Chapter

Biliary Atresia and Other Disorders

11 of the Extrahepatic Bile Ducts

Jorge A. Bezerra, Akihiro Asai, Greg Tiao, Bhargava Mullapudi, and William F. Balistreri

Introduction “neonatal hepatitis” with a subsequent evolution to biliary

atresia [5].
Biliary atresia and related disorders of the biliary tract, such as
In biliary atresia, triggering insults may involve viruses and
choledochal cysts, must be considered in the differential diag-
toxins. Although several viruses have been proposed as an initial
nosis of prolonged conjugated hyperbilirubinemia in the new-
insult, no specific viral agent has been reproducibly detected in
born (neonatal cholestasis).
tissue from affected infants, and there is limited conclusive
Neonatal hepatobiliary diseases, including biliary atresia,
serologic evidence of their presence [6]. Other theories (dis-
choledochal cysts, and “idiopathic” neonatal hepatitis, have his-
cussed below) include defective embryogenesis or an innate or
torically been viewed as a continuum – a gradation of manifesta-
development-specific dysregulation of the immune response to
tions of a basic underlying disease process in which hepatocyte
injury [7]. Greater understanding of how the neonatal immune
injury (with or without giant cell transformation) is strongly
system responds to a perinatal viral insult will provide insight
associated with inflammation at any level of the hepatobiliary
into mechanisms that disrupt the mucosal integrity of the bile
tract. These disease entities may be polar end-points of a com-
ducts, obstruct the lumen, and sustain the activation of cells that
mon initial insult, as originally stated in the unifying hypothesis
produce the ongoing liver injury [6, 7]. Further studies are
of Landing [1]. The end result represents the sequelae of the
warranted; biliary atresia and related disorders continue to
inflammatory process at the primary site of injury. Landing
offer clinicians and scientists stimulating challenges.
suggested that this inflammatory process may injure bile duct
This chapter reviews the current status of diagnosis and
epithelial cells, leading to either duct obliteration (biliary atresia)
management of these disorders, as well as advances in the
or weakening of the bile duct wall with subsequent dilatation
intriguing quest for an understanding of their pathogenesis.
(choledochal cyst). The lesions may be dependent on the stage of
fetal or early postnatal development when the injury occurs and
the site within the developing hepatobiliary tree at which the Biliary Atresia
injury occurs [1, 2]. The subsequent observation that extrahepa- Biliary atresia is the end result of a destructive, inflammatory
tic bile ducts develop cystic dilatations following rotavirus infec- process that affects intra- and extrahepatic bile ducts, leading to
tion in newborn mice genetically primed to have a prominent T fibrosis and obliteration of the biliary tract, and eventual devel-
helper lymphocyte type 2 response suggests that the lesions may opment of biliary cirrhosis [6]. This disorder should be of interest
also be dependent on the type of immune response to the viral to all individuals involved in basic and clinical studies of diseases
insult [3]. A relationship between the pathogenesis of these of the liver; the rapidly progressive fibro-obliterative process may
obstructive cholangiopathies of infancy and the process of devel- represent a paradigm for other forms of hepatobiliary injury,
opment (embryogenesis) is suggested by the association with perhaps reflecting an inter-relationship between genetic predis-
disorders of situs determination such as the polysplenia syn- position and exposure to environmental factors [6].
drome and the observation of the so-called ductal plate malfor- Biliary atresia is the most common cause of chronic cho-
mation within the liver of some patients with biliary atresia. The lestasis in infants and children, and because of the high rate of
ductal plate malformation is postulated to represent either a progression to end-stage liver disease, it is the most frequent
primary developmental anomaly secondary to genetic mutations indication for liver transplantation in the pediatric age group.
or disruption of a developmental sequence early in fetal life, There is general agreement that the older theory that biliary
resulting in incomplete regression of the immature bile ducts atresia was caused by failure of recanalization of embryonic
[2, 4]. Most patients with biliary atresia do not manifest the bile ducts should be abandoned. The lesion, in most patients, is
ductal plate malformation or non-hepatic syndromic features, not a true congenital malformation but seems to be acquired in
therefore the injury probably occurs after the anatomic forma- late gestation or after birth. Studies of liver samples obtained
tion of intra- and extrahepatic bile ducts [4]. from patients with biliary atresia at the time of diagnosis
The dynamic nature of the underlying process has been revealed unique pro-inflammatory features [8, 9]. How the
further suggested by an apparent postnatal evolution of patent inflammatory process produces complete or partial sclerosis
to atretic ducts: patients may show histological features of of the extrahepatic (and intrahepatic) biliary ducts is the
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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

subject of ongoing studies [6–9]. This idiopathic process leads In patients with the syndromic form of biliary atresia
to obliteration or discontinuity of the hepatic or common bile genetic factors likely predominantly contribute to the patho-
ducts at any point from the porta hepatis to the duodenum. In genesis, in the form of defective embryogenesis. These two
most patients, cordlike remnants of the extrahepatic ducts are forms have not been distinguished on the basis of histology
encountered at surgery. of porta hepatis specimens; both forms may have inflamed and
obliterated bile duct segments in this resected tissue mass.
Incidence In the series of Davenport et al. [11] of 308 patients with
biliary atresia, 23 (7.5%) had polysplenia, two had double
Biliary atresia occurs worldwide, affecting an estimated one in
spleens, and two had asplenia. All 27 splenic anomalies were
8,000–15,000 live births. There is a slight female predominance in
grouped into the term “biliary atresia splenic malformation
most published series. One population-based birth defects sur-
syndrome (BASM).” Infants with this syndrome had a lower
veillance system for infants with biliary atresia in metropolitan
birth weight and a higher incidence of maternal diabetes com-
Atlanta calculated an incidence rate of 0.73 per 10,000 live births
pared with non-syndromic cases. The extrahepatic anatomy of
[10]. In one report there was significant seasonal clustering of the
the biliary tract also reportedly was different, including
disease, with rates three times higher in infants born between
instances of what they termed biliary agenesis. These findings
December and March; reported rates were significantly higher
suggest that either the timing or the nature of the biliary lesion
among non-white infants. The demonstration of significant sea-
of this subgroup may differ from the more common non-
sonal clustering in this and other studies supports the theory that
syndromic form, in which a virus- or toxin-induced injury to
biliary atresia may be caused by environmental exposure (con-
cholangiocytes causes a progressive obliteration of extrahepa-
sistent with a viral cause) during the perinatal period [6].
tic bile ducts, with some degree of intrahepatic bile duct injury
[6, 12]. In both clinical forms, the injury appears to involve an
Clinical Forms ongoing inflammatory process that produces complete sclero-
At least two different forms of biliary atresia are recognized, sis of extrahepatic bile ducts and progression to cirrhosis.
with disparate pathogenesis: a syndromic or embryonic form Whether the lesion noted in the intrahepatic bile ducts results
and a non-syndromic or perinatal form. In patients with the less from an extension of the extrahepatic lesion or is a conse-
common syndromic form (10–20% of all patients), cholestasis is quence of cholestasis is not defined. It is believed that ductal
present from birth, with no jaundice-free interval. Bile duct plate malformation and segmental agenesis of bile ducts in
remnants may not be detectable in the hepatic hilum and porta hepatis specimens are identified more commonly in the
there is a high frequency of associated malformations such as syndromic form, but an analysis of portal tracts from eight
polysplenia, which may be associated with cardiovascular infants with the non-syndromic form of biliary atresia and six
defects, asplenia, situs inversus, intestinal malrotation, and posi- infants with biliary atresia splenic malformation syndrome
tional anomalies of the portal vein and hepatic artery. identified no association between ductal plate malformation
Extrahepatic anomalies reported in patients with biliary atresia and either clinical form of disease [13].
are outlined in Table 11.1. A third form or clinical variant is defined by the presence of
cystic dilatation of extrahepatic bile ducts, in addition to the
fibrosing obstruction of duct segments. Some of the biliary
Table 11.1 Extrahepatic Anomalies Reported in Patients with Biliary Atresia
cysts are detected prenatally during routine ultrasound exam-
System Anomalies ination of the fetus; jaundice and acholic stools may present
soon after birth or after a variable period of time. In a review of
Splenic anomalies Polysplenia, double spleen, a large cohort with biliary atresia, biliary cysts occurred in
asplenia
approximately 8% of patients [14]. Infants with this “cystic
Portal vein anomalies Preduodenal position, absence, variant” were younger at presentation, but a delay in perform-
cavernous transformation ing a portoenterostomy beyond 70 days of age was associated
Abdominal Situs inversus, intestinal with poor long-term survival with the native liver. The anato-
abnormalities malrotation, annular pancreas, mical details of this variant, the earlier age at presentation, and
duodenal atresia, esophageal the differences in outcome raise the possibility that the patho-
atresia, jejunal atresia genic mechanism of disease is unique.
Cardiac anomalies Dextrocardia, atrial situs
ambiguous, ventricular inversion Clinical Features
Despite the presumed multifactorial pathogenesis, there is
Immotile cilia Neonatal respiratory distress;
syndrome frequent lung, sinus and middle
consistency in the clinical features of biliary atresia: affected
ear (Kartagener syndrome) infants present with jaundice (conjugated hyperbilirubinemia)
and acholic stools. The presence of hepatomegaly, failure to
Renal anomalies Polycystic kidney, renal agenesis, thrive, pruritus, and coagulopathy depends on the level of
hypoplastic kidneys progression of disease. Affected infants usually are born at
Cranio-facial Cleft palate term, are of normal birth weight, and weight gain is appro-
priate early in the course. Patients with biliary atresia

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 Section II: Cholestatic Liver Disease

occasionally present with bleeding as a result of vitamin K Cause and Pathogenesis

deficiency. Examination may reveal hepatomegaly and spleno-
The ultimate goals are to define the pathogenesis of biliary
megaly. Ascites and wasting may be seen as late manifestations
atresia and establish preventive strategies. Although our
if biliary cirrhosis has supervened. Increased awareness to
understanding of the cause of biliary atresia has remained
ensure early diagnosis and development of methods to prevent
unchanged for several decades, there is now greater knowl-
progressive hepatic fibrosis are essential. Early recognition of
edge regarding the pathogenesis of the disease from
babies who have biliary atresia is particularly critical for opti-
patient-based studies and the use of experimental models
mal intervention; ideally, biliary atresia should be identified by
of bile duct injury [6, 7]. Theoretic considerations of the
the time of the two-week well-baby visit. The importance of a
cause of biliary atresia have been based on epidemiologic
prompt and precise diagnosis must be stressed to all pediatric
and clinical features. Two critical clinical features offer
healthcare providers. In the UK, an educational effort (the
potential clues to the chief biologic processes. The first is
Yellow Alert campaign) was established to indicate the signifi-
that the onset of disease is restricted to the perinatal or
cance of jaundice persisting after 14 days of age. Population
immediate postnatal period (<4 months). The second is the
screening also has been considered, including the use of stool
presence of inflammation and fibrosis of the extrahepatic
color cards to identify at-risk infants. In Taiwan, population
bile ducts. In the “typical” patient, the structural changes
screening with these cards resulted in an increase in the
present in the hepatobiliary tract suggest a progression of
national rate of portoenterostomy before 60 days of age from
the lesion from acute cholangitis to fibrotic obliteration of
60% to 74% [15].
the ducts (Figure 11.1). The dynamic nature of the

(a) (b)

(c) (d)

Figure 11.1 Stages of biliary atresia. (a) Patent bile duct in a specimen from the porta hepatis exhibits periductal inflammation and epithelial erosion; elsewhere in this
patient, the duct was obliterated by reactive tissue (magnification 37×). (b) Detail of eroded bile duct shows regressive epithelial change, periductal edema, and mild
inflammation (magnification 250×). (c) At the autopsy of a patient with biliary atresia, a minute remnant of common bile duct has intact epithelium (magnification 100×).
(d) Minute fibrous cord represents the final stage of biliary atresia (magnification 100×). In many patients, the atretic duct is not visible to the naked eye. (Hematoxylin
and eosin staining.)

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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

obliterative process is illustrated by the fact that atresia has cause an obliterative cholangiopathy in weanling mice; a simi-
been found at autopsy or re-exploration in infants pre- larity exists between the hepatitis with biliary tract inflamma-
viously shown to have patent extrahepatic ducts or “neo- tion induced by reovirus type 3 infection in the weanling
natal hepatitis.” mouse model and the progressive postnatal fibrotic oblitera-
Multiple studies have focused on normal and altered bile duct tion of the extrahepatic bile ducts and liver cell injury noted in
morphogenesis and the role of various factors (infectious or toxic biliary atresia [6]. Reovirus type 3 infection, therefore, has been
agents and metabolic insults) in isolation or in combination with implicated as the initial insult in the sequence of events result-
a genetic or immunologic susceptibility to biliary atresia [4, 6]. ing in the observed lesions. Murine reovirus infection may lead
The absence of documented recurrence in siblings of infants with to necrosis of the bile duct epithelium and hepatocytes, inflam-
biliary atresia and reports of dizygotic and monozygotic twins matory infiltration, and possibly identifiable viral inclusions in
discordant for biliary atresia appears to exclude simple Mendelian bile duct epithelial cells. Pathologic changes in reovirus-
inheritance in the vast majority of patients [4, 6]. The concept infected mice, including distal stenosis of the common bile
that an acquired obliterative process underlies biliary atresia is duct and dilation of the proximal bile duct, remain after infec-
attractive and suggests that a virus- or toxin-related inflammation tious virus or viral antigens can no longer be detected [19].
may initiate the sequence that leads to fibrosis and luminal Infection of newborn mice with reovirus in the first days of life,
obstruction. In support of this concept, giant multinucleate hepa- however, did not produce obstruction of extrahepatic bile
tocytes have been noted in up to 40% of liver biopsy samples ducts [20]. Previous attempts to show an association between
obtained early in life from patients with biliary atresia. reoviruses and human hepatobiliary disease have yielded con-
flicting results.
Viral Infection Reoviruses have not been isolated from human hepatobili-
ary tissue, but reovirus antigen was detected in the bile duct
A favored theory implicates subclinical viral infection as the
remnant resected from an infant with biliary atresia, and reo-
inciting mechanism. The demonstration of significant seasonal
virus-like virion particles were seen in this tissue by electron
clustering provides support for the theory that biliary atresia
microscopy [19]. Using reverse transcriptase polymerase chain
may be caused by environmental exposure (consistent with a
reaction, reovirus was found in hepatobiliary samples of 55%
viral cause) during the perinatal period. Multiple potential
of patients with biliary atresia and 78% with choledochal cyst,
etiopathogenic viruses have been ruled out as “suspects.”
whereas the virus was present in tissues of only 8–21% of
Hepatitis A, B, and C virus infections are not related to biliary
appropriately matched controls [21]. More work is needed to
atresia [6], and there was no apparent increase in the incidence
establish or exclude a causative relationship between reovirus
of biliary atresia during rubella epidemics. Cytomegalovirus
and biliary atresia.
(CMV), which characteristically infects the biliary epithelium,
Riepenhoff-Talty et al. [22] reported the development of
has been suggested as a cause of biliary atresia. For example, a
extrahepatic biliary obstruction in newborn mice orally inocu-
Swedish study showed a higher prevalence of CMV antibodies
lated with group A rotavirus. These investigators also pre-
in mothers of infants with biliary atresia, and CMV DNA was
sented evidence for polymerase chain reaction amplification
present in livers from nine of 18 infants with biliary atresia
of group C rotavirus sequences from livers of patients with
[16]. A role for CMV in the pathogenesis of biliary atresia,
biliary atresia, for immunoreactivity to group C rotavirus in
however, was not supported by studies examining porta hepa-
serum of patients with biliary atresia, and for group C rotavirus
tis specimens by in situ hybridization and polymerase chain
particles in the stool of patients with biliary atresia [23].
reaction using CMV DNA probes [17]. Yet, exposure to CMV
Additional studies in infected newborn mice have clearly
remains a potential causative factor because of the viral trop-
shown the induced injury to reside in the biliary epithelium.
ism to the bile duct epithelium, but future studies will need to
This model of rotavirus-induced biliary injury has proved
employ new approaches that detect virus-specific epitopes in
valuable in studying the mechanisms of biliary atresia because
memory lymphocytes. A high prevalence of human papilloma-
it recapitulates two consistent clinical features of the disease in
virus has been detected in liver tissue and in cervical swabs
humans: the onset of disease in the immediate neonatal period
from mothers of patients with biliary atresia. There is no
and the progressive cholangiopathy [6].
animal model, however, demonstrating the consequences of
Additional studies are needed to further investigate a rela-
human papillomavirus infection in an immature liver, nor
tionship between reovirus, rotavirus, or any other virus in the
have these findings been confirmed. Mason et al. [18] detected
pathogenesis of biliary atresia. Investigation into the contribu-
retroviral antibody reactivity in patients with biliary atresia
tion of virus-initiated immune or autoimmune mechanisms of
attributable either to an autoimmune response to antigenically
hepatobiliary injury may yield information essential for devel-
related cellular proteins or to an immune response to unchar-
opment of treatment or prevention strategies. One example is
acterized viral proteins that share antigenic determinants with
the observation that the incidence of biliary atresia appeared to
these retroviruses. Further studies are needed.
decrease in Taiwan after the introduction of rotavirus vaccine
The viral agents most frequently implicated in the patho-
[24]. It is unlikely, however, that antiviral therapy alone would
genesis of biliary atresia include reovirus and rotavirus.
alter the natural history of biliary atresia if the pathologic
Serologic reactivity to reovirus type 3 and reovirus particles
process is an immunologic reaction to a preceding viral injury,
in the porta hepatis has been found in children with biliary
without ongoing viral replication.
atresia [6]. It had been known for some time that this virus can

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 Section II: Cholestatic Liver Disease

Defect in Morphogenesis A series of observations clarified the morphogenesis and

differentiation of the intrahepatic bile ducts [2, 28]. In a study
The hypothesis that a defect in morphogenesis of the biliary
of human liver samples from different stages of fetal devel-
tract underlies the pathogenesis of biliary atresia is appeal-
opment and immunostaining with anti-cytokeratin antibo-
ing, particularly considering the co-existence of other
dies specific for bile duct epithelial cells, investigators showed
anomalies, such as anomalies of visceral organ symmetry
that bile ducts arise within the mesenchyme surrounding
(Table 11.1) that occur in 10–20% of infants with biliary
portal vein radicals. Presumed primitive hepatic precursor
atresia. Tan et al. [25] compared the developing biliary
cells differentiate into a single layer of cytokeratin-staining
system of normal human embryos and fetuses with the
cells and then form a double layer. At focal points, these cells
resected extrahepatic biliary remnants from 205 patients
then scatter and remodel as a single layer around a lumen. In
with biliary atresia. At the porta hepatis level, the primary
livers from some infants with biliary atresia, there was evi-
biliary ductal plate underwent a specific sequence of remo-
dence for an arrest in remodeling such that lumens are not
deling between 11 and 13 weeks after fertilization, resulting
formed (ductal plate malformation) [2, 28]. Studies in mice
in the formation of large tubular bile ducts surrounded by
showed that extrahepatic bile ducts arise from a PDX1
thick mesenchyme. Luminal continuity with the extrahepatic
+/SOX17+ domain and then segregate into SOX17+ bile
biliary tree was maintained throughout gestation. Contrary
ducts and PDX1+ ventral pancreas; the requirement of
to previous speculation, no “solid phase” was documented
Sox17 for normal development was supported by the report
during the development of the extrahepatic bile duct.
of abnormal bile ducts in Sox17 heterozygous mice [4].
Examination of the biliary remnants from patients with
Histological and functional abnormalities in the biliary tract
biliary atresia showed that the porta hepatis was encased
have been reported in mice with genetic mutations in Jagged,
in fibrous tissue, with a variable pattern of obliteration of
Notch, Hes1, Hnf6, Hnf1b, Foxm1b, Foxf1, Foxa1/Foxa2,
the common hepatic and common bile ducts. There were
Sox17, and Lgr4, which raises questions about the potential
similarities on anti-cytokeratin immunostaining between the
role of these genes as susceptibility factors or modifiers of
abnormal ductules within the porta hepatis in biliary atresia
disease in humans [6, 7, 26].
and the normal developing bile ducts during the first trime-
ster. The investigators proposed that biliary atresia may be
caused by failure of the remodeling process at the hepatic Pro-Inflammatory Mechanisms of Disease
hilum, with persistence of fetal bile ducts poorly supported Several lines of evidence point to a pro-inflammatory response
by mesenchyme. They further postulated that, as bile flow that targets the bile ducts in patients with biliary atresia. One
increases perinatally, bile leakage from these abnormal ducts theory holds that a viral or toxic insult to the biliary epithelium
may trigger an intense inflammatory reaction, with subse- leads to newly expressed antigens on the surface of bile duct
quent obliteration of the biliary tree. It remains to be epithelia, which in the proper genetically determined immu-
demonstrated whether these processes are causative or nologic milieu (e.g., the presence of major histocompatibility
whether the histological features result from the activation molecules) are recognized by T-lymphocytes that elicit a cel-
of cellular circuits in response to poorly defined insults. lular immune injury. In support of this notion, Silveira et al.
Among these are infectious or immune insults that can [29] reported an association of the human leukocyte antigen
interfere with the normal remodeling process at the hepatic (HLA)-B12 allele and haplotypes HLA-A9B5 and HLA-
hilum and with ductal plates within the liver. A28B35 with biliary atresia. Other haplotypes of potential
involvement include HLA-Cw4/7, HLA-A33, HLA-B44, and
HLA-DR6 and a higher prevalence of specific polymorphisms
Genetic Factors in selected genes, such as SNP rs17095355 on 10q24 of ADD3
Several genes have been implicated in the abnormal develop- gene [30]. This path of inquiry will benefit from future valida-
ment of the biliary system and potentially in the pathogenesis tion studies in a large patient population.
of biliary atresia [6, 7, 26]. Anomalies of visceral organ sym- Histological and immunostaining analyses of the liver and
metry, including complete abdominal situs inversus, severe extrahepatic remnants suggest that lymphocytes, dendritic
jaundice, and death within the first week of life, have been cells, and Kupffer cells play key roles in the regulation of
reported in transgenic mice that have a recessive insertional inflammation and destruction of bile ducts in infants with
mutation in the proximal region of mouse chromosome 4 and biliary atresia. Both CD4 T-cells and natural killer cells are
deletion of the inversin (inv) gene, but the role in pathogenesis increased in livers at diagnosis and are associated with epithe-
of biliary atresia remains undefined in view of the inability to lial cell pyknoses within intrahepatic portal tracts, porta hepa-
detect abnormalities of INV in children with laterality defects tis, and common bile duct remnants [7, 31]. The liver expresses
and biliary atresia [27]. high levels of cytokines and receptors, such as tumor necrosis
Gene sequencing studies have reported variants associated factor-α, interleukin-2 and its receptor, the transferring recep-
with biliary atresia; FOXA2 variants were found in members of a tor CD71, and interferon-γ. More direct evidence for an effec-
single family and ADD3 and GPC1 variants in surveys of cohorts tor role of T-lymphocytes emerged from a report that liver and
of children with biliary atresia [4]. Other variants reported in bile duct remnants of patients with biliary atresia have oligo-
larger cohorts include PKD1L1 (encoding a ciliary protein) and clonal expansion of CD4 and CD8 T-cells [32]. These techni-
EFEMP1 (encoding the elastic fiber protein fibulin-3) [4]. cally challenging experiments add functional relevance to this
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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

group of antigen-specific T-cells, and set the stage for future circumstantial. Another relates to the paucity of regulatory
studies investigating their relationship to molecular epitopes in T-lymphocytes in the liver and other peripheral tissues in the
cholangiocytes. One example is the detection of elevated levels first three days of life in mice. These regulatory cells have an
of anti-enolase antibodies in ~35% of infants with biliary important immunomodulatory function; their absence leads to
atresia [33]. an array of autoimmune phenotypes. Regulatory T-cells were
The prevailing hypothesis that pro-inflammatory cytokines reported to be nearly absent from mouse livers following
are important to the pathogenesis of biliary atresia has been rotavirus challenge in the first three days of life [36]. In con-
tested in the rotavirus-mouse model. In this model, blocking of trast, when rotavirus was injected at seven days of age, a time
signals regulated by interferon-γ, α2-integrin and interleukin- when the liver was populated by regulatory T-cells, mice were
15 prevented bile duct obstruction and the phenotype of biliary resistant to the biliary atresia phenotype. How these results
atresia [7, 34]. Searching for the cellular basis of cytokine apply to susceptibility to biliary injury in humans, however, is
production and biliary obstruction, individual mononuclear unknown.
cells were depleted in newborn mice to examine their contri- The combined genetic and cell depletion studies in mice
bution to the atresia phenotype. While the loss of CD4 cells had uncover a continuum of biological events that produce
no obvious influence on the biliary injury, individual depletion obstruction of extrahepatic bile ducts in a fashion that recapi-
of CD8 lymphocytes, NK lymphocytes, dendritic cells, or tulates some features of the disease in humans. The events
macrophages decreased the epithelial injury and/or prevented begin with a viral infection (e.g., rotavirus) that targets the
the obstruction of extrahepatic bile ducts, with improved bile duct epithelium and primes macrophages and dendritic
growth and long-term survival in experimental mice [3, 7, cells (“initiating” phase). This is followed by activation of NK
35]. The similarities between the phenotypes produced by the cells that injure cholangiocytes and disrupt mucosal continuity
loss of these cell types and cytokines suggest that they work in (phase of epithelial injury). An amplification of the adaptive
concert to promote duct obstruction, and may constitute ther- immune response by CD4 and CD8 T-cells and by the release
apeutic targets to block progression of liver disease. of pro-inflammatory cytokines form a cellular plug at the site
One feature that deserves special note is the restriction of of epithelial injury (phase of obstruction), followed by the
onset of disease to the first few months of life in infants and the evolution to collagen deposition to produce the atresia pheno-
first few days of life in mice, suggesting that the mechanisms of type (Figure 11.2).
disease are substantially influenced by developmental factors.
This feature may be explained by the influence of genes reg- Environmental Toxic Exposure
ulating embryogenesis, such as PKD1L1, FOXA2, EFEMP1,
To date, the only supportive patient-based evidence for a toxic
and others as discussed above [4, 29]. However, the lack of
insult as a causative factor of biliary atresia is the time–space
congenital malformations in the majority of patients opens the
clustering of cases. In animals, unusual outbreaks of hepato-
possibility of a greater influence of other biological processes.
biliary injury in lambs and calves in New South Wales,
Among them is an inflammatory response triggered by the
Australia, occurred in 1964 and 1988, with pathologic speci-
presence of rare maternal cells in the liver of affected infants
mens displaying features akin to the pathology seen in humans
(maternal chimerism). Evidence for this process is largely
with biliary atresia [37]. Investigators have been able to isolate

Figure 11.2 Proposed model of the pathogenesis of biliary

atresia identifies a continuum of disease, in which an initial
insult targets the bile duct epithelium and activates an
immune response that obstructs the duct lumen
(inflammatory plug) and rapidly progresses to fibrosis and
atresia. At the stage of epithelial injury, macrophages (M),
neutrophils (N), dendritic cells (DC) and natural killer (NK) cells
work collaboratively to injure cholangiocytes via several
effector cytokines. Regulatory T (Treg) lymphocytes are
proposed to suppress the response of dendritic cells and
lymphocytes. At the stage of inflammatory plug, the adaptive
immune system makes use of DC, NK, and CD8 T-cells and
cytokines to amplify the inflammatory response. In the later
stages of atresia, alternatively activated macrophages and
fibrosis-related cytokines promote tissue fibrosis. IFNγ:
interferon-γ; IL: interleukin; TNFα: tumor necrosis factor-α;
NKG2D: activating receptor on NK cells; RAE-1: mRNA export
factor; MIP-2: macrophage inflammatory protein 2; TGFβ:
transforming growth.

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 Section II: Cholestatic Liver Disease

and synthesize a toxin (named “biliatresone”) from plants Box 11.1 Evaluation of Infants with Cholestasis
eaten by pregnant rams and showed that it causes selective
extrahepatic biliary damage in larval zebrafish and in mice. General Evaluation
There is no evidence that patients with biliary atresia have been
1. Clinical evaluation (family and gestational history,
exposed to biliatresone, but the identification of key structural
feeding history, physical examination, assessment of
motifs may allow detection of toxins with human relevance.
stool color).
2. Serum bilirubin (fractionated), aminotransferase levels,
Vascular Abnormalities index of hepatic synthetic function (prothrombin time,
Developmental abnormalities in the position of the portal vein international normalized ratio), level of matrix
and in hepatic artery anatomy at the porta hepatis are common metalloproteinase-7 (MMP-7).
in patients with biliary atresia. There are no consistent experi- 3. Cultures (blood, urine, spinal fluid) as indicated.
mental data, however, to confirm the hypothesis that there is a 4. Determination of serum bile acid levels (if normal or low
vascular basis, such as ischemia, as a cause of the progressive in the presence of direct hyperbilirubinemia, proceed
with qualitative analysis of urinary bile acid profile).
duct injury seen in biliary atresia [38]. In utero devasculariza-
5. Serum gamma-glutamyltransferase level.
tion or ligation of the extrahepatic bile duct has been attempted
6. Serum electrolytes (to exclude acidosis).
in some animal models, and lesions similar to the less common
“correctable” variants of biliary atresia have been produced; Specific Evaluation (to Exclude or Confirm a Specific Diagnosis)
however, other studies have been inconclusive.
• α-1-antitrypsin phenotype.
• Thyroxine and thyroid-stimulating hormone.
Diagnosis of Biliary Atresia • Sweat chloride-CFTR mutational analysis (to exclude cystic
Various laboratory tests, imaging methods, and biopsy samples fibrosis).
have been utilized in attempts to establish the diagnosis of • Ferritin–transferrin concentration and saturation.
biliary atresia, particularly in differentiating it from various • Metabolic screen (urine-reducing substances, urine/serum
forms of intrahepatic cholestasis (idiopathic neonatal hepati- amino acids, organic acids, succinyl acetone).
tis). Liver histopathology is highly informative and reliable in • Hepatitis B surface antigen, anti-HIV, and Venereal Disease
deciding when to perform an intraoperative cholangiogram, to Research Laboratory titers for syphilis.
directly assess bile duct patency. Liver biopsy interpretation • Abdominal ultrasonography.
offers a diagnostic accuracy of 95% if a sample of adequate size,
• Liver biopsy.
containing five to seven portal spaces, is obtained and carefully
interpreted. A new serum biomarker, matrix metalloprotei-
nase-7 (MMP-7), has been reported to have sensitivity and
specificity >95% to discriminate biliary atresia from other prevent spontaneous, life-threatening bleeding, such as
causes of neonatal cholestasis [4]. intracranial hemorrhage.
3. “Idiopathic” neonatal intrahepatic cholestasis must be
Evaluation differentiated from biliary atresia because the prognosis
Our approach to the work-up of an infant with cholestasis is and management differ significantly. In infants with biliary
shown in Box 11.1. We recommend the following sequential atresia, progressive fibrosis rapidly occurs; therefore, a
approach: significant delay in diagnosis or treatment must be avoided.
1. Prompt recognition of cholestasis is essential. Jaundice in No single test is entirely satisfactory in discriminating intra-
an infant must not be attributed erroneously to physiologic hepatic cholestasis from biliary atresia; however, historical and
hyperbilirubinemia or to breast-feeding. Fractionation of clinical features may aid in the differential diagnosis. Neonatal
the serum bilirubin usually separates out these later hepatitis is reported to have a familial incidence of 15–20%; in
conditions, which cause a predominant elevation (>80%) of contrast, the intrafamilial recurrence risk is negligible for biliary
unconjugated bilirubin levels. atresia. Infants with biliary atresia may look well, become clini-
2. The evaluation should be expeditiously performed to rule cally jaundiced at three to six weeks of age, and have slowly
out potentially devastating illnesses such as sepsis, progressive elevation of serum bilirubin levels but seldom have
endocrine disorders, and nutritional hepatotoxicity pruritus or skin xanthoma as seen in forms of intrahepatic
attributable to metabolic disease (e.g., galactosemia). cholestasis). The liver is enlarged and firm; splenomegaly occurs
Definitive detection is usually straightforward, and as cirrhosis develops. Stools of patients with biliary atresia are
institution of appropriate treatment for these conditions acholic at presentation, but early in the course, during the
may prevent further liver injury. Early recognition of evolving process of bile duct obliteration, they may contain
specific, treatable primary causes of neonatal cholestasis some bile pigment. Acholic stools are either intermittent or
also allows particular clinical issues to be addressed. For delayed in onset in a quarter of patients with biliary atresia
example, hypoprothrombinemia may be present regardless and are present in some patients with neonatal hepatitis. The
of the cause of cholestasis; administration of vitamin K may consistent presence of pigmented stools excludes biliary atresia.

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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

Hepatobiliary scintigraphy using iminodiacetic acid analo- Role of Liver Biopsy

gues has been used to provide discriminatory data. In biliary
In our experience, clinical examination, careful and repeated
atresia, hepatocyte function is intact early in the disease; there-
examination of the stool, and needle biopsy of the liver cor-
fore, uptake of the imaging agent is unimpaired but excretion
rectly identify the majority of patients with biliary atresia. In
into the intestine is absent. Conversely, in intrahepatic choles-
most patients, biopsy can be performed safely via percutaneous
tasis, tracer uptake is sluggish or impaired but excretion into
route with or without ultrasound guidance with sedation and
the bile and intestine eventually occurs. Oral administration of
local anesthesia or general anesthesia. An accurate, biopsy-
phenobarbital, 5 mg/kg daily for five days before the study, is
based diagnosis is possible in up to 95% of patients and avoids
required to enhance biliary excretion of the isotope and, there-
unnecessary surgery in patients with intrahepatic disease. Early
fore, the sensitivity of the procedure. However, in our experi-
in the progression of biliary atresia, the liver shows preserva-
ence, this may delay the evaluation process and is rarely
tion of the basic hepatic architecture, with bile ductular pro-
definitive, therefore we do not recommend the use of scinti-
liferation, canalicular and cellular bile stasis, and portal or
graphy. Techniques that are used extensively in evaluation of
perilobular edema and fibrosis (Figure 11.3). Bile plugs in the
adults with cholestatic disease, such as percutaneous transhe-
portal ducts are relatively specific but are found in only 40% of
patic and endoscopic retrograde cholangiography, are not of
biopsy specimens. Portal fibrosis with wide swaths of connec-
proven value in children. Ultrasonography may detect dilation
tive tissue extending into the liver substance develops in older
of the biliary tract, the presence of a choledochal cyst, or, in
infants but may be already present at diagnosis. Approximately
patients with biliary atresia, absence of the gallbladder.
25–40% of infants have portal inflammatory infiltration and
Ultrasound can also identify a sonographic finding known as
hepatocyte giant cell transformation indistinguishable from
a triangular cord, a fibrous cone of tissue at the bifurcation of
neonatal hepatitis. These portal tract findings contrast with
the portal vein that has been associated with biliary atresia [39].
those of neonatal hepatitis, in which variable, often severe,
Numerous diagnostic algorithms incorporating these fea-
intralobular cholestasis may be accompanied by focal hepato-
tures have been proposed in an attempt to select those infants
cellular necrosis. Bile ducts show little or no alteration in
who are surgical candidates and to avoid unnecessary surgery.
idiopathic intrahepatic cholestasis. Portal inflammatory infil-
Discriminatory analysis of clinical, biochemical, and histolo-
trates are present in both conditions and tend to be more
gical data obtained from 288 infants younger than three
prominent in idiopathic intrahepatic cholestasis. Portal area
months presenting with neonatal cholestasis allowed for an
stroma is more likely to show edema in patients with biliary
accurate differentiation in 85% of the patients [40]. The follow-
atresia. Giant cell transformation and extramedullary hemato-
ing features occurred significantly more frequently in infants
poiesis, particularly sinusoidal erythropoiesis, are found in a
with intrahepatic disease, than in infants with biliary atresia:
large percentage of infants with either condition and have no
male gender, low birth weight, later onset of jaundice (mean of
diagnostic specificity. In very young infants, the initial biopsy
23 vs. 11 days of age), later onset of acholic stools (mean of 30
may be inconclusive; re-biopsy after 7–14 days may be more
vs. 16 days), and pigmented stools within ten days after admis-
definitive.
sion (79% vs. 26%). Patients with biliary atresia more fre-
The scoring systems discussed above have been evaluated
quently had hepatomegaly, and the liver usually had a firm or
in the differential between obstructive and non-obstructive
hard consistency. Despite the use of scoring systems such as
forms of neonatal cholestasis [41, 42]. The accuracy, sensitiv-
this, about 10% of infants with intrahepatic cholestasis cannot
ity, and specificity rates reported by Zerbini et al. were all 94%
be distinguished from those with biliary atresia. Unnecessary
[42]. The model then was applied to a new sample of 74 needle
surgical explorations are to be avoided; however, delay in
liver biopsy specimens. The accuracy, sensitivity, and specifi-
establishing a diagnosis also is unwarranted because the data
city rates were 91%, 100%, and 76%, respectively. In a multi-
suggest that the success rate for surgical management of
center study, analysis of 97 liver biopsy samples was carried out
patients with biliary atresia rapidly declines with age.
by a group of pediatric pathologists; the histological features

Figure 11.3 Histological changes in patients with biliary atresia. (a) Portal tract expansion with increased bile duct profiles, edema, and a bile plug (arrow)
(magnification 200×). (b) Biopsy with a predominant inflammatory infiltrate (magnification 200×). (c) Biopsy with porto-portal fibrosis (with minimal inflammatory
cells, magnification 100×). All biopsy slides were stained with hematoxylin and eosin.

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 Section II: Cholestatic Liver Disease

that best predicted biliary atresia on the basis of logistic regres- in the hepatoportoenterostomy. For example, extension of the
sion were bile duct proliferation, portal fibrosis, and absence of dissection beyond the portal vein bifurcation, which incorpo-
sinusoidal fibrosis, with a positive predictive value of 91% [41]. rates a larger amount of biliary remnants, improves bile flow.
This suggests that if extrahepatic obstruction cannot be ruled The principles of contemporary surgical management for
out, limited exploration with cholangiography and repeat nee- biliary atresia are based, in part, on the conclusions of the 1983
dle or wedge biopsy of the liver should be performed; if atresia National Institutes of Health Consensus Conference on Liver
is apparent, the biliary tract can be explored further. Transplantation: (1) hepatoportoenterostomy should be the
primary surgical therapy for patients with biliary atresia; (2)
Role of Surgical Exploration transplantation is an appropriate therapy for patients with
biliary atresia who fail primary hepatoportoenterostomy; (3)
When the suspicion of biliary obstruction is high, operative
liver transplantation should be delayed as long as possible to
exploration should be performed to document the presence
permit maximum growth; (4) transplantation should be
and the site of obstruction and to direct attempts at surgical
deferred until progressive cholestasis, hepatocellular decom-
drainage. Cholangiography and meticulous exploration of the
pensation, or severe portal hypertension supervenes; and (5)
entire biliary tree should be carried out. The decision made at
multiple attempts to revise an unsuccessful Kasai procedure
the operating table may be aided by observations of features
are not warranted because they can make liver transplantation
usually associated with biliary atresia, such as consistency
more difficult and dangerous [6, 48, 49].
(coarse, fibrotic) and color (green) of the liver, and the pre-
sence of subcapsular telangiectasia (early vascular obstruction
secondary to fibrosis). Surgical Management
The approach outlined here is not without pitfalls; caution
Sequential surgical therapy for biliary atresia is divided into
should be exercised in interpretation of certain studies, par-
two steps: the establishment of a secure diagnosis, then the
ticularly in very young infants. In four patients reported by
construction of the portoenterostomy. The importance of
Markowitz et al. [43], scintigraphy suggested biliary atresia,
establishing an unequivocal diagnosis before proceeding to
and intraoperative cholangiography failed to demonstrate
hepatoportoenterostomy cannot be overstated. The initial
any proximal intrahepatic biliary radicals; therefore, hepato-
step in the exploration should both confirm the diagnosis of
portoenterostomy was performed. There was inadequate
biliary atresia and exclude other diagnoses not improved by
postoperative drainage with cholangitis, development of cir-
operative intervention, such as various forms of intrahepatic
rhosis in two, and death from hepatic failure in one infant.
cholestasis. This can be done through direct observation and
Subsequently, a histological and clinical diagnosis of intrahe-
definition of the distal biliary ductal anatomy using cholecys-
patic cholestasis (Alagille syndrome) was made in each of the
tocholangiography. The liver in patients with biliary atresia is
four patients. The progression of the hepatic disease in these
firm and shows a cholestatic brown–green discoloration often
patients suggested that portoenterostomy had adversely
accompanied by multiple sub-capsular telangiectasias. The
altered the course of their disease (compared to the natural
gallbladder remnant is usually fibrotic but may contain a
history of Alagille syndrome). During cholangiography, an
small amount of clear mucoid secretions. Early in the course
absence of retrograde flow into the proximal intrahepatic
of the disease, the hilar structures and the biliary ductal rem-
ducts does not exclude the presence of a patent, albeit hypo-
nant may show a considerable amount of edema. In older
plastic, extrahepatic biliary duct system in a patient with
children, these structures are fibrotic and more difficult or
intrahepatic disease. The liver disease in intrahepatic choles-
impossible to identify. If these findings are accompanied by a
tasis syndromes, such as Alagille syndrome, is not amenable
fibrotic gallbladder, cholangiography may not be possible and
to surgical correction, and portal dissection should not be
biliary atresia is confirmed. If the gallbladder is not obliterated,
attempted.
gentle cholecystocholangiography is undertaken to further
define the operative course. Because of the small gallbladder
Management of Patients with Biliary Atresia volume and minimal ductal size in infants, the cholangiogram
At present, there is no specific medical therapy for patients with should be visualized from its onset using fluoroscopy to avoid
biliary atresia. The first breakthrough in the surgical therapy of overdistension and extravasation, which preclude successful
patients with biliary atresia occurred in the late 1950s when Dr. visualization of ductal structures. If the ductal system is normal
Morio Kasai and associates described microscopic bile ducts or the bile ducts are small/hypoplastic but patency confirmed
within the fibrous remnant of the atretic biliary tree at the with contrast in the intrahepatic biliary system as well as in the
porta hepatis [44]. This led to the important observation that duodenum, a generous wedge and needle biopsies are
if the extrahepatic bile ducts were removed at a time at which obtained; however, biliary reconstruction should be specifi-
there was continuity between the microscopic ducts in the ductal cally avoided. If flow into the distal biliary tract is seen but
plate at the porta hepatis and the intrahepatic biliary system, the no proximal flow is documented, a light spring-loaded vascular
progression of biliary atresia could be arrested. This operation, occlusion clamp should be placed on the supraduodenal biliary
the Kasai hepatoportoenterostomy, thus became the standard structures before additional attempts to visualize the proximal
surgical approach [44–48]. As experience has grown, there ductal system. The Kasai hepatoportoenterostomy should be
have been minor, though significant, technical improvements undertaken if no proximal patency is documented.

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Anatomic Variants of Biliary Atresia to the dorsal aspect of the anterior portal vein branch and over
the bifurcation of the anterior and posterior portal vein
The anatomy of the abnormal extrahepatic bile ducts in
branches. The left portal vein is also dissected to the umbilical
patients with biliary atresia is variable. The currently accepted
point, which often requires division of the parenchymal bridge
classification of anatomic variants of biliary atresia is based on
surrounding the round ligament between segments 3 and 4 of
that proposed by the Japanese Society of Pediatric Surgeons,
the liver [45, 46]. The fibrous remnant tissue is divided sharply
which divides the abnormal anatomy into three principal
along a plane parallel to and at the level of the hepatic capsule.
types: type 1, atresia of the common bile duct; type 2, atresia
Deeper dissections into the hepatic parenchyma have not led to
of the common hepatic duct; and type 3, atresia of the right and
improved results. Hemostasis at the transected remnant is
left hepatic ducts. Further subdivisions include the variable
achieved by warm irrigation and direct pressure. Suture liga-
morphology of the gallbladder/distal common bile duct and
tion and electrocautery are discouraged because they may
the hilar plate. Absence of the proximal biliary tree has been
damage the small ductal remnants critical for success.
termed biliary agenesis. “Correctable” lesions – distal common
Roux-en-Y drainage using a 35–40 cm isoperistaltic retro-
bile duct atresia with a patent portion of the extrahepatic duct
colic jejunal limb is preferred because this limb may be used
up to the porta hepatis and joining the intrahepatic ducts –
later for biliary reconstruction during transplantation if neces-
allow direct drainage into a Roux-en-Y anastomosis. The most
sary. This limb should be fashioned from the most proximal
commonly encountered lesion (seen in 75–85%), however, is
portion of the jejunum, allowing bile to return to the proximal
obliteration of all of the ducts throughout the porta hepatis
intestine, improving nutrient and medication absorption. The
(type 3), presenting an apparently “non-correctable” type of
Roux-en-Y hilar anastomosis should be undertaken using
atresia. In these patients, minute bile duct remnants or residual
absorbable monofilament suture material to avoid the pre-
channels may be present in the fibrous tissue within the porta
sence of a nidus for later infection. This suture margin is placed
hepatis. These channels are often in continuity with the intra-
just outside of the divided hilar tissue margin to avoid transfix-
hepatic ductal system and, therefore, could provide drainage. If
ing any ductal remnants. The anastomotic suture line should
flow is not established rapidly in these ducts, progressive oblit-
surround or invaginate the vascular branches, incorporating all
eration ensues. Biliary drainage is attempted by excision of the
the fibrous tissue within the lumen. This technique excludes
obliterated extrahepatic ducts and reconstruction of the
the portal vein wall from the cut surface and inhibits its
resected surface of the transected porta hepatis to the bowel
attachment to and scarring of the potential ductal drainage
mucosa in a Roux-en-Y hepatoportoenterostomy fashion – the
area. Anti-reflux valves are not recommended, but the jejuno-
Kasai procedure. The patient with “agenesis” in porta hepatis
jejunal anastomosis is fashioned in an isoperistaltic manner to
specimens does not respond to Kasai drainage procedures.
inhibit enteric flow into the drainage limb.
In patients in whom cholangiography indicates distal
Hepatoportoenterostomy patency of the common bile duct with good luminal caliber
When the diagnosis of biliary atresia is confirmed, the second and proximal biliary ductal atresia, a hepatic portocholecys-
phase of the operative procedure, the Kasai hepatoportoenter- tostomy (gallbladder Kasai) procedure may be created as an
ostomy, is begun. The traditional dissection of the portal alternative to conventional hepatoportoenterostomy. In this
fibrous mass begins by transecting the distal duct remnant procedure, the gallbladder is mobilized from its hepatic fossa,
above the duodenal margin, mobilizing the gallbladder rem- protecting the cystic arterial supply. The distal gallbladder is
nant from its hepatic bed, and dissecting this fibrous remnant transected, and an opening is sutured to the biliary hilum,
from the anterior portal vein wall. It is important to emphasize replacing the Roux-en-Y drainage limb. In these patients,
that in biliary atresia, the bile ducts are not absent but rather drainage through the distal biliary structure and intact sphinc-
replaced by fibrous tissue. The anatomic course of the ductal ter of Oddi virtually eliminates ascending cholangitis in the
remnants follows the normal biliary position within the portal postoperative period, as long as the distal biliary structures are
triad to reach the liver hilum. The fibrous remnant then pro- large enough to accommodate normal bile flow. If a gallbladder
ceeds posteriorly and passes superior to, but within the bifur- Kasai is performed and drainage does not occur, a low thresh-
cation of, the portal vein to reach the capsular surface of the old to re-explore and to convert to the standard Roux-en-Y
liver [47, 48]. Individual small portal vein branches passing conduit should be considered.
directly into the fibrous mass must be divided. This allows
downward displacement of the portal vein bifurcation, which Prognosis after Surgery
facilitates full dissection of the fibrous triangular mass before A proportion of patients with biliary atresia will derive long-
its transection at the level of the liver capsule (Figure 11.4). term benefit from hepatoportoenterostomy. In most patients,
In the original Kasai hepatoportoenterostomy, the fibrous however, variable degrees of hepatic dysfunction persist, often
triangle was dissected and divided between the right and left because of severe intrahepatic cholangiopathy. The long-term
branches of the portal vein at the level of the posterior surface prognosis is related directly to the establishment of successful
of the portal vein. Further revision of this technique has shown bile flow and the disappearance of jaundice, with increased
that meticulous dissection of the lateral fibrous triangle tissues long-term survival with the native liver in children with serum
allows more of the segmental biliary structures to be included bilirubin <1 mg/dL within three months of hepatoportoenter-
in the divided hilar tissue. On the right, the dissection is carried ostomy; in these children the ten-year survival ranges from

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 Section II: Cholestatic Liver Disease

(a) (b)

(c)

Figure 11.4 The Kasai hepatoportoenterostomy. (a) Division site. Fibrous triangle (arrows) dissected superior to the bifurcation of the portal vein before division.
The portal vein must be retracted inferiorly to visualize the posterior surface of the fibrous mass and the liver capsule. (b) Kasai procedure. Schematic representation of
fibrous triangular mass before its division and the location (stippled areas) of the primary biliary remnants within the classic dissection limits (small arrows) and within
the extended dissection areas (broad arrows). (c) Completed hilar dissection. The fibrous mass is divided parallel and at the level of the liver capsule within the
bifurcation of the portal vein (small arrows). Divided fibrous mass margins outlined with arrowheads.

73% to 92% [4, 6, 26]. In those patients in whom jaundice 49, 50]. The success rate drops dramatically, to under 20%, in
remains and bile flow is inadequate, the three-year survival rate those older than 90 days at the time of operation.
decreases to 20%. Even in patients with transient bile flow Consequently, performance of the Kasai procedure after
whose jaundice does not resolve, some benefit, namely growth three months of age may be justified, but only in selected
to a size sufficient to receive a transplant, is often achievable. cases. A second factor is size of the ducts visualized in tissue
The variable prognosis after hepatoportoenterostomy is from the porta hepatis. Microscopic ductal patency of more
related to several factors. A factor is age at operation. With than 150 μm should determine successful postoperative bile
the Kasai procedure, the timing of the surgery correlates with flow, although this concept is not universally recognized. For
outcome. In some series, it has been reported that bile flow can those patients with smaller or no identifiable epithelial-lined
be re-established in more than 80% of infants who were structures in fibrous tissue, the success rate is low [51, 52].
referred for surgery within 60 days after birth [4, 6, 26, 44, Prognosis after portoenterostomy procedures may also be

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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

correlated with the degree or proliferation of the periductular drainage with suspected mechanical obstruction originating in
glands; the hilar biliary plexus may act as a drainage route for the intestinal conduit.
bile in these patients. A third determinant is the experience and The increased intraperitoneal and perihepatic adhesions
operative technique of the surgeon. that complicate subsequent liver transplantation are most
The rate of progression of the liver disease may be the often the consequence of repetitive but misdirected attempts
overall limiting factor; a nearly universal finding is the pre- to re-operate on poorly selected candidates with a poor prog-
sence of a persistent intrahepatic inflammatory process, which nosis for improvement or recurrent episodes of bacterial
may partially account for the poor results and the development peritonitis
of portal hypertension. The continuing nature of the disease
process may be caused by an immunologically mediated injury Medical Treatment Following
or the toxicity of retained bile acids. Examining histological
markers at diagnosis may be predictive of clinical outcome and
Hepatoportoenterostomy
prognosis. For example, quantification of the extent of portal The goals of postoperative management of infants with biliary
fibrosis by applying a computerized system or detecting the atresia are three-fold: (1) prevention of cholangitis, (2) stimula-
presence of extensive bile duct proliferation may portend a tion of choleresis, and (3) nutritional support. Infants typically
poor outcome. Other prognostic indicators include the pre- receive parenteral broad-spectrum antibiotics perioperatively
sence of molecular signature for inflammation or fibrosis at the and for two to five days after surgery, followed by oral prophy-
time of hepatoportoenterostomy, with markers of fibrosis indi- laxis with trimethoprim-sulfamethoxazole (5 mg/kg trimetho-
cating decreased survival with the native liver [7]. Other factors prim daily) or another antibiotic for 3 to 12 months.
affecting prognosis include secondary postoperative complica- Ursodeoxycholic acid (10 mg/kg per day), a more hydrophilic
tions, namely bacterial cholangitis, which is a constant threat bile acid, has been used to improve choleresis. Although a few
and may lead to re-obstruction [51, 53–56]. Patients who pre- studies have documented the efficacy of ursodeoxycholic acid in
viously had good bile excretion may have repeated episodes of promoting choleresis, weight gain, decreased pruritus, and
fever, increased jaundice, acholic stools, leukocytosis, and improved liver enzymes, it has no obvious impact on long-
occasionally evidence of bacteremia. Intrahepatic portal vein term survival or the need for transplant [57]. The use of corti-
thrombosis can aggravate pre-existing presinusoidal resistance costeroids postoperatively was not shown to be effective in
caused by progressive parenchymal fibrosis, which is the end improving bile flow in a double-blind, randomized, placebo-
result of intrahepatic inflammation or recurrent bouts of controlled trial [58], but may be effective when used in infants
ascending cholangitis. Intrahepatic biliary cysts have been having hepatoportoenterostomy before 45 days of age [59].
noted in about 20% of patients with biliary atresia; episodes Future multicenter clinical trials that take into account age at
of cholangitis may precede discovery of the cysts. Hepatic diagnosis and the biological makeup are required to determine
artery resistance index has been measured by Doppler ultra- objectively the role of corticosteroids as an adjunct therapy
sonography and has been found to predict rapid deterioration following portoenterostomy.
and death in children with biliary atresia [6]. Infants should receive approximately 125% of the recom-
mended dietary calorie allowance based on weight for height at
the 50th percentile, with additional calories often needed if
Role of Reoperation Following biliary drainage is marginal. If cholestasis is present, infants
Hepatoportoenterostomy require supplementation and close monitoring to prevent the
Several series have emphasized the potential value of reopera- consequences of vitamin deficiencies: vitamin A 5,000–25,000
tion in patients with cessation of bile flow after initial success IU/day, vitamin D 1,200–4,000 IU/day, vitamin E 25 IU/kg per
or in patients with refractory cholangitis. In many patients, day (in a miscible form: d-α-tocopheryl polyethylene glycol
debridement or revision of the scarred area may result in the 1000 succinate (TPGS)), and vitamin K 2.5 mg three times
re-establishment of bile flow. If a patient had poor bile flow per week. Doses must be adjusted based on serum levels of
initially, reoperation is usually unsuccessful in establishing specific vitamins and prothrombin time/international normal-
flow. Reoperation should be limited to infants in whom suc- ized ratio (for vitamin K). Unfortunately, malnutrition fre-
cessful bile drainage was achieved after the initial operative quently develops with persistent cholestasis; liver disease
procedure, leading to an anicteric state which was then fol- progresses despite adequate nutritional support, and coagulo-
lowed by an abrupt cessation of bile excretion. Evaluation for pathy not responsive to vitamin K supplementation develops
reoperation is usually considered after appropriate treatment late in the course of the liver disease.
of the infant with antibiotics and corticosteroids for the possi-
bility of ascending cholangitis. These infants should have had Outcome
favorable hepatic histology and biliary ductal remnants at their Progressive biliary cirrhosis and hepatic failure may occur
initial operation. Reconstitution of suitable bile flow following despite apparent success in achieving bile drainage. Factors
debridement or revision of the scarred hilar area is successful that contribute to failure include stenosis of the anastomosis,
in more than half the patients undergoing reoperation using ascending cholangitis, and progressive loss of intrahepatic
these highly selective criteria [47, 56]. Subsequent tertiary re- bile ducts that may have been injured before the drainage
exploration should be limited to patients with established bile procedure. Liver transplantation is necessary in infants with

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 Section II: Cholestatic Liver Disease

a failed hepatoportoenterostomy, manifest by progressive Liver Transplantation

hepatocellular decompensation, jaundice, refractory growth
Biliary atresia remains the primary indication for liver trans-
failure with hepatic synthetic dysfunction and the develop-
plantation in the pediatric age group, constituting about 50%
ment of a coagulopathy, or intractable portal hypertension
of children undergoing transplantation. Liver transplantation
with recurrent gastrointestinal hemorrhage or hypersplen-
should be delayed as long as possible to permit maximal
ism. The risk of death or need for liver transplantation has
growth. Repeated attempts at revision of the hepatoportoen-
been estimated at 50% at six years after the initial episode of
terostomy or portosystemic shunting may be ineffective and
esophageal variceal hemorrhage. Patients with a serum bilir-
render eventual transplantation more difficult.
ubin <4 mg/dL at the first episode of esophageal variceal
Children undergoing liver replacement today can expect sur-
hemorrhage had a transplant-free survival rate of more than
vival rates approaching 95% as a result of improved techniques of
80% for four years after this episode; those with serum
preoperative management, resolution of major intraoperative
bilirubin of 4–10 mg/dL had 50% survival at one year, and
technical problems associated with microvascular reconstruction
those with serum bilirubin >10 mg/dL had 50% survival at
of the hepatic vasculature, and precise postoperative immunosup-
four months [60]. Therefore, compared with the risk for an
pression and management of infectious diseases [62]. The remain-
age-matched child who did not have esophageal variceal
ing factor that limits widespread application and prevents access
hemorrhage, the risk of death or transplant for child with
by all pediatric candidates to transplantation is the scarcity of
esophageal variceal hemorrhage was 12-fold greater when
adequate donor organs. The surgical techniques necessary to
the total serum bilirubin was >10 mg/dL, seven-fold when
allow all variations of whole, split liver, and living donor trans-
it was 4–10 mg/dL, and 0.6-fold when it was 4 mg/dL or less.
plantation were developed in an attempt to meet this desperate
A late complication of biliary atresia-associated portal
need, yet increasing numbers of potential recipients overwhelm
hypertension is the hepatopulmonary syndrome, defined as
these resources. The disparity in size-matched pediatric donors is
intrapulmonary vascular dilatation with shunting and arterial
compounded by the preponderance of children with biliary atresia
desaturation. This syndrome is associated with decreased
among the candidates for liver transplantation in the pediatric
exercise tolerance and digital clubbing and seems to correlate
population; 55% of deaths in children from liver diseases occur
with the presence of cutaneous spider telangiectasia.
before two years of age. In these patients, liver replacement is
Hepatopulmonary syndrome may be reversed by liver trans-
necessary at a very young age and small size, in view of the rapid
plantation; however, patients with hepatopulmonary syn-
progression of the hepatic disease and poor nutritional status. This
drome are more susceptible to postoperative complications.
creates an “epidemiologic disparity” because most pediatric
Portopulmonary hypertension, another of the pulmonary
donors are of school age or older. The use of reduced-size liver
vascular disorders complicating chronic liver disease, is
transplantation as an initial strategy is successful in both improv-
defined as pulmonary arterial hypertension associated with
ing patient survival and decreasing the waiting-list mortality rate
severe liver disease or portal hypertension. Portopulmonary
[63]. Before the introduction of reduced-size liver transplantation
hypertension, when left untreated, is fatal. The criteria for
at our center, 29% of children listed for transplantation died
portopulmonary hypertension include an elevated mean pul-
because of the lack of donor organ availability Since the institution
monary arterial pressure (>25 mmHg at rest), increased pul-
of segmental transplantation at Cincinnati Children’s Hospital
monary vascular resistance, and normal pulmonary capillary
Medical Center, the number of deaths while awaiting donor
wedge pressure in the presence of portal hypertension.
organ availability and the incidence of hepatic artery thrombosis
Clinical symptoms are subtle and may be overlooked.
has been substantially reduced. After the implementation of
Children with portal hypertension who develop a new heart
reduced-size liver transplant techniques, the waiting-list mortality
murmur, dyspnea, or syncope, or who are being evaluated for
rate has been reduced to 2% in our center, with similar reductions
liver transplantation, require evaluation for portopulmonary
in other centers. Although 45% of children still undergo trans-
hypertension. Electrocardiography and chest radiography are
plantation with a status of high medical urgency, the wider range
insensitive screening tests; hence an echocardiogram and
of donors available using reduced-size allografts has allowed the
cardiology evaluation may be needed to confirm the
selection of donors with improved hemodynamic stability and
diagnosis.
liver function. These procedures established the successful techni-
Although the success rate for biliary enteric anastomosis
ques needed to advance both living donor and split liver trans-
in patients with biliary atresia cannot be predicted, it remains
plantation, both of which increase the donor pool rather than
the most reasonable initial approach. A retrospective study
redistributing the resources. However, these procedures encom-
was carried out to define the long-term outcome of children
pass increased perioperative risks to the recipient (and living
who have undergone surgery for biliary atresia [61]. Of 122
donor) [64]. Reduced-size liver transplantation is not the ideal
children, 38% were alive after ten years; however, firm
solution; however, expansion of the donor pool may be possible
hepato- and splenomegaly were present in about 75%.
through extension of the surgical techniques used to prepare
Normal liver enzymes and an absence of portal hypertension
reduced-size allografts. The need for orthotopic liver transplanta-
were observed in only 9% of the children. These results
tion in small children stimulated the development of other inno-
suggest that although hepatoportoenterostomy may be help-
vative operative procedures based on the concept of reduced-size
ful, about 80% of such children eventually require liver
allografts; these include split liver transplantation and the use of
transplantation.

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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

living, related organ donors. Liver transplantation survival rates Jaundiced Infant
for living donor, split, and reduced-size transplantation are similar
to those with whole-organ graft transplantation in children older
than two years. High conjugated bilirubin Late presentation
Despite the high overall success rate of liver transplantation in Obstructive pattern on liver biopsy Cirrhosis at presentation
children, multiple challenges remain, including improvement of
methods of preoperative management to address the problems of
Intraoperative cholangiogram
malnutrition, improvement of methods of immune suppression to
Hepatoportoenterostomy
prevent graft loss and avoid lympho-proliferative disease and
other infectious complications, and development of protocols
to avoid growth suppression. Children are particularly sensitive
to the consequences of both under-immunosuppression (linked to Bile drainage No bile drainage
Anicteric Jaundiced
rejection) and over-immunosuppression (linked to post-trans-
plantation lympho-proliferative disease, renal insufficiency, infec- Jaundice
tion). The latter is complicated by the fact that children appear to Unresponsive to medical treatment

be more immunoresponsive than adults.

Follow-up Consider surgical revision Transplant
Liver Transplantation as Primary Therapy No
improvement

for Biliary Atresia Figure 11.5 Flow chart for surgical interventions for patients with biliary atresia.
With clinical and histological features of biliary atresia, sequential management of
The selection of candidates for primary transplantation is best intraoperative cholangiogram followed by hepatoportoenterostomy (HPE) is the
accepted in patients in whom liver disease is so advanced best strategy to restore bile drainage. If successful, close follow-up may enable
(advanced age and cirrhosis) that bile flow cannot be restored. growth and development. If the infant had biliary drainage after HPE and
developed jaundice that did not respond to medical treatment, a surgical revision
Conservative decision-making should be practiced in this regard, can be considered. Delayed diagnosis (missed biliary atresia), poor bile drainage
knowing that even partial return of bile flow may allow transplan- after HPE, or persistent jaundice despite surgical intervention are best treated by
tation to be performed at an age at which prognosis is more liver transplantation.
favorable and a donor organ more readily available.
The limitations and potential pitfalls of primary liver trans- for patients with biliary atresia can be achieved through the
plantation have led to adaptation of a sequential approach in complementary and sequential utilization of early primary
the management of biliary atresia (Figure 11.5). therapy with the Kasai portoenterostomy followed by liver
Hepatoportoenterostomy would obviate the need for trans- transplantation if necessary. This series also emphasized the
plantation for patients in whom the procedure was a long- value of “center experience” in achieving these high success
term success or delay transplantation in a significant propor- rates [65]. The Kasai procedure is technically difficult, and
tion. In our opinion, therefore, sequential surgical therapy for success in achieving bile flow is related to the skill with which
biliary atresia should begin with creation of an hepatoportoen- this procedure is performed. Studies such as this argue for
terostomy. Infants with poor response will undergo transplan- conservative decision-making in this regard. Optimizing the
tation within the first two years. Children with initially outcome of the hepatoportoenterostomy can be obtained by
“successful” drainage but with progressive liver disease with addressing the controllable factors involved in the prognosis:
portal hypertension, hypersplenism, variceal hemorrhage, and early diagnosis and referral to a center experienced in the care
malnutrition will need orthotopic liver transplantation at a of children with this disorder.
later date. Future longitudinal studies of young adults with
biliary atresia will determine the ultimate proportion of biliary
atresia patients who require transplantation.
Outcome of Orthotopic Liver Transplantation
Chardot et al. [65] reviewed all patients with biliary atresia in Children
living in France and born between the years 1986 and 1996. A The most important factor determining post-transplant survi-
total of 472 patients were identified; the ten-year overall survi- val at our center is the severity of the patient’s illness at the time
val rate was 68%. Independent prognostic factors for overall of transplantation. Survival in infants has improved with
survival were the performance of the Kasai operation, age at increasing experience. This increase in survival results from
operation, anatomic pattern of extrahepatic bile ducts, poly- technical operative improvements and experienced care man-
splenia syndrome, and experience of the managing center. agement. A major challenge is the high frequency of virus-
Survival with native liver depended on the same independent related disease in children, particularly Epstein–Barr virus-
prognostic factors. These data support the concepts that the related. As the survival rates following orthotopic liver trans-
Kasai operation should remain the first-line treatment of bili- plantation in children have increased, healthcare providers
ary atresia and that early performance of this operation and have begun to measure the overall health status of liver trans-
treatment in an experienced center should reduce the need for plant recipients (functional outcome) as a complement to
liver transplantation in infancy and childhood and provide traditional measures of medical outcomes. The overriding
children with the best chance of survival. High survival rates objective of hepatic transplantation in children is complete

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 Section II: Cholestatic Liver Disease

rehabilitation with improved quality of life, as discussed in births in Japan. There is a marked female predominance (4:1)
Chapters 43 and 44. Factors contributing to the attainment of regardless of the racial origin. A choledochal cyst (or con-
this goal include improved nutritional status with appropriate genital bile duct cyst) may be detected at any age and in any
growth and development as well as enhanced motor and cog- portion of the bile duct. Choledochal cysts can be classified
nitive skills, allowing social reintegration. into five subtypes (Figure 11.6; Table 11.2). With the advent
of screening ultrasounds during pregnancy, antenatal diag-
Future nosis of cystic lesions in the hilum of the liver has become
common. The differential diagnosis for these lesions includes
The ultimate goal is to prevent biliary atresia. To accomplish that choledochal cysts and cystic biliary atresia. Cysts are present
objective, a multicenter, multifaceted effort is necessary. The US in up to 2% of infants with obstructive jaundice. Infants
National Institutes of Health have established a consortium – present in a manner simulating biliary atresia and, if unrec-
The Childhood Liver Disease Research Network – consisting of ognized, may have progressive disease. Prolonged obstruc-
15 pediatric clinical research centers in the USA ([Link] tion results in biliary cirrhosis, portal hypertension resulting
[Link]). The individual centers and a data-coordinating from cirrhosis, and pressure on the portal vein by the
center will accelerate advances in the understanding, diagnosis,
and clinical management of biliary atresia and related pediatric Table 11.2 Classification of Bile Duct Cysts
liver diseases. Their goals are to (1) determine the etiology of the
disorder; (2) develop rapid and sensitive means for diagnosis; (3) Type Features
define the natural history of biliary atresia; (4) determine the I Cystic dilatation of the common bile duct
optimal medical and surgical treatment strategies; and (5) iden-
tify risk factors for progression of the disease. Ia Large saccular cystic dilatation
The consortium has developed a prospective clinical data- Ib Small localized segmental dilatation
base and a repository of tissue, serum, and plasma samples and
Ic Diffuse (cylindric) fusiform dilatation
reports the outcomes of infants with biliary atresia. This data-
base will be a valuable resource in the quest to achieve the goals II Diverticulum of the common bile duct and/or the
outlined here and thus represents an important first step in our gallbladder
fight against this disease. III Choledochocele
IV Multiple cysts
Choledochal Cyst IVa Intrahepatic and extrahepatic (most common
Choledochal cysts are congenital anomalies of the biliary tract form)
characterized by varying degrees of cystic dilatation at various
segments of the biliary tract (extrahepatic or intrahepatic). IVb Extrahepatic only
The frequency of choledochal cysts is about one in 15,000 live V Fusiform intrahepatic dilatations (relation to Caroli
births in Western countries and as high as one in 1,000 live disease?)

Figure 11.6 Classification of congenital bile duct cysts; see Table 11.2 for descriptions of each type.

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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

distended cyst. Recurrent pancreatitis is an unusual compli-

cation of the malformation.

Clinical Features
The classic triad of intermittent abdominal pain, jaundice,
and right epigastric mass varies in incidence; this triad is
usually not present in infants and is uncommon in older
children, occurring in about 20%. Jaundice (conjugated
hyperbilirubinemia) is the common manifestation.
Abdominal pain may be a presenting symptom, often with
elevated serum amylase levels. The lesion may be detected at
any age, with 18% appearing before one year of age. Older
children may have mild chronic liver disease, which may
reflect variable degrees of common bile duct obstruction. In
certain patients, the lesion appears to be a true congenital
malformation and is associated with other anomalies of the
Figure 11.7 CT scan of an infant with a type I choledochal cyst. A large arrow
biliary tree, such as double common duct, double gallbladder, indicates the cyst, a small arrow the gallbladder.
and accessory hepatic ducts, as well as polycystic and hypo-
plastic kidneys. Complete distal biliary obstruction may also
be seen in infants, with no detectable biliary remnant at the Diagnosis
site of the distal common bile duct. In these infants, the In most infants, the diagnosis is suggested if non-invasive
histological changes in the liver are indistinguishable from imaging studies are undertaken for vague right upper quadrant
biliary atresia and may constitute a distinct clinical subgroup symptoms (Figure 11.6). Ultrasonography should be the initial
[66]. Adults with choledochal cyst disease commonly have procedure in the evaluation of suspected choledochal cyst.
acute biliary tract or pancreatic symptoms. It is possible that Radiographs of the upper gastrointestinal tract may outline
the variability in age and clinical course represents two dis- the mass as it displaces the first and second portion of the
tinct entities: congenital disease (in infants) vs. acquired dis- duodenum but are unnecessary.
ease (in older children). Ultrasonography may be helpful in the preoperative differ-
Spontaneous perforation of a choledochal cyst in infancy ential diagnosis of choledochal cysts in neonates and infants.
may occur. Of 187 patients with infantile choledochal cyst Cysts are larger, intrahepatic ducts are dilated, and gallblad-
treated at one hospital, 13 cases of spontaneous perforation ders are not atretic in patients with choledochal cysts com-
were encountered; eight patients were found to have biliary pared with patients with biliary atresia.
peritonitis, and five had a sealed perforation [67]. The cause of Magnetic resonance cholangiopancreatography (MRCP) is
the perforation is postulated to be biliary epithelial irritation as being utilized to establish the diagnosis and assess the anato-
a result of reflux of pancreatic juice caused by pancreaticobili- mical variants following an ultrasound. Benefits include a non-
ary malunion associated with mural immaturity, rather than invasive approach to definitively establish the diagnosis with-
an abnormal rise in ductal pressure or congenital mural weak- out radiation exposure. Drawbacks include availability, cost
ness at a certain point. and possibly requiring anesthesia based on age.
Some centers perform endoscopic retrograde cholangio-
pancreatography (ERCP) after the initial ultrasound for diag-
Pathogenesis nosis and to identify the presence of anomalous pancreatic
The pathogenesis of choledochal cysts is undetermined; duct for which a pre-emptive sphincterotomy is sometimes
there are several theories. Cysts may represent anomalous performed. ERCP can be reserved for postoperative manage-
union of the common bile duct and the pancreatic duct ment of pancreatitis related to anomalous pancreatic duct
proximal to the sphincter of Oddi, which may permit insertion if necessary and thus avoiding an invasive procedure
reflux of pancreatic enzymes into the common bile duct in all patients with choledochal cyst.
with resultant inflammation, localized weakness, and dila- The accuracy of antenatal ultrasonography in the diagnosis
tation; congenital segmental weakness of the common bile of choledochal cysts is not known. We detected choledochal
duct wall; or obstruction of the distal common bile duct cysts in five patients through antenatal ultrasonography (at
leading to dilatation. A study in a mouse model of rota- 17–35 weeks of gestational age). All had cystic dilatation of the
virus-induced biliary atresia showed a high incidence of common bile duct (type I cysts). All those with distal obstruction
dilatation of extrahepatic bile ducts in mice with overex- by operative cholangiography had varying degrees of fibrosis.
pression of T helper lymphocyte type 2 cytokines, suggest- Each improved following surgical excision and porto- or chole-
ing that the formation of cysts may depend, at least in part, dochoenterostomy. Redkar et al. [68] studied three patients with
on the type of tissue response following an injury [3]. proven biliary disease who had abnormal antenatal scans at a
Further research is needed. mean of 20 weeks. Two infants had type I cystic biliary atresia,
and one had a non-communicating segmental dilatation of the

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 Section II: Cholestatic Liver Disease

bile duct in a type III biliary atresia. The remainder had chole- diagnosis is made in childhood or adulthood, timing of surgi-
dochal cysts and included two patients with intrahepatic cysts. cal intervention depends on the presentation. If cholangitis or
The correct diagnosis was made antenatally in only two patients pancreatitis is the presenting symptom, intervention might
(15%). Of the remaining patients, seven were diagnosed with have to be delayed until the inflammation subsides.
intra-abdominal cysts of unknown cause, three with duodenal The goal is complete surgical excision of the cyst mucosa, with
atresia, and one with an ovarian cyst. Antenatal diagnosis offers a Roux-en-Y choledochojejunostomy proximal to the most distal
the possibility of early definitive surgery for uncomplicated lesion. This allows direct bile duct mucosa-to-bowel mucosa ana-
choledochal dilatation and the chance for improved outcome stomosis, with the lowest risk of stenosis or stricture. This strategy
for surgically treated biliary atresia. has evolved from historic attempts at aspiration and external
drainage, internal decompression and drainage into the duode-
Treatment num (cyst duodenostomy), or direct anastomosis of the cyst to a
jejunal Roux-en-Y loop. Each of these drainage techniques
Timing of surgical intervention has been somewhat controver-
retained the wall of the cyst with its abnormal mucosa. Poor
sial and depends on prenatal diagnosis, age of presentation and
drainage leads to stasis and persistent cyst inflammation resulting
concurrent symptoms. When the diagnosis is made in the
in stricture formation, biliary lithiasis, and an increased risk of
prenatal or early postnatal period, definitive surgery has tradi-
malignant evolution within the cyst wall. The recommended treat-
tionally been employed at three to six months of age in part due
ment currently includes elimination of the entire cyst mucosal wall
to caution of general anesthesia and surgery in neonates. A
by complete excision of the extrahepatic cyst and of the extrahe-
prospective randomized study showed varying grades of fibro-
patic biliary tree and the creation of a retrocolic, isoperistaltic
sis in almost 75% of the cases postnatally. Diagnosis at an early
jejunal Roux-en-Y loop of 35–45 cm. Internal or external biliary
gestational age correlated to severity of fibrosis which could be
transanastomotic stents rarely are needed because of the large size
due to longer duration of cholestasis and hepatocellular injury.
of the anastomosis (Figure 11.8). Laparoscopic hepaticojejunos-
Definitive surgery is safe and feasible in the neonatal period
tomies and hepaticoduodenostomies are being performed with
with similar postoperative course and morbidities compared to
comparable outcomes.
delayed surgery in the postnatal period [78]. When a delayed

(A) (B)

Figure 11.8 Surgical management of choledochal cyst. (A) Operative photograph of the “Lilly” dissection showing the inflammatory wall of the proximal
choledochal cyst separated from the internal lining “mucosa” (arrow). The distal cyst wall is identified by the arrowhead. (B) Transection of the mucosal dissection just
proximal to the proper hepatic duct bifurcation and prepared for reconstruction as an end-to-side choledochojejunostomy using an isoperistaltic jejunal Roux-en-Y
loop. Arrows outline the retained outer wall of the choledochal cyst.

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 Chapter 11: Biliary Atresia and Other Disorders of the Extrahepatic Bile Ducts

In patients in whom prolonged or recurrent inflammation cyst excision, even in asymptomatic patients, including
within and surrounding the cyst has complicated identifica- those with prior cyst enterostomies.
tion of the portal vasculature, the cyst can be transected along
its anterolateral wall, allowing complete excision of the Spontaneous Perforation of the Common
mucosa while retaining the fibrous cyst wall overlying the
hepatic artery and portal vein. This protects the critical portal Bile Duct
vascular structures and allows excision of all of the abnormal Spontaneous perforation of the common bile duct is a rare
lining of the cyst. occurrence. The typical onset of symptoms (mild jaundice,
The distal remnant of the common bile duct should be ascites, acholic stools, poor weight gain, and vomiting)
closed through the open base of the choledochal cyst, occurs before three months of age. Progressive abdominal
taking great care not to injure the often ectopically located distension occurs, with bile staining of umbilical and ingu-
pancreatic duct junction. Failure to remove this distal, inal hernias and of the abdominal wall. The diagnosis is
often retroduodenal, portion of the cyst may lead to suggested by the relatively modest degree of conjugated
recurrence. hyperbilirubinemia with minimal elevation of aminotrans-
It is important to define the extent of any intrahepatic ferase levels in association with acholic stools. Sonography
cystic disease at the time of choledochal cyst excision. This may reveal ascites or loculated fluid around the gallbladder
is best undertaken with an intraoperative cholangiogram or [69]. Hepatobiliary scintigraphy may demonstrate evidence
through preoperative percutaneous transhepatic or endo- of activity outside the biliary tract [70]. Abdominal para-
scopic retrograde cholangiography. If the cystic disease is centesis yields clear, bile-stained ascitic fluid. Histologically,
in continuity with the primary bile duct cyst and no inter- the liver manifests cholestasis with a normal lobular pattern.
vening strictures leading to stasis are present, reconstruc- Operative cholangiography usually demonstrates the pre-
tion at the hepatic hilum is the most appropriate therapy. sence of the perforation, frequently in association with
If intrahepatic cystic disease with interposed areas of ste- obstruction at the distal end of the common bile duct,
nosis (Caroli disease) is present, these decompressive meth- secondary to stenosis, segmental atresia, or inspissated bile.
ods are not applicable. Segmental multifocal cystic disease The rather constant location of the perforation at the junc-
isolated to a single hepatic lobe can be treated successfully tion of the cystic and common bile ducts is highly sugges-
by cyst excision and hepatic lobectomy. If the intrahepatic tive of a developmental weakness at this site (Figure 11.9).
disease is diffuse and involves all hepatic lobes, liver trans- Drainage with suture closure of the perforation may be a
plantation may be necessary if complete and successful satisfactory treatment. Internal diversion through a Roux-
decompressive drainage is not possible. en-Y loop of jejunum may be used for drainage in some
infants.

Complications and Outcome

In a meta-analysis incidence of cholangitis was around 2.5%
and was similar between Roux-en-Y procedure and hepatico-
duodenostomy. Similarly, bile leaks and anastomotic stric-
tures are comparable between the two procedures and the
incidence is <3% and <2% respectively. Incidence of reflux
gastritis is specific to hepaticoduodenostomy procedure
(5.8%) and not Roux-en-Y procedure. Pancreatitis is uncom-
mon but may occur secondary to proximal pancreatic duct or
sphincter stenosis or stones.

Malignancy in Choledochal Cysts

Carcinoma has been reported in residual cystic tissue in up
to 26% of patients, an incidence that is 20 times greater
than that in the general population. The typical malignancy
is adenocarcinoma of the bile duct or gallbladder; less
commonly squamous cell carcinoma and cholangiocarci-
noma have been described. The risk of developing malig-
nancy increases with age, making complete excision of the
cyst and proximal bile duct mucosa an essential component
of the operation in older patients. Malignant change also
may occur in areas of the biliary tree remote from the cyst. Figure 11.9 An infant with a bile duct stricture at the junction of the cystic
duct with the proper hepatic duct (arrow). The hypoplastic distal common bile
The increased risk of malignant degeneration and the dis- duct is seen. The patient was treated with a choledochojejunostomy into an
mal prognosis once cancer has developed warrant complete isoperistaltic jejunal Roux-en-Y loop.

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 Section II: Cholestatic Liver Disease

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