1. Introduction

2. Clinical scenarios and timelines

3. Kasai portoenterostomy

4. Post-operative management

5. Adjuvant pharmacological

therapy

6. Maximization of good

outcome

7. Expert opinion

Review

Improving treatment outcomes inpatents with biliary atresiaRakesh Kumar Thakur & Mark Davenport†

†King’ s College Hospital, Department of Paediatric Surgery, London, UK

Introduction: Biliary atresia (BA) remains one of the most challenging

conditions in pediatric hepatology and surgery. The main therapeutic

approach is entirely surgical with an initial attempt to restore bile flow and

preserve the native liver using a Kasai portoenterostomy (KPE). Liver

transplantation is usually offered if this fails and it remains the biggest single

indication during childhood.

Areas covered: The role of adjuvant medical therapy is still unclear and

conclusive evidence of benefit is lacking. The review covers the current evi-

dential basis for corticosteroids, prophylactic antibiotics, and choleretic

agents such as ursodeoxycholic acid.

Expert opinion: There are obvious areas for improving outcome in BA such as

diminishing the time to KPE and concentration of resources to achieve a

throughput of > 5 cases/year. High-dose steroids can improve the proportion

of infants who clear their jaundice to normal levels by about 10 -- 15%. It is

not clear whether such improvements can be translated into a reduction in

the number of transplants required however.

Keywords: biliary atresia, cholangitis, kasai, liver transplant, portoenterostomy, steroids,

ursodeoxycholic acid

Expert Opinion on Orphan Drugs [Early Online]

1. Introduction

Biliary atresia (BA) is a condition peculiar to the newborn period and characterizedby an abnormal extrahepatic biliary tree with parts missing or atretic. The level ofmost proximal obstruction defines the type with the commonest, type 3 being atthe level of the porta hepatis. The other two less commonly seen types are definedas an obstruction in the common hepatic (type 2) and common bile ducts(type 1) respectively. The other facet, unappreciated by the surgeon is the abnormalcharacter of the intrahepatic bile ducts as well. In some, there is preservation of a‘tree-like’ structure, whereas in others there is only a network of fine, interconnect-ing, ductules emanating from the porta hepatis.

Early surgical attempts were made to identify proximal bile-containing structuresand restore intestinal bile drainage. These were only ever successful in the less com-mon types 1 and 2 and foundered when confronted by an apparently solid proximalbiliary remnant. The term ‘uncorrectable’ being applied to the latter scenario.

The 1960s became the key decade for true advances in the treatment of BAalthough it took a few more decades before its effects became truly realized. Justbefore the start of this decade, Morio Kasai had published his first report on the sur-gical treatment of BA in the Japanese surgical journal ‘Shujitsu’ in 1959 [1]. He rec-ognized that the apparently solid proximal biliary remnant actually contained amyriad of microscopic biliary channels, which still retained a communicationwith the intrahepatic bile duct system. Thus, if enough of these could be exposedin the porta hepatis and thereby drained into a Roux loop, then sufficient bileflow could be restored and jaundice recede. Then in 1963 Thomas Starzl, workingin Denver, Colorado, published the results from the first three liver transplants ever

10.1517/21678707.2014.973402 © 2014 Informa UK, Ltd. e-ISSN 2167-8707 1All rights reserved: reproduction in whole or in part not permitted

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performed [2]. The first ever was a girl who had been bornwith BA and was dying on a ventilator of end-stage liver dis-ease. Starzl and his team obtained a donor liver and undertookthe operation in March 1963. Unfortunately because of cata-strophic bleeding she did not survive. However the next twoadults did survive the surgery but not the subsequent acuterejection process. Still in those 4 years the cornerstones ofthe modern management of BA had been laid.Before going much farther it is important to try and detail

what causes BA. This is not straightforward and currentthinking suggests that the term covers a number of indepen-dent conditions with different causations, the only commonthing being the appearance at the end -- so-called aetiologicalheterogeneity. We can define several variants by their clinicalcharacteristics.(i) Syndromic BA -- characterized by other anomalies with

the vast majority having an unusual combination of anomaliessuch as splenic anomalies, situs inversus, vascular anomalies(absence of the inferior vena cava and a preduodenal portalvein), and so on [3,4].(ii) Cystic BA -- characterized by cystic dilatation of the

common bile duct in association within an atretic biliarytree [5].(iii) Isolated BA - whatever is left after exclusion of (i), (ii),

and (iv).(iv) CMV IgM +ve BA -- characterized by the presence of

anti-CMV (cytomegalovirus) IgM antibodies suggestingneonatal exposure.The order in which we list these variants also suggests the

onset of the occlusive pathology. Thus it is axiomatic thatthe cause of (i) is a failure of early, first trimester bile ductdevelopment, and specifically affecting extrahepatic bile ductdevelopment. Cases of cystic BA (ii) can actually be detectedby the second trimester on antenatal ultrasound and some ofthem have a relatively intact intrahepatic tree-like structuresuggesting onset after 12 weeks gestation. Both (i) and (ii),because they must be evident at the time of birth, can bedefinitively labeled as developmental BA. By contrast, it isimplied that there is normal development of the bile ducts

in (iv) and then secondary damage initiated either directlyor indirectly by a virus (in this case CMV). The animal mod-els which exist for BA show atretic-like bile duct pathologyinduced by perinatal viral exposure [6].

The largest group remains (iii) isolated BA and accounts forabout 70 -- 80% of all cases in the West for which no obviouscause is evident.

2. Clinical scenarios and timelines

A small proportion of those with developmental BA will pres-ent early because of an abnormal maternal ultrasound scan(US) or the effects of another anomaly (e.g., malrotation).The remainder will have persisting conjugated jaundice, andas a consequence of a lack of bile in the intestine, pale stools,and dark urine. Progressive biliary obstruction leads todamaging liver fibrosis and cirrhosis though these take time(usually months) to develop, so most cases are otherwise nor-mal and thriving infants. Those that do present later may havehepatosplenomegaly, ascites, prominent abdominal wall veins,and obvious malnutrition. About 2 -- 3% will present with theeffects of Vitamin K-deficient coagulopathy and clinicallyabnormal bleeding. In some this may be as catastrophic asan intracerebral bleed.

Jaundice in the newborn is common, unconjugated, andphysiological, and therein lies the problem of diagnosis. It isregarded as a benign sign to be watched and it will slowly van-ish within a few weeks. Statistically this is the usual scenariofor the vast majority of infants with jaundice but for thoseunfortunate few it can mean the ticking away of the opportu-nity of effective surgical correction. So, how to pick out thosewhere BA may be the underlying cause? The red flags areposed by questions asking of the color of the infant’s stooland urine. The absence of pigmentation and pale stools man-dates further investigation with the key biochemical test beingthe split bilirubin, which should show that this is a conjugatedtype of jaundice.

Professional bodies in the UK and elsewhere emphasize theneed for further investigation when jaundice persists beyond2 weeks of life, though this is frequently ignored in clinicalpractice. The median time at Kasai portoenterostomy (KPE)in England and Wales is about 55 days (i.e., 7 -- 8 weeks),which illustrates just how little this exhortation has had inreal life.

The diagnostic process depends upon exclusion of a varietyof medical causes of conjugated jaundice such as Alagille’ssyndrome, a-1-anti trypsin deficiency, parenteral-nutritionassociated cholestasis, and so on, before considering a surgicalcause. Expert ultrasonography should show the dilated bileducts of other surgical causes such as choledochal malforma-tion and inspissated bile syndrome, whereas in BA it canshow the suggestive image of an atrophic empty gallbladderor in ~20% of cases a normal appearing gallbladder. Invari-ably, if it does turn out to be BA, this appearance is due tothe gallbladder containing mucus rather than bile.

Article highlights.

. Biliary atresia has an incidence of 1 in 17,000 live-birthsin the UK resulting in about 50 infants with conditioneach year.

. It remains the commonest single cause for livertransplantation in Europe and North America.

. Aetiology is not known and it is likely that a number offactors may be responsible rather than one singleexplanation for all.

. Centralization of surgical resources has improvedoutcome.

. Surgical results can be improved by the use of high-dosesteroids following Kasai portoenterostomy.

This box summarizes key points contained in the article.

R. K. Thakur & M. Davenport

2 Expert Opinion on Orphan Drugs (2014) 2 (12)

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The triangular cord sign appears as a triangular or conicalechogenic density representing a fibrous remnant of the extra-hepatic bile duct at the porta hepatis seen just in front of theportal bifurcation. A Japanese study [7] combined it with otherultrasound findings and reported a positive predictive value of98% and a negative predictive value of 100%. However, otherstudies have found it less sensitive and non-specific. Thus, themulticenter study reported by Shneider et al. [8] could notidentify it in any of their 104 infants with BA. Thus, unfortu-nately its usefulness needs to be principally determined by theoperator in each individual centre.

There are no specific blood investigations which confirm adiagnosis of BA: liver enzymes (e.g., aspartate aminotransfer-ase) will be raised (usually modestly), g-glutamyl transferase(GGT) will be raised (but can be normal), and usually albu-min and protein levels are normal. Further diagnostic testsinclude a percutaneous liver biopsy or dynamic radioisotopeimaging typically using technetium-labeled iminodiaceticacid derivatives. The former test has certainly been the main-stay in the centralized high-volume UK centers to try andarrive at the correct pre-operative diagnosis. For larger infantswith borderline-diagnostic biopsies ERCP may avoid the needfor exploratory surgery. Its chief value is to show the chol-angiogram in those without BA. In many places, early laparot-omy together with cholangiography remains the ultimatediagnostic test.

Evaluation of the fitness of the infant to undergo KPE isimportant. There will be a small proportion of infants whopresent late (arbitrarily beyond 90 -- 100 days) where thereare already established features of cirrhosis. This can beappreciated on (US) as a ‘heterogeneous’ appearance to theliver and ascites, and biochemically as a raised (> 2.0) aspar-tate-amniotransferase-to-platelet ratio (APRi) [9]. For somein this group primary liver transplantation (if available) maywell be the best solution though simple age at surgery shouldnot exclude an attempt at native liver salvage [10].

3. Kasai portoenterostomy

The aim of KPE is to restore bile flow while preserving thenative liver. Most surgeons have adopted a wide, radical dis-section of the portal plate extending from the ‘umbilicalpoint’ (umbilical vein joins left portal vein) on the left tothe bifurcation of the vascular pedicle on the right. The biliaryremnant is then excised flush with the liver capsule and inmost there is an obvious plane of dissection. Having maxi-mized the denuded portal plate then this is anastomosed toa Roux loop measuring about 40 cm, which seems to offerthe lowest rates of post-operative cholangitis.

It is not an operation for the novice and in many placesindividual experience and familiarity will be limited. Earlyaudits of outcome from the UK suggested that surgeons’ expe-rience had a measurable effect and suggested that ‡ 5 KPE/year really should be the aim in centers [11].

Minimally invasive surgery has had a major impact in manyspecialties and this approach has been tried in relation toKPE. A laparoscopic KPE showing its feasibility was firstreported in 2002 by Esteves et al. [12], and small case seriesemerged gradually thereafter technique [13,14]. Stated advan-tages of laparoscopic KPE were reduced surgical trauma, fasterpost-operative recovery, the potential for fewer adhesions, anda better cosmetic appearance. It was also stated that thetechnology offered improved magnified vision and bettervisualization of portal structures [15].

However, in practice the outcome and results of laparo-scopic KPE have been mixed with few surgeons reportinggood results [13,15,16]. Some centers for instance, in Hannoverand Hong Kong, compared their own experience with theopen alternative and have found the laparoscopic KPE to bedemonstrably worse and reverted to the open approach[15,17,18].

The actual reasons for inferior results may be related to theunforgiving learning curve associated with complex surgery;the inordinate use of diathermy instead of sharp dissectionfor division of the portal vein tributaries and hemostasis andeven the deleterious effects of prolonged CO2 pneumoperito-nium [18-20].

3.1 Benchmarks of outcomeTable 1 illustrates recent reported national and quasi-nationalseries from around the world concentrating on comparablemeasures of outcome. The earliest definable outcome is sim-ple, clearance of jaundice, though the actual level of bilirubinattained should be quoted. In Europe this has become strin-gent, achieving a level consistent with the normal upper limitof 20 µmol/L, whereas in North America this is a little higherat 1.5 mg/dL (» 35 µmol/L). The second key outcomemeasure is what happens in the medium term and brings inthe concept of native liver survival, again best illustrated byKaplan--Meier curves. For most countries with relativelystraightforward access to effective safe liver transplantprograms, then this denotes the effectiveness not only ofsurgery, but effective treatment of the complications (poornutrition, bleeding varices, cholangitis, etc.). Clearance ofjaundice ranges from 40 to 60% with median 5-year nativeliver survival reported from 30 to 60%. Overall survivalshould approximate to 85 -- 90% at 5 years.

4. Post-operative management

4.1 NutritionInfants with BA will have a diminished oral intake and mayshow early satiety due to organomegaly and ascites. Lack ofbile in the intestine leads to malabsorption of fat and fat-soluble vitamins. There is also increased energy requirementsdue to the hypermetabolic state associated with end-stage liverdisease [21-23].

Maintenance of good nutrition and restoration of growthare vital to the post-operative outcome. It is even more

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important in infants who have failed to clear their jaundiceand are heading down the transplant pathway. Demonstrableimprovements in nutritional status can be related to bettertransplant outcomes [24-26]. Malnutrition is one of the param-eters used in calculation of the Paediatric End-Stage LiverDisease score used in the USA to prioritize children for livertransplantation [27].Growth failure, defined as height or weight < 2 standard

deviations, is a major risk factor for poor outcome and arecent report from the BA Research Consortium identifiedthis as a key measure of outcome associated with transplanta-tion or death by 24 months of age [28]. Similarly, Studies inPaediatric Liver Transplantation looked at 775 children withBA awaiting transplantation and again identified growth fail-ure as an independent risk factor for pre-and post-transplantmortality and graft failure [25].So, how to achieve better nutrition? This may simply be in

adopting a more reliable mode of calorie delivery, soChin et al. and Holt et al. achieved higher growth rates withsupplemental feedings via a naso-gastric tube [29-31]. Overallcalorie prescription should aim for 110 -- 160% of normalcaloric intake and may need to consist of semi-elemental for-mula, medium chain triglycerides (MCT) (by up to 60% offat provided) and maybe supplements of branched chainamino acids. In infants our standard prescribed formula feedhas included Heparon� Junior and Caprilon� (higherproportion of MCT) (UK manufacturer, SHS international)providing ~ 120 -- 150 kcal/kg/day. In some children whereNG feeding is not being tolerated then short-term parenteralnutrition should be considered and can improve the nutri-tional status of children on the waiting list [21].Aggressive correction of vitamin (D, A, K, and E) and

mineral deficiencies may forestall complications rickets, path-ological bone fractures, coagulopathy, spontaneous bleeding,even cerebellar ataxia and impaired vision. There should be

routine supplementation of fat soluble vitamins and is partic-ularly important in those failing to clear their jaundice [32,33].

Neurocognitive function may also be affected in childrenwith BA and there this is directly proportional to the severityand duration of illness and malnutrition. In one Americanstudy of 51 children, neurocognitive function was seen to besignificantly deficient in 10 -- 15, 26% had learning disabil-ities, and almost 40% had special educational needs [34].Such detailed studies have not been done in the UK to thesame degree and such worrying outcomes do not appear tobe replicated in our long-term survivors [35].

5. Adjuvant pharmacological therapy

A number of adjuvant therapies have been suggested to tryand improve the bile flow post KPE. Most have a long historyof initially empirical use with later attempts at evidence-basedcomparison rather than expert assertion. Still because of thesmall numbers and rarity of BA in the population little canbe absolutely relied upon as fact.

The commonest drugs will be discussed, and evidencepresented.

5.1 CorticosteroidsInflammation can be an element within the pathological pro-cess causing BA [36,37]. This is apparent histologically withabnormal infiltrate of activated mononuclear cells (principallyTh1 and Th17 cells) in response to abnormal expression ofHLA Class II antigens, intercellular adhesion molecule(ICAM), vascular adhesion molecule (VCAM), and E-selectins on biliary and vascular epithelium [38].The inflam-matory process is also apparent in blood with abnormal levelsof adhesion molecules such as sICAM and sVCAM, and cyto-kines such as TNF-a, IL-2, IL-12 and extends for at least

Table 1. Recent national (and quasi-national) experience from Europe and North America with biliary atresia.

Series Period

Country

n Age at Kasai

portoenterostomy

in days (median)

Clearance of

jaundice*

Native liver

survival

Schreiber et al. [90] 1985 -- 2002Canada

349 55 n/a 36%(4 years)

Schneider et al. (2006) [8]z 1997 -- 2000USA

104 61 40% 56%(2 years)

Serinet et al. (2006) [94] 1997 -- 2002France

271 57 40% 35%(5 years)

Davenport et al. (2011) [86] 1999 -- 2009UK

443 54 55% 46 %(5 years)

Chardot et al. (2013) [89] 1986 -- 2009France

1044 59 38% 40%(5 years)

Superina et al. (2011) [95]z 2004 -- 2010USA

136 64 46% 47%(2 years)

*Achieving a level of < 20 µmol/L (or 1.5 mg/dL).zNon-national consortium experience (USA): BARC (Biliary Atresia Research Consortium)/ChiLDREN (Childhood Liver Disease Research and Education Network).

R. K. Thakur & M. Davenport

4 Expert Opinion on Orphan Drugs (2014) 2 (12)

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6 months post-operatively before subsiding at least in thosewhere the jaundice has cleared [39].

Steroids have been used on the assumption that they can bean anti-inflammatory and immunomodulatory thereby reduc-ing hepatic damage and subsequent fibrosis [40]. It should notbe forgotten that steroid also have a measurable cholereticeffect and this may be of equal importance. This actionappears to be by induction of Na+ K+ ATPase which increasescanalicular transport [41,42].

Empirical use of steroids dates back to early Japanese seriesbut at least in the West was first advocated by John Lilly fromDenver in the form of a short-term (or blast) therapy to tryand improve bile flow in recalcitrant cholangitis or in casesof sudden cessation or reduction of bile flow in cases wherebile flow has been established before [43]. Intravenousmethyl-prednisolone was given with an initial dose of10 mg/kg and then tapered over 4 -- 7 days. Small seriesfrom the USA were then published advocating its use as partof a routine protocol. These included series from Hershey,PA, and Salt Lake City, Utah [44,45].

The first randomized, placebo-controlled trial was reportedin 2007 from Leeds and London using an admittedly low-dose 6-week prednisone regimen starting at 2 mg/kg/day in73 infants. This showed that there was a statistically signifi-cant reduction in early (1 month) bilirubin levels most obvi-ous in those < 70 days post KPE but this did not translateto reduction in the need for transplantation [46]. A follow-upstudy was reported more recently from the London group,which added a high-dose prednisone cohort (starting at5 mg/kg/day) [47]. This showed the same beneficial biochem-ical effects (now including a reduction in aspartate amino-transferase and APRi levels) with an increased proportion ofthose who cleared their jaundice in the steroid groups (67%[41/62] vs 52%(47/91); p = 0.04).

The only comparable study involving a placebo elementwas reported last year -- the START Trial [48]. They random-ized 70 infants to a steroid arm using initially IV methylpred-nisolone 4 mg/kg/day for first 3 days followed by oralprednisolone (4 mg/kg/day till 2nd wk, 2 mg/kg � 2 wk, fol-lowed by a tapering protocol over the next 9 week period).Although there was a difference in the main primary endpoint(clearance of jaundice) from 48.6% in the placebo group to58.6% in the steroid group this did not attain statistical signif-icance. As the median time to KPE was relatively high in thisstudy, they also did a sub-group analysis of infants < 70 daysat KPE (n = 76). This showed that 72% (28/39) in the steroidgroup cleared their jaundice compared to 57% (21/37) in theplacebo group, still not statistically different (p = 0. 36), butnoticeably the same magnitude as was found in the UK study.There is therefore a clear possibility of a type 2 error (i.e.,accepting the null hypothesis when there actually is atrue difference).

Prednisolone is the most frequently prescribed steroid inmost studies [43,46,48-55] with a usual starting dose of 4 or5 mg/kg/day. Some protocols begin this with intravenous

methyl prednisolone [45,48] although there is little evidenceto suggest this has any extra effect. The Japanese BA grouppublished a randomized trial of 4 versus 2 mg/kg/day oralprednisolone [53]. Sixty-nine infants were included and attwo post-operative time-points bilirubin levels were lower inthe high dose group (< 70 days old at surgery) though otherliver function was comparable. Dexamethasone has also beenrecommended by one UK centre beginning oral dexametha-sone (0.3, 0.2, and 0.1 mg/kg twice daily for 5 days), begin-ning on postoperative day 5 [56].

There are potential side effects of steroids though none hasactually been reported in the papers presented so far. Howeverpossible side effects include increased risk of infection, poorwound healing, hyperglycemia, hypertension, gastrointestinalbleeding, poor growth, and an inadequate response to routineimmunizations [47].

A systematic analysis was reported by Sarkhy et al. in2011 concluding that there was no significant benefit of ste-roid use although given the real lack of anything other thansmall case series it is difficult to believe whether this has anymore validity [57].

There has been one significant publication since this review,which was a large non-randomized cohort study from Shang-hai, China [58]. This compared the outcome of low- andhigh-dose steroids in two consecutive periods 2004 -- 06 and2007 -- 09. In the high-dose group, intravenous prednisolone(4 mg/kg/day tapering to 2 mg/kg over 9 days) was started1 week after surgery, followed by 8 -- 12 weeks of oral prednis-olone (starting at 4 mg/kg on alternate days) at day and thengradually tapered until patients became jaundice-free. Chil-dren in the low-dose steroid group received 4 mg/kg/d initiallytapered to 2 mg/kg/d over 1 -- 2 weeks. During the study380 (n = 253 in high dose group) infants underwent theKPE. There was a significant difference in mean age at KPE(74 vs 66 days; p = 0.03). Nonetheless there was a significantdifference in the proportion to clear their jaundice (39 vs53%; p = 0.007) and a difference in the proportion of thosewith cholangitis in the first year (48 vs 32%).

Despite the lack of research evidence many centers con-tinue to use steroids in a variety of regimens. It is particularlyhigh in Japan with >90% of the institutions using some formsteroids after KPE. Its use in the USA is a little more restrictedbut still 46% of the infants were being prescribed steroids inone survey [59]. All three of the English specialist centers usea variety of post-KPE steroid regimens.

5.2 Antibiotics for prevention or treatment of

cholangitisCholangitis is a common life-threatening complication fol-lowing KPE. The incidence is the highest in the first 2 yearsfollowing operation [60-62] and the usual organisms are theenteric bacteria Klebsiella spp., Escherichia coli, Pseudomonasaeruginosa, Escherichia cloacae, Acinetobacter baumani, Strepto-coccus mitis, and Salmonella typhi [63-65]. The mechanism is

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most likely to be an ascending cholangitis via the Roux loopinto the intrahepatic duct system, primitive and distortedthough it is.Other contributory mechanisms may also be involved

including bacterial overgrowth of bacteria in the gut, translo-cation from lymphatics and hematogenous spread via the por-tal vein. However there is little real evidence to show thesehave real clinical importance [60,62,65]. What is clear is thatin that proportion who do not drain any bile following KPEdo not risk cholangitis, whatever other problems they have.The incidence ranges in surgical series between 40 and 93%[60,65-68].In early 1980s, second-generation cephalosporins with or

without aminoglycosides were used, and but nowadaysthird-generation cephalosporins are preferred. They are ableto attain therapeutic levels in bile by passive secretion withthe benefit of one or twice daily administration, which issuitable for home therapy. There is some evidence to suggestsynergistic action of third-generation cephalosporin withaminoglycosides [65,67,68].Many protocols also advocate long-term prophylactic anti-

biotic use to reduce the incidence of cholangitis [64,65,69]

though again the evidence is thin. Bu et al. reported a prospec-tive randomized study of 19 children who had had at least oneprevious episode of cholangitis to evaluate the efficacy of tri-methoprim/sulphamethoxole or neomycin as oral prophylac-tic agents to prevent cholangitis. Though there was nodifference between the two treated groups they did have alower frequency of cholangitis and a higher survival rate com-pared to historical controls [64]. Some centers are more aggres-sive in their use of antibiotic and use long-term indwellingcatheters for prolongation of an IV course [66]. Again actualevidence of benefit is lacking.Native liver survival decreases markedly if there are

repeated episodes of cholangitis especially within the first2 years of surgery. In one recent study of 76 infants,Koga et al. showed that liver transplantation was required byall jaundice-free children who had had cholangitis within3 months of the KPE [70].Cholangitiis occurring after some years of sepsis-free life in

children who have cleared their jaundice should make onesuspicious of an actual mechanical problem with Roux loopdrainage [62,67]. Following acute antibiotic therapy then thesechildren should be fully investigated with radionuclide imag-ing, ultrasound and MRCP (to look for intrahepatic cyst for-mation as an alternative explanation) and balloon enteroscopy(if available). Proximal Roux loop dilatation is the key diag-nostic feature and if there is sufficient evidence of this thenlaparotomy should be embarked upon [62].A number of modifications to the Roux loop have been

suggested as reducing the risk of cholangitis. Thus, bringingthe Roux loop out as a stoma, or creation of a ‘valve’ in theloop by intussuscepting mucosa have all at one time beenadvocated [71-73] though none have really stood the test oftime [61,65,74]. Other variants have been used in small series,

for instance, the appendix can be used as a conduit to the duo-denum, though with no great advantage and poor long-termresults [75]. One technique which does significantly reducecholangitis is avoiding a Roux loop altogether and drainingthe denuded portal plate into the opened out native gallblad-der as a portocholecystostomy [76]. This has been a particularfavorite of the French group in Bictre, Paris, and is anatomi-cally possible in about 10 -- 20% of KPE where the gallblad-der is a mucocele and the common bile duct is patent. Thesubsequent cholangitis rate approaches zero, but the revisionrate is higher as the drainage is more tenuous (personalcommunication).

Finally, it is known that the treatment of cholangitis is aparticularly expensive part of overall care of these children.One study from North American estimated that each episodeof cholangitis leads to an expenditure of nearly $10,000 [66].

5.3 Ursodeoxycholic acidThe use of ursodeoxycholic acid (UDCA) in the treatment ofliver diseases dates back to the traditional Chinese medicineduring the Tang Dynasty. For centuries, the Chinese drug‘shorea spp. ’, derived from the bile of adult black bears, hasbeen used to cure various hepatobiliary disorders. In 1927,Shoda, from Okayama University, Japan, isolated UDCAfrom bear bile imported from China and named it UDCA(urso being Latin for bear).

UDCA is a hydrophilic bile acid that has been used in adultcholestatic diseases such as primary biliary cirrhosis and pri-mary sclerosing cholangitis with evidence of benefit for severalyears. It has also been used in the dissolution of cholesterolgallstones in adult populations. It certainly increases cholere-sis, and in some way appears protective of chloangiocytesand hepatocytes. It may also have immunomodulatory func-tions and can change expression of HLA-1 antigen expressionon cell surfaces and suppress the production of immunoglob-ulin [77,78].

A crossover trial in stable children with treated BA has beenreported from a French group using UDCA. Thus, Willotet al. [79] assessed the effect of UDCA (25 mg/kg/day TDS)on liver function in children > 1 year post-KPE in a discontin-uation/re-introduction fashion. Sixteen children with BA werestudied and all had cleared their jaundice. Six months afterstopping UDCA one had worsened clinically with recurrenceof jaundice and all but two had significant worsening of theirliver enzymes. On restart their biochemistry improved. Incontrast, a large retrospective study from Egypt looked at acohort of 141 infants of which 108 had received UDCAand suggested that this group had had a worse outcome [80].However, this may just reflect poor results -- only 19 (13%)infants overall cleared their jaundice.

5.4 Chinese herbsBA is characterized by relatively early-onset aggressive hepaticfibrosis which leads ultimately to cirrhosis. This may lead lateron to clinically significant portal hypertension, the

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development of varices, and less commonly ascites. Modula-tion or even abbreviation of this pathological process wouldhave immense benefit but so far seems elusive.

Both Japanese and Chinese centers routinely prescribe theChinese herb ‘Inchinko-to’ to infants post KPE and one ofthe claimed benefits includes inhibition of apoptosis and inhi-bition of liver fibrosis [81,82]. For instance, Tamura et al. [82]

reported a prospective study of 21 children post-KPE whohad cleared their jaundice but who had persistent elevatedliver enzymes and GGT. Inchinko-to was given to 12 for upto 3 years whereas the remainder persisted in their standardregimen without any herb. Liver enzymes, bile acids, andmarkers of liver fibrosis were measured sequentially. Therewere no side effects of treatment. In the Inchinko-to group,markers of liver fibrosis (e.g., hylauronic acid) were signifi-cantly decreased at 1 and 3 years without change in liverenzymes, bile acids, or bilirubin [82].

5.5 MiscellaneousPhenobarbitone and its derivatives have a long history ofempirical use in pediatric hepatology and have been withinour Kings College Hospital protocol since the 1970s (pre-scribed as phenobarbitone 15 mg o.d. increasing to 45mg insteps of 15 mg/week). Similarly the bile acid sequestrant, cho-lestyramine (1 sachet t.d.s.) is also part of our protocol, againempirically without any real evidence of benefit. Its use prob-ably started following publication of a randomized Frenchtrial of 80 infants post-KPE looking at both agents individu-ally together with a comparative control group [83]. Ironically,no significant differences were identified.

6. Maximization of good outcome

Much remains in the management of BA where improve-ments in outcome can be made. Certainly the KPE is a palli-ative operation, which allows about 50% of infants to cleartheir jaundice if done by experienced surgeons in infants pre-senting within a reasonable period from birth. This bench-mark should always be dissected from surgical series as it isthe one measure of outcome that closely reflects the surgicaltechnique. If much lower rates of clearance are seen then nomatter what is given pharmacologically nothing will change.This usually implies some form of centralization where thehealth system can dictate such an arrangement (e.g., England& Wales, Netherlands, Finland, Denmark). This originallystarted in England and Wales where the Department ofHealth took note of two outcome studies [11,84] published inthe 1980s and 1990s, which showed unequivocally that thosetreated in large centers had better outcomes. Thus from Janu-ary 1999, all infants suspected of BA had to be referred to oneof only three centers. The initial short-term [85] and medium-term [86] results following this policy change showed that goodoutcomes were being achieved nationally. This improvementin national outcome has also been shown in other Europeancenters such as Denmark [87] and Finland [88]. Conversely

those countries such as France, which failed to centralizeshow no improvement over time [89]. In other countries theremay well be significant geographical constraints to such a pol-icy (e.g., Canada [90]). Still the days of isolated surgeons doingone or two KPE a year should be past.

7. Expert opinion

Although the main buttresses to a successful management

program for BA remain surgical -- the KPE and a safe timelytransplant if necessary -- there is so much more that could

be done to facilitate the process rendering it safer and moreeffective. These can be broken down into two main themes:i) organizational and ii) adjuvant pharmacology. First it is

important to realize that the management of the individualis not just down to a single individual working in isolation

whether that be the child’s personal physician, the hepatolo-gist, the surgeon, or the transplant surgeon. There are manypossible outcomes and complications in this disease that strat-

egies have to cover a multitude of specialties. Only an effectivemultidisciplinary team working together will ensure that child

has the best possible outcome. The entire process frompresentation has to be complementary and seamless [85].That is, initial diagnosis should not be delayed because of

lazy thinking or management by the child’s doctor or healthvisitor. “It can’t possibly be BA -- it’s so rare, I’ve never seensuch a condition…” or “ we will see you in 2 weeks to see if

it fades, just let your baby see lots of sunshine…”, “it willbe the breast milk…”. Once recognized as a possibility the

pediatrician shouldn’t have to read textbooks and workthrough a list of possible alternative diagnoses -- ordering testsone by one…in succession. The surgeon (and team) should be

entirely familiar and conversant with the KPE -- and really notcoerced by peer pressure or hospital management to under-

take what might be an operation in foreign territory -- theporta hepatis is not the normal working place for 99% ofpediatric surgeons. If the KPE is not working, and this is evi-

dent within 2 months, then it never will. Move on and expe-dite the move to the transplant pathway. Waiting lists are

long, and hazardous to help. Children will continue to diepredictably on waiting lists of unresolved end-stage liverdisease. Organ donor shortage had not been solved in any

major country.So where can adjuvant therapy help? Predictable augmenta-

tion of bile flow following KPE would be a major advance.The literature is still ambivalent on high-dose steroids buttoo much reliance should not be given to an underpoweredNorth American trial designed to detect a 25% improvementin primary outcome [48]. That is a huge leap of faith and if ste-roids were that effective we would not need a trial! High-doseprednisolone (or dexamethasone) improves outcome by10 -- 15% and probably only in those who have had a suffi-ciently good KPE done by an experienced surgical team inthe first place [47,56,58]. I believe strongly that there is enough

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evidence of benefit of high-dose steroids that this should beroutinely prescribed in those infants, young enough to beable to benefit (arbitrarily < 70 days). Much older infantswill invariably have significant fibrosis and cirrhosis and betoo far gone for effect. Furthermore, those livers already badlydamaged by chronic inflammation and fibrosis will be too fargone for effective adjuvant remedy. But its only one step, animportant step undoubtedly.Given clearance of jaundice -- and that should be seen in

over half the patients following KPE then the native liverneeds to be nursed to long-term health. Recurrent cholangitisis the main threat and should prompt IV antibiotics and anearly recourse to a prolonged period of prophylactic antibiot-ics, intravenous if needs be. But there needs to be efficient tri-als on the effectiveness of oral antibiotics or even probiotics inprophylaxis. The threat is high in the first 12 months andthen something happens to ameliorate the balance betweenhost defense and innate biliary immunity, and the microfloraof the Roux loop. Might there be tests of susceptibility be theyhematological or immunological? It follows on that havingcleared their jaundice, this cohort will have the best chanceof survival to adolescence with their native liver.Cirrhosis, present in about 10% of infants at the time of

KPE [9], awaits about half of the long-term survivors by thetime of adolescence [91]. Almost certainly this will limit thenatural lifespan of the Kasai survivor and the specter oftransplant will once more emerge. Effective anti-fibrotic drugsremain tantalizingly close but none seems ready for real clini-cal application [92]. Many pharmacological agents that dimin-ish oxidative stress (e.g., S-adenosyl methionine, N-acetyl

cysteine, vitamin E) and at a cellular level reduce the pro-inflammatory cytokine cascade (e.g., infliximab, etanercept)and limit hepatic stellate cell activation and minimize myofi-broblast proliferation (e.g., cannabinoid antagonists) havebeen identified.

In current practice, UDCA is widely used albeit indiscrim-inantly. Realistically it needs to be targeted at those alreadywho have cleared their jaundice and established bile flow. Inaddition to stimulating choleresis and in particular stimulat-ing bile secretion of potentially toxic hydrophobic bile acidsit also appears to have anti-apoptotic and anti-inflammatoryeffects [93]. Thus, UDCA can modulate the composition ofmicelles to favor the phospholipid component and these inmixed micelles protect cholangiocyte membranes againstdamage by hydrophobic bile acids perhaps reducing the ten-dency to fibrogenesis. There has been a single trial -- showingpositive effects -- there needs to be more. The evidence, Ithink, for other choleretics is less strong but prescription ofUDCA appears to be without side effects and in those whohave cleared their jaundice a reasonable option.

Declaration of interest

The authors have no relevant affiliations or financial involve-ment with any organization or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript. This includes employment,consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.

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AffiliationRakesh Kumar Thakur1 FRCS (Paeds) &

Mark Davenport†2 ChM FRCS (Paeds)†Author for correspondence1Senior Clinical Fellow,

King’s College Hospital, Department of

Paediatric Surgery, London, UK2Professor of Paediatric Surgery,

King’s College Hospital, Department of

Paediatric Surgery, Denmark Hill,

London SE5 9RS, UK

Tel: +0044 0 203 299 3350;

Fax: +0044 0 203 299 4021;

E-mail: Markdav2@ntlworld.com

Improving treatment outcomes in patents with biliary atresia

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