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Pathogenesis and Treatment Opportunities for

Biliary Atresia

Claus Petersen, MDDepartment of Pediatric Surgery, Hannover Medical School, Carl-Neuberg Strasse 1,

30625 Hannover, Germany

Biliary atresia is a devastating liver disease of the newborn with an un-

predictable outcome occurring in about 1 in 14,000 live births. The first clinical

symptoms of this rare disease are difficult to distinguish from the frequent and

mostly benign neonatal (physiologic) jaundice. Therefore, diagnosis and surgical

therapy often occur late, reducing the chance for a good outcome. Despitesuccessful surgery, fibrosis of the liver often becomes an ongoing process and

results in cirrhosis in the majority of patients. As a consequence, biliary atresia is

the most frequent indication for liver transplantation in childhood.

The long and eventful history of this disease is a story of innovative ideas

and promising therapeutic options as well as frustrating curative attempts against

an etiologically incomprehensible entity. Nowadays, interdisciplinary and inter-

national initiatives enable experts to coordinate their individual competence,

taking up the challenge to uncover the cause and to improve the outcome of pa-

tients who have biliary atresia.

Pathogenesis

History and classification

More than 100 years ago, the observation of destruction and obliteration of

extrahepatic bile ducts with progression to biliary cirrhosis was first described

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E-mail address: [email protected]

Clin Liver Dis 10 (2006) 7388


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in children undergoing autopsies [1,2]. This observation had no impact or any

therapeutic consequences, however. In the early twentieth century, the obstruc-

tion of the common bile duct was considered to be one reason for prolongedneonatal jaundice and cholestasis in newborns. The disease was named con-

genital extrahepatic biliary atresia, and for the first time a classification strat-

egy was proposed: patients presenting with an isolated distal and short atresia

of the common bile duct were considered surgically curable if the proximal

ducts were still patent and wide enough to be drained by a biliodigestive anas-

tomosis. Unfortunately, most of the patients remained surgically not curable,

and their outcome was death within the first 2 years of life. Another surgical

approach was developed at the end of the 1950s, when Kasai introduced porto-

enterostomy to correct the uncorrectable [3]. Through this innovative tech-nique, more knowledge of the diversity of changes along the extrahepatic biliary

tree was gained. During the following years, more classifications and sophis-

ticated subgroups were defined to improve the understanding of biliary atresia

[4,5]. In 1972, Landing [6] theorized that biliary atresia might be an ongoing

inflammatory process induced by an external agent such as viral infection. From

then on, etiologic possibilities were that biliary atresia is a congenital morpho-

genic disorder or that biliary atresia is an acquired disease. As a consequence,

the attribute congenital was dropped, and the term extrahepatic biliary atresia

became widely used.Despite Kasais successful procedure with initially good bile flow, several pa-

tients presented with continuous deterioration of the liver function. This phe-

nomenon was the turning point in realizing that biliary atresia is an ongoing

inflammatory process of the extra- and the intrahepatic bile ducts with an un-

predictable clinical course. Therefore the limiting factor for the outcome in

patients who have biliary atresia is related not only to the timely removal of atretic

extrahepatic bile ducts and the surgical restoration of bile flow but rather is an

autonomous and probably self-limiting process of intrahepatic inflammation. To

encompass this spectrum, the disease is usually referred to as biliary atresia,which includes all types of destructive obliteration along the whole bile duct

system. Hence, the challenge for the future and a potential key for a new and

useful classification is to uncover the still unknown pathogenic mechanisms of

biliary atresia.

Defective morphogenesis

With regard to the unknown origin, the onset of morphologic or functional

changes in patients who have biliary atresia is of crucial interest. Antenatal

detection of prestenotic cystic dilatation of the common bile duct has been

reported in rare cases [7,8]. In these patients, biliary atresia is not necessarily

combined with other anomalies, such as polysplenia, a preduodenal portal vein,

and an interrupted inferior portal vein, which are summarized by the term biliary

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atresiasplenic malformation [9] or various congenital laterality defects. It is

still unclear whether these patients form a subgroup in which a defective

embryogenesis of the biliary tree might play a causative role. Therefore, whetherthe so-called ductal plate malformation, which is defined as the persistence or

lack of remodeling of the embryonic ductal plate [10], relates to the pathogenesis

of biliary atresia and several other diseases of the intrahepatic bile ducts remains a

matter of discussion. Studies of biliary remnants in patients who had biliary

atresia revealed morphologic similarities with the remodeling process of the

ductal plate in fetuses with a gestational age between 11 and 13 weeks [11,12].

A recent study exploring the molecular basis for biliary atresia found a liver

gene expression profile that differentiates patients who have biliary atresia from

patients who have other cholestatic liver diseases [13]. A similar specific approachwas applied to a different group of patients and found a coordinate expression of

regulatory genes that distinguished the so-called embryonic and perinatal forms of

biliary atresia [14]. These studies provide preliminary results of a new and

promising research direction. Before continuing these important basic studies,

which also focus on the morphogenetic aspect, it is necessary to generate a better

definition for etiologically relevant terms, such as embryonic, syndromic,

congenital, acquired, perinatal, and other forms of biliary atresia [15].

Viral infection

In the early1970s, Landing [16] and Hays [17] proposed that a single, probably

infective, cause induces inflammation of the intra- and extrahepatic bile ducts or

the liver parenchyma, clinically manifesting as neonatal hepatitis, choledochal

cyst, or biliary atresia. This hypothesis was the starting point for several studies

searching for hepatotropic viruses in patients who had biliary atresia. Starting in

the 1980s, different viruses were sporadically found in patients who had biliaryatresia, but the studies were inconclusive. A few years later, when the polymerase

chain reaction (PCR) technique became routine, larger series of patients were

tested. Within the last 10 years, many studies have been published focusing mainly

on four specific viruses. Compiling the results from several studies, 34% (range,

0%50%) of 50 liver biopsies were positive for cytomegalovirus [1821], and

14% (range, 0%55%) of 79 patients were positive for reovirus [2225]. Rota-

virus C was detected in 50% of 18 liver biopsies [23], and human papilloma

virus was found in 16 of 18 patients [26]. It still remains unclear whether viruses

are an important etiologic factor for biliary atresia. The main problems with thesestudies are threefold: first, patients who have biliary atresia are such a hetero-

geneous group that the number of biopsies performed in each series is too small.

Second, all studies are restricted to one or two viruses; it would be much more

effective to test all candidate hepatotropic viruses in a large series of liver biop-

sies. Third, the most important and overriding problem is the time at which

samples are obtained for the PCR studies. Biopsies are taken when the disease

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has already reached an advanced stage and the patients present with severe clini-

cal symptoms. Therefore, it is impossible to distinguish, whether findings are a

trace of an etiologically relevant process or simply represent an unrelated orsecondary effect. The crucial point, and the dilemma in most clinical research

programs addressing the viral etiology of biliary atresia, is that investigations

begin too late in the disease course for viral causation to be determned.

Immunologic factors

The same problems exist in immunologic investigations in patients whohave biliary atresia, who present with well-established disease and an ongoing

inflammatory process. First, immunologic parameters were tested to evaluate

whether they determine the outcome after Kasais procedure. Some factors, such

as CD68 and intracellular adhesion molecule (ICAM)-1, seem to be related to

the postoperative course [27]. Nevertheless, it is obvious that at the time of diag-

nosis livers of patients who have biliary atresia display a T-cellmediated inflam-

mation [28]. Several factors of this immunologic cascade have been described

in these patients. Antigen-presenting cells, such as Kupffers cells, have been

reported [29], as have CD4+

cells and natural killer cells [27], which differentiateinto T-helper 1 or T-helper 2 cells (cellular or humoral-mediated immunity, re-

spectively) [30]. Major histocompatibility complex class I and class II mole-

cules, which are necessary to allow T cells recognize foreign antigens, have also

been described [31,32], although their function in biliary atresia remains ques-

tionable [33]. Additionally, the expression of cell adhesion molecules (ICAM-1,

vascular adhesion cell molecules, leukocyte factor antigen-1, nerve cell adhesion

molecule), which are involved in leukocyte recruitment, is increased in biliary

atresia [27,34]. Cytokines, such as interferon-a, tumor necrosis factor-b, and os-

teopontin, also play an important role in the signaling pathways of T-cell andmacrophage-mediated immune reaction and can be found in liver biopsies of

patients who have biliary atresia [35,36].

Collectively, these data support the hypothesis that the ongoing inflammatory

process in the liver of patients who have biliary atresia is closely related to T-cell

activity and cytotoxicity. It remains unclear whether these observations are the

result of any secondary effects or if the immune response is induced by a trig-

gering agent that is etiologically relevant. Therefore, it is necessary to search for

genomic signatures of biliary atresia. A study by Bezerra and colleagues [37]

focusing on the inflammatory aspect revealed a predominant cluster of genesthat regulate immunity and inflammatory processes in the liver of patients who

have biliary atresia. The overexpression of osteopontin and interferon-g matches

the abovementioned findings and supports the theory of an inflammatory

pathogenesis of biliary atresia. At this point, further studies are mandatory to

extend the knowledge about the genetic background of the ongoing process in

biliary atresia and to trace this back process to its origin.

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Other mechanisms

Apart from these hypothetic approaches, several other factors may be involvedin the genesis of biliary atresia. A population-based study from Sweden identified

several risk factors that facilitate exogenous factors to induce the development of

biliary atresia [38], but in contrast to other studies [39], seasonal clustering could

not be found [40]. The observation of risk factors matches the two-hit theory

from Schreiber and Kleinman [41], who speculated that a still unknown exoge-

nous factor meets a genetically predisposed condition of the innate immune

system, which is restricted to the perinatal period. Nevertheless, hereditary trans-

mission of biliary atresia or any predisposing additional factor is not likely,

because recurrence in siblings is rare, as is concordance in dizygotic and mono-zygotic twins [42].

Other potential pathogenetic mechanisms in biliary atresia have also been

discussed. Ischemia-related biliary obstruction can be induced by a vasculopathy

of the hepatic vessels, potentially associated with an autoimmune process. It is

also possible that other nonviral agents, such as bacteria, toxins, or environmental

factors are responsible for triggering inflammatory processes that finally lead

to biliary atresia. No consistently evidence has been shown for this triggering as

a mechanism of disease [43].

Animal models

If the pathogenesis of a disease cannot be elucidated in humans, it might be

useful to simulate it in animals. In biliary atresia, numerous attempts have been

made to occlude the extrahepatic bile ducts in different species or by infecting

mice with reovirus. Those studies were helpful in investigating the consequences

of artificially induced cholestasis but failed to simulate the dynamic pattern of

developing biliary atresia [44]. In the early 1990s, Riepenhoff-Talty and colleagues[45] reported that newborn Balb/c-mice that were orally infected with rhesus

rotavirus developed irreversible bile duct obstruction. This observation was the

starting point for establishing a reproducible animal model for biliary atresia

[46]. Further studies revealed that this model is based on the hepatotropic effect

of rhesus rotavirus, which targets the biliary system during the immunologic gap

when the immune system of newborn Balb/c-mice is immature. The virus seems

to trigger a T-cellmediated immune response independently from the virus load

of the liver [47]. These observations were confirmed by an interesting study

from Shivakumar and colleagues [48], who observed that interferon IFN-g playsa key role in developing biliary atresia in Balb/c-mice. Despite remarkable simi-

larities between the model and patients who have biliary atresia, it is not possi-

ble to relate the findings in mice directly to the human disease. Nevertheless,

the pathogenesis of developing biliary atresia in Balb/c-mice is relatively clear.

Descendants of nonimmunized mothers present postpartum with a short immu-

nologic gap and are susceptible to a virus-triggered T-cellmediated immune

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response, finally leading to fibrotic obstruction of the bile ducts. The missing

link in the pathogenetic cascade is the biologic basis for the localized atresia

within the extrahepatic, but not the intrahepatic, bile ducts. Inflammatory reactionof the arterioles, which are potentially mediated by interferon and autoimmunity

factors, may induce an ischemia-related fibrotic transformation of the extra-

hepatic bile ducts. This hypothesis matches a study in patients who had biliary

atresia, which described arteriopathy from the trunk of the common hepatic ar-

tery to its peripheral branches supplying the entire biliary tree [49,50].

All these observations support the hypothesis that biliary atresia is an acquired

disease and throw a new light on Perlmutters provocative speculation as to

whether biliary atresia is a single disease or a phenomenon of superior patho-

genic mechanism [51]. Therefore discovering more details of the pathogenesisof biliary atresia in the mouse model is a priority.

Treatment opportunities

The first therapeutic opportunities were restricted to patients who had the so-

called correctable form of biliary atresia [52]. Therefore, the most patients

were still incurable until Kasais portoenterostomy was introduced. This

procedure was the first breakthrough in the treatment of patients who had biliaryatresia. The second milestone was liver transplantation, which continues to

be perfected. Today, surgical treatment is still the only approach, although the

outcome of patients who have biliary atresia depends on multiple diagnostic

and therapeutic factors and close interdisciplinary cooperation.

Diagnosis and Kasais procedure

The first hurdle with biliary atresia is to identify babies who have pathologichyperbilirubinemia among the large number of newborns who present with

common and uncomplicated jaundice. It is important to refer these patients to a

pediatric hepatologist when the clinical signs of cholestasis persist longer than

2 weeks. The second hurdle is to exclude the most frequent diseases that also

present with direct hyperbilirubinemia by using a reasonable diagnostic algo-

rithm. Imaging and functional methods, such as ultrasound (the triangular cord

sign [53]), MRI cholangiography [54], and hepatobiliary scintigraphy, are indis-

pensable tools, but they are not accurate enough to exclude the presence of bili-

ary atresia. The same is true for liver biopsies, which are helpful either to ruleout several other liver diseases or to be consistent with an extrahepatic bile duct

obstruction. If the bile duct obstruction cannot definitely be ruled out, the entire

biliary tree must be visualized, because biliary atresia is still defined as fibrotic

obstruction of the extrahepatic bile ducts. In pediatric centers where endoscopic

retrograde cholangiopancreatography in babies is routine, the patency of the

common bile duct can be shown by this less-invasive method, probably sparing

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an unnecessary laparotomy. In all other cases, an open cholangiogram, which can

also be performed by a minimally invasive approach, is necessary to confirm

the diagnosis.If the intraoperative cholangiogram reveals that the extrahepatic bile duct is

partially or completely atretic, a portoenterostomy can be performed during

the same operative procedure. The technical recommendations originating from

Kasais first papers are still state of the art. Meticulous preparation of the

duodenal ligament is necessary to identify the branches of the hepatic artery and

the portal vein as well as the remnants of the hepatic ducts. The gallbladder must

be dissected, and the remnants of the extrahepatic bile ducts are the guide to the

fibrous cone in the porta hepatis. The original description of the Kasai procedure

restricts the preparation of the porta hepatis to a central area, which is surroundedby the bifurcation of the portal vein [55]. Today, a much more extensive portal

dissection is recommended to open as many small intrahepatic bile ducts as

possible and to make better bile flow possible [56]. This change is the only

variation of the original technique that is accepted worldwide as a new standard.

Numerous modifications of the original Kasai hepatic portojejunostomy ver-

sion have been proposed, which can be summarized as total or partial diversion

of a biliary conduit with or without intestinal valve formation. None of these

variations proved to be beneficial, however, and most surgeons returned to the

original procedure, using a 4- to 60-cm Roux-en-Y loop [57,58]. The porto-enteral anastomosis must be performed so that the funnel-shaped end of the

jejunal loop overrides the completely transected porta hepatis, so as to catch

every drop of bile. From the surgical point of view, the preparation and the tran-

section of the porta hepatis is as important as the perfect placement of the intes-

tinal funnel.

The postoperative management after the Kasai procedure is a matter of

ongoing discussion. The benefit of peri-, postoperative, and long-term antibiotic

prophylaxis is indisputable, although the drug used, its administration, and the

duration of therapy, vary widely [57]. Long-term treatment with cholereticagents and administration of fat-soluble vitamins are widely used; a high-caloric

formula with medium-chain triglyceride oil is recommended [42]. Positive ef-

fects on the outcome of postoperative treatment with corticosteroids are fre-

quently reported. The design and many details of single-institution studies are

incongruent, however, and no recommendation can yet be made [5961]. Hence,

a prospective multicenter study is mandatory to determine whether corticoste-

roids are really helpful in improving the outcome of patients who have biliary

atresia after the Kasai procedure.

The criterion for successful portoenterostomy in patients who have biliaryatresia is survival with their own liver. Over the years the results have im-

proved remarkably, but the data from single-institution and national multicenter

studies vary greatly. The rate of survival with native liver ranges between 32%

and 60% after 5 years and between 22% and 53% after 10 years [57,61,62].

The results for jaundice-free survival are significantly worse, and after 20 years

nearly all patients are expected to suffer from liver cirrhosis (Table 1) [63,64].

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Determination of variables that might influence the outcome of portoenter-ostomy reveals that age at operation is a crucial factor. The highest rate of bile

flow restoration can be achieved in patients who are operated on before they are

60 days old, and the success rate decreases dramatically beyond the 90-day limit

[57]. Denomination of these limits should not exclude patients from a surgical

approach, however, because a successful clinical course can also be seen in pa-

tients who were older than 3 months when the Kasai procedure was performed

[65,66]. There is agreement that, apart from exceptional cases, portoenterostomy

should be performed in all patients who have biliary atresia, at least to bridge

the time between diagnosis and liver transplantation. Achieving long-term,jaundice-free survival is an important goal for every patient who has biliary atre-

sia, but prolonged survival with the native liver is always desirable. Another im-

portant factor influencing the outcome is the experience of the center [67,68].

Although it could be shown that the surgical outcome is related to the frequency

of operations, successful treatment of patients who have biliary atresia depends

both on the professional skills of the surgeon and on the interlocking coopera-

tion of pediatric surgeons, pediatric gastrologists and hepatologists, and trans-

plant surgeons.

Early complications that may influence the postoperative prognosis are as-cending bacterial cholangitis and mechanical obstruction of the Roux-en-Y loop.

Early diagnosis and adequate treatment of the cholangitis are essential to pre-

vent deterioration of the intrahepatic bile flow [69]. Primary or secondary con-

struction of antirefluxive intestinal valves has not been beneficial and is not

recommended. On the other hand, recurrent episodes of ascending cholangitis

can be induced by mechanically impaired bile flow along the biliodigestive

conduit and should be verified by hepatobiliary scintigraphy. In these cases, and

after acute cessation of initial good bile flow, a surgical revision of the situs

would be useful (eg, correction of a secondary kinking of the Roux-en-Y-loop).Debridement or revision of the porta hepatis has been advocated mainly by

Japanese centers and should be left for specific cases [70].

Because of the unpredictable outcome of patients who have biliary atresia,

several attempts were made to identify prognostic parameters facilitating the

postoperative management and a potential marker for an indication for liver

transplantation. Most of the studies focused on fibrosis markers or on clinical,

Table 1

Five- and 10-year survival results in patients who have biliary atresia

Study

5-year survival 10-year survival

Overall

With native

liver Overall

With native

liver

Davenport et al 1997 [89] 68% 60% 43% 22%

Chardot et al 1999 [67] 70% 32% 68% 27%

Ohi 2000 [57] 70% 60% 68% 53%

Nio et al 2003 [99]

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morphologic, and immunologic parameters, but none of the criteria proved to be

valuable for predicting the individual prognosis [29,7175]. The only outcome-

related classification can be made by assessing the parameters of liver functionwithin the first 6 months after the Kasai procedure. Patients who have normal

bilirubin levels and no signs of portal hypertension seem to have a relatively

favorable outcome [7678]. As long as the ongoing postoperative destructive

process of the liver in biliary atresia is not understood, these investigations

overlap with programs studying the etiology of biliary atresia.

In conclusion, surgery in biliary atresia is a symptomatic approach to an

enigmatic and self-limiting process of the liver, which manifests along the intra-

and extrahepatic biliary tree. Despite the limited therapeutic options, every effort

must be made to reinforce early detection, timely diagnosis, perfectly performedKasai procedure, and optimal postoperative care of patients who have biliary

atresia. These measures will help increase the jaundice-free survival with the

native liver and decrease the number of liver transplantations in children who

have biliary atresia.

Liver transplantation

The replacement of the affected organ signifies the beginning of a newchapter that carries no specific holdovers from the first disease. The introduction

and rapid development of liver transplantation have been highly beneficial for

patients who have biliary atresia, because the overall survival exceeds 80%,

and the outcome of liver transplantation in these patients is not different from

that in patients who have other end-stage liver diseases [7982]. Technical inno-

vations, such as split-graft or living related-donor liver transplantation, continu-

ously improve the long-term results [83], and liver transplantation in children

younger than 1 year has already become routine in highly specialized centers

[8486]. Pediatric liver transplantation is reviewed elsewhere in this issue byTiao and Ryckman.

In most patients, biliary atresia is an ongoing process, with progressive portal

hypertension and deterioration of the liver function sooner or later requiring liver

transplantation. The question has been raised as to whether primary liver trans-

plantation should be recommended. In the light of continuously improving re-

sults of liver transplantation, especially in infants, advocates argued that primary

liver transplantation would spare the risks of the Kasai procedure and its post-

operative complications; also, an untouched situs offers better conditions for the

transplantation and decreases peritransplantation complications [87]. On theother hand, more than 50% of the patients who have biliary atresia are jaundice

free after the Kasai procedure, and most of them have a realistic chance of

surviving with their native liver for more than 10 years. Therefore, portoenter-

ostomy still remains a curative option for a minority of patients who have biliary

atresia and for all others is an important bridge to the expected liver transplan-

tation. Given these arguments, sequential surgical therapy must be recommended

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in all cases of biliary atresia. It is obvious that a correctly performed Kasai

procedure does not interfere with the transplantation, although multiple opera-

tions should be avoided [8891]. In some specific cases, however, determiningthe right procedure is difficult. Late referrals of patients who have biliary atre-

sia, presenting with complete liver cirrhosis and clinical signs of portal hyper-

tension, do not necessarily profit from the Kasai procedure. In these rare cases,

the optimal treatment for each individual must be found by mutual consent be-

tween all participating disciplines.

A crucial problem of the sequential surgical therapy of patients who have

biliary atresia is the optimal timing for liver transplantation. There are no

available parameters that reliably monitor the ongoing intrahepatic process of

the disease. Therefore, the clinical sequelae of portal hypertension and impairedphysical development are the only criteria for timing of liver transplantation.

Close cooperation within the interdisciplinary team is also mandatory because

any therapeutic decision depends on the physical condition of the recipient

[92,93].

No fundamental breakthrough in surgery for biliary atresia seems to be in

sight. In series from experienced centers, outcomes after the Kasai procedure are

comparable, and over the years the rate of bile flow restoration remains un-

changed. It cannot be expected that further development of the Kasai procedure

will improve the survival with native liver of patients who have biliary atresia.Nevertheless, technical innovations, such as minimally invasive surgery or ro-

botically assisted procedures, are feasible and might be beneficial in relieving

the perioperative stress of the patients [94,95]. Because the surgical approach to

biliary atresia addresses only the symptoms of the disease, it will never address

its cause. Until there is an origin-related therapeutic approach, every effort must

be made to optimize the results of the Kasai portoenterostomy.

Future prospects

In the face of so many unsolved problems in biliary atresia, the challenges

for the near future are clear. The first is that health care providers should refer

every baby with neonatal jaundice lasting more than 14 days. Screening pro-

grams are feasible [96] and essential, but in most countries, they are not available

for economic reasons. Therefore, the second condition becomes more evident:

every neonate thought to be suffering from biliary atresia must immediately be

referred to a center with expertise in pediatric hepatobiliary disorders. There a

modern management strategy will be available to rule out other diseases, andthe Kasai portoenterostomy is a familiar procedure for the team. In addition to

early diagnosis and adequate surgical therapy, long-term postoperative care is

indispensable to improving the overall outcome. Unfortunately, despite optimal

treatment modalities, the deterioration of the liver is an ongoing process in

most patients who have biliary atresia; the tools to slow the process are limited,

and there is no way to stop it. Hence, the third challenge has the highest prior-

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ity: to develop curative treatment strategies, every effort must be made to un-

cover the cause of biliary atresia. This discovery is the only way to understand

the pathogenesis, to guide the treatment opportunities effectively toward the keypathogenetic mechanisms of disease, or, optimally, to prevent newborns from

developing biliary atresia [62,97,98].

During the several last years, more and more working groups have accepted

this challenge, and several activities have been initiated or intensified. Existing

biliary atresia registries in Japan and France and treatment-optimization

programs in the United Kingdom stimulated the community of researchers in

biliary atresia to coordinate their activities and increase their effectiveness

[67,68,99]. In the United States, the new Biliary Atresia Research Consortium

(www.med.umich.edu/borc/barc/sites.htm) is a network of 10 clinical centersthat serves as a clinical database and a coordinating center for clinical and basic

research studies [100]. In Europe, the Biliary Atresia Registry (www.biliary-

atresia.com) was founded to coordinate the data from the participating countries

[101], and the new European Foundation for Biliary Atresia Research (www.

orpha.net) uses the existing infrastructure to sponsor multicenter research studies.

Intensive and close cooperation among these initiatives helps improve the in-

terim results and achieve the definite objective: uncovering the etiology and

pathogenesis of biliary atresia and finding a cure.

Summary

Biliary atresia is a cholestatic disease affecting the intra- and the extrahe-

patic bile ducts of the newborn; with unpredictable outcome, it is the main indi-

cation for pediatric liver transplantation. The cause of this rare entity still remains

unclear, hypothetically ranging from defective morphogenesis to viral infection

or an immunologic defect. Although most patients finally need liver transplan-tation, the interim objective is to optimize patients survival with their native

liver. Early diagnosis, timely and perfectly performed portoenterostomy, and op-

timal postoperative care are indispensable to reduce the frequency of liver trans-

plantation for biliary atresia. The sequential surgical approach to biliary atresia

(obligatory Kasai procedure and optional liver transplantation) improves the

symptoms of the disease but does not address its cause. Therefore, clinical and

basic research is mandatory to elucidate the origin of biliary atresia. To compen-

sate for the infrequency of biliary atresia, international multicenter studies

should focus on clinical and on etiologic aspects. Unfortunately, basic researchin biliary atresia is retrospective, because it always starts when the disease has

already reached an advanced stage. Using animal models, the dynamic pattern of

biliary atresia can be simulated, and with a coordinated research program the

pathogenesis of the disease can be better understood. Intensive and close inter-

disciplinary cooperation will be beneficial for the patients and will help solve

the riddle of biliary atresia.

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