IgM ⫹ve associated BA. The remainder, and still the largest group, may be termed isolated BA. There is a wide variation in incidence across the globe from 1 in 5000 in Taiwan to 1 in 20,000 live births in Northern Europe, although the reasons for such a disparity remain obscure. Management remains primarily surgical with an attempt to restore bile flow by resection of extrahepatic biliary remnants and a reconstruction portoenterostomy (the Kasai procedure), reserving liver transplantation for those where this fails or complications of chronic liver disease supervene. Clearance of jaundice to normal values has been achieved in 40%-55% of cases in large series from around the world, with an expectation of 5-year native liver survival of similar proportions. © 2012 Elsevier Inc. All rights reserved.
There are few diseases where so much is known yet so little understood than the condition of biliary atresia (BA). However, given that a strategy has evolved that allows perhaps 80%-90% of affected infants to survive to adolescence—some with their native liver and others derived from cadaveric or living donor— does it matter? Well, raw survival data obscure much morbidity along the way. Thus, about half of even biochemically normal adolescent survivors will have histologic cirrhosis,1 with the potential for later decompensation, portal hypertension, and even the risk of malignancy.2 Similarly, the majority of those with successfully transplanted organs still need to remain pharmacologically immunosuppressed with all that entails for potential morbidity, including the risk of developing malignant posttransplant lymphoproliferative disorders.
Address reprint requests and correspondence: Mark Davenport, ChM, FRCS (Paeds), Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London SE5 9RS. E-mail: [email protected].
1055-8586/$ -see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.sempedsurg.2012.05.010
Etiologic heterogeneity BA is not a single disease, certainly not one with a single cause. In all probabilities, it is a phenotype resulting from a number of different and entirely separate etiologies.3 There are perhaps 4 broad groups, which can be defined clinically as follows: 1. Syndromic BA and associated malformations. These can be subdivided into those where the malformations amount to a syndrome (ie, BA splenic malformation (BASM) syndrome,4,5 cat-eye syndrome6), and those where the malformations appear more random (eg, esophageal atresia, jejunal atresia). Female predominant. 2. Cystic BA (CBA)7—where there is a cystic change in an otherwise obliterated biliary tract. These are unlike obstructed choledochal cysts but typically do retain some connection and continuity with intrahepatic bile ductules. Female predominant (Figure 1A-C). 3. Cytomegalovirus (CMV)-associated BA—the infant has demonstrably positive serology (IgM antibodies), with the infection presumed to arise during perinatal period. 4. Isolated BA—the largest group, but it is still far from homogenous with variation in time of presentation, degree of inflammation, and obliteration of biliary tree.
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Figure 1 Cystic biliary atresia. A 40-day-old jaundiced female infant with 2 cm diameter “cyst” evident on ultrasound. (A) Operative appearance with cholangiogram catheter in situ. Bilestained fluid on aspiration. (B) Radiographic imaging showing cyst and contiguous “cloud-like” appearance of intrahepatic ductules. (C) Resected specimen with no visible bile ducts at transection margin consistent with type 3 cystic biliary atresia.
Epidemiologically, there is wide geographic (and presumed racial) variation across the world from about 1 in 5000 births in Taiwan to about 1 in 20,000 in Northern Europe, with no obvious seasonal variation and an equal gender split overall.7-9 Notwithstanding this national variation, regional
Seminars in Pediatric Surgery, Vol 21, No 3, August 2012 variation can also be shown, and this may be because of inherent racial differences within a national population.9 Developmental BA is a term that we have used, and it includes those in groups (1) and (2), where the onset is almost certainly prenatal, evident by the time of birth and where there is female predominance.9 The onset of occlusion in groups (3) and (4) is much more contentious, and some authorities hold that the bile duct can be normal and patent at the time of birth becoming occluded secondarily by virally mediated damage for instance, as is most obviously implied in group (3). Can we assume that these infants once had an intact biliary tree during fetal life and then obliteration occurred as a secondary perinatal phenomenon—which is probably the current orthodox view.10 Actually, there is not much clinical evidence for this assumption. A French group looked at ⬎10,000 samples of amniotic fluid for, among other enzymes, the levels of the hepatic exclusive enzyme ␥-glutamyl transpeptidase and found that the 3 infants who ultimately proved to have BA had the lowest values, highly suggestive of a prenatal onset and absence of bile from the fetal gastrointestinal tract.11 Mustaq et al12 have also looked at the levels of various bile acids in Guthrie blood spots using tandem mass spectrometry in newborn infants. Fortyseven (77%) of 61 infants who later proved to have BA had elevated total bile acids (⬎97th percentile, 33 mol/L), with no difference if the blood had been taken at ⬍7 or ⬎10 days. Furthermore, there was no difference in bile acid concentrations between those with BA and neonates with a clear genetic basis for their cholestasis, such as Alagille syndrome (JAG1) or ␣-1-anti trypsin deficiency (SERPINA1). A study from the Texas Children’s Hospital of split bilirubin levels on newborn infants (⬍48 hours old) was recently reported.13 This involved retrospective review of 31 infants who later turned out to have BA but had had their conjugated bilirubin levels measured at 24-48 hours of life. In all, their levels were abnormally high and distinct from controls, jaundiced or otherwise. Such studies can be interpreted as suggesting that cholestasis is already obvious (if looked for) during the first postnatal week, indeed by the evidence of the Texas study the first 48 hours of life, in most infants who later present clinically with isolated BA.
Classification BA is an occlusive panductular cholangiopathy, and thus it affects both intra- and extrahepatic bile ducts. The most common classification, based on that of the Japanese Association of Pediatric surgeons, divides BA into 3 types based on the most proximal level of occlusion of the extrahepatic biliary tree (Figure 2). In the most common, type 3, the intrahepatic bile ducts are grossly abnormal with myriad small ductules coalescing at the porta hepatis. In types 1 and
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Biliary Atresia: Clinical Aspects
177 development (eg, JAG1, HNF-6) and visceral and somatic symmetry (eg, INV, CFC-1), although correlation with the human condition is patchy. A possible genetic link has recently been reported by a French group who found an increased frequency of mutations of the CFC-1 gene (heterozygous transition c.433G⬎A (Ala145Thr) located in exon 5 on Ch 2q21.1).15 Typically in BASM, the extrahepatic biliary remnant is scanty, non-inflamed with a recognizably absent CBD, and the liver may be central and symmetric—whatever the situs.
Clinical and laboratory features
Figure 2
Schematic illustration of biliary atresia classification.
2 where there is a degree of preservation of structure and where there is usually of the intrahepatic bile ducts, there is still blunting, irregularity, and pruning (and absence of dilatation, even when obstructed). There is a second level of category based on status of the distal ducts, and one of these subtypes is worth mentioning. About 20% of all type 3 BAs have a patent common bile duct (CBD) and to all intents and purposes a normal gallbladder (subtype a). The gallbladder actually contains a few milliliters of crystal-clear mucus and will be perceived on the ultrasound (US) scan as “normal.”
The key features of BA are conjugated jaundice persisting beyond 14 days of age, acholic stools, and dark urine in an otherwise healthy term neonate. At birth, there is no difference in gestational age or birth weight between those with developmental compared with isolated BA, but both cohorts then show failure to thrive by the time they are admitted.9 Fat malabsorption is the presumed mechanism for this and will also cause deficiency of the fat-soluble vitamins D, A, E, and, most importantly, K. As a result, some infants will present with a bleeding tendency, even intracranial hemorrhage. The US examination is a key part of the diagnostic protocol, as it usually excludes other possible surgical diagnoses (eg, choledochal malformation, inspissated bile
BASM syndrome Although the association of BA with polysplenia had been recognized for some time, recognition of an etiologic relationship with maternal diabetes (as had been found with sacral agenesis and transposition of the great vessels) only occurred in 1993.4 The constellation of other anomalies is peculiar; absence of the inferior vena cava and a preduodenal portal vein (remnant of the paired vitelline veins) argue for events in the late embryonic period (27-32 days); and situs inversus in about half (Figure 3) suggest a much earlier fundamental event (possibly involving cilia), leaving determination of right/left asymmetry to chance. In this context, it is interesting that a recent study of cholangiocyte cilia showed marked abnormalities of shape and activity but in both syndromic and nonsyndromic BA.14 The common embryologic insult in BASM may simply be timing (30-35 days) rather than a specific genetic defect. There are key genes that are important in both bile duct
Figure 3 Situs inversus. Infant of a diabetic mother who presented with jaundice and was found to have situs inversus, rightsided polysplenia, a preduodenal portal vein, and biliary atresia.
178 syndrome, etc.). All of these are characterized by intrahepatic or CBD dilatation. US may be suggestive of BA as a diagnosis— by showing an atrophic gallbladder, with no evidence of filling between feeds. A more specific but still controversial feature is the so-called “triangular cord sign,” which was first identified by Park et al16 in 1997 and purports to represent the sonographic appearance of the solid proximal biliary remnant in front of the bifurcation of the portal vein. Some authors believe it to be highly accurate and specific for BA,17 others are more sceptical.18 Some infants with CBA will present with an abnormal maternal US scan, typically at around 20 weeks gestation.19 Clinicians need to recognize BA as a possibility for this scenario and facilitate a postnatal US and timely referral. The differential is that of a cystic choledochal malformation, but these also need early effective surgery if obstructed. By comparison, the cystic component in CBA tends to be smaller and may or may not contain bile. Nonvisualization of the gallbladder during the 2nd trimester by contrast is rarely because of BA, and it is either seen in fetuses with multiple anomalies (⬃25%) or they turn out to be normal (⬃75%).20 Liver fibrosis and cirrhosis are time-dependent features, which seem to begin perinatally even in those infants with developmental BA. Makin et al21 described 3 infants who later were confirmed as BA and who had had laparotomies and liver biopsies within the first week of life. All had normal hepatic histology, despite the obvious developmental BA in all. Still, fibrosis and cirrhosis occur relatively early in BA as compared with other neonatal cholestatic diseases, such as Alagille syndrome or ␣-1-antitrypsin deficiency. It is invariable in infants beyond 100 days and should be evident on US as liver heterogeneity, ascites, and splenomegaly. Portal venous pressure can be measured at the time of laparotomy, and it is elevated in half of all infants (even higher in those who are CMV IgM ⫹ve) and correlates reasonably with age at surgery, serum aspartate aminotransferase (AST), and bilirubin levels.22 Perhaps surprisingly, it does not correlate well with measures of outcome, such as clearance of jaundice or need for later transplant. The AST/platelet ratio index can be used as a surrogate of liver fibrosis in many liver diseases, including BA. Our group has recently shown that this correlates significantly with age at surgery and was also much higher in the CMV IgM ⫹ve group (Figure 4). Macroscopic cirrhosis (n ⫽ 22), evident at laparotomy, could also be predicted using a cutoff value of 1.2, with reasonable sensitivity (75%) and specificity (84%) in a large cohort of infants (n ⫽ 260) (unpublished observation). What you do with such information however is moot. Although a Kasai operation can be beneficial even in those with cirrhosis, prediction of benefit is difficult. These are also the infants in whom there is a highest risk of postoperative morbidity, such as wound failure. Primary liver transplantation is an option in some countries and may be one way forward.
Seminars in Pediatric Surgery, Vol 21, No 3, August 2012
Figure 4 AST/platelet ratio index (APRi) in biliary atresia. Infants with biliary atresia (n ⫽ 260), divided by variant (ie, CMV IgM ⫹ve BA, cystic BA, BASM, and isolated BA). (*P ⬍ 0.05, **P ⬍ 0.01, ***P ⬍ 0.001).
Percutaneous liver biopsy is the usual method of achieving a diagnosis preoperatively, at least in the West, but its interpretation can be difficult. A recent histologic study involved a panel of pathologists reviewing the histologic features that best predicted BA, and these turned out to be bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis. Overall, the positive predictive value of biopsy for BA was 91%.23 Currently, there are 2 methods of achieving cholangiography short of a full laparotomy: endoscopic retrograde cholangiopancreatography (ERCP)24 or laparoscopy.25 ERCP is technically challenging even with the right equipment, but can avoid laparotomy in the larger infants. Laparoscopy and direct puncture of the gallbladder are also relatively straightforward as an access point for a cholangiogram. In some centers, particularly in Asia, simple placement of a nasoduodenal tube and aspiration over 24 hours is the principle method of making the diagnosis. Radio-isotopelabeled hepatobiliary scans are a more sophisticated method of detecting intestinal bile but suffer from relatively poor discrimination in those with severe cholestasis from whatever cause.
Screening for BA Some countries have adopted a population screening program for BA. The most well developed has been that in Taiwan,8 where mothers are issued with color-coded cards and asked to compare it with their infant’s stool. Recognition of pale stool prompts further investigation and referral. This has shortened their time to surgery, with the median age at KP being ⬍50 days, and it is
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Biliary Atresia: Clinical Aspects
Figure 5 Exposure of the liver and porta hepatis at Kasai portoenterostomy.
currently the best achieved anywhere in national terms. The key achievement, I believe, has been the marked reduction in late-presenting infants who have already developed obvious cirrhosis.26
179 using currently available laparoscopic instruments. As stated earlier in the text, radical resection of all extrahepatic biliary remnants from all biliary sectors and a wide portoenterostomy encompassing all the margins of that resection are the key features to maximize results, and it can be a difficult delicate dissection in the open without all the constraints of videosurgery. Patency of the native gallbladder and CBD might tempt one to consider a portocholecystostomy, as it does have the advantage of abolishing postoperative cholangitis. However, the anastomosis is not as flexible as a standard Roux loop, and revisions for repeated biliary obstruction have been described with a poorer long-term outcome compared with a standard Roux loop.29 In some circumstances, the anatomy of the less common type 1 and 2 BAs, typically manifest as CBA, would allow a hepaticojejunostomy to be performed, as there is still a bile duct to join to. However, this is tenuous at best, and although these groups do have a better long-term outcome,6,30,31 it is probably more sensible to dissect it higher and clear the portal plate as in a standard KPE.
Adjuvant therapy for BA Surgery The Kasai portoenterostomy (KPE) operation consists of resecting gallbladder and the extrahepatic biliary tree, leaving a denuded porta hepatis, which is then reconstructed into a long Roux loop. To achieve this, we exteriorize the liver by division of triangular and coronary ligaments (Figure 5). Some divide and extract only the left lobe, whereas others leave the liver in situ but sling the portal pedicles to achieve the necessary porta exposure. Whatever alternative approach is used, meticulous dissection and demonstration of the margins of the porta hepatis is a key maneuver in the open operation. In most descriptions of the radical or extended KPE, the encompassed porta should extend from the “umbilical point” on the left to include an area between the bifurcation of the right portal pedicle. Posteriorly, one should ligate small veins arising from the bifurcation of the portal vein to expose the margins of the caudate lobe (Figure 6). Laparoscopic Kasai operations continue to be reported by minimally invasive enthusiasts (see Yamataka, et al, “Laparoscopic Surgery for Biliary Atresia and Choledochal Cyst,” in this issue), but this has not been taken up by the larger centers performing the standard KPE on a regular basis in either Europe or North America. It has become apparent that laparoscopic Kasai surgery does not offer anything advantageous to the child beyond a better scar and an adhesion-free abdominal cavity for the transplant surgeon. Results are certainly not better and rarely comparable, and major centers, for example China and Germany, have reverted to the standard open approach.27,28 This is likely to be because of the difficulties with portal plate dissection
Although a number of drugs have the potential to improve the outcome of KPE, there has been little published in the way of scientific data to provide credible support for any. Nonetheless, 2 classes of drug deserve exposition.
Corticosteroids Steroids may have an effect in 2 principle ways. There is an undoubted inflammatory element to BA, which may be driven by an immune process susceptible to pharmacologic manipulation. Steroids may limit this inflammatory response. Alternatively, steroids also increase the bile salt independent fraction of bile flow, and their effect may simply be one of choleresis.
Figure 6 Schematic illustration of the porta hepatis. Extended resection of proximal biliary remnants from left (junction of umbilical vein and left portal vein) to right (bifurcation of anterior and posterior branches of right portal vein).
180 Small uncontrolled series have suggested benefit in terms of increased bile flow post KPE,32,33 and postoperative steroids remain popular. However, there is only a single prospective, double-blind, randomized, placebo-controlled trial using a low-dose of prednisolone (2 mg/kg/d) from 2 UK centers.34 This showed a significant increased rate of jaundice clearance (especially in young livers) in the steroid group but did not translate to a reduced need for transplant or improve overall survival. More recent data from our group using a higher dosage regimen (starting at 5 mg/kg/d) have shown the same beneficial effect on postoperative bilirubin levels and now also a significantly higher proportion of those who cleared their jaundice (unpublished observation). Notwithstanding this, a large open-label German trial using a starting dose of 10 mg/kg/d prednisolone for 5 days did not find any evidence of benefit whatsoever.35 This trial was noteworthy in that the jaundice clearance rates were relatively low in both groups (27% after 2 years). Most recently, Sarkhy et al36 performed a systematic review of 16 observational studies (n ⫽ 160) and the 1 randomized controlled trial (n ⫽ 73) and concluded that there was no significant effect on jaundice clearance or need for transplant. There is 1 randomized North American study currently in progress, which has recruited 140 infants (START: http://clinicaltrials.gov NCT 294,684). This at least promises to offer enough statistical power to determine the key question of efficacy.
Ursodeoxycholic acid Ursodeoxycholic acid (UDCA) is hydrophilic bile acid found more commonly (as the name suggests) in bears than in humans. In the latter it makes up about 1%-4% of total bile acids. Exogenous administration has shown biochemical, histologic, and clinical benefit in adults with primary biliary cirrhosis and sclerosing cholangitis in reducing the need for transplant. An early trial from the United States, albeit reported only in abstract form in the 1990s, suggested some clinical and biochemical benefit.37 More recently, a crossover trial has been reported from a French group. In this study, Willot et al38 assessed the effect of UDCA on liver function in children aged ⬎1 year post-KPE in a discontinuation/reintroduction manner. Sixteen children with BA were studied, and all had cleared their jaundice. These were all treated with UDCA (25 mg/kg/d in 3 divided doses) for 18 months at which point treatment was stopped, and their clinical and biochemical status was monitored. Six months later, only one had worsened clinically with recurrence of jaundice; however, all but 2 had sustained significant worsening in liver enzymes. These were all then restarted on UDCA, and 6 months later, all of these had a significant reduction in their liver enzymes. Enrichment of the bile acid pool with exogenous UDCA is believed not only to increase clearance of “toxic” endogenous bile acids whatever that may mean, but it may also have an immunomodulatory effect on mononuclear cells.
Seminars in Pediatric Surgery, Vol 21, No 3, August 2012
Postoperative complications Ineffectiveness of the KPE and continuation of the natural history of BA is the most common problem leading to end-stage liver disease. Jaundice will worsen accompanied by abdominal distension and ascites with failure to thrive and malnutrition. Such infants require urgent consideration for liver transplantation. There are some specific complications, which can occur independently of this process though.
Cholangitis Restoration of a biliointestinal link predisposes to ascending cholangitis, and it is seen in up to 50% of large series.39 This is much more likely to occur in those with BA compared with those with choledochal malformations, as the latter’s bile flow is better than even the best KPE. The risk is apparent in the first 2 years postsurgery, although the reason for this is obscure, but, presumably, there is some timedependent change in local immunologic defense within the residual cholangioles. Most children will present with pyrexia, worsening jaundice, and a change in liver biochemistry, and they should be treated aggressively with broad-spectrum intravenous antibiotics effective against Gram-negative organisms (eg, gentamicin, meropenem, Tazocin piperacillin/tazobactam]).
Portal hypertension and esophageal varices Portal venous pressure, when measured at KPE, is abnormally high in about 70% of BA infants and is caused by increasing liver fibrosis and correlates with age at KPE, bilirubin level, and US -measured spleen size.22 It, however, is a poor predictor of outcome either in terms of response to KPE or even in those who will develop varices. This confirms the results of a previous study from King’s College Hospital where original liver histology at KPE was graded and compared with variceal formation as assessed endoscopically in 77 children, some 2-4 years later.40 The implication from both is that it is the result of the KPE in terms of clearance of jaundice and more importantly the abbreviation and perhaps attenuation of the hepatic fibrotic process, rather than the early state of the liver, which determines variceal formation. Varices take time to develop, and bleeding is unusual before 9 months of age but usually occurs from 2 to 3 years. Using endoscopic surveillance about 60% of children surviving beyond 2 years will have definite varices and of these about 20%-30% will bleed.41,42 In common with other large centers, we therefore recommend that each child with BA enter a program of endoscopic surveillance to try and preempt variceal bleeding. The key variceal signs that should prompt prophylactic endoscopic treatment are the presence of significant red wales in grade II/III esophageal varices and obvious (usually lesser curve) gastric varices.42 Emergency treatment of bleeding varices specifically includes the use of vasopressin (eg, terlipressin) or somatosta-
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181
tin analogs (eg, octreotide), but sometimes even a Sengstaken-pattern tube has to be used.43 Most varices in BA can be treated endoscopically with banding or in the very young injection sclerotherapy.41 In those with reasonable restoration of liver function, this should be all that is necessary; however, those who are still significantly jaundiced will require transplant assessment. Oral propranolol (1-2 mg/kg/d) may be a role in prophylaxis of bleeding (typically secondary) in some children with cirrhosis caused by BA but again actual published evidence of benefit is unavailable.44
Ascites This is related to portal hypertension in part, but there are other contributory factors include hypoalbuminemia and hyponatremia. It also predisposes to spontaneous bacterial peritonitis. Conventional treatment includes a low salt diet, fluid restriction, and the use of diuretics particularly spironolactone. It is often seen in settings of malnutrition and end-stage liver disease, and a nutritional supplementation is important to try and increase calorie and protein intake.
Prognostic factors A number of factors can be identified as important, although the outcome in individual cases is largely unpredictable.
Age at Kasai portoenterostomy If a bile-obstructed liver is left alone, then delayed surgery will be associated with less good results as the liver ultimately becomes cirrhotic and unsalvageable. This as a factual observation is undeniable; however, the effect is neither simple nor linear and depends crucially on the type and variant of BA. Furthermore, it does seem that even in the developmental forms of BA, detrimental liver fibrosis and inflammation only begin at the time of birth—not before.21 The best way of determining an effect of age in a BA is by so-called age-cohort analysis, and this was first reported by Serinet et al45 using the French national cohort. It requires large numbers to create enough age-groups stratified by single type to allow meaningful statistical analysis. In our series of 225 infants from a single center (2 surgeons), we used such age-defined cohorts and separated them into 3 variants (isolated, BASM, and CBA). Using clearly defined measures of outcome that were rigorous (clearance of jaundice to normal values, and transplantation by 2 years of age), we only observed an obvious age-effect for CBA and BASM. There was barely any discernable effect until about 90 days of age in those with isolated BA.46 There were certainly no cutoffs at 6, 8, or 10 weeks (Figure 7).
Figure 7 Effect of age on outcome. (A) Clearance of jaundice (⬍20 mol/L) and (B) 2-year native liver survival when analyzed by age cohort and cumulatively for infants with isolated biliary atresia (n ⫽ 177). King’s College Hospital series.
Centralization—who should do the Kasai portoenterostomy? Older studies from the United Kingdom confirmed the not very radical concept that the more KPE you do as a center, the better the outcome.47,48 This led to superspecialization of pediatric hepatobiliary surgery in England and Wales to 3 centers for a population of about 53 million. This approach has been adopted by smaller European countries, such as Finland49 and Denmark,50 and there has been an increased awareness of the need to improve collaboration and communication between centers in others (eg, France, United States, Canada).31,51,52
Liver histology and biliary remnant—the anatomical effect There is improved outcome in types 1 and 2 compared with type 3 BA; and CBA compared with noncystic BA.6,45,46 Almost certainly this is because of preservation of some of the connections between the intra- and extrahepatic bile ducts and ductules. Infants with BASM have a worse prog-
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nosis, and typically their remnants are fairly scanty.5 Infants with CMV IgM associated BA do worst of all, although this is because of ongoing immunologic destruction of intrahepatic biliary ductules requires further study. Prospective evaluation of the macroscopic features of the hepatobiliary elements (hardness of the liver, presence of ascites, etc.) has been relatively poorly predictive of outcome with only actual size of resected biliary remnants being really discriminatory.53 Microscopic examination of the transected bile duct remnant will show a varying amount of residual ductules. Older series suggested that only those showing large ductules (⬎300 m) had a distinctly better outcome,54 but the converse is also true—minimal or no ductules in the remnant is predictive of lack of effect of KPE.55 More esoteric immunohistochemical studies of the quantification of various infiltrating cell subsets or quantification of fibrosis need repeating by other groups and in larger studies before they have real clinical meaning.56
Outcome and results It is important to standardize reporting in BA surgery to enable appropriate comparison. There are 3 measures of outcome in the management, which address different elements within the cohort under consideration. These are (1) median age at KPE, (2) percentage clearance of jaundice (to achieve normal values of bilirubin), and (3) actuarial native liver and true survival at 5 and 10 years. The first measure reflects on the effectiveness of primary care practitioners (doctors, health visitors, etc.) in detecting potential cases of
Table 1
BA and the efficiency of the diagnostic process in secondary and tertiary units in coming to timely surgical intervention. The second measure is a reflection on the surgeon and surgery performed in an infant with a retrievable liver. The third is more complex and reflects not only on the success of the KPE but also on the medical management of the postKPE infant; judicious and effective treatment of complications; the availability and then the delivery of a safe liver transplant. Initial reports of results were confined to single, often Japanese, centers but these only up until relatively recently reflected on the “raw” results of the KPE, as transplantation was not readily available. For example, in the original Kasai series from Sendai,57 the 10-year survival rate for the first 63 patients treated from 1953 to 1967 was 10%; for 44 cases from 1968 to 1972, 27%; and for 61 cases from 1973 to 1977, 48%. Of these, about 2⁄3 were jaundice free (⬍20 mol/L). It is worth bearing these figures in mind when surgeons hark back to the “original” Kasai operation—for the time these were exceptional, in comparison with current results they seem outmoded. Therefore, current results, by comparison, have improved greatly with a dramatic improvement in survival particularly (because of transplantation) so that in England and Wales, we would now expect a 10-year survival of ⬃90%.58 Table 1 illustrates current results reported for the past 10 years on the outcome of BA using a combination of KPE and liver transplantation. National data sets or large consortium data sets have been used59 – 62 wherever possible to try and reduce the effect of positive bias reporting by individual centers.
National and consortium outcome statistics in biliary atresia (1985-2010)
Series
Country
North America †Schneider et al, 200659 USA‡ Schreiber et al, 200752 Canada §Superina et al31 USA‡ Europe Serinet et al, 200651 France Wildhaber et al, 200860 Switzerland Davenport et al, 201158 England and Wales De Vries et al, 201261 Netherlands Asia Nio et al, 200362 Japan Hsiao et al, 20088
Taiwan
N
Median or mean time to KPE Period
Native liver survival (%) Clearance of jaundice* 4/5 year
Overall survival (%)
10 year 4/5 year
104 61 349 55 136 64
1997-2000 ⬃40% 1985-1995 n/a 2004-2010 46%
56 (2 year) 35 40-47 (2 years)
86 (2 year) 74 n/a
271 57 48 68 443 54
1997-2002 40% 1994-2004 n/a 1999-2009 55%
35 37 46
87 92 90
104 59
1998-2008
42
108 65⫹ 129 65⫹ 75 55
1989-1999 62% 1994 n/a 2004-2005 59%**
38%
62 53
40
10 year
89
76 53
69 78
*Defined as achieving a level of ⬍20 mol/L (or 1.5 mg/dL). † USA–(Biliary atresia research consortium–9 centers). ‡ Defined as achieving a level of ⬍20 mol/L (or ⬍2 mg/dL). § USA–(Biliary atresia research consortium–16 centers)—somewhat selected as only those outside trial reported (47% of original series). **⬍2 mg/dL.
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Some observations are pertinent from analysis of this table. Socialized health systems or countries where active screening programs exist have the lowest median age at KPE. Surgeons with greater experience and throughput tend to have a better initial clearance of jaundice rates and anything above 50% should be the benchmark. Similarly, an overall survival rate of about 90% is also attainable in most countries with access to quality transplant programs freely available to all those in need. Still, deaths on waiting lists occur but are definitely preventable, given improvements in the donor organ pool and early recognition of the need for transplant. In conclusion, although the actual cause of BA remains far from clear, a complementary system of surgical treatment has evolved during the past 35 years, which has improved the overall survival to adulthood in affected infants from a dismal 10% to about 90%. Not many surgical diseases can claim such a change in outlook. The future will see improvements in understanding the basis for this enigmatic disease, but it is noteworthy that all currently successful treatments have been surgical and of these only liver replacement is actually curative. Effective pharmacologic methods to control the early onset of liver fibrosis—a characteristic feature of BA—are sorely needed to really alter the natural history of the disease.63 An alternative strategy has been suggested by Sharma et al64 from India who infused autologous (bone marrow derived) stem cells at the time of KPE and observed some improvements in liver biochemistry and survival, although their infants were very late presenters by Western standards. Without such advances then those who have no response to KPE and the most pressing need for liver transplantation during infancy will remain at severe risk.
References 1. Hadzic´ N, Davenport M, Tizzard S, et al. Long-term survival following Kasai portoenterostomy: Is chronic liver disease inevitable? J Pediatr Gastroenterol Nutr 2003;37:430-3. 2. Hadžic´ N, Quaglia A, Portmann B, et al. Hepatocellular carcinoma in biliary atresia: King’s College Hospital experience. J Pediatr 2011; 159:617-22. 3. Hartley JL, Davenport M, Kelly DA. Biliary atresia. Lancet 2009;374: 1704-13. 4. Davenport M, Savage M, Mowat AP, et al. The biliary atresia splenic malformation syndrome. Surgery 1993;113:662-8. 5. Davenport M, Tizzard SA, Underhill J, et al. The biliary atresia splenic malformation syndrome: A 28-year single-center retrospective study. J Pediatr 2006;149:393-400. 6. Caponcelli E, Knisely AS, Davenport M. Cystic biliary atresia: An etiologic and prognostic subgroup. J Pediatr Surg 2008;43:1619-24. 7. Chardot C, Carton M, Spire-Bendelac N, et al. Epidemiology of biliary atresia in France: A national study 1986-96. J Hepatol 1999;31:1006-13. 8. Hsiao CH, Chang MH, Chen HL, et al. Universal screening for biliary atresia using an infant stool color card in Taiwan. Hepatology 2008; 47:1233-40.
183 9. Livesey E, Cortina Borja M, Sharif K, et al. Epidemiology of biliary atresia in England and Wales (1999-2006). Arch Dis Child Fetal Neonatal Ed 2009;94:F451-455. 10. Sokol RJ, Mack C, Narkewicz MR, et al. Pathogenesis and outcome of biliary atresia: Current concepts. J Pediatr Gastroenterol Nutr 2003; 37:4-21. 11. Muller F, Oury JF, Dumez Y, et al. Microvillar enzyme assays in amniotic fluid and fetal tissues at different stages of development. Prenat Diagn 1988;8:189-98. 12. Mushtaq I, Logan S, Morris M, et al. Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry. BMJ 1999;319:471-7. 13. Harpavat S, Finegold MJ, Karpen SJ. Patients with biliary atresia have elevated direct/conjugated bilirubin levels shortly after birth. Pediatrics 2011;128:e1428-33. 14. Chu AS, Russo PA, Wells RG. Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod Pathol 2012;25: 751-7. 15. Davit-Spraul A, Baussan C, Hermeziu B, et al. CFC1 gene involvement in biliary atresia with polysplenia syndrome. J Pediatr Gastroenterol Nutr 2008;46:111-2. 16. Park WH, Choi SO, Lee HJ, et al. A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: Comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis. J Pediatr Surg 1997;32:1555-9. 17. Humphrey TM, Stringer MD. Biliary atresia: US diagnosis. Radiology 2007;244:845-51. 18. Mittal V, Saxena AK, Sodhi KS, et al. Role of abdominal sonography in the preoperative diagnosis of extrahepatic biliary atresia in infants younger than 90 days. Am J Roentgenol 2011;196:W438-45. 19. Hinds R, Davenport M, Mieli-Vergani G, et al. Antenatal presentation of biliary atresia. J Pediatr 2004;144:43-6. 20. Shen O, Rabinowitz R, Yagel S, et al. Absent gallbladder on fetal ultrasound: Prenatal findings and postnatal outcome. Ultrasound Obstet Gynecol 2011;37:673-7. 21. Makin E, Quaglia A, Kvist N, et al. Congenital biliary atresia: Liver injury begins at birth. J Pediatr Surg 2009;44:630-3. 22. Shalaby A, Makin E, Davenport M. Portal venous pressure in biliary atresia. J Pediatr Surg 2012;47:363-6. 23. Russo P, Magee JC, Boitnott J, et al. (Biliary Atresia Research Consortium). Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. Clin Gastroenterol Hepatol 2011;9:357-62. 24. Shanmugam NP, Harrison PM, Devlin J, et al. Selective use of endoscopic retrograde cholangiopancreatography in the diagnosis of biliary atresia in infants younger than 100 days. J Pediatr Gastroenterol Nutr 2009;49:435-41. 25. Nose S, Hasegawa T, Soh H, et al. Laparoscopic cholecystocholangiography as an effective alternative exploratory laparotomy for the differentiation of biliary atresia. Surg Today 2005;35:925-8. 26. Tseng JJ, Lai MS, Lin MC, et al. Stool color card screening for biliary atresia. Pediatrics 2011;128:e1209-15. 27. Wong KK, Chung PH, Chan KL, et al. Should open Kasai portoenterostomy be performed for biliary atresia in the era of laparoscopy? Pediatr Surg Int 2008;24:931-3. 28. Ure BM, Kuebler JF, Schukfeh N, et al. Survival with the native liver after laparoscopic versus conventional Kasai portoenterostomy in infants with biliary atresia: A prospective trial. Ann Surg 2011;253:826-30. 29. Zhao R, Li H, Shen C, et al. Hepatic portocholecystostomy (HPC) is ineffective in the treatment of biliary atresia with patent distal extrahepatic bile ducts. J Invest Surg 2011;24:53-8. 30. Davenport M, Kerkar N, Mieli-Vergani G, et al. Biliary atresia: The King’s College Hospital experience (1974-1995). J Pediatr Surg 1997; 32:479-85. 31. Superina R, Magee JC, Brandt ML, et al. The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and
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early postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg 2011;254:577-85. Meyers RL, Book LS, O’Gorman M, et al. High dose steroids, ursodeoxycholic acid and chronic intravenous antibiotics improve bile flow after Kasai procedure in infants with biliary atresia. J Pediatr Surg 2004;38:406-11. Kobayashi H, Yamataka A, Koga H, et al. Optimum prednisolone usage in patients with biliary atresia postportoenterostomy. J Pediatr Surg 2005;40:327-30. Davenport M, Stringer MD, Tizzard SA, et al. Randomized, doubleblind, placebo-controlled trial of corticosteroids after Kasai portoenterostomy for biliary atresia. Hepatology 2007;46:1821-7. Petersen C, Harder D, Melter M, et al. Postoperative high-dose steroids do not improve mid-term survival with native liver in biliary atresia. Am J Gastroenterol 2008;103:712-9. Sarkhy A, Schreiber RA, Milner RA, et al. Does adjuvant steroid therapy post-Kasai portoenterostomy improve outcome of biliary atresia? Systematic review and meta-analysis. Can J Gastroenterol 2011; 25:440-4. A-Kader HH, Santangelo JD, Setchell KDR, et al. The effects of ursodeoxycholic acid therapy in biliary atresia: A double blind, randomized, placebo controlled trial. Pediatr Res 1993;33:97A. Willot S, Uhlen S, Michaud L, et al. Effect of ursodeoxycholic acid on liver function in children after successful surgery for biliary atresia. Pediatrics 2008;122:e1236-41. Ecoffey C, Rothman E, Bernard O, et al. Bacterial cholangitis after surgery for biliary atresia. J Pediatr 1987;111:824-9. Kang N, Davenport M, Driver M, et al. Hepatic histology and the development of esophageal varices in biliary atresia. J Pediatr Surg 1993;28:63-6. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989;24:438-42. Duché M, Ducot B, Tournay E, et al. Prognostic value of endoscopy in children with biliary atresia at risk for early development of varices and bleeding. Gastroenterology 2010;139:1952-60. Eroglu Y, Emerick KM, Whitingon PF, et al. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr 2004;38:41-7. Sökücü S, Süoglu OD, Elkabes B, et al. Long-term outcome after sclerotherapy with or without a beta-blocker for variceal bleeding in children. Pediatr Int 2003;45:388-94. Serinet MO, Wildhaber BE, Broué 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;123:1280-6. Davenport M, Caponcelli E, Livesey E, et al. Surgical outcome in biliary atresia: Etiology affects the influence of age at surgery. Ann Surg 2008;247:694-8. McClement JW, Howard ER, Mowat AP. Results of surgical treatment for extrahepatic biliary atresia in United Kingdom 1980-2. Survey conducted on behalf of the British Paediatric Association Gastroen-
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terology Group and the British Association of Paediatric Surgeons. BMJ 1985;290:345-7. McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome of biliary atresia in the UK and Ireland. Lancet 2000;355:25-9. Lampela H, Ritvanen A, Kosola S, et al. National centralization of biliary atresia care to an assigned multidisciplinary team provides high-quality outcomes. Scand J Gastroenterol 2012;47:99-107. Kvist N, Davenport M. Thirty-four years’ experience with biliary atresia in Denmark: A single center study. Eur J Pediatr Surg 2011; 21:224-8. Serinet MO, Broué P, Jacquemin E, et al. Management of patients with biliary atresia in France: Results of a decentralized policy 1986-2002. Hepatology 2006;44:75-84. Schreiber RA, Barker CC, Roberts EA, et al. Biliary atresia: The Canadian experience. J Pediatr 2007;151:659-65. Davenport M, Howard ER. Macroscopic appearance at portoenterostomy—A prognostic variable in biliary atresia. J Pediatr Surg 1996; 31:1387-90. Howard ER, Driver M, McClement J, et al. Results of surgery in 88 consecutive cases of extrahepatic biliary atresia. J R Soc Med 1982; 75:408-13. Tan CE, Davenport M, Driver M, Howard ER. Does the morphology of the extrahepatic biliary remnants in biliary atresia influence survival? A review of 205 cases. J Pediatr Surg 1994;29:1459-64. Davenport M, Gonde C, Redkar R, et al. Immunohistochemistry of the liver and biliary tree in extrahepatic biliary atresia. J Pediatr Surg 2001;36:1017-25. Ohi R. Biliary atresia: Long-term results of hepatic portoenterostomy. In: Howard ER, ed. Surgery of Liver Disease in Childhood. London, Butterworth-Heinemann, 1991, pp 60-71. Davenport M, Ong E, Sharif K, et al. Biliary atresia in England and Wales: Results of centralization and new benchmark. J Pediatr Surg 2011;46:1689-94. Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 2006;148:467-74. Wildhaber BE, Majno P, Mayr J, et al. Biliary atresia: Swiss national study, 1994-2004. J Pediatr Gastroenterol Nutr 2008;46:299-307. de Vries W, de Langen ZJ, Groen H, et al. Biliary atresia in The Netherlands: Outcome of patients diagnosed between 1987 and 2008. J Pediatr 2012;160:638-44. Nio M, Ohi R, Miyano T, et al. Five- and 10-year survival rates after surgery for biliary atresia: A report from the Japanese biliary atresia registry. J Pediatr Surg 2003;38:997-1000. Huang HP, Chang MH, Chen YT, et al. Persistent elevation of hepatocyte growth factor activator inhibitors in cholangiopathies affects liver fibrosis and differentiation. Hepatology 2012;55:161-72. Sharma S, Kumar L, Mohanty S, et al. Bone marrow mononuclear stem cell infusion improves biochemical parameters and scintigraphy in infants with biliary atresia. Pediatr Surg Int 2011;27:81-9.
Biliary atresia: clinical aspects Mark Davenport, ChM, FRCS (Paeds) From the Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London, United Kingdom. KEYWORDS Biliary atresia; Clinical features; Cystic biliary atresia; BASM; Outcome
Biliary atresia (BA) remains an enigmatic disease with a degree of etiologic heterogeneity. A number of variants can be defined clinically, and these include the syndromic group (typically BA splenic malformation), cystic BA, and cytomegalovirus (CMV) IgM ⫹ve associated BA. The remainder, and still the largest group, may be termed isolated BA. There is a wide variation in incidence across the globe from 1 in 5000 in Taiwan to 1 in 20,000 live births in Northern Europe, although the reasons for such a disparity remain obscure. Management remains primarily surgical with an attempt to restore bile flow by resection of extrahepatic biliary remnants and a reconstruction portoenterostomy (the Kasai procedure), reserving liver transplantation for those where this fails or complications of chronic liver disease supervene. Clearance of jaundice to normal values has been achieved in 40%-55% of cases in large series from around the world, with an expectation of 5-year native liver survival of similar proportions. © 2012 Elsevier Inc. All rights reserved.
There are few diseases where so much is known yet so little understood than the condition of biliary atresia (BA). However, given that a strategy has evolved that allows perhaps 80%-90% of affected infants to survive to adolescence—some with their native liver and others derived from cadaveric or living donor— does it matter? Well, raw survival data obscure much morbidity along the way. Thus, about half of even biochemically normal adolescent survivors will have histologic cirrhosis,1 with the potential for later decompensation, portal hypertension, and even the risk of malignancy.2 Similarly, the majority of those with successfully transplanted organs still need to remain pharmacologically immunosuppressed with all that entails for potential morbidity, including the risk of developing malignant posttransplant lymphoproliferative disorders.
Address reprint requests and correspondence: Mark Davenport, ChM, FRCS (Paeds), Department of Paediatric Surgery, King’s College Hospital, Denmark Hill, London SE5 9RS. E-mail: [email protected].
1055-8586/$ -see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.sempedsurg.2012.05.010
Etiologic heterogeneity BA is not a single disease, certainly not one with a single cause. In all probabilities, it is a phenotype resulting from a number of different and entirely separate etiologies.3 There are perhaps 4 broad groups, which can be defined clinically as follows: 1. Syndromic BA and associated malformations. These can be subdivided into those where the malformations amount to a syndrome (ie, BA splenic malformation (BASM) syndrome,4,5 cat-eye syndrome6), and those where the malformations appear more random (eg, esophageal atresia, jejunal atresia). Female predominant. 2. Cystic BA (CBA)7—where there is a cystic change in an otherwise obliterated biliary tract. These are unlike obstructed choledochal cysts but typically do retain some connection and continuity with intrahepatic bile ductules. Female predominant (Figure 1A-C). 3. Cytomegalovirus (CMV)-associated BA—the infant has demonstrably positive serology (IgM antibodies), with the infection presumed to arise during perinatal period. 4. Isolated BA—the largest group, but it is still far from homogenous with variation in time of presentation, degree of inflammation, and obliteration of biliary tree.
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Figure 1 Cystic biliary atresia. A 40-day-old jaundiced female infant with 2 cm diameter “cyst” evident on ultrasound. (A) Operative appearance with cholangiogram catheter in situ. Bilestained fluid on aspiration. (B) Radiographic imaging showing cyst and contiguous “cloud-like” appearance of intrahepatic ductules. (C) Resected specimen with no visible bile ducts at transection margin consistent with type 3 cystic biliary atresia.
Epidemiologically, there is wide geographic (and presumed racial) variation across the world from about 1 in 5000 births in Taiwan to about 1 in 20,000 in Northern Europe, with no obvious seasonal variation and an equal gender split overall.7-9 Notwithstanding this national variation, regional
Seminars in Pediatric Surgery, Vol 21, No 3, August 2012 variation can also be shown, and this may be because of inherent racial differences within a national population.9 Developmental BA is a term that we have used, and it includes those in groups (1) and (2), where the onset is almost certainly prenatal, evident by the time of birth and where there is female predominance.9 The onset of occlusion in groups (3) and (4) is much more contentious, and some authorities hold that the bile duct can be normal and patent at the time of birth becoming occluded secondarily by virally mediated damage for instance, as is most obviously implied in group (3). Can we assume that these infants once had an intact biliary tree during fetal life and then obliteration occurred as a secondary perinatal phenomenon—which is probably the current orthodox view.10 Actually, there is not much clinical evidence for this assumption. A French group looked at ⬎10,000 samples of amniotic fluid for, among other enzymes, the levels of the hepatic exclusive enzyme ␥-glutamyl transpeptidase and found that the 3 infants who ultimately proved to have BA had the lowest values, highly suggestive of a prenatal onset and absence of bile from the fetal gastrointestinal tract.11 Mustaq et al12 have also looked at the levels of various bile acids in Guthrie blood spots using tandem mass spectrometry in newborn infants. Fortyseven (77%) of 61 infants who later proved to have BA had elevated total bile acids (⬎97th percentile, 33 mol/L), with no difference if the blood had been taken at ⬍7 or ⬎10 days. Furthermore, there was no difference in bile acid concentrations between those with BA and neonates with a clear genetic basis for their cholestasis, such as Alagille syndrome (JAG1) or ␣-1-anti trypsin deficiency (SERPINA1). A study from the Texas Children’s Hospital of split bilirubin levels on newborn infants (⬍48 hours old) was recently reported.13 This involved retrospective review of 31 infants who later turned out to have BA but had had their conjugated bilirubin levels measured at 24-48 hours of life. In all, their levels were abnormally high and distinct from controls, jaundiced or otherwise. Such studies can be interpreted as suggesting that cholestasis is already obvious (if looked for) during the first postnatal week, indeed by the evidence of the Texas study the first 48 hours of life, in most infants who later present clinically with isolated BA.
Classification BA is an occlusive panductular cholangiopathy, and thus it affects both intra- and extrahepatic bile ducts. The most common classification, based on that of the Japanese Association of Pediatric surgeons, divides BA into 3 types based on the most proximal level of occlusion of the extrahepatic biliary tree (Figure 2). In the most common, type 3, the intrahepatic bile ducts are grossly abnormal with myriad small ductules coalescing at the porta hepatis. In types 1 and
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177 development (eg, JAG1, HNF-6) and visceral and somatic symmetry (eg, INV, CFC-1), although correlation with the human condition is patchy. A possible genetic link has recently been reported by a French group who found an increased frequency of mutations of the CFC-1 gene (heterozygous transition c.433G⬎A (Ala145Thr) located in exon 5 on Ch 2q21.1).15 Typically in BASM, the extrahepatic biliary remnant is scanty, non-inflamed with a recognizably absent CBD, and the liver may be central and symmetric—whatever the situs.
Clinical and laboratory features
Figure 2
Schematic illustration of biliary atresia classification.
2 where there is a degree of preservation of structure and where there is usually of the intrahepatic bile ducts, there is still blunting, irregularity, and pruning (and absence of dilatation, even when obstructed). There is a second level of category based on status of the distal ducts, and one of these subtypes is worth mentioning. About 20% of all type 3 BAs have a patent common bile duct (CBD) and to all intents and purposes a normal gallbladder (subtype a). The gallbladder actually contains a few milliliters of crystal-clear mucus and will be perceived on the ultrasound (US) scan as “normal.”
The key features of BA are conjugated jaundice persisting beyond 14 days of age, acholic stools, and dark urine in an otherwise healthy term neonate. At birth, there is no difference in gestational age or birth weight between those with developmental compared with isolated BA, but both cohorts then show failure to thrive by the time they are admitted.9 Fat malabsorption is the presumed mechanism for this and will also cause deficiency of the fat-soluble vitamins D, A, E, and, most importantly, K. As a result, some infants will present with a bleeding tendency, even intracranial hemorrhage. The US examination is a key part of the diagnostic protocol, as it usually excludes other possible surgical diagnoses (eg, choledochal malformation, inspissated bile
BASM syndrome Although the association of BA with polysplenia had been recognized for some time, recognition of an etiologic relationship with maternal diabetes (as had been found with sacral agenesis and transposition of the great vessels) only occurred in 1993.4 The constellation of other anomalies is peculiar; absence of the inferior vena cava and a preduodenal portal vein (remnant of the paired vitelline veins) argue for events in the late embryonic period (27-32 days); and situs inversus in about half (Figure 3) suggest a much earlier fundamental event (possibly involving cilia), leaving determination of right/left asymmetry to chance. In this context, it is interesting that a recent study of cholangiocyte cilia showed marked abnormalities of shape and activity but in both syndromic and nonsyndromic BA.14 The common embryologic insult in BASM may simply be timing (30-35 days) rather than a specific genetic defect. There are key genes that are important in both bile duct
Figure 3 Situs inversus. Infant of a diabetic mother who presented with jaundice and was found to have situs inversus, rightsided polysplenia, a preduodenal portal vein, and biliary atresia.
178 syndrome, etc.). All of these are characterized by intrahepatic or CBD dilatation. US may be suggestive of BA as a diagnosis— by showing an atrophic gallbladder, with no evidence of filling between feeds. A more specific but still controversial feature is the so-called “triangular cord sign,” which was first identified by Park et al16 in 1997 and purports to represent the sonographic appearance of the solid proximal biliary remnant in front of the bifurcation of the portal vein. Some authors believe it to be highly accurate and specific for BA,17 others are more sceptical.18 Some infants with CBA will present with an abnormal maternal US scan, typically at around 20 weeks gestation.19 Clinicians need to recognize BA as a possibility for this scenario and facilitate a postnatal US and timely referral. The differential is that of a cystic choledochal malformation, but these also need early effective surgery if obstructed. By comparison, the cystic component in CBA tends to be smaller and may or may not contain bile. Nonvisualization of the gallbladder during the 2nd trimester by contrast is rarely because of BA, and it is either seen in fetuses with multiple anomalies (⬃25%) or they turn out to be normal (⬃75%).20 Liver fibrosis and cirrhosis are time-dependent features, which seem to begin perinatally even in those infants with developmental BA. Makin et al21 described 3 infants who later were confirmed as BA and who had had laparotomies and liver biopsies within the first week of life. All had normal hepatic histology, despite the obvious developmental BA in all. Still, fibrosis and cirrhosis occur relatively early in BA as compared with other neonatal cholestatic diseases, such as Alagille syndrome or ␣-1-antitrypsin deficiency. It is invariable in infants beyond 100 days and should be evident on US as liver heterogeneity, ascites, and splenomegaly. Portal venous pressure can be measured at the time of laparotomy, and it is elevated in half of all infants (even higher in those who are CMV IgM ⫹ve) and correlates reasonably with age at surgery, serum aspartate aminotransferase (AST), and bilirubin levels.22 Perhaps surprisingly, it does not correlate well with measures of outcome, such as clearance of jaundice or need for later transplant. The AST/platelet ratio index can be used as a surrogate of liver fibrosis in many liver diseases, including BA. Our group has recently shown that this correlates significantly with age at surgery and was also much higher in the CMV IgM ⫹ve group (Figure 4). Macroscopic cirrhosis (n ⫽ 22), evident at laparotomy, could also be predicted using a cutoff value of 1.2, with reasonable sensitivity (75%) and specificity (84%) in a large cohort of infants (n ⫽ 260) (unpublished observation). What you do with such information however is moot. Although a Kasai operation can be beneficial even in those with cirrhosis, prediction of benefit is difficult. These are also the infants in whom there is a highest risk of postoperative morbidity, such as wound failure. Primary liver transplantation is an option in some countries and may be one way forward.
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Figure 4 AST/platelet ratio index (APRi) in biliary atresia. Infants with biliary atresia (n ⫽ 260), divided by variant (ie, CMV IgM ⫹ve BA, cystic BA, BASM, and isolated BA). (*P ⬍ 0.05, **P ⬍ 0.01, ***P ⬍ 0.001).
Percutaneous liver biopsy is the usual method of achieving a diagnosis preoperatively, at least in the West, but its interpretation can be difficult. A recent histologic study involved a panel of pathologists reviewing the histologic features that best predicted BA, and these turned out to be bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis. Overall, the positive predictive value of biopsy for BA was 91%.23 Currently, there are 2 methods of achieving cholangiography short of a full laparotomy: endoscopic retrograde cholangiopancreatography (ERCP)24 or laparoscopy.25 ERCP is technically challenging even with the right equipment, but can avoid laparotomy in the larger infants. Laparoscopy and direct puncture of the gallbladder are also relatively straightforward as an access point for a cholangiogram. In some centers, particularly in Asia, simple placement of a nasoduodenal tube and aspiration over 24 hours is the principle method of making the diagnosis. Radio-isotopelabeled hepatobiliary scans are a more sophisticated method of detecting intestinal bile but suffer from relatively poor discrimination in those with severe cholestasis from whatever cause.
Screening for BA Some countries have adopted a population screening program for BA. The most well developed has been that in Taiwan,8 where mothers are issued with color-coded cards and asked to compare it with their infant’s stool. Recognition of pale stool prompts further investigation and referral. This has shortened their time to surgery, with the median age at KP being ⬍50 days, and it is
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Figure 5 Exposure of the liver and porta hepatis at Kasai portoenterostomy.
currently the best achieved anywhere in national terms. The key achievement, I believe, has been the marked reduction in late-presenting infants who have already developed obvious cirrhosis.26
179 using currently available laparoscopic instruments. As stated earlier in the text, radical resection of all extrahepatic biliary remnants from all biliary sectors and a wide portoenterostomy encompassing all the margins of that resection are the key features to maximize results, and it can be a difficult delicate dissection in the open without all the constraints of videosurgery. Patency of the native gallbladder and CBD might tempt one to consider a portocholecystostomy, as it does have the advantage of abolishing postoperative cholangitis. However, the anastomosis is not as flexible as a standard Roux loop, and revisions for repeated biliary obstruction have been described with a poorer long-term outcome compared with a standard Roux loop.29 In some circumstances, the anatomy of the less common type 1 and 2 BAs, typically manifest as CBA, would allow a hepaticojejunostomy to be performed, as there is still a bile duct to join to. However, this is tenuous at best, and although these groups do have a better long-term outcome,6,30,31 it is probably more sensible to dissect it higher and clear the portal plate as in a standard KPE.
Adjuvant therapy for BA Surgery The Kasai portoenterostomy (KPE) operation consists of resecting gallbladder and the extrahepatic biliary tree, leaving a denuded porta hepatis, which is then reconstructed into a long Roux loop. To achieve this, we exteriorize the liver by division of triangular and coronary ligaments (Figure 5). Some divide and extract only the left lobe, whereas others leave the liver in situ but sling the portal pedicles to achieve the necessary porta exposure. Whatever alternative approach is used, meticulous dissection and demonstration of the margins of the porta hepatis is a key maneuver in the open operation. In most descriptions of the radical or extended KPE, the encompassed porta should extend from the “umbilical point” on the left to include an area between the bifurcation of the right portal pedicle. Posteriorly, one should ligate small veins arising from the bifurcation of the portal vein to expose the margins of the caudate lobe (Figure 6). Laparoscopic Kasai operations continue to be reported by minimally invasive enthusiasts (see Yamataka, et al, “Laparoscopic Surgery for Biliary Atresia and Choledochal Cyst,” in this issue), but this has not been taken up by the larger centers performing the standard KPE on a regular basis in either Europe or North America. It has become apparent that laparoscopic Kasai surgery does not offer anything advantageous to the child beyond a better scar and an adhesion-free abdominal cavity for the transplant surgeon. Results are certainly not better and rarely comparable, and major centers, for example China and Germany, have reverted to the standard open approach.27,28 This is likely to be because of the difficulties with portal plate dissection
Although a number of drugs have the potential to improve the outcome of KPE, there has been little published in the way of scientific data to provide credible support for any. Nonetheless, 2 classes of drug deserve exposition.
Corticosteroids Steroids may have an effect in 2 principle ways. There is an undoubted inflammatory element to BA, which may be driven by an immune process susceptible to pharmacologic manipulation. Steroids may limit this inflammatory response. Alternatively, steroids also increase the bile salt independent fraction of bile flow, and their effect may simply be one of choleresis.
Figure 6 Schematic illustration of the porta hepatis. Extended resection of proximal biliary remnants from left (junction of umbilical vein and left portal vein) to right (bifurcation of anterior and posterior branches of right portal vein).
180 Small uncontrolled series have suggested benefit in terms of increased bile flow post KPE,32,33 and postoperative steroids remain popular. However, there is only a single prospective, double-blind, randomized, placebo-controlled trial using a low-dose of prednisolone (2 mg/kg/d) from 2 UK centers.34 This showed a significant increased rate of jaundice clearance (especially in young livers) in the steroid group but did not translate to a reduced need for transplant or improve overall survival. More recent data from our group using a higher dosage regimen (starting at 5 mg/kg/d) have shown the same beneficial effect on postoperative bilirubin levels and now also a significantly higher proportion of those who cleared their jaundice (unpublished observation). Notwithstanding this, a large open-label German trial using a starting dose of 10 mg/kg/d prednisolone for 5 days did not find any evidence of benefit whatsoever.35 This trial was noteworthy in that the jaundice clearance rates were relatively low in both groups (27% after 2 years). Most recently, Sarkhy et al36 performed a systematic review of 16 observational studies (n ⫽ 160) and the 1 randomized controlled trial (n ⫽ 73) and concluded that there was no significant effect on jaundice clearance or need for transplant. There is 1 randomized North American study currently in progress, which has recruited 140 infants (START: http://clinicaltrials.gov NCT 294,684). This at least promises to offer enough statistical power to determine the key question of efficacy.
Ursodeoxycholic acid Ursodeoxycholic acid (UDCA) is hydrophilic bile acid found more commonly (as the name suggests) in bears than in humans. In the latter it makes up about 1%-4% of total bile acids. Exogenous administration has shown biochemical, histologic, and clinical benefit in adults with primary biliary cirrhosis and sclerosing cholangitis in reducing the need for transplant. An early trial from the United States, albeit reported only in abstract form in the 1990s, suggested some clinical and biochemical benefit.37 More recently, a crossover trial has been reported from a French group. In this study, Willot et al38 assessed the effect of UDCA on liver function in children aged ⬎1 year post-KPE in a discontinuation/reintroduction manner. Sixteen children with BA were studied, and all had cleared their jaundice. These were all treated with UDCA (25 mg/kg/d in 3 divided doses) for 18 months at which point treatment was stopped, and their clinical and biochemical status was monitored. Six months later, only one had worsened clinically with recurrence of jaundice; however, all but 2 had sustained significant worsening in liver enzymes. These were all then restarted on UDCA, and 6 months later, all of these had a significant reduction in their liver enzymes. Enrichment of the bile acid pool with exogenous UDCA is believed not only to increase clearance of “toxic” endogenous bile acids whatever that may mean, but it may also have an immunomodulatory effect on mononuclear cells.
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Postoperative complications Ineffectiveness of the KPE and continuation of the natural history of BA is the most common problem leading to end-stage liver disease. Jaundice will worsen accompanied by abdominal distension and ascites with failure to thrive and malnutrition. Such infants require urgent consideration for liver transplantation. There are some specific complications, which can occur independently of this process though.
Cholangitis Restoration of a biliointestinal link predisposes to ascending cholangitis, and it is seen in up to 50% of large series.39 This is much more likely to occur in those with BA compared with those with choledochal malformations, as the latter’s bile flow is better than even the best KPE. The risk is apparent in the first 2 years postsurgery, although the reason for this is obscure, but, presumably, there is some timedependent change in local immunologic defense within the residual cholangioles. Most children will present with pyrexia, worsening jaundice, and a change in liver biochemistry, and they should be treated aggressively with broad-spectrum intravenous antibiotics effective against Gram-negative organisms (eg, gentamicin, meropenem, Tazocin piperacillin/tazobactam]).
Portal hypertension and esophageal varices Portal venous pressure, when measured at KPE, is abnormally high in about 70% of BA infants and is caused by increasing liver fibrosis and correlates with age at KPE, bilirubin level, and US -measured spleen size.22 It, however, is a poor predictor of outcome either in terms of response to KPE or even in those who will develop varices. This confirms the results of a previous study from King’s College Hospital where original liver histology at KPE was graded and compared with variceal formation as assessed endoscopically in 77 children, some 2-4 years later.40 The implication from both is that it is the result of the KPE in terms of clearance of jaundice and more importantly the abbreviation and perhaps attenuation of the hepatic fibrotic process, rather than the early state of the liver, which determines variceal formation. Varices take time to develop, and bleeding is unusual before 9 months of age but usually occurs from 2 to 3 years. Using endoscopic surveillance about 60% of children surviving beyond 2 years will have definite varices and of these about 20%-30% will bleed.41,42 In common with other large centers, we therefore recommend that each child with BA enter a program of endoscopic surveillance to try and preempt variceal bleeding. The key variceal signs that should prompt prophylactic endoscopic treatment are the presence of significant red wales in grade II/III esophageal varices and obvious (usually lesser curve) gastric varices.42 Emergency treatment of bleeding varices specifically includes the use of vasopressin (eg, terlipressin) or somatosta-
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181
tin analogs (eg, octreotide), but sometimes even a Sengstaken-pattern tube has to be used.43 Most varices in BA can be treated endoscopically with banding or in the very young injection sclerotherapy.41 In those with reasonable restoration of liver function, this should be all that is necessary; however, those who are still significantly jaundiced will require transplant assessment. Oral propranolol (1-2 mg/kg/d) may be a role in prophylaxis of bleeding (typically secondary) in some children with cirrhosis caused by BA but again actual published evidence of benefit is unavailable.44
Ascites This is related to portal hypertension in part, but there are other contributory factors include hypoalbuminemia and hyponatremia. It also predisposes to spontaneous bacterial peritonitis. Conventional treatment includes a low salt diet, fluid restriction, and the use of diuretics particularly spironolactone. It is often seen in settings of malnutrition and end-stage liver disease, and a nutritional supplementation is important to try and increase calorie and protein intake.
Prognostic factors A number of factors can be identified as important, although the outcome in individual cases is largely unpredictable.
Age at Kasai portoenterostomy If a bile-obstructed liver is left alone, then delayed surgery will be associated with less good results as the liver ultimately becomes cirrhotic and unsalvageable. This as a factual observation is undeniable; however, the effect is neither simple nor linear and depends crucially on the type and variant of BA. Furthermore, it does seem that even in the developmental forms of BA, detrimental liver fibrosis and inflammation only begin at the time of birth—not before.21 The best way of determining an effect of age in a BA is by so-called age-cohort analysis, and this was first reported by Serinet et al45 using the French national cohort. It requires large numbers to create enough age-groups stratified by single type to allow meaningful statistical analysis. In our series of 225 infants from a single center (2 surgeons), we used such age-defined cohorts and separated them into 3 variants (isolated, BASM, and CBA). Using clearly defined measures of outcome that were rigorous (clearance of jaundice to normal values, and transplantation by 2 years of age), we only observed an obvious age-effect for CBA and BASM. There was barely any discernable effect until about 90 days of age in those with isolated BA.46 There were certainly no cutoffs at 6, 8, or 10 weeks (Figure 7).
Figure 7 Effect of age on outcome. (A) Clearance of jaundice (⬍20 mol/L) and (B) 2-year native liver survival when analyzed by age cohort and cumulatively for infants with isolated biliary atresia (n ⫽ 177). King’s College Hospital series.
Centralization—who should do the Kasai portoenterostomy? Older studies from the United Kingdom confirmed the not very radical concept that the more KPE you do as a center, the better the outcome.47,48 This led to superspecialization of pediatric hepatobiliary surgery in England and Wales to 3 centers for a population of about 53 million. This approach has been adopted by smaller European countries, such as Finland49 and Denmark,50 and there has been an increased awareness of the need to improve collaboration and communication between centers in others (eg, France, United States, Canada).31,51,52
Liver histology and biliary remnant—the anatomical effect There is improved outcome in types 1 and 2 compared with type 3 BA; and CBA compared with noncystic BA.6,45,46 Almost certainly this is because of preservation of some of the connections between the intra- and extrahepatic bile ducts and ductules. Infants with BASM have a worse prog-
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nosis, and typically their remnants are fairly scanty.5 Infants with CMV IgM associated BA do worst of all, although this is because of ongoing immunologic destruction of intrahepatic biliary ductules requires further study. Prospective evaluation of the macroscopic features of the hepatobiliary elements (hardness of the liver, presence of ascites, etc.) has been relatively poorly predictive of outcome with only actual size of resected biliary remnants being really discriminatory.53 Microscopic examination of the transected bile duct remnant will show a varying amount of residual ductules. Older series suggested that only those showing large ductules (⬎300 m) had a distinctly better outcome,54 but the converse is also true—minimal or no ductules in the remnant is predictive of lack of effect of KPE.55 More esoteric immunohistochemical studies of the quantification of various infiltrating cell subsets or quantification of fibrosis need repeating by other groups and in larger studies before they have real clinical meaning.56
Outcome and results It is important to standardize reporting in BA surgery to enable appropriate comparison. There are 3 measures of outcome in the management, which address different elements within the cohort under consideration. These are (1) median age at KPE, (2) percentage clearance of jaundice (to achieve normal values of bilirubin), and (3) actuarial native liver and true survival at 5 and 10 years. The first measure reflects on the effectiveness of primary care practitioners (doctors, health visitors, etc.) in detecting potential cases of
Table 1
BA and the efficiency of the diagnostic process in secondary and tertiary units in coming to timely surgical intervention. The second measure is a reflection on the surgeon and surgery performed in an infant with a retrievable liver. The third is more complex and reflects not only on the success of the KPE but also on the medical management of the postKPE infant; judicious and effective treatment of complications; the availability and then the delivery of a safe liver transplant. Initial reports of results were confined to single, often Japanese, centers but these only up until relatively recently reflected on the “raw” results of the KPE, as transplantation was not readily available. For example, in the original Kasai series from Sendai,57 the 10-year survival rate for the first 63 patients treated from 1953 to 1967 was 10%; for 44 cases from 1968 to 1972, 27%; and for 61 cases from 1973 to 1977, 48%. Of these, about 2⁄3 were jaundice free (⬍20 mol/L). It is worth bearing these figures in mind when surgeons hark back to the “original” Kasai operation—for the time these were exceptional, in comparison with current results they seem outmoded. Therefore, current results, by comparison, have improved greatly with a dramatic improvement in survival particularly (because of transplantation) so that in England and Wales, we would now expect a 10-year survival of ⬃90%.58 Table 1 illustrates current results reported for the past 10 years on the outcome of BA using a combination of KPE and liver transplantation. National data sets or large consortium data sets have been used59 – 62 wherever possible to try and reduce the effect of positive bias reporting by individual centers.
National and consortium outcome statistics in biliary atresia (1985-2010)
Series
Country
North America †Schneider et al, 200659 USA‡ Schreiber et al, 200752 Canada §Superina et al31 USA‡ Europe Serinet et al, 200651 France Wildhaber et al, 200860 Switzerland Davenport et al, 201158 England and Wales De Vries et al, 201261 Netherlands Asia Nio et al, 200362 Japan Hsiao et al, 20088
Taiwan
N
Median or mean time to KPE Period
Native liver survival (%) Clearance of jaundice* 4/5 year
Overall survival (%)
10 year 4/5 year
104 61 349 55 136 64
1997-2000 ⬃40% 1985-1995 n/a 2004-2010 46%
56 (2 year) 35 40-47 (2 years)
86 (2 year) 74 n/a
271 57 48 68 443 54
1997-2002 40% 1994-2004 n/a 1999-2009 55%
35 37 46
87 92 90
104 59
1998-2008
42
108 65⫹ 129 65⫹ 75 55
1989-1999 62% 1994 n/a 2004-2005 59%**
38%
62 53
40
10 year
89
76 53
69 78
*Defined as achieving a level of ⬍20 mol/L (or 1.5 mg/dL). † USA–(Biliary atresia research consortium–9 centers). ‡ Defined as achieving a level of ⬍20 mol/L (or ⬍2 mg/dL). § USA–(Biliary atresia research consortium–16 centers)—somewhat selected as only those outside trial reported (47% of original series). **⬍2 mg/dL.
66
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Some observations are pertinent from analysis of this table. Socialized health systems or countries where active screening programs exist have the lowest median age at KPE. Surgeons with greater experience and throughput tend to have a better initial clearance of jaundice rates and anything above 50% should be the benchmark. Similarly, an overall survival rate of about 90% is also attainable in most countries with access to quality transplant programs freely available to all those in need. Still, deaths on waiting lists occur but are definitely preventable, given improvements in the donor organ pool and early recognition of the need for transplant. In conclusion, although the actual cause of BA remains far from clear, a complementary system of surgical treatment has evolved during the past 35 years, which has improved the overall survival to adulthood in affected infants from a dismal 10% to about 90%. Not many surgical diseases can claim such a change in outlook. The future will see improvements in understanding the basis for this enigmatic disease, but it is noteworthy that all currently successful treatments have been surgical and of these only liver replacement is actually curative. Effective pharmacologic methods to control the early onset of liver fibrosis—a characteristic feature of BA—are sorely needed to really alter the natural history of the disease.63 An alternative strategy has been suggested by Sharma et al64 from India who infused autologous (bone marrow derived) stem cells at the time of KPE and observed some improvements in liver biochemistry and survival, although their infants were very late presenters by Western standards. Without such advances then those who have no response to KPE and the most pressing need for liver transplantation during infancy will remain at severe risk.
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