Diseases of the Gallbladder and Bile Ducts - part 10 ppsx

Chapter 23: Biliary disease in infants and children 395
a measure of biliary obstruction. Precise imaging is best
achieved with cholangiography, but because of its invasive
nature this procedure is only recommended as a prerequisite
for surgery (Fig. 23.8).
Sclerosing cholangitis
Sclerosing cholangitis may be primary or secondary. It also
may be associated with a number of chronic infl ammatory
conditions that produce ascending infl ammation into the
biliary tree resulting in progressive damage and destruction
of major and minor bile ducts (Fig. 23.9).
Primary sclerosing cholangitis (PSC), first described in
1924, is rare in childhood and generally occurs in association
with other underlying diseases. The cause of PSC is un-
known, but its association with other diseases that are con-
sidered to be autoimmune in origin makes it likely that an
underlying autoimmune phenomenon is also at work in PSC.
Infl ammatory bowel disease and the presence of serum auto-
antibodies such as the antineutrophil cytoplasmic antibody
make an immunological cause likely.
Secondary sclerosing cholangitis may be associated with
numerous conditions such as chronic or repeated bacterial
cholangitis, biliary obstruction, neoplasia, and graft-versus-
host disease in patients following bone marrow transplanta-
tion. Viral infections such as CMV and HIV infections can
result in histological features very similar to those seen in
children with PSC.
Primary sclerosing cholangitis
Etiology and pathogenesis The strong association between PSC
and other autoimmune diseases suggests that a component of
autoimmunity is at least partly responsible for the damage to

the biliary tract in patients with PSC. Moreover, a number of
autoantibodies are commonly found in patients with PSC.
Ninety-seven percent of patients with PSC are positive for at
least one autoantibody and more than 80% are positive for at
least two. A few that have been found include antineutrophil
cytoplasmic antibodies (pANCA), and less commonly anti-
colon antibodies, antineutrophil nuclear antibodies, and
antismooth muscle antibodies. Circulating immune com-
plexes may also be found in the majority of patients. Other
immunological aberrations include a high ratio of CD4 to
CD8 positive cells, hypergammaglobulinemia, high serum
IgM, and decreased levels of complement (C
3
). In addition,
major histocompatibility complex Class II antigens are
highly expressed in the bile duct epithelium of patients with
PSC suggesting that these cells serve as prime targets for
activated immune cells such as T cells.
The frequent association of PSC with ulcerative colitis
indicates a common etiology. Autoantibodies that cross react
between epitopes shared between biliary and colonic epithe-
lium have been described [157]. Bacterial translocation into
the portal circulation in combination with a higher concen-
tration of bile acids in the portal vein may cause activation of
Kupfer cells and increased synthesis of tumor necrosis factor
(TNF). There is, however, no clear association between the
severity of PSC and ulcerative colitis in the same patient. One
may precede the other or not occur at all in the same patient.
Although it may be possible for a subclinical pattern of dis-
ease in one organ to incite or propagate damage in the other,

bacterial translocation may not be solely responsible for the
frequent link between ulcerative colitis and PSC. PSC may
develop in children long before symptoms of colonic disease
or even after colectomy, thus defl ecting the importance of
the role of the gut as an etiological factor in the genesis of
PSC.
A genetic predisposition to PSC may also play a role in the
initiation and exacerbation of the disease. PSC has been
described in families. HLA Class II antigens DR3, Drw52,
DR2, and DR4 have been shown to occur at a high frequency
in patients with HSC, or be associated with a younger onset
of age (DR2), or a marker of rapid progression of disease
(DR4) [158]. HLA Class I A1 and Cw7 loci have been linked to
PSC.
Figure 23.8 Cholangiography of bile duct stricture
secondary to choledocholithiasis. The proximal ducts are
filled with stones.
396 Section 3: Specific conditions
Other factors that are less likely to play a role include absti-
nence from smoking, prior viral infections, particularly with
cytomegalovirus, and ischemic damage to the bile ducts.
Some have suggested a link between PSC and autoimmune
hepatitis. The evidence includes the increasing number of
children who have features of both diseases, the similar auto-
antibody profile in the two diseases, and the high incidence
of patients with specific HLA types in PSC and autoimmune
hepatitis [159]. It may be that PSC with autoantibodies and
autoimmune hepatitis are one and the same disease with dif-
ferent symptoms. Both diseases, moreover, have a similar
response rate to treatment.

In children with Langerhans’ cell histiocytosis, primary
involvement of the bile duct walls with specific histiocytic
infiltration or progressive scarring of portal areas leads to dis-
tortion of die bile ducts. Ductular necrosis is more prominent
in these patients compared to those with infl ammatory bowel
disease and PSC, and this necroinfl ammatory process pro-
duces a rapid progression to biliary cirrhosis. Major biliary
strictures, often at the hepatic duct confluence, and the
presence of sludge or stones in the intrahepatic bile ducts
are more common in PSC associated with Langerhans’ cell
histiocytosis.
Clinical manifestations and diagnosis PSC occurs predominan-
tly in males, and it can occur at any age. It has been described
both in neonates, where it can be confused with biliary atre-
sia, as well as in older children. Its peak incidence in older
children is between the ages of 10 and 16 years. Over 80% of
children have associated infl ammatory bowel disease, most-
ly ulcerative colitis, but a signifi cant minority (up to 15%)
may present with Crohn’s disease or colitis of indeterminate
type. Some of the important differences in the presentation
of PSC between children and adults are listed in Table 23.5.
Figure 23.9 This 10-year-old girl presented with cholangitis.
Transhepatic cholangiogram demonstrated a tight stricture at
the distal end of the common bile duct, proximal bile duct
dilatation, and a very long common channel between the
distal common bile dust and pancreatic duct.
Chapter 23: Biliary disease in infants and children 397
The defining clinical complication of PSC is stricturing of
the extra- and intrahepatic bile ducts. However, the initial
clinical presentation of PSC is quite varied. Apart from the

broad age range at presentation, PSC can present with vague
abdominal pain, fatigue, and pruritus as well as the full-
blown clinical picture of jaundice, fever, and hepatomegaly.
Some children may have stones in the biliary tree, which
may further complicate the process of arriving at the correct
diagnosis. In some, cirrhosis and portal hypertension may be
the first indication of a severe underlying hepatic problem.
However, the most frequent finding in PSC in older children,
and the one that causes the most morbidity, is the develop-
ment of biliary strictures that are located in both the extra-
and intrahepatic biliary tree.
PSC should be considered whenever the diagnosis of in-
fl ammatory bowel disease is being entertained in association
with a hepatobiliary symptom or sign. Abdominal pain is the
most frequent abdominal complaint, (40%), followed by
fatigue, jaundice, splenomegaly, fever, weight loss, and pru-
ritus [160]. In another series [161], the mean age of presenta-
tion was much younger, at 4 years of age, and almost 25%
presented in the newborn period. Hepatomegaly, spleno-
megaly, and jaundice were the most frequent findings in this
younger group of children. It appears that children present-
ing in the neonatal period are a unique group in whom con-
sanguinity is common in the parents [161,162]. A signifi cant
proportion of patients with infl ammatory bowel disease and
PSC are asymptomatic with regards to the liver and are diag-
nosed with PSC on the basis of abnormal laboratory parame-
ters. Associated conditions include autoimmune thyroiditis,
arthritis, celiac disease, epidermolysis bullosa, hyperpara-
thyroidism, sacroiliitis, systemic lupus erythematosus, and
diabetes mellitus. Conversely, patients with PSC may have

asymptomatic infl ammatory bowel disease that may only be
detectable by colonoscopy and biopsy. Therefore, it is recom-
mended that all children diagnosed with PSC should undergo
colonoscopy even in the absence of diarrhea, hematochezia,
or other symptoms of infl ammatory bowel disease.
Laboratory tests normally will show grossly abnormal al-
kaline phosphatase, transaminase levels, and gamma gluta-
myltransferase. However, the abnormalities in the liver
function tests may be quite variable and a small proportion of
children may have liver enzymes in the normal range;
gamma glutamyltransferase, however, was proven to be
abnormal in 94% of patients in one series of children [160].
Serum cholesterol may also be elevated in up to 50% of
children.
The diagnosis is suspected by clinical presentation, but
confirmed with imaging and liver biopsy. Ultrasound exami-
nation of the liver may be totally normal in the absence of
stones. However, the ultrasound finding of a large resting
gallbladder volume may be a sign of PSC. Cholangiography,
by endoscope or by magnetic resonance imaging, is the imag-
ing modality of choice that is the most likely to demonstrate
an abnormality. ERCP and MRCP are highly sensitive meth-
ods of visualizing the biliary tree and should be performed
before any consideration is given to open cholangiography or
operative intervention.
Classic findings on cholangiography are beading and struc-
turing of the extra and intrahepatic biliary tree (Fig. 23.10).
A signifi cant stricture in a major duct amenable to stenting is
seen only in a minority of children. However, in a signifi cant
proportion of children, particularly small babies and infants,

the cholangiogram may not show any signifi cant abnor-
mality, and confirmation of the diagnosis may depend on
liver biopsy. This variant of PSC, in which only the ducts too
small to visualize on cholangiography are affected, is termed
small-duct PSC (Fig. 23.11). Small-duct PSC, at least in adults,
is thought to carry a better prognosis than PSC that presents
with large duct disease from the outset [163,164]. MR imag-
ing may also demonstrate regenerative nodules, fibrosis, and
parenchymal peripheral wedging, as well as hypertrophy of
the caudate lobe in over half of adult patients. Cholangiogra-
phy may be unhelpful in arriving at the diagnosis in children
and infants with small duct disease.
Pathology A liver tissue sample is not necessarily diagnostic
of sclerosing cholangitis, but it can identify a bile-duct-
destructive process. The early stages of sclerosing cholangitis
are characterized by infl ammatory damage of bile ducts,
with infiltration of bile duct epithelium by mononuclear
cells, particularly lymphocytes. Degenerative changes of bile
duct epithelium accompany the cellular infiltrate (Plate 22,
facing p. 84). Bile duct and ductular proliferation are ob-
served. Portal infl ammation is usually also present, com-
posed by lymphocytes, plasma cells, and neutrophils, and an
interface hepatitis pattern indistinguishable from autoim-
mune hepatitis may be observed. With disease progression,
portal fibrosis becomes more evident, with bridging and
eventually cirrhosis. The characteristic concentric periductal
fibrosis (“onion-skinning” fibrosis), accompanied by bile
duct damage and atrophy, is observed in a minority of cases,
Table 23.5 Differences in clinical manifestation of primary sclerosing
cholangitis in children and adults.

Children Adults
A lk al in e p hosp ha ta se Nor mal in 2 5– 50 % o f pa tien ts High
Positive for autoimmune 25–35% 10%
hepatitis markers
Inflammatory bowel disease 50% 90%
Small duct disease 50% 10%
Recurrence often, liver Rare 20%
transplant
398 Section 3: Specific conditions
Figure 23.10 MRCP showing irregular intrahepatic
bile ducts and beading in a 17-year-old boy with
sclerosing cholangitis.
Figure 23.11 CT scan of the patient in Fig. 23.10
showing dilated left and right hepatic ducts
proximal to a common hepatic duct stricture.
Chapter 23: Biliary disease in infants and children 399
most likely related to sampling, due to the focal nature of the
process (Plate 23, facing p. 84). In advanced stages, bile ducts
may appear like solid cores of tissue.
Treatment and prognosis Treatment is both pharmacological
and interventional. Medical therapy includes UDCA, in
conjunction with immunosuppressive therapy comprising
corticosteroids, azathioprine, and, rarely, pentoxyfilline.
The use of steroids in children has been limited because of the
known deleterious effects on growth and the lack of proven
effi cacy in altering the course of the disease. Trials in adults
using combinations of drugs such as UDCA in addition to
prednisolone and azathioprine have shown promising
results.
Interventional radiological therapy or endoscopic therapy

has played an increasingly larger role in the treatment of
some of the complications of PSC. Therapy is aimed at dilat-
ing or stenting major biliary strictures that exacerbate stasis,
produce cholangitis, and thus accelerate progression of liver
disease to cirrhosis and liver decompensation. An aggressive
approach with endoscopic intervention coupled with com-
bination drug therapy, including UDCA, has been shown
to increase survival without liver transplantation. Almost
one-third of patients require endoscopic balloon dilatation of
a major obstructing lesion in the bile duct. In adults with PSC,
as many as 30% with dominant strictures develop cholan-
giocarcinoma, particularly in those with ulcerative colitis or
cirrhosis. In contrast, malignancy is extremely rare in chil-
dren, even after follow-up periods as long as 16 years.
Surgical resection of dominant strictures coupled with en-
teric drainage procedures is now used much less commonly
with the advent of improved endoscopic management of
strictures. In addition, the possibility that major hepatobili-
ary surgery may decrease the chances of a successful outcome
after liver transplantation may have also decreased enthusi-
asm for major surgery for PSC complications. Liver trans-
plantation is the definitive treatment for PSC and represents
the only possibility for cure for this disease. Over one-third of
children die or require liver transplantation at a mean of 7
years after the diagnosis of PSC is made. Unfortunately, re-
currence of PSC in the new graft may also occur, but at a lower
rate in children than in adults. Patient survival after liver
transplantation is in the order of 85%; the overall median
survival without transplantation is between 10 and 15 years.
In the Mayo clinic series [160], splenomegaly, low platelet

count, and older age at diagnosis were independently associ-
ated with poorer outcome.
Cholangiocarcinoma has been reported at a much higher
rate than in the normal population in patients with PSC.
Risk factors for the development of carcinoma include long-
standing portal hypertension and ulcerative colitis. It ap-
pears that those patients who develop cholangiocarcinoma,
do so early in the course of their disease. Hepatocellular car-
cinoma can be found incidentally in the explanted liver, and
in those patients, the prognosis is good. Patients with known
cholangiocarcinoma prior to transplantation have tradition-
ally had a very high recurrence rate so that, in some centers,
it was considered a relative contra indication for transplanta-
tion. With aggressive protocols, liver transplant survival after
transplantation for PSC complicated by carcinoma may have
better graft and patient survival.
In many children with PSC, the goals of therapeutic inter-
vention are to provide symptomatic relief of pruritus and
other symptoms, to improve nutrition and growth by amelio-
rating steatorrhea and preventing fat-soluble vitamin defi -
ciency, and to decrease pain, often due to cholangitis or
biliary colic. There are anecdotal reports of improvement in
biochemical parameters and liver histology in children with
PSC who were treated with prednisone or a combination of
prednisone and azathioprine, but no controlled trials have
been performed.
For now, the focus on PSC in children must be to treat their
nutritional needs, including vitamin therapy, with great care
and attention. Later in life, strictures may increase the inten-
sity and complexity of care. Finally, liver transplantation

holds the promise of cure in these children, but must be ap-
proached with caution until all other avenues of care have
been exhausted.
Cystic diseases of the intrahepatic bile ducts
Cystic diseases of the intrahepatic bile ducts represent a wide
range of disorders that include both sporadically occurring
and inherited conditions. When cysts communicate with the
biliary tree, they are more likely to cause clinical disease.
Communicating duct cysts are often associated with cholan-
gitis, intrahepatic stone formation, and even rarely neopla-
sia. Noncommunicating duct cysts are usually asymptomatic,
but if sufficiently large can present as an abdominal mass or
biliary obstruction. Many of the signifi cant intrahepatic cys-
tic lesions of the bile ducts in children are variations on ductal
plate malformations. Embryologically, the intrahepatic ducts
develop by a process of differentiation from the hepatocytes
at the margins of the portal tracts. This differentiation results
in the formation of the ductal plate, which is then remodeled
by duplication and formation into tubular structures that
eventually bud off and migrate to the center of the portal tract
to become the interlobular bile ducts. The ductal plate cells
around the periphery of the portal tract normally involute,
but some elements remain to form the ducts of Herring that
provide the functional link between the bile canaliculi and
the interlobular ducts. This process continues for up to 1
month after birth. The ductal plate malformation reflects
some degree of failure of the normal formation of the inter-
lobular bile ducts, and results in a characteristic portal tract
lesion consisting of persistence of some remnant of the ductal
plate resulting in misshapen, often enlarged ductular struc-

tures, an increase in duct elements, and an increase in portal
fibrous tissue. The ductal plate malformation is found most
400 Section 3: Specific conditions
often in a variety of polycystic diseases seen in childhood,
with the prime example being congenital hepatic fibrosis.
Congenital hepatic fibrosis
Congenital hepatic fibrosis is a complex disease affecting the
liver in a number of ways, and often is associated with renal
disease of varying severity. First described in 1962 [165], the
most important features of the disease and the complications
that accompanied the patients affected by it were also later
described by Kerr [166]. The disease is characterized by hep-
atomegaly, portal hypertension, increased periportal fibrosis
in the liver, a ductal plate lesion that gives rise to both extra-
and intrahepatic cystic malformations of the bile ducts, and
renal disease characterized by multiple cortical and medul-
lary cysts.
It is now generally felt that both the hepatic and renal com-
ponents of congenital hepatic fibrosis (CHF) are part of the
same condition and that CHF and autosomal recessive poly-
cystic kidney disease (ARPKD) are manifestations of the
same genetic disorder that, for unclear reasons, are expressed
to varying degrees even among members of the same kindred
[167,168]. The genetic defect responsible for ARPKD has
been mapped to a 3.8-cM interval on chromosome 6,
6p21.1-pl2.
CHF is a manifestation of a ductal plate malformation.
Table 23.6 illustrates some of the related diseases generally
included in the category of ductal plate malformations. CHF
is only one disease characterized by dilatation of the seg-

ments of intrahepatic bile ducts and variable amounts of fi -
brosis [169]. Caroli’s disease (see below) represents a ductal
plate lesion of the larger intrahepatic ducts. Caroli’s syn-
drome combines the duct lesion of Caroli’s disease with the
fibrosis of CHF. Finally, ductal plate malformations may give
rise to the mesenchymal hamartoma of infancy in which a
portion of the liver is replaced by lesions with both cystic and
solid components (Fig. 23.12).
Pathology Bile ducts are markedly dilated, with angulated
shapes, and form a discontinuous ring at the periphery of the
portal tract (Plate 24, facing p. 84). Normal interlobular bile
ducts are usually not observed. There are broad bands of
portal-to-portal fibrosis. The lobular architecture of the he-
patic parenchyma is usually preserved, that is there is no
well-defined cirrhosis.
Clinical presentation The clinical features of CHF are many.
One of the most common presenting complaints is bleeding
from gastroesophageal varices secondary to portal hyperten-
sion. Other presenting features include abdominal disten-
sion, failure to thrive, recurrent episodes of cholangitis,
arterial hypertension, and renal failure. On clinical grounds
alone, upper gastrointestinal bleeding in association with
massive enlargement of the liver and kidneys is very sugges-
tive of CHF.
The pathogenesis of the portal hypertension is not fully
understood but is thought to be related to the hepatic fibrosis.
In addition, a paucity of the portal vein branching leads to a
higher resistance to blood flow in the mesenteric circulation
through the liver independent of the amount of fibrosis [170].
Portal hypertension leads to splenic enlargement and

hypersplenism, thrombocytopenia, and leucopenia. In most
patients, the biochemical parameters of hepatic synthetic
function are normal and the bilirubin and aminotransfera-
ses are likewise normal or only mildly elevated. The serum
creatinine may be elevated in patients with signifi cant renal
dysfunction.
Ultrasonography with Doppler assessment of the portal
vasculature is helpful and will show evidence of portal
hypertension, splenomegaly, intense hepatic echogenicity,
and large echogenic kidneys (Fig. 23.13). CT scanning
may demonstrate dramatic examples of prominent cystic
changes in both the liver and the kidneys in association with
vascular changes associated with portal hypertension.
Table 23.6 Ductal plate malformations.
Disease Ductal lesion Inheritance Renal association Symptoms Treatment
Caroli’s disease Congenital dilatation Autosomal recessive, Not associated with Abdominal pain, episodes Supportive
of the larger IHBD possibly not renal abnormalities of cholangitis, portal Treat cholangitis
inherited (Desmet) hypertension, bile duct Liver resection
ectasia Liver transplant
Caroli’s syndrome Congenital dilatation Inherited autosomal Associated with Cholangitis, cholelithiasis, Supportive
of the larger IHBD recessive CHF lesions, renal portal hypertension Treat cholangitis
disease Liver transplant
Congenital hepatic Dilatation of smaller Inherited autosomal Renal polycystic Hematemesis, hematochezia, Splenorenal
fibrosis (ARPKD) IHBD recessive disease melena, hepatomegaly, Shunt for portal
splenomegaly hypertension
Kidney transplant for
renal insufficiency
Chapter 23: Biliary disease in infants and children 401
Other associated conditions include Jeune syndrome with
pulmonary hypoplasia and less severe CHF, Meckel–Gruber

syndrome with encephalocele, hepatosplenomegaly, and
renal and hepatic cysts, and Ivermark’s syndrome with CHF
in association with severe renal interstitial fibrosis. At the
time of diagnosis of CHF, renal dysfunction is already present
in approximately 20% of patients. The course of the renal
disease is quite variable, and renal disease may lead to the
consideration of renal transplantation early in the life of
affected children [171].
Bleeding from portal hypertension must be managed
within the context of the severity of the liver disease. In
patients with well-preserved liver function and advanced
portal hypertension, selective distal splenorenal shunting
Figure 23.12 Mesenchymal hamartoma
presenting with a giant hepatic cyst.
Figure 23.13 CT scan of patient with congenital
hepatic fibrosis and intrahepatic bile duct cysts.
402 Section 3: Specific conditions
is the procedure of choice [171]. Advanced hypersplenism
with profound depression of platelets and white blood cells is
also an indication for shunting since splenic decompression
allows for the hypersplenism to resolve at least in part. Sple-
nectomy has been advocated in the past but must be avoided
since it does little to address the fundamental problem of
portal hypertension and may exacerbate the bleeding from
varices in the stomach and esophagus.
One of the more intriguing aspects of CHF is the associa-
tion with cysts of the extrahepatic biliary tree. Patients with
ARPKD, CHF, and choledochal cysts of the common bile duct
may require excision of the cyst as either an independent
procedure or as a prelude to renal transplantation before

immune suppression can be safely started in someone at risk
for cholangitis.
The prognosis for children with CHF is good. In children
with advanced hepatic or renal dysfunction, transplantation
offers excellent results although this is only necessary in a
minority of children with CHF. Recurrent cholangitis and
biliary cirrhosis in the presence of severe intrahepatic cho-
lestasis may require liver transplantation. Severe organo-
megaly may require liver replacement of its own accord as it is
debilitating for a child who also has an enlarged spleen and
kidneys. In a child with severe renal and hepatic dysfunc-
tion, transplantation of one organ may lead to improvement
in the function of the nontransplanted system. Morbidity
and mortality is still considerable from the complications of
CHF even in patients with successful kidney transplants
[171]. Therefore careful consideration should be given to
transplanting the liver at the time or just after a renal trans-
plant in patents whose liver function may be compromised.
Conversely, renal function can improve or stabilize in
children undergoing liver transplant for CHF with renal
dysfunction, although some may go on to require kidney
transplantation as well [172].
Caroli’s disease
Caroli’s disease was first described in 1958 and is character-
ized by congenital segmental saccular dilatation of the
larger intrahepatic bile ducts [173]. Caroli’s syndrome, on
the other hand, is more frequently encountered and refers to
the association of intrahepatic choledochal cysts, periportal
fibrosis, and portal hypertension. Caroli’s disease refers to
the ductal plate lesion leading to dilatation of the larger intra-

hepatic bile ducts. Stagnant bile in both affected and nonaf-
fected ducts leads to infection with stone and sludge
formation. Both Caroli’s disease and Caroli’s syndrome are
thought to be inherited in an autosomal recessive manner
and also may be associated with the renal lesions related to
ARPKD disease.
Caroli’s disease may be universally spread throughout the
liver or unilobular. In the largest series published to date
[174], which included 12 patients with Caroli’s syndrome
and eight with Caroli’s disease, polycystic renal disease was
present in 42% of those with Caroli’s syndrome and 25% of
those with Caroli’s disease. If one includes radiographic or
histologic features of medullary sponge kidney or tubular ec-
tasia, a higher percentage of patients have renal lesions. Al-
though it is often associated with ARPKD and autosomal
recessive inheritance, there is recent information that sug-
gests an autosomal dominant mode of inheritance with vari-
able penetrance and expressivity [175]. Studies of siblings
and parents of children with Caroli’s disease who themselves
are asymptomatic have revealed evidence of intrahepatic
biliary cystic lesions.
Caroli’s disease presents during adolescence or early adult-
hood with repetitive bouts of abdominal pain, and episodes
of cholangitis (64%), clinical evidence of portal hyperten-
sion (22%), and radiographic findings of macroscopic bile
duct ectasia demonstrated by abdominal computed tomo-
graphy (CT) scan or ultrasound. Jaundice is rare. Portal
hypertension can develop, although this occurs only rarely.
Presentation in younger children and infants has been re-
ported. Prenatally, the presence of the ARPKD gene, PKHD1,

may be suggested by fetal ultrasound findings normally asso-
ciated with Caroli’s disease [176].
There are rare reports of a neonatal presentation associated
with neonatal cholestasis, pulmonic valve stenosis, diffuse
cystic dilatation of the intrahepatic bile ducts, and enlarged
kidneys with rapidly progressive deterioration in renal
function. It is unclear whether these cases truly represent a
pure form of Caroli’s disease, patients with Caroli’s syn-
drome, or patients with variants of the ARPKD in whom
the full spectrum of liver anomalies had not yet developed.
Cholangiography confirms the diagnosis and demonstrates
continuity of the multiple cystic lesions with the biliary
tree. In more advanced cases, biliary sludge formation and
intrahepatic stone formation will be present. Black pig-
mented calcium bilirubinate stones appear as filling defects
within the intrahepatic biliary tree. Bile duct strictures and
wall irregularities may form as a consequence of repeated
episodes of bacterial cholangitis. Long-term consequences
of repeated bouts of cholangitis, biliary abscesses, and
septicemia include cirrhosis, hepatic failure, amyloidosis,
and cholangiocarcinoma.
Surgical treatment of Caroli’s disease is limited. In cases
of unilobar disease, resection of the affected lobe has been
reported to successfully ameliorate the symptoms [177].
In patients with diffuse disease, treatment is supportive.
Antibiotic treatment of cholangitis and endoscopic or radio-
logical dilation of strictures or drainage of infected collec-
tions in dilated bile ducts can successfully control local
infections or strictures [178]. Ultimately, biliary cirrhosis
may supervene, requiring liver transplantation as the only

option [179].
Chapter 23: Biliary disease in infants and children 403
Questions
1. Biliary atresia is not seen before the age of 3 months: true or
false?
a. true
b. false
2. Which of the following is not considered a potential cause of
biliary atresia?
a. viral infection of the liver
b. developmental anomaly
c. autoimmune disorder
d. ascending bacterial cholangitis of the newborn
3. Which of the following statements about biliary atresia is true?
a. biliary atresia is more common in premature babies than full
term ones
b. the Kasai procedure is successful in 80 to 90% of patients in
causing resolution of the jaundice
c. the highest incidence of biliary atresia is seen in patients of
African descent
d. biliary atresia is the commonest indication for liver
transplantation in children
4. Which of the following statements about choledochal cysts is
not true?
a. the most common form of cyst is a diverticulum of the common
duct
b. malignant degeneration of an untreated cyst can occur later in
life
c. choledochal cysts are associated with anomalous junctions of
the bile and pancreatic ducts

d. choledochal cysts can be diagnosed during intrauterine life
5. Which of the following statements is not true about Alagille’s
syndrome
a. the syndrome is inherited in an autosomal dominant fashion
b. the genetic defect can be traced to the gene encoding for the
bile salt exporter pump and results in intrahepatic cholestasis
c. patients with Alagille’s syndrome often have associated cardiac
defects
d. Alagille’s syndrome is associated with paucity of the
intrahepatic bile ducts
6. Which of the following choices regarding spontaneous
perforation of the bile is correct?
a. most children can be treated nonoperatively with
percutaneous drainage
b. most children will require a complex biliary reconstruction in
order to deal with the ductal damage
c. children with spontaneous bile duct perforation present with
jaundice and ascites
d. the commonest etiology of spontaneous biliary perforation is
primary bile duct malignancy
7. Patients with Alagille’s syndrome and profound cholestasis
should have a portal dissection and portoenterostomy if the
cholangiogram demonstrates hypoplastic extrahepatic bile
ducts and a paucity of intrahepatic bile ducts since the
prognosis is better than in those who undergo cholangiogram
alone. True or false?
a. true
b. false
8. Congenital hepatic fibrosis is associated with all of the following
except

a. autosomal recessive polycystic kidney disease
b. portal hypertension
c. Caroli’s disease
d. congenital heart disease
9. Byler’s disease is characterized by all of the followings excluding
a. normal serum cholesterol
b. elevated GGTP
c. a genetic defect localized to the FIC 1 gene
d. the symptoms may be alleviated by partial biliary diversion
10. Progressive familial intrahepatic cholestasis type 2 is
characterized by which of the following?
a. electron microscopy demonstrates electron-dense material
within the endoplasmic reticulum
b. a mutation in the bile salt export pump gene located on
chromosome 2q24 resulting in bile with high concentrations of
bile acids
c. liver transplantation is ultimately necessary in the majority of
patients with this form of PFIC
d. patients with this disease have typical facial features
characterized by frontal bossing
11. In pediatric cholelithiasis, which of the following statements is
false?
a. asymptomatic stones in transplant patients should be
removed
b. hemolytic diseases are common underlying disorders in
children with cholesterol stones
c. patients with lithogenic bile include those from Native America
ethnic groups
d. common duct stones can be treated with ursodeoxycholic acid
since most of them will dissolve after 1 year

12. Nonobstructive hydrops of the gallbladder can result from all of
the following except
a. Kawasaki’s disease
b. Moya-Moya disease
c. Henoch–Schonlein purpura
d. HIV positive patients with cryptosporidium infection
404 Section 3: Specific conditions
13. In patients with cystic fi brosis, which of the following factors is not
considered significant in contributing to biliary tract pathology?
a. relative obstruction of the distal common bile duct from an
indurated and sometimes enlarged pancreas
b. increased hemolysis from hypersplenism resulting in increased
bilirubin excretion in bile with resulting crystallization
c. an increased bile viscosity resulting from defective water and
chloride regulation of bile
d. abnormal bile composition resulting from fat malabsorption
and a defective enterohepatic bile salt circulation
14. Biliary dyskenisia is suggested if which of the following findings
is present?
a. a gallbladder evacuation fraction of 20%
b. stones in the common bile duct that move up and down the
duct after the administration of cholecystokinin
c. a fusiform dilatation of the bile duct on ultrasound examination
of the bile duct
d. a sonoluscent area around the gallbladder wall on CT
examination
15. Which of the following statements regarding primary
sclerosing cholangitis in children is true?
a. liver biopsy results and diagnostic imaging findings may be
minimal and the diagnosis is made principally by the clinical

presentation
b. Crohn’s disease is associated with PSC in over 80% of patients
and ulcerative colitis occurs less commonly
c. although PSC may occur in families, there has been very little
HLA typing evidence that suggests a genetic causality of the
disease
d. liver transplantation is required in over one-third of patients
with PSC
Acknowledgement
The assistance of Dani Sher in the preparation of the manu-
script is gratefully acknowledged.
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Answers
Chapter 1, Anatomy and physiology of the biliary
tree and gallbladder
1. b
2. c

3. b
4. d
5. d
6. c
7. a
8. b
9. b
10. b
Chapter 2, Pathology of the intrahepatic and
extrahepatic bile ducts and gallbladder
1. b
2. c
3. a
4. d
5. False
6. d
7. True
8. False
9. a
10. c
Chapter 3, Epidemiology of diseases of the bile ducts
and gallbladder
1. a, e
2. b, c, e
3. a, b, c
4. a, b, c
5. a, c
6. a
7. b, d
8. b

9. a, b, c , d
10. a, c, d, e
411
Chapter 4, Noninvasive imaging of the biliary
system
1. a
2. e
3. d
4. e
5. a
6. d
7. a
8. e
9. c
10. b
11. c
Chapter 5, Endoscopic diagnosis and treatment of
disorders of the biliary tree and gallbladder
1. d
2. e (the fifth component is hypotension not hypertension)
3. c
4. d
5. a
6. b
7. a
Chapter 6, Percutaneous biliary imaging and
intervention
1. d
2. c
3. c

4. a
5. e
6. c
7. c
8. d
9. e
10. c
Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition
Edited By Pierre-Alain Clavien, John Baillie
Copyright © 2006 by Blackwell Publishing Ltd
412 Answers
Chapter 7, Radiation therapy for disease of the
biliary tree and gallbladder
1. c
2. a
3. b
4. b
5. e
6. c
7. b
8. c
9. b
10. b
11. c
12. e
13. b
14. a
Chapter 8, Surgery of the biliary system
1. b
2. a

3. e
4. b
5. e
6. e
7. b
8. e
9. a
10. e
11. c
12. d
Chapter 9, Laparoscopic treatment for diseases of
the gallbladder and biliary tree
1. c
2. b
3. e
4. c
5. a
Chapter 10, Laparoscopic biliary injuries
1. b
2. e
3. e
4. d
5. d
6. e
7. b
8. c
Chapter 11, Medical and innovative therapies for
biliary malignancies
1. a
2. a

3. c
4. a
Chapter 12, Natural history and pathogenesis of
gallstones
1. b
2. e
3. c
4. b
5. b, c
6. a, b
7. a
8. b
9. e
Chapter 13, Acute and chronic cholecystitis
1. a
2. c
3. d
4. a
5. b
6. c
7. a
8.1. d
8.2. c
8.3. a
Chapter 14, Biliary fistula, gallstone ileus, and
Mirizzi’s syndrome
1. a
2. d
3. d
4. c

5. b
6. e
7. d
Chapter 15, Benign and malignant gallbladder
tumors
1. b
2. e
3. b
4. c
5. c
6. b
7. e
8. c
9. b
10. d
11. b
Answers 413
Chapter 16, Acute cholangitis
1. e
2. a
3. f
4. a
5. e
6. b
7. d
8. b
9. a
10. c
Chapter 17, Cystic diseases of the biliary system
1. c

2. c, e (the other alternatives occur only very rarely in patients with
polycystic liver disease)
3. d
4. c
5.1. a, followed by d
5.2. c
5.3. f (after treatment of cholangitis with antibiotics)
Chapter 18, Biliary complications of liver
transplantation
1. a
2. e
3. a
4. e
5. b
6. e
7. d
8. b
9. d
10. e
11. c
12. b
13.1. e
13.2. d
13.3. b
Chapter 19, Primary sclerosing cholangitis
1. d
2. d
3. d
4. e
Chapter 20, Cholangiocarcinoma

1. d
2. e
3. a
4. d
5.1. a
5.2. d
5.3. c
Chapter 21, Primary biliary cirrhosis
1. c
2. e
3. d
4. e
5. a
6. e
7. e
8. d
9. e
10. b
Chapter 22, Intrahepatic cholestasis
1. c
2. d
3. c
Chapter 23, Biliary disease in infants and children
1. b
2. d
3. d
4. a
5. b
6. c
7. b

8. d
9. d
10. c
11. d
12. b
13. b
14. a
15. d
Index
A
ABCB4 gene, 223
abscess(es)
intrahepatic, cholangitis and, 85, 85f
liver, post-transplantation, 298
adenocanthoma, 158
adenocarcinoma, ampulla of Vater, 63
adenoma
bile duct, 41–42, 42f
gallbladder, 49, 252–253
adenomatosis, 60
adenomatous polyps (gallbladder), 394
adenomyoma, 49, 51f
adenomyomatosis, 110
adjuvant therapy
bile duct tumors, 206
gallbladder carcinoma, 257
adolescents see children
adoptive immunotherapy, 211
adriamycin, 5-fluorouracil with, 155
adult idiopathic ductopenia, 28–29, 29f, 41

Alagille’s syndrome, 40–41, 41f
children, 377
clinical features, 385
diagnosis, 385
hepatocellular carcinoma risk, 386, Plate
17
infants, 385–386
prognosis, 385–386
treatment, 385
alcohol, cholestasis and, 367
alcoholic foamy fatty disease, 367
alcoholic liver disease, 367
allergy, contrast agents, 98
α-naphthylisothiocyanate (ANIT), 370
ampulla of Vater, 63
ampullary carcinoma, 128
amyloidosis, cholestasis and, 368
analgesia
acute acalculous cholecystitis, 234
acute calculous cholecystitis, 232
percutaneous biliary imaging, 121
anaplastic carcinoma, 158
anastomotic strictures, post-liver
transplantation, 294f
antiangiogenic therapy, bile duct tumors,
211
antibiotics
acute acalculous cholecystitis, 234
acute calculous cholecystitis, 232
acute cholangitis, 268, 269, 269t

bile leaks, post liver transplant, 296–297
endoscopy prophylaxis, 98
nonanastomotic strictures, post liver
transplant, 294, 296
surgery prophylaxis, 165
see also specifi c drugs
antihistamines, contrast allergy, 98
antimitochondrial antibodies (AMA),
primary biliary cirrhosis, 343,
346–347
antimitochondrial antibody (AMA)-
negative primary biliary cirrhosis
(PBC), 23–24
antisense oligonucleotides, 211
apical sodium dependent bile acid
transporter (ASBT), 358, 362
apoptosis induction, bile duct tumors, 211
appendectomy, primary sclerosing
cholangitis and, 309, 311
arachidonic acid (AA), gallbladder motility,
15
Ascariasis, 265
Ascaris lumbricoides, 265
ascites, percutaneous transhepatic
cholangiography, 122–123
atherosclerotic diseases, acute acalculous
cholecystitis, 234
ATP8B1 gene, 365–366
ATP binding cassette (ABC), 358, 359
415

Notes: Key abbreviations used in subentries are as described on pages xi–xii.
Page numbers followed by ‘f’ indicate fi gu re s: page nu mb er s f ol lowed by ‘ t’ in di cat e t ab le s.
Plates are indexed by number.
autoimmune cholangitis, 23–24
autoimmune hepatitis see hepatitis,
autoimmune
autosomal dominant polycystic liver
disease, 279–280
autosomal recessive polycystic kidney
disease (ARPKD), 402
congenital hepatic fibrosis and, 35, 400
polycystic liver disease and, 36
autosomal recessive polycystic liver disease,
280
azathioprine, 317
B
bacterial cholangitis, 31, 60, 319
bacterobilia, acute cholangitis, 266
“balloon sphincteroplasty,” 104–105
Balthazar’s sign, 243, 244f
Banff Consensus Schema, 28, 28t
benign recurrent intrahepatic cholestasis
(BRIC), 359, 364, 365–366, 387
bile
canalicular excretion, 358–360
composition, 12, 219, 221
flow, 13, 355–356
formation mechanisms, 355–360
regulation, 360–363
functions, 11

leakage see bile leak(s)
nuclear transcription factor effects,
360–363, 361f, 361t
production, 11–13
reabsorption, 12
secretion, 11
abnormalities in, 12–13
intrahepatic bile ducts, 6–7
sinusoidal membrane uptake, 357–358
spillage in laparoscopic cholecystectomy,
178
transcellular movement, 358
Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition
Edited By Pierre-Alain Clavien, John Baillie
Copyright © 2006 by Blackwell Publishing Ltd
416 Index
bile acid, inborn errors of metabolism, 386
bile canaliculus, 6–7
bile duct(s)
brushing specimens, 21
cystic dilatation, 86, 88f
cystic fibrosis, abnormalities in, 391,
Plate 21
drug-induced injury, 29–30
extrahepatic see ex tr ahe pa tic bile du ct s
imaging, 81–88, 83f, 84f
intrahepatic see int ra he pa tic bi le d uc t s
large, diseases affecting, 30–34
lesion evaluation, stains for, 22, 22t
obstruction see biliary obstruction

paucity, drug-associated, 29–30, 30f
radiation tolerance, 148t
small, diseases affecting, 22–30,
341–406
strictures see biliary strictures
bile duct adenoma, 41–42, 42f
bile duct carcinoma, 321
bile duct cysts, 61, 280–285
biliary cystadenocarcinoma, 285
biliary cystadenoma, 285
Caroli’s disease, 281–282, 281f
Caroli’s syndrome, 281–282
choledochal see choledochal cyst(s)
classifi cation, 61, 61f
multiple periductal, 280–281
bile duct stones (choledocholithiasis), 60,
221–222, 390–391
acute cholangitis, 265
blood clots vs., 125
cholangiography, 124–125, 124f, 125f
cholangitis, 103
cholecystitis, 233
endoscopic ultrasound see endoscopic
ultrasound (EUS)
endoscopy, 101–110
ERCP, 107–108, 108f
gallbladder carcinoma and, 128, 129f
gallstone (biliary) pancreatitis, 102–103
imaging, 83–85, 84f
impaction, 125

laparoscopic treatment, 175
magnetic resonance
cholangiopancreatography, 102
pigment, 222
post-liver transplantation, 297, 298f
transabdominal ultrasound, 101
bile duct tumors
adjuvant therapy, 206
antiangiogenic therapy, 211
apoptosis induction, 211
Bismuth classifi cation, 114
brush cytology, 113, 113f
bystander effect, 211
chemoradiotherapy, 205–206
chemotherapy
combination, 209–210
neoadjuvant, 205–206
resistance mechanisms, 210
single-agent, 206, 207–208t, 209
toxicity, 210
endoscopy, 112
fine-needle aspiration, 97, 113
fluorescent in situ hybridization, 114
forceps biopsy, 113, 114f
gene therapy, 211
immunotherapy, 210–211
k-ras oncogene, 114
liver infiltration, 149
management, 205–214
molecular biology, 210, 211–212

molecular markers, 114
palliative care, 206, 209–210
photodynamic therapy, 115
positron emission tomography, 74, 74t
radiation therapy, 205, 206
regional lymph node involvement,
149–150
signaling inhibitors, 211–212
staging, 114
stenting, 114 –115, 115f
telomerase, 114
tissue sampling, 113–114
TNM classifi cation, 114
bile fistula see biliary fistula(s)
bile leak(s), 128, 130–131
biliary decompression, 135
cholescintigraphy, 91f, 92
cystic duct stump, 108, 109f
drainage, 130
ERCP, 108–109, 130
laparoscopic cholecystectomy, 178
percutaneous biliary imaging, 121–122
percutaneous transhepatic
cholangiography, 108, 130–131
post-liver transplantation, 296–297, 296f
postoperative/post-traumatic patients,
91f, 92
bile peritonitis, 122
bile salt(s), 219, 355
bile salt excretory peptide (BSEP), 359

bile salt export pump disease, 387–388
bilhemia, 241
biliary atresia
children, 38–40, 40f
cholestasis, 364
classifi cation, 380, 380t
clinical presentation, 378–379
definition, 378
diagnostic tests, 378–379, 379f
embryonic form, 378
epidemiology, 378
etiology, 378
extrahepatic, 38–40, 40f
infants, 378–381
morphological features, 39–40, 40f
pathology, 379, Plate 10, Plate 11
perinatal form, 378
prognosis, 379–380, 381
surgical management, 379–380
biliary bypass, gallbladder carcinoma, 256
biliary colic, 60, 101
biliary cystadenocarcinoma, 47, 48f, 285
biliary cystadenoma, 42, 42f, 285
biliary decompression
acute cholangitis, 268, 273
bile leaks, 135
biliary disease
children, 38–41, 388–402
infants, 378–384
see also specifi c diseases/disorders

biliary dyskinesia, 235, 393–394
biliary–enteric bypass operations, 125, 125f
biliary–enteric fistulas, 239–241, 240t
biliary excreted contrast agents, 73
biliary fistula(s), 239–242
external, 242
internal, 239–242
bilhemia, 241
biliary obstruction, 241–242
laparoscopic biliary injuries, 195
orthotopic liver transplantation, 137
percutaneous interventions, 133, 135,
136–137f, 137, 138f
see also specifi c types
biliary microhamartoma, 41–42
biliary obstruction
biliary–vascular fistulas, 241–242
cholangiocarcinoma and, 333
cholangiography, 123
cholestasis and, 363, 364
large ducts, 30–31, 31f
biliary outflow reconstruction, 168–171
cholangitis prevention, 168
end-to-side hepaticojejunostomy,
168–169, 169f, 170f
left common hepatic duct, 169, 171f
Longmire procedure, 170
round ligament approach, 169–170, 171f
biliary parasites, bile duct stones, 102–103
biliary perforation, spontaneous in infants,

381–382
biliary pressure, acute cholangitis, 266
biliary reconstruction
liver transplantation, 289, 291f
choledochocholedochostomy, 289,
290–292, 291f, 292f
Roux-en-Y choledochojejunostomy,
289, 292–293, 293f
see also biliary outflow reconstruction
biliary sludge, 222–223, 222f, 297
Index 417
biliary strictures, 394–395
anastomotic, 294f
benign
biliary–enteric bypass operations, 125,
125f
causes, 125–126
cholangiography, 125–126, 125f, 126f
choledochojejunostomy, 125, 126f
malignant vs., 109–110
orthotopic liver transplantation, 126
percutaneous interventions, 142
computed tomography, 109–110
malignant
ampullary carcinoma, 128
benign vs., 109–110
causes, 127–128
cholangiography, 126, 128
imaging, 128
metastases, 128, 130f, 131f

pancreatic carcinoma, 128, 129f
Mirizzi’s syndrome, 109, 109f
nonanastomotic, 294, 294f, 296
post-liver transplantation, 293–295,
294f, 296
postsurgical, ERCP, 108f, 109–110, 110f
PSC and, 319, 320f
biliary system/tract
drainage, percutaneous interventions,
133, 135f
dysmotility, 16
imaging, 71–96
motility, 13–16
MRI, 73
neoplasms, 41–47
benign, 41–42
malignant, 42–43
physiology, 11–16
biliary tree
cystic fibrosis, assessment in, 392
imaging techniques, 97, 112–113
infection, PSC and, 310
laparoscopic treatment, 178–179, 179f
tumors, 111t
biliary–vascular fistulas, 241–242
bilirubin, 221
bilomas
laparoscopic biliary injury, 194
post-liver transplantation, 297, 297f
biopsies

core needle, 21
forceps, bile duct tumors, 113, 114f
liver see liver biopsy
percutaneous interventions, 140
Bismuth classifi cation
bile duct tumors, 114
cholangiocarcinoma, 166, 332–333, 333f
laparoscopic biliary injuries, 182,
183 –184
black gallstones, 47, 58, 221, 388, 389, 402
bleeding
control, laparoscopic biliary injuries, 194
laparoscopic cholecystectomy, 177–178
percutaneous transhepatic
cholangiography, 122
blood clots vs. bile duct stones, 125
blood supply
common bile duct, 10–11, 11f
extrahepatic bile ducts, 10–11, 11f
gallbladder, 8, 10f
liver, 4–6
Bouveret’s syndrome, 243f, Plate 7
bronchobiliary fistulas, 241
brown gallstones, 47, 58–59, 221
brush cytology, 21, 113, 113f
Budd-Chiari syndrome, 7
Burkitt’s lymphoma, 394
“butterfly area,” 345, Plate 8
“Byler bile,” 387, 387f, Plate 18
Byler’s disease see progressive familial

intrahepatic cholestasis (PFIC), type
1 (Byler’s disease)
bystander effect, bile duct tumors, 211
C
Calot’s triangle, 11, 192, 193–194
canalicular bile salt transporter, 359
canalicular excretion of bile, 358–360
canalicular organic anion transport,
359–360
canalicular phospholipid flippase, 359
canalicular space, 356
canaliculus see gallstone(s)
canals of Hering, 7
Cantlie’s line, 3
capecitabine, 209
carcinoma see specifi c types
Caroli’s disease, 35, 36f, 61, 281–282, 281f
children, 400, 400t, 402
choledochal cysts and, 384
cystic biliary disease, 124
Caroli’s syndrome, 35, 281–282, 400, 400t,
402
caudate lobe removal, 166
cautery-induced injuries, 191–192, 194
cephalic response, 13
Charcot’s triad, 175, 266
charged particles, radiation therapy,
156–157, 157f
chemical dissolution of bile duct stones,
106 –107

chemotherapy
cholangiocarcinoma, 205, 336
gallbladder carcinoma, 258–259, 258t
radiation therapy with, 155, 155t, 158
bile duct tumors, 205–206
cholangiocarcinoma, 205
chenodeoxycholate, 362
chenodeoxycholic acid (CDCA), 225
children, 388–402
acalculous gallbladder disease, 392–395
Alagille’s syndrome, 377
biliary atresia, extrahepatic, 38–40, 40f
biliary disease in, 38–41, 388–402
biliary dyskinesia, 393–394
Caroli’s disease, 402
cholecystitis
acalculous, 392–393, 393f
calculous, 388–391
cholestasis, 38–41, 378
common bile duct disease, 394–395,
394f, 395f
congenital hepatic fi brosis, 400–402,
400t, 401f
cystic diseases of the intrahepatic bile
ducts, 399–402
cystic fi brosis and biliary disease, 378,
391–392
gallbladder, congenital anomalies, 392
gallbladder tumors, 394
gallstones, 377, 388–391

genetic abnormalities, 377–378, 392
hydrops, 392
intrahepatic bile duct paucity, 40–41, 41f
sclerosing cholangitis, 395–399, 396f
immunodeficiency and, 34
primary, 34, 395–399, 397t, 398f
see also infants
Chlamydia pneumoniae, 343
cholangiocarcinoma, 42–43, 126, 126f,
127f, 332–339
associated disorders, 332
bile duct resection, 165–167
Caroli’s disease and, 282
central/hilar (perihilar), 43–44, 43f, 44t,
151
chemotherapy, 205, 336
classifi cation, 332–333, 333f
clinical presentation, 333–334
diagnosis, 334
digital reconstructed radiograph, 157,
Plate 5
endoscopic ultrasound, 111–112, 112f
endoscopy, 111–115
epidemiology, 62–63, 332
etiology, 62, 63t, 332
extrahepatic, 332, 334
hepatocellular carcinoma, mixed, 47
hilar see hilar cholangiocarcinoma;
Klatskin tumors
imaging, 86–88, 89f

intraductal ultrasonography, 111–112
liver transplantation, 336–337
mid duct, axial view, 157, Plate 6
palliative treatment, 337
418 Index
peripheral/intrahepatic, 42–43, 44–47,
155–156, 334
clinical associations, 45
differential diagnosis, 46–47, 46t
etiology, 45
gross features, 45, 46f
microscopic features, 45
prognostic factors, 45
staging, 45, 45t
presentation, 126
prognosis, 321–322, 334–335
PSC and, 31, 62, 321–322, 399
radiation therapy, 150, 151, 205, 336
recurrent pyogenic cholangitis and, 31
resection, 334–336, 335t
risk factors for, 321
treatment, 334–337
tumor markers, 321
cholangiography, 99
bile duct stones, 124–125, 124f, 125f
biliary atresia, 380
biliary obstruction, 123
biliary strictures, 395, 395f
benign, 125–126, 125f, 126f
malignant, 126, 128

Caroli’s disease, 402
computed tomography, 82, 83f
cystic biliary disease, 124
interpretation, 123–131
Couinard nomenclature, 123
intraoperative, 178
PSC, 123–124, 124f, 397, 398f
classifi cation, 307, 307t
diagnosis, 313
surgery, 163, 164f
cholangiopathies
chronic nonsuppurative granulomatous
intrahepatic see primary biliary
cirrhosis (PBC)
immune-mediated transplant-associated
see immune-mediated transplant-
associated cholangiopathies
infectious, 34
secondary sclerosing, 34
cholangitis
acute, 85, 265–276
bacteriology, 266, 266t, 267t
clinical features, 266–267
complications, 267, 267t
etiology, 265
imaging, 267–268
laboratory findings, 267
management, 268–273
morbidity/mortality, 267
pathogenesis, 265–266

autoimmune, 23–24
bacterial, 31, 60, 319
bile duct stones, 103
Caroli’s disease, 282
cholecystitis and, 389
chronic nonsuppurative destructive,
PBC, 23
endoscopic ultrasound, 101
imaging, 85–86, 85f
Mirizzi’s syndrome vs., 247
post-liver transplantation, 260, 298
prevention, biliary outflow
reconstruction, 168
primary sclerosing see primary sclerosing
cholangitis (PSC)
recurrent pyogenic, 31, 32f
sclerosing see sclerosing cholangitis
stent complication, 337
type B laparoscopic biliary injuries, 183,
185f, 196
type C laparoscopic biliary injuries, 183,
186f
cholate, 362
cholecystectomy
acute cholangitis, 272
bile acid storage after, 12
biliary dyskinesia, 393–394
“dome down” technique, 177
duct of Luschka injury during, 9
gallbladder carcinoma, 255

gallstones, 390
cholecystic-sphincter of Oddi reflex, 16
cholecystitis, 229–238
acute
Charcot triad, 175
cholescintigraphy, 90, 90f
computed tomography, 75–76, 80f
external biliary fistulas, 242
gallstone complication, 60
laparoscopic cholecystectomy, 175
laparoscopic treatment, 174 –175
Murphy sign, 175
pathology, 49
acute acalculous, 49, 60, 233–234
acute calculous, 229–233
complications, 230–231
differential diagnosis, 230
epidemiology, 230
histology, 229–230
imaging, 231–232, 231f, 232f
nonsurgical therapy, 232
pathophysiology, 229–230, 230f
presentation, 230
surgical therapy, 232–233
bile duct stones, 233
children
acalculous, 392–393, 393f
calculous, 388–391
cholangitis and, 389
chronic

acalculous, 92, 235
calculous, 234–235
imaging, 76–77
pathology, 49, 50f
clinical presentation, 389
diagnosis, 389
eosinophilic, 47, 49
gallbladder wall thickness, 111
gallstones, 224
gangrenous, 230–231
imaging, 75–77, 79f, 80f, 81f
management, 389–391
in pregnancy, 233
xanthogranulomatous, 49
cholecystobiliary fistulas, 246
cholecystocolic fistulas, 239–240
cholecystoduodenal fistula, 239, 240f
cholecystoduodenal fistula, spontaneous,
240–241
cholecystokinin (CCK)
cholesci ntigraphy, for, 91–92
feeding effect, 13
gallbladder emptying studies, 393
gallbladder motility, 13
sphincter of Oddi motility, 15–16
cholecystostomy
acute acalculous cholecystitis, 234
gallstones in common bile duct, 391
choledochal cyst(s), 38, 39f, 282–285
Caroli’s disease and, 384

cholangiocarcinoma and, 332
classifi cation, 38, 38t, 61f, 282–283, 282f,
382, 382t
clinical manifestations, 383
computed tomography, 86
diagnosis, 283, 383, 383f
differential diagnosis, 283
endoscopy, 115
epidemiology, 61
etiology, 382–383
follow up post removal, 384
infants, 382–384
magnetic resonance cholangiogram, 86,
88f
malignant transformation, 394
pathology, 383, Plate 12, Plate 13
pathophysiology, 382–383, 383f
prevalence, 283
treatment, 283–285, 383–384, Plate 14,
Plate 15
liver transplantation, 284–285
surgical excision, 283–284, 284f
choledochocholedochostomy (CDCD)
biliary reconstruction, 289, 290–292,
291f, 292f
liver transplantation, 289, 290–292,
291f, 292f
living donor, 300–301
choledochoduodenal junction, 10f
Index 419

choledochoduodenostomy, 247
choledochoenterostomy, choledochal cyst,
384, Plate 14, Plate 15
choledochojejunostomy, biliary strictures,
125, 126f
choledocholithiasis see bile duct stones
cholehepatic shunt, 356
cholelithiasis see gallstone(s)
cholescintigraphy, 88–92, 90f, 91f
biliary leak, 91f, 92
cholecystokinin administration and,
91–92
common bile duct obstruction diagnosis,
91
disadvantages, 89–90
indications, 90
radioisotope, 231–232
cholestasis, 355–373
acute, 22, 29–30
amyloidosis and, 368
benign recurrent intrahepatic, 359, 364,
365–366, 387
bile duct obstruction and, 363, 364
children, 38–41, 378
chronic, 22, 368, 369t
clinical approaches to, 363–370
congenital/inherited see progressive
familial intrahepatic cholestasis
(PFIC)
cytokines and, 363, 367–368

diagnosis, 364
drug-induced, 29–30, 363, 368–370,
368t
chronic, 368, 369t
pathogenesis, 369f
endotoxin effects, 363
estrogen and, 363, 366
ethanol and, 367
etiology, 364, 364t
genetic causes, 364–366, 384t
see also progressive familial
intrahepatic cholestasis (PFIC)
inborn errors of bile acid metabolism,
386
infants, 384–388
interlobular bile duct paucity, 385–386
intrahepatic bile duct paucity, 384, Plate
16
lipopolysaccharide effects, 363
oral contraceptive-associated, 363, 366
paraneoplastic, 367–368
pathology, 21–22
post-liver transplantation, 298
of pregnancy, 363, 366, 388
progressive familial intrahepatic see
progressive familial intrahepatic
cholestasis (PFIC)
sepsis-associated, 366, 367
total parenteral nutrition and, 366
viral hepatitis and, 29, 366–367

cholesterol
bile and, 12, 219
saturation index, 12, 13f
sources of, 12
transport, 359
cholesterolosis, 49, 60
cholesterol polyps, 49, 51f, 60–61, 110
cholesterol stones, 47, 58, 100, 219–221,
220f, 389
formation, 12
chronic nonsuppurative granulomatous
intrahepatic cholangiopathy see
primary biliary cirrhosis (PBC)
cirrhosis
cystic fibrosis, 391, Plate 20
primary biliary see primary biliary
cirrhosis (PBC)
cisplatin, 209
clipping injury during laparoscopy, 194
Clonorchiasis, 265
Clonorchis sinensis, 265
coagulation parameters, 164–165
colchicine, 316
“collision tumors,” 47
colonic toxins, 309t
colorectal carcinoma, 47
common bile duct (CBD)
anatomy, 9–11
blood supply, 10–11, 11f
closure, laparoscopic treatment, 179–180

diameter, 9–10
diseases in children, 394–395, 394f, 395f
gallstones in see bile duct stones
innervation, 11
lymphatic drainage, 11
obstruction, diagnosis, 91–92
common bile duct stones see bile duct stones
communicating duct cysts, 399
computed tomography (CT), 72
bile duct imaging, 81–82
bile duct strictures, 109–110
cholangiocarcinoma, 86–87, 334
cholangitis
acute, 268
primary sclerosing, 398f
cholecystitis, 75–76, 80f
acalculous, 393
acute calculous, 231, 231f
choledochal cysts, 86
choledocholithiasis, 83, 84
congenital hepatic fi brosis, 400, 401f
gallbladder carcinoma, 77, 82f, Plate 1
gallbladder imaging, 75
gallstone ileus, 244, 244f
gallstones, 75
laparoscopic biliary injuries, 194
liver cysts, 278, 278f
mechanism of action, 72
Mirizzi’s syndrome, 247
multislice, 72

pre-surgery, 165
spontaneous biliary perforation in
infants, 381
congenital hepatic fibrosis (CHF), 35, 35f,
280, 400t
associated disorders, 401, 402
children, 400–402, 400t, 401f
clinical presentation, 400
diagnosis, 400, 401f
pathogenesis, 400
pathology, 400, Plate 24
prognosis, 402
congenital intrahepatic biliary dilatation
see Caroli’s disease
constitutive androgen receptor (CAR,
NR1I3), 361f, 361t, 362–363
contrast agents
allergy, 98
biliary excreted, 73
intravascular, 71–72
copper
metabolism abnormalities, 309
PSC and, 309, 312
core needle biopsy, 21
corticosteroids, 316, 347–348
Couinard nomenclature, 123
covered stents, 139–140
cross-sectional imaging modalities, 71–75
cyclophosphamide, 206
cyclosporine, 317

cyst(s)
bile duct see bile duct cysts
choledochal see choledochal cyst(s)
ciliated hepatic foregut, 34
communicating duct, 399
liver, 277–279, 278f, 278t
perihilar, 34
simple sporadic, 34
cystadenocarcinoma
biliary, 47, 48f, 285
liver, 278–279
cystadenoma
biliary, 42, 42f, 285
liver, 278–279
cystic artery, 7, 10f, 11
cystic biliary disease, 277–288
Caroli’s diseases, 124
cholangiography, 124
complications, 124
cystic dilatation of bile duct, 86, 88f
cystic duct
anatomy, 8–9
misidentifi cation in laparoscopy, 189f,
190, 190f, 191f
420 Index
obstruction, acute calculous
cholecystitis, 229
occlusion, laparoscopy injury, 191
stump, bile leakage, 108, 109f
cystic fibrosis

bile duct abnormalities, 391, Plate 21
biliary disease in children, 378, 391–392
biliary tree assessment, 392
epidemiology, 61–62
etiology, 62
gallstones in, 391
liver cirrhosis, 391, Plate 20
cystic fibrosis transmembrane regulator
(CFTR), 62, 391
cystic vein, 9
cytokines, cholestasis and, 363,367–368
cytomegalovirus infection, 41
D
diabetes mellitus, gallstones with, 224
diet, gallstones and, 223
diffuse sclerosing carcinoma vs. primary
sclerosing cholangitis, 124
digital reconstructed radiograph (DRR),
cholangiocarcinoma, 157, Plate 5
dissection techniques, 192, 193f
“dome down” technique, cholecystectomy,
177
Down syndrome, gallstones with, 223
drainage, surgery and, 163–164
dry eyes, primary biliary cirrhosis and, 347
Dubin-Johnson syndrome, 359
ductal plate malformation, 399–400, 400t,
plate 24
duct of Luschka, 9
duct of Santorini, 10

duct of Wirsung, 10
ductopenia, adult idiopathic, 28–29, 29f, 41
duodenal obstruction, gallstone ileus, 243,
243f, Plate 7
duodenum, radiation tolerance, 148t
dysmotility
gallbladder, 16
sphincter of Oddi, 16
E
electrohydraulic lithotripsy (EHL), 105
electrolyte status, 165
endobiliary brush cytology, 44
endoscopic balloon dilation
anastomotic strictures, post liver
transplant, 294
PSC, 399
endoscopic drainage, acute cholangitis,
269–272
endoscopic retrograde cholangiography
(ERC)
Caroli’s disease, 282
cholangiocarcinoma, 334
cholangitis
acute, 268
primary sclerosing, 313–314, 315, 320,
321
choledochal cysts, 283, 283f
endoscopic retrograde
cholangiopancreatography (ERCP),
97–99, 120

bile/bile duct leaks, 108–109, 130
bile duct stones, 84, 101, 102–110, 103f
biliary parasites, 102–103
chemical dissolution, 106–107
common bile duct, 107–108, 108f,
390–391
difficult extractions, 105
electrohydraulic lithotripsy, 105
extracorporeal shockwave lithotripsy,
106, 106f
laser lithotripsy, 106f
mechanical lithotripsy, 105, 105f
sphincterectomy, 104,104f
stenting, 107, 107f
stone extraction, 104–105
cholangiocarcinoma, 86
cholangitis
acute, 269–270
primary sclerosing, 319–320, 397
choledochal cyst, 383
indications, 97, 98t
intraluminal transcatheter
brachytherapy with, 152–153
laparoscopic biliary injury management,
194, 196
laparoscopic cholecystectomy vs.,
107–110
Mirizzi’s syndrome, 247–248
morbidity, 98
mortality, 98

postsurgical biliary strictures, 108f,
109 –110, 110f
pre-surgery, 165
stent placement, 86
endoscopic sphincterectomy, acute
cholangitis, 272
endoscopic ultrasound (EUS), 97–99
bile duct stones, 101–102
extrahepatic bile duct, 101–102, 102f
“risk stratifi cation,” 102, 103f
cholangiocarcinoma, 111–112, 112f
cholelithiasis, 100–101
gallbladder lesions, 110–111
indications, 97, 101
endoscopy, 97–119
anatomical variation, 98–99, 99f
antibiotic coverage, 98
bile duct stones, 101–110
bile duct tumors, 112
cholangiocarcinoma, 111–115
choledochal cysts, 115
cholelithiasis, 100–101
contrast allergy, 98
informed consent, 98
liver transplantation, biliary
complications, 299
patient preparation, 98
sclerosing cholangitis, 115
sphincterectomy, 104
see also specifi c methods

endothelialitis, hepatic allograft rejection,
25
endotoxins, cholestasis and, 363
end-to-side hepaticojejunostomy, 168–169,
169f, 170f
enterolithotomy, gallstone ileus treatment,
245, 245t
enterotomy
biliary atresia, 380
choledochal cyst, 383
eosinophilic cholecystitis, 47, 49
epidemiology, 58–67
see also specifi c diseases/disorders
epidermal growth factor receptor (EGFR),
211–212
esophagus, radiation tolerance, 148t
estrogen, cholestasis and, 363, 366
etanercept, 318
ethanol, cholestasis and, 367
ethnicity, gallstones, 223
external beam radiation therapy (ERBT)
bile duct tumors, 206
gallbladder carcinoma, 257–258
external biliary fistulas, 242
extracorporeal shockwave lithotripsy
(ESWL)
bile duct stones, 106, 106f
gallstones treatment, 225
extrahepatic bile ducts
anatomy, 7–8, 9f

blood supply, 10–11, 11f
carcinoma, 44
endoscopic ultrasound, 101–102, 102f
lymphatic drainage, 11
pathology, 21–57
extrahepatic biliary atresia, 61
F
farsenoid X receptor (FXR, NR1H4), 361f,
361t, 362
fasting, acute calculous cholecystitis, 232
fatigue, primary biliary cirrhosis and, 345,
347
feeding effects, 13
fibropolycystic diseases, 34–38
pathogenesis, 36, 38
see also specifi c diseases
Index 421
fine-needle aspiration
bile duct tumors, 97, 113
as diagnostic tool, 21
fistula(s) see biliary fistula(s); specific types
florid duct lesion, primary biliary cirrhosis,
23
fluorescent in situ hybridization (FISH),
114
fluorodeoxyuridine (FUDR), 205
5-fluorouracil (5-FU)
adriamycin with, 155
bile duct tumors, 205, 206, 209
chemotherapy with, 209

gallbladder carcinoma, 258
mitomycin with, 155
radiation therapy with, 155, 205
forceps biopsy, bile duct tumors, 113, 114f
four-dimensional radiation therapy, 156
G
gallbladder
acalculous disease, children, 392–395
acute distension (hydrops), 392
adenomyomatosis, 110
anatomy, 8–9
anomalies, 8, 8t
arterial supply, 8, 10f
benign neoplasms, 49
cholecystitis see cholecystitis
cholelithiasis see gallstone(s)
congenital anomalies in children, 392
differential diagnosis, 110
dysmotility, 16
ejection fraction, 92
emptying studies, 393
endoscopic ultrasound, 110–111
imaging, 75–81
infl ammatory conditions, 47, 49
innervation, 9, 13
lymphatic drainage, 9
motility, 13–15
mucosa, malignancy precursor lesions,
50
mucosal erosions/ulcers, 234

pathology, 47–53
percutaneous interventions see
percutaneous interventions
perforation, 231
polyps, 49
cholesterol, 110
stasis, 221, 224
“strawberry,” 252
trauma, laparoscopic cholecystectomy,
178
tumors, 252–262
benign/pseudotumors, 252–253, 253f,
254f
children, 394
malignant see gallbladder carcinoma
polypoid lesions, 252–253
venous drainage, 9
wall integrity, 111
gallbladder adenoma, 49, 252–253
gallbladder carcinoma, 49–53, 128,
253–259, 394
adjuvant therapy, 257
bile duct stones and, 128, 129f
chemotherapy, 258–259, 258t
clinical features, 77, 253–254
diagnosis, 253–254, 254
epidemiology, 62
etiology, 50
gallstones as risk factor, 224, 253
gross morphology, 50–52, 52f

imaging, 77, 80–81, 82t, 254, 255f
incidence, 253
microscopic appearance, 52, 52f
palliative therapy, 256
precursor lesions in gallbladder mucosa,
50
prognosis, 52–53
radiation therapy, 257–258
risk factors, 77, 253
in situ, 168, 255
staging, 52, 53, 53t
surgery, 167–168, 254–256, 257t
carcinoma in situ, 168, 255
cholecystectomy, 255
metastases, 255, 256
symptoms, 254
TNM staging, 254, 256t
unresectable, 168
gallstone(s), 8, 58–60, 219–228
black pigment, 47, 58, 221, 388, 389, 402
brown pigment, 47, 58–59, 221
children, 377, 388–391
cholecystitis, 224
cholesterol see cholesterol stones
chronic calculous cholecystitis, 234
classifi cation, 47, 58–59, 388
clinical presentation, 389
common bile duct, in see bile duct stones
(choledocholithiasis)
complications, 224

composition, 58–59
cracking, 75, 78f, 79f
cystic fibrosis and, 391
diabetes mellitus and, 224
diagnosis, 389, 390f
differential diagnosis, 224
drug associated, 59
endoscopic ultrasound, 100–101
endoscopy, 100–101
epidemiology, 58, 59t, 219
etiology, 58
external biliary fistulas, 242
formation, 12–13
gallbladder carcinoma association, 253
imaging, 77f,78f, 79f
management, 389–391
natural history, 59–60, 224–225
pathogenesis, 219–223
biliary sludge, 222–223, 222f
common duct stones, 221–222
pathology, 47
pigmented, 47, 100, 219, 221
prevalence, 100
removal, percutaneous interventions,
141
risk factors, 59, 223–224, 223t, 388,
389t
silent (asymptomatic), 390
symptomatic, 60, 389, 390
transabdominal ultrasound, 100

treatment, 174, 225
types, 219
see also specifi c types
gallstone ileus, 242–246
Balthazar’s sign, 243, 244f
clinical signs, 243
diagnostic imaging, 243–244, 244f
duodenal obstruction, 243, 243f, Plate 7
impaction sites, 243, 243t
incidence, 242–243
morbidity/mortality, 245t, 246
pneumobilia, 243
stone size, 242–243
treatment, 245–246, 245t
gallstone (biliary) pancreatitis, 102–103
gangrenous cholecystitis, 230–231
gastric outlet obstruction, 243, 243f, Plate 7
gemcitabine, 209–210
general anesthesia, laparoscopic
cholecystectomy, 175
gene therapy, bile duct tumors, 211
graft-versus-host-disease (GVHD)
acute, 25–28
chronic, 27
clinical features, 25
grading, 28
histopathologic features, 25–26, 26f
H
hamartoma
mesenchymal, of infancy, 400, 401f

mucinous, 280–281
Hartmann’s pouch, 8
Hasson technique, 176
heart and estrogen/progrestin replacement
study (HERS II), 348
helical scanners see computed tomography
(CT)
hemihepatectomy, bile duct resection,
166