Diseases of the Gallbladder and Bile Ducts - part 10 ppsx

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

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 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 (C3) 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.

anti-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

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 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.

pro-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

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 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.

al-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 ing modality of choice that is the most likely to demonstrate

imag-an abnormality ERCP imag-and MRCP are highly sensitive ods of visualizing the biliary tree and should be performed before any consideration is given to open cholangiography or operative intervention.

meth-Classic findings on cholangiography are beading and turing of the extra and intrahepatic biliary tree (Fig 23.10)

struc-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 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,

bile-duct-Table 23.5 Differences in clinical manifestation of primary sclerosing

cholangitis in children and adults

Alkaline phosphatase Normal in 25–50% of patients High

hepatitis markers

transplant

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

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 stentdilat-ing 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 tion With aggressive protocols, liver transplant survival after transplantation for PSC complicated by carcinoma may have better graft and patient survival.

transplanta-In many children with PSC, the goals of therapeutic 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.

inter-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

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

segments 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.

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

Caroli’s syndrome Congenital dilatation Inherited autosomal Associated with Cholangitis, cholelithiasis, Supportive

of the larger IHBD recessive CHF lesions, renal portal hypertension Treat cholangitis

Congenital hepatic Dilatation of smaller Inherited autosomal Renal polycystic Hematemesis, hematochezia, Splenorenal

fibrosis (ARPKD) IHBD recessive disease melena, hepatomegaly, Shunt for portal

Kidney transplant for

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

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 hood with repetitive bouts of abdominal pain, and episodes

adult-of cholangitis (64%), clinical evidence adult-of portal 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-

hyperten-ported Prenatally, the presence of the ARPKD gene, PKHD1,

may be suggested by fetal ultrasound findings normally ciated with Caroli’s disease [176].

asso-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].

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

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?

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

12 Nonobstructive hydrops of the gallbladder can result from all of

the following except

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.

References

1 Shim WK, Kasai M, Spence MA Racial influence on the

inci-dence of biliary atresia Prog Pediatr Surg 1974;6:53–62

2 Krauss AN Familial extrahepatic biliary atresia J Pediatr

1964;65:933–7

3 Poovorawan Y, Chongsrisawat V, Tanunytthawongse C, et al

Extrahepatic biliary atresia in twins: zygosity determination

by short tandem repeat loci J Med Assoc Thai 1996;79 Suppl 1:

S119–24

4 Danesino C, Spadoni E, Buzzi A Familial biliary atresia Am J

Med Genet 1999;85:195

5 Ando K, Miyano T, Fujimoto T, et al Sibling occurrence of

bili-ary atresia and bilibili-ary dilatation J Pediatr Surg 1996;31:

1302–4

6 Zhang DY, Sabla G, Shivakumar P, et al Coordinate expression

of regulatory genes differentiates embryonic and perinatal forms of biliary atresia Hepatology 2004;39:954–62

7 Silveira TR, Salzano FM, Donaldson PT, et al Association tween HLA and extrahepatic biliary atresia J Pediatr Gastro-enterol Nutr 1993;16:114–17

be-8 Qiao H, Zhaori G, Jiang Z, et al Detection of group C rotavirus antigen in bile duct and liver tissues of an infant with extrahe-patic biliary atresia Chin Med J (Engl) 1999;112:93–5

9 Tyler KL, Sokol RJ, Oberhaus SM, et al Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts Hepatology 1998;27:1475–82

10 Petersen C, Bruns E, Kuske M, von Wussow P Treatment of trahepatic biliary atresia with interferon-alpha in a murine in-fectious model Pediatr Res 1997;42:623–8

ex-11 Szavay PO, Leonhardt J, Czech-Schmidt G, Petersen C The role of reovirus type 3 infection in an established murine model for biliary atresia Eur J Pediatr Surg 2002;12:248–50

12 Kobayashi H, Li Z, Yamataka A, Lane GJ, Miyano T Role of munologic costimulatory factors in the pathogenesis of biliary atresia J Pediatr Surg 2003;38:892–6

im-13 Sokol RJ, Mack C Etiopathogenesis of biliary atresia Semin Liver Dis 2001;21:517–24

14 Mack CL, Tucker RM, Sokol RJ, et al Biliary atresia is

associat-ed with CD4+ Th1 cell-mediated portal tract infl ammation Pediatr Res 2004;56:79–87

15 Park WH, Choi SO, Lee HJ The ultrasonographic “triangular cord” coupled with gallbladder images in the diagnostic pre-diction of biliary atresia from infantile intrahepatic cholesta-sis J Pediatr Surg 1999;34:1706–10

16 Farrant P, Meire HB, Mieli-Vergani G Improved diagnosis of extraheptic biliary atresia by high frequency ultrasound of the gall bladder Br J Radiol 2001;74:952–4

17 Visrutaratna P, Wongsawasdi L, Lerttumnongtum P, et al Triangular cord sign and ultrasound features of the gall blad-der in infants with biliary atresia Australas Radiol 2003;47:252–6

18 Azarow KS, Phillips MJ, Sandler AD, et al Biliary atresia: should all patients undergo a portoenterostomy? J Pediatr Surg 1997;32:168–72;discussion 172–4

19 Kasai M, Kimura S, Assecura Y Surgical treatment of biliary atresia J Pediatr Surg 1968;3:665–75

20 Ibrahim M, Miyano T, Ohi R, et al Japanese biliary atresia istry, 1989 to 1994 Tohoku J Exp Med 1997;181:85–95

reg-21 Ohi R, Chiba T, Endo N Morphologic studies of the liver and bile ducts in biliary atresia Acta Paediatr Jpn 1987;29:584–9

22 Kimura S [Progress and problems in pediatric surgery – a study group on congenital biliary atresia] Nippon Geka Gak-kai Zasshi 1984;85:1192–5

23 Gautier M, Eliot N Extrahepatic biliary atresia Morphological study of 98 biliary remnants Arch Pathol Lab Med 1981;105:397–402

24 Lopez PG, Gomezese S, de la Cruz R, et al [Modified Kasai

technique for the treatment of biliary atresia] Cir Pediatr

1989;2:55–7

25 Sartorelli KH, Holland RM, Allshouse MJ, et al The

intussus-ception antireflux valve is ineffective in preventing cholangitis

in biliary atresia J Pediatr Surg 1996;31:403–6

26 Honna T, Tsuchida Y, Kawarasaki H, et al Further experience

with the antireflux valve to prevent ascending cholangitis in

biliary atresia J Pediatr Surg 1997;32:1450–2

27 Ogasawara Y, Yamataka A, Tsukamoto K, et al The

intussus-ception antireflux valve is ineffective for preventing

cholangi-tis in biliary atresia: a prospective study J Pediatr Surg 2003;

38:1826–9

28 Suruga K, Miyano T, Arai T, et al A study of patients with

long-term bile flow after hepatic portoenterostomy for biliary

atre-sia J Pediatr Surg 1985;20:252–5

29 Suruga K, Miyano T, Arai T, Deguchi E A study on hepatic

por-toenterostomy for the treatment of atresia of the biliary tract

Surg Gynecol Obstet 1984;159:53–8

30 Chardot C, Iskandarani F, De Dreuzy O, et al Spontaneous

perforation of the biliary tract in infancy: a series of 11 cases

Eur J Pediatr Surg 1996;6:341–6

31 Spigland N, Greco R, Rosenfeld D Spontaneous biliary

perfo-ration: does external drainage constitute adequate therapy? J

Pediatr Surg 1996;31:782–4

32 Davenport M, Saxena R, Howard E Acquired biliary atresia J

Pediatr Surg 1996;31:1721–3

33 Shocket E, Hallenbeck GA, Hayles AB Choledochal cyst:

re-port of cases Mayo Clin Proc 1955;30:83–9

34 Stillwater K, Zbikowski J, et al Idiopathic dilatation of the

common bile duct, choledochal cyst J Pediatr 1950;36:247–

51

35 Alonso-Lej F, Rever WB, Jr., Pessagno DJ Congenital

chole-dochal cyst, with a report of 2, and an analysis of 94, cases Int

Abstr Surg 1959;108:1–30

36 Lee SS, Min PC, Kim GS, Hong PW Choledochal cyst A report

of nine cases and review of the literature Arch Surg 1969;99:

19–28

37 Somasundaram K Choledochal cyst and dilatation of the bile

ducts in infancy and childhood Aust N Z J Surg 1972;42:

163–7

38 Spitz L The surgical treatment of choledochal cyst S Afr J Surg

1972;10:161–5

39 Kobayashi A, Ohbe Y Choledochal cyst in infancy and

child-hood Analysis of 16 cases Arch Dis Child 1977;52:121–8

40 Todani T, Watanabe Y, Narusue M, et al Congenital bile duct

cysts: Classifi cation, operative procedures, and review of

thir-ty-seven cases including cancer arising from choledochal cyst

Am J Surg 1977;134:263–9

41 Angel JL, Knuppel RA, Trabin J Choledochal cyst

complicat-ing a twin gestation South Med J 1985;78:463–6

42 Gallivan EK, Crombleholme TM, D’Alton ME Early prenatal

diagnosis of choledochal cyst Prenat Diagn 1996;16:934–7

43 Wiedman MA, Tan A, Martinez CJ Fetal sonography and natal scintigraphy of a choledochal cyst J Nucl Med 1985;26:893–6

neo-44 Dudin A, Abdelshafi M, Rambaud-Cousson A Choledochal cyst associated with rare hand malformation Am J Med Genet 1995;56:161–3

45 Fieber SS, Nance FC Choledochal cyst and neoplasm: a prehensive review of 106 cases and presentation of two origi-nal cases Am Surg 1997;63:982–7

com-46 Kim S, Idowu O, Chen E Choledochal cyst in Simpson–Golabi–Behmel syndrome Am J Med Genet 1999;87:267–70

47 Ohita H, Yamaguchi Y, Yamakawa O, et al Biliary tosis with the point mutation of K-ras gene arising in congeni-tal choledochal cyst Gastroenterology 1993;105:1209–12

papilloma-48 Iwasaki Y, Shimoda M, Furihata T, et al Biliary papillomatosis arising in a congenital choledochal cyst: report of a case Surg Today 2002;32:1019–22

49 Babbitt DP, Starshak RJ, Clemett AR Choledochal cyst: a cept of etiology Am J Roentgenol Radium Ther Nucl Med 1973;119:57–62

con-50 Komi N, Kuwashima T, Kuramoto M, et al Anomalous rangement of the pancreaticobiliary ductal system in chole-dochal cyst Tokushima J Exp Med 1976;23:37–48

ar-51 Kimura K, Tsugawa C, Ogawa K, et al Choledochal cyst logical considerations and surgical management in 22 cases Arch Surg 1978;113:159–63

Etio-52 Jona JZ, Babbitt DP, Starshak RJ, et al Anatomic observations and etiologic and surgical considerations in choledochal cyst J Pediatr Surg 1979;14:315–20

53 Tanaka M, Ikeda S, Kawakami K, Nakayama F The presence of

a positive pressure gradient from pancreatic duct to chal cyst demonstrated by duodenoscopic microtransducer manometry: clue to pancreaticobiliary reflux Endoscopy 1982;14:45–7

choledo-54 Todani T, Watanabe Y, Fujii T, Uemura S Anomalous ment of the pancreatobiliary ductal system in patients with a choledochal cyst Am J Surg 1984;147:672–6

arrange-55 Yamashiro Y, Miyano T, Suruga K, et al Experimental study of the pathogenesis of choledochal cyst and pancreatitis, with special reference to the role of bile acids and pancreatic en-zymes in the anomalous choledocho-pancreatico ductal junc-tion J Pediatr Gastroenterol Nutr 1984;3:721–7

56 Yoshikawa K, Yoshida K, Shirai Y, et al A case of carcinoma arising in the intrapancreatic terminal choledochus 12 years after primary excision of a giant choledochal cyst Am J Gas-troenterol 1986;81:378–84

57 Shimotakahara A, Yamataka A, Yanai T, et al Roux-en-Y hepaticojejunostomy or hepaticoduodenostomy for biliary reconstruction during the surgical treatment of choledochal cyst: which is better? Pediatr Surg Int 2005;21:5–7

58 Liu DC, Rodriguez JA, Meric F, Geiger JL Laparoscopic sion of a rare type II choledochal cyst: case report and review of the literature J Pediatr Surg 2000;35:1117–9

exci-59 Lee H, Hirose S, Bratton B, Farmer D Initial experience with

complex laparoscopic biliary surgery in children: biliary

atre-sia and choledochal cyst J Pediatr Surg

2004;39:804–7;dis-cussion 804–7

60 Li L, Feng W, Jing-Bo F, et al Laparoscopic-assisted total cyst

excision of choledochal cyst and Roux-en-Y

hepatoenteros-tomy J Pediatr Surg 2004;39:1663–6

61 Lopez RR, Pinson CW, Campbell JR, et al Variation in

man-agement based on type of choledochal cyst Am J Surg 1991;

161:612–15

62 Yamataka A, Ohshiro K, Okada Y, et al Complications after

cyst excision with hepaticoenterostomy for choledochal cysts

and their surgical management in children versus adults J

Pediatr Surg 1997;32:1097–102

63 Furuya KN, Roberts EA, Canny GJ, Phillips MJ Neonatal

hep-atitis syndrome with paucity of interlobular bile ducts in cystic

fibrosis J Pediatr Gastroenterol Nutr 1991;12:127–30

64 Li L, Krantz ID, Deng Y, et al Alagille syndrome is caused by

mutations in human Jagged1, which encodes a ligand for

Notch1 Nat Genet 1997;16:243–51

65 Krantz ID, Colliton RP, Genin A, et al Spectrum and

fre-quency of jagged1 (JAG1) mutations in Alagille syndrome

pa-tients and their families Am J Hum Genet 1998;62:1361–9

66 Halvorsen RA Jr, Garrity S, Kuni C, et al Arteriohepatic

dys-plasia (Alagille’s syndrome): unusual hepatic architecture and

function Abdom Imaging 1995;20:191–6

67 Alagille D, Estrada A, Hadchouel M, et al Syndromic paucity of

interlobular bile ducts (Alagille syndrome or arteriohepatic

dysplasia): review of 80 cases J Pediatr 1987;110:195–200

68 Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al

Out-come of syndromic paucity of interlobular bile ducts (Alagille

syndrome) with onset of cholestasis in infancy J Pediatr 1995;

127:220–4

69 Ismail H, Kalicinski P, Markiewicz M, et al Treatment of

pro-gressive familial intrahepatic cholestasis: liver transplantation

or partial external biliary diversion Pediatr Transplant

1999;3:219–24

70 Kurbegov AC, Setchell KD, Haas JE, et al Biliary diversion for

progressive familial intrahepatic cholestasis: improved liver

morphology and bile acid profile Gastroenterology 2003;125:

1227–34

71 Kalicinski PJ, Ismail H, Jankowska I, et al Surgical treatment

of progressive familial intrahepatic cholestasis: comparison of

partial external biliary diversion and ileal bypass Eur J Pediatr

Surg 2003;13:307–11

72 Melter M, Rodeck B, Kardorff R, et al Progressive familial

in-trahepatic cholestasis: partial biliary diversion normalizes

serum lipids and improves growth in noncirrhotic patients

Am J Gastroenterol 2000;95:3522–8

73 van Mil SW, van der Woerd WL, van der Brugge G, et al

Benign recurrent intrahepatic cholestasis type 2 is caused by

mutations in ABCB11 Gastroenterology 2004;127:379–84

74 Chen HL, Chang PS, Hsu HC, et al FIC1 and BSEP defects in

Taiwanese patients with chronic intrahepatic cholestasis with

low gamma-glutamyltranspeptidase levels J Pediatr 2002;140:119–24

75 de Vree JM, Jacquemin E, Sturm E, et al Mutations in the MDR3 gene cause progressive familial intrahepatic cholesta-sis Proc Natl Acad Sci USA 1998;95:282–7

76 Passon RG, Howard TA, Zimmerman SA, et al Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and chole-lithiasis in children with sickle cell anemia J Pediatr Hematol Oncol 2001;23:448–51

77 Williams CN, Johnston JL, McCarthy S, Field CA Biliary lipid, bile acid composition, and dietary correlations in Micmac Indian women A population study Dig Dis Sci 1981;26:42–9

78 Safford SD, Safford KM, Martin P, et al Management of lithiasis in pediatric patients who undergo bone marrow trans-plantation J Pediatr Surg 2001;36:86–90

chole-79 Chiu B, Superina R Extrahepatic portal vein thrombosis is sociated with an increased incidence of cholelithiasis J Pediatr Surg 2004;39:1059–61

as-80 Maccherini M, Borlini G, Branchi M, et al induced cholelithiasis] Pediatr Med Chir 1998;20:341–3

[Ceftriaxone-81 Schaad UB, Wedgwood-Krucko J, Tschaeppeler H Reversible ceftriaxone-associated biliary pseudolithiasis in children Lancet 1988;2:1411–13

82 Heim-Duthoy KL, Caperton EM, et al Apparent biliary dolithiasis during ceftriaxone therapy Antimicrob Agents Chemother 1990;34:1146–9

pseu-83 Blais C, Duperval R Biliary pseudolithiasis in a child

associat-ed with 2 days of ceftriaxone therapy Passociat-ediatr Radiol 1994;24:218–19

84 Toscano E, Trivellini V, Andria G Cholelithiasis in Down’s syndrome Arch Dis Child 2001;85:242–3

85 Shiffman ML, Kaplan GD, Brinkman-Kaplan V, Vickers FF Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very-low-calorie diet pro-gram Ann Intern Med 1995;122:899–905

86 Erlinger S Gallstones in obesity and weight loss Eur J enterol Hepatol 2000;12:1347–52

Gastro-87 Alimoglu O, Ozkan OV, Sahin M, et al Timing of tomy for acute biliary pancreatitis: outcomes of cholecystec-tomy on first admission and after recurrent biliary pancreatitis World J Surg 2003;27:256–9

cholecystec-88 Cosentini A, Stranieri G, Capillo S, et al Acute pancreatitis in the paediatric age group: a personal experience Eur Rev Med Pharmacol Sci 2005;9:33–40

89 Rescorla FJ Cholelithiasis, cholecystitis, and common bile duct stones Curr Opin Pediatr 1997;9:276–82

90 Debray D, Pariente D, Gauthier F, et al Cholelithiasis in infancy: a study of 40 cases J Pediatr 1993;122:385–91

91 Sakopoulos AG, Gundry S, Razzouk AJ, et al Cholelithiasis in infant and pediatric heart transplant patients Pediatr Trans-plant 2002;6:231–4

92 Uchiyama K, Onishi H, Tani M, et al Timing of laparoscopic

cholecystectomy for acute cholecystitis with

cholecystolithia-sis Hepatogastroenterology 2004;51:346–8

93 Fendrick AM, Gleeson SP, Cabana MD, Schwartz JS

Asymp-tomatic gallstones revisited Is there a role for laparoscopic

cholecystectomy? Arch Fam Med 1993;2:959–68

94 Michail S, Preud’Homme D, Christian J, et al Laparoscopic

cholecystectomy: effective treatment for chronic abdominal

pain in children with acalculous biliary pain J Pediatr Surg

2001;36:1394–6

95 Holcomb GW 3rd, Morgan WM 3rd, Neblett WW 3rd,

et al Laparoscopic cholecystectomy in children: lessons

learned from the first 100 patients J Pediatr Surg 1999;34:

1236–40

96 Newman KD, Powell DM, Holcomb GW, 3rd The management

of choledocholithiasis in children in the era of laparoscopic

cholecystectomy J Pediatr Surg 1997;32:1116–19

97 Kim PC, Wesson D, Superina R, Filler R Laparoscopic

chole-cystectomy versus open cholechole-cystectomy in children: which is

better? J Pediatr Surg 1995;30:971–3

98 Holcomb GW, 3rd, Sharp KW, Neblett WW, 3rd, et al

Laparo-scopic cholecystectomy in infants and children: modifi cations

and cost analysis J Pediatr Surg 1994;29:900–4

99 Vinograd I, Halevy A, Klin B, et al Laparoscopic

cholecystec-tomy: treatment of choice for cholelithiasis in children World

J Surg 1993;17:263–6

100 Moir CR, Donohue JH, van Heerden JA Laparoscopic

cholecystectomy in children: initial experience and

recom-mendations J Pediatr Surg 1992;27:1066–8;discussion 1068–

70

101 Sigman HH, Laberge JM, Croitoru D, et al Laparoscopic

chole-cystectomy: a treatment option for gallbladder disease in

chil-dren J Pediatr Surg 1991;26:1181–3

102 Chapman WC, Abecassis M, Jarnagin W, et al Bile duct

inju-ries 12 years after the introduction of laparoscopic

cholecys-tectomy J Gastrointest Surg 2003;7:412–16

103 Farrow GB, Dewan PA, Taylor RG, et al Retained

common-duct stones after open cholecystectomy and common-duct exploration

in children Pediatr Surg Int 2003;19:525–8

104 Kumar R, Nguyen K, Shun A Gallstones and common bile

duct calculi in infancy and childhood Aust N Z J Surg 2000;

70:188–91

105 Kalimi R, Cosgrove JM, Marini C, et al Combined

intraopera-tive laparoscopic cholecystectomy and endoscopic retrograde

cholangiopancreatography: lessons from 29 cases Surg

En-dosc 2000;14:232–4

106 Pencev D, Brady PG, Pinkas H, Boulay J The role of ERCP in

patients after laparoscopic cholecystectomy Am J

Gastroen-terol 1994;89:1523–7

107 Colombo C, Battezzati PM, Crosignani A, et al Liver disease in

cystic fibrosis: A prospective study on incidence, risk factors,

and outcome Hepatology 2002;36:1374–82

108 Diwakar V, Pearson L, Beath S Liver disease in children with

cystic fibrosis Paediatr Respir Rev 2001;2:340–9

109 Sokol RJ, Durie PR Recommendations for management of liver and biliary tract disease in cystic fibrosis Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group J Pediatr Gastroenterol Nutr 1999;28 Suppl 1:S1–13

110 Feigelson J, Anagnostopoulos C, Poquet M, et al Liver sis in cystic fibrosis – therapeutic implications and long term follow up Arch Dis Child 1993;68:653–7

cirrho-111 Dietrich CF, Chichakli M, Hirche TO, et al Sonographic ings of the hepatobiliary-pancreatic system in adult patients with cystic fibrosis J Ultrasound Med 2002;21:409–16

find-112 Patriquin H, Lenaerts C, Smith L, et al Liver disease in dren with cystic fibrosis: US-biochemical comparison in 195 patients Radiology 1999;211:229–32

chil-113 Gaskin KJ, Waters DL, Howman-Giles R, et al Liver disease and common-bile-duct stenosis in cystic fibrosis N Engl J Med 1988;318:340–6

114 Waters DL, Dorney SF, Gruca MA, et al Hepatobiliary disease

in cystic fibrosis patients with pancreatic sufficiency ogy 1995;21:963–9

Hepatol-115 Strandvik B, Lindblad A Cystic fibrosis Is treatment with sodeoxycholic acid of value? Scand J Gastroenterol Suppl 1994;204:65–7

ur-116 Lazaridis KN, Gores GJ, Lindor KD Ursodeoxycholic acid

“mechanisms of action and clinical use in hepatobiliary ders” J Hepatol 2001;35:134–46

disor-117 Nousia-Arvanitakis S, Fotoulaki M, Economou H, et al term prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease J Clin Gastroenterol 2001;32:324–8

Long-118 Lindblad A, Glaumann H, Strandvik B A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease Hepatology 1998;27:166–74

119 Colombo C, Battezzati PM, Podda M, et al Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis Hepatology 1996;23:1484–90

120 Colombo C, Bertolini E, Assaisso ML, et al Failure of oxycholic acid to dissolve radiolucent gallstones in patients with cystic fibrosis Acta Paediatr 1993;82:562–5

ursode-121 Gangbo E, Lacombe D, Alberti EM, et al Trisomy 22 with roid isthmus agenesis and absent gall bladder Genet Couns 2004;15:311–15

thy-122 Satpathy RC Congenital absence of the gall bladder J Indian Med Assoc 1966;47:130–1

123 Ramanathan T Congenital duplication of the gall bladder: view of the literature and report of a case Med J Malaya 1971;25:305–6

re-124 Orava S, Leiviska T Hypoplasia and aplasia of the gall-bladder

A report of two cases Acta Chir Scand 1972;138:420–4

125 Brisset S, Joly G, Ozilou C, et al Molecular characterization of partial trisomy 16q24.1-qter: clinical report and review of the literature Am J Med Genet 2002;113:339–45

126 Hengstschlager M, Mittermayer C, Prusa AR, et al Prenatal

diagnosis of a de novo inversion of chromosome (2)(p21q11)

Arch Gynecol Obstet 2003;268:230–2

127 Seller MJ, Fear C, Kumar A, Mohammed S Trisomy 16 in a

mid-trimester IVF foetus with multiple abnormalities Clin

Dysmorphol 2004;13:187–9

128 Gautam A, Kala S, Kumar M, Sharma CL Double gall bladder

with two disease processes Indian J Gastroenterol 1999;18:

179

129 Mitchell J, Punthakee Z, Lo B, et al Neonatal diabetes, with

hypoplastic pancreas, intestinal atresia and gall bladder

hypo-plasia: search for the aetiology of a new autosomal recessive

syndrome Diabetologia 2004;47:2160–7

130 Gergely M, Csipo L, Gyory-Kiss F Interposition of the gall

bladder: a rare congenital malformation of the extrahepatic

bile ducts Acta Chir Acad Sci Hung 1979;20:335–40

131 Principe A, Spangaro M, Lapilli A, et al [Congenital anomalies

of the gallbladder A case of retrohepatic gallbladder contained

in the coronary ligament] Minerva Chir 1979;34:879–84

132 Chowbey PK, Wadhwa A, Sharma A, et al Ectopic gallbladder:

laparoscopic cholecystectomy Surg Laparosc Endosc Percutan

Tech 2004;14:26–8

133 Gilljam T, McCrindle BW, Smallhorn JF, et al Outcomes of left

atrial isomerism over a 28-year period at a single institution

J Am Coll Cardiol 2000;36:908–16

134 Herman TE Special imaging casebook Left-isomerism

(poly-splenia) with congenital atrioventricular block and biliary

atresia J Perinatol 1999;19:155–7

135 Westrope C, Acharya A Diarrhea and gallbladder hydrops in

an immunocompetent child with Cryptosporidium infection

Pediatr Infect Dis J 2001;20:1179–81

136 Imhof M, Ohmann C, Roher HD [The intensive care

gallblad-der – a transient phenomenon or a problem requiring

therapy?] Chirurg 1995;66:360–5

137 Fernandes ET, Hollabaugh RS, Boulden TF, Angel C

Gangre-nous acalculous cholecystitis in a premature infant J Pediatr

Surg 1989;24:608–9

138 Croteau D, Signer RD, Chaet MS Acalculous cholecystitis in a

two year old J Soc Laporoendosc Surg 2001;5:183–5

139 Imamoglu M, Sarihan H, Sari A, Ahmetoglu A Acute

acalcu-lous cholecystitis in children: Diagnosis and treatment J

Pedi-atr Surg 2002;37:36–9

140 Middleton GW, Williams JH Is gall bladder ejection fraction a

reliable predictor of acalculous gall bladder disease? Nucl Med

Commun 1992;13:894–6

141 Cay A, Imamoglu M, Kosucu P, et al Gallbladder dyskinesia: a

cause of chronic abdominal pain in children Eur J Pediatr

Surg 2003;13:302–6

142 Campbell BT, Narasimhan NP, Golladay ES, Hirschl RB

Bili-ary dyskinesia: a potentially unrecognized cause of abdominal

pain in children Pediatr Surg Int 2004;20:579–81

143 Carney DE, Kokoska ER, Grosfeld JL, et al Predictors of

suc-cessful outcome after cholecystectomy for biliary dyskinesia J

Pediatr Surg 2004;39:813–16;discussion 813–16

144 Wood J, Holland AJ, Shun A, Martin HC Biliary dyskinesia: is the problem with Oddi? Pediatr Surg Int 2004;20:83–6

145 Ersoz C, Uguz A, Ergoren Y, Koc Z A tubulopapillary adenoma

of the gallbladder in a child of 3 years Pediatr Surg Int 2004;19:789–90

146 Mullick S, Gothi R, Mukerjee A Case report: papillary

adeno-ma of the gall-bladder in a child of 9 years Clin Radiol 1993;47:432–3

147 Kikiros C, Arunachalam P, Lam MH Adenomatous plastic polyp of the gall bladder associated with cholelithiasis

hyper-in a child Pediatr Surg Int 2003;19:118–19

148 Hemminki K, Li X Familial liver and gall bladder cancer: a nationwide epidemiological study from Sweden Gut 2003;52:592–6

149 Linstedt-Hilden M, Brambs HJ Two different manifestations

of botryoid sarcoma (embryonal rhabdomyosarcoma) of the biliary tree Bildgebung 1994;61:40–3

150 Lee MJ, Chang ML, Huang PH, Lue WC Biliary tree myosarcoma: report of one case Zhonghua Min Guo Xiao Er

rhabdo-Ke Yi Xue Hui Za Zhi 1996;37:458–60

151 Sanz N, de Mingo L, Florez F, Rollan V Rhabdomyosarcoma of the biliary tree Pediatr Surg Int 1997;12:200–1

152 Pollono DG, Tomarchio S, Berghoff R, et al coma of extrahepatic biliary tree: initial treatment with che-motherapy and conservative surgery Med Pediatr Oncol 1998;30:290–3

Rhabdomyosar-153 Balkan E, Kiristioglu I, Gurpinar A, et al Rabdomyosarcoma

of the biliary tree Turk J Pediatr 1999;41:245–8

154 Iwai N, Deguchi E, Yanagihara J, et al Cancer arising in a choledochal cyst in a 12-year-old girl J Pediatr Surg 1990;25:1261–3

155 Watanabe Y, Toki A, Todani T Bile duct cancer developed after cyst excision for choledochal cyst J Hepatobiliary Pancreat Surg 1999;6:207–12

156 Shi LB, Peng SY, Meng XK, et al Diagnosis and treatment of congenital choledochal cyst: 20 years’ experience in China World J Gastroenterol 2001;7:732–4

157 Mendes FD, Lindor KD Primary sclerosing cholangitis Clin Liver Dis 2004;8:195–211

158 Portincasa P, Vacca M, Moschetta A, et al Primary sclerosing cholangitis: updates in diagnosis and therapy World J Gastro-enterol 2005;11:7–16

159 Gregorio GV, Portmann B, Karani J, et al Autoimmune titis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study Hepatology 2001;33:544–53

hepa-160 Feldstein AE, Perrault J, El-Youssif M, et al Primary sclerosing cholangitis in children: a long-term follow-up study Hepatol-ogy 2003;38:210–17

161 Debray D, Pariente D, Urvoas E, et al Sclerosing cholangitis in children J Pediatr 1994;124:49–56

162 Bar Meir M, Hadas-Halperin I, Fisher D, et al Neonatal ing cholangitis associated with autoimmune phenomena J Pediatr Gastroenterol Nutr 2000;30:332–4

scleros-163 Nikolaidis NL, Giouleme OI, Tziomalos KA, et al Small-duct

primary sclerosing cholangitis A single-center seven-year

experience Dig Dis Sci 2005;50:324–6

164 Bjornsson E, Boberg KM, Cullen S, et al Patients with small

duct primary sclerosing cholangitis have a favourable long

term prognosis Gut 2002;51:731–5

165 Kerr DN, Harrison CV, Sherlock S, Walker RM Congenital

hepatic fibrosis Q J Med 1961;30:91–117

166 Kerr DN, Okonkwo S, Choa RG Congenital hepatic fibrosis:

the long-term prognosis Gut 1978;19:514–20

167 Blyth H, Ockenden BG Polycystic disease of kidney and

liver presenting in childhood J Med Genet 1971;8:257–

84

168 Kaplan BS, Kaplan P, de Chadarevian JP, et al Variable

expres-sion of autosomal recessive polycystic kidney disease and

con-genital hepatic fibrosis within a family Am J Med Genet 1988;

29:639–47

169 Desmet VJ Ludwig symposium on biliary disorders – part I

Pathogenesis of ductal plate abnormalities Mayo Clin Proc

1998;73:80–9

170 Fauvert R, Benhamou JP, Meyer P [Congenital hepatic

fibro-sis.] Rev Fr Etud Clin Biol 1964;26:375–7

171 Khan K, Schwarzenberg SJ, Sharp HL, et al Morbidity from

congenital hepatic fibrosis after renal transplantation for

auto-somal recessive polycystic kidney disease Am J Transplant

2002;2:360–5

172 Arikan C, Ozgenc F, Akman SA, et al Impact of liver plantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease Pediatr Transplant 2004;8:558–60

trans-173 Caroli J, Couinaud C, Soupault R, et al [A new disease, doubtedly congenital, of the bile ducts: unilobar cystic dilation

un-of the hepatic ducts.] Sem Hop 1958;34:496–502/SP

174 Summerfield JA, Nagafuchi Y, Sherlock S, et al Hepatobiliary

fi bropolycystic diseases A clinical and histological review of

51 patients J Hepatol 1986;2:141–56

175 Tsuchida Y, Sato T, Sanjo K, et al Evaluation of long-term sults of Caroli’s disease: 21 years’ observation of a family with autosomal “dominant” inheritance, and review of the litera-ture Hepatogastroenterology 1995;42:175–81

re-176 Sgro M, Rossetti S, Barozzino T, et al Caroli’s disease: prenatal diagnosis, postnatal outcome and genetic analysis Ultrasound Obstet Gynecol 2004;23:73–6

177 Tamiolakis D, Arvanitidou V, Nikolaidou S, et al Caroli’s drome A case report and review of the literature Minerva Gastroenterol Dietol 2004;50:179–81

syn-178 Madjov R, Chervenkov P, Madjova V, Balev B Caroli’s disease Report of 5 cases and review of literature Hepatogastroenter-ology 2005;52:606–9

179 Waechter FL, Sampaio JA, Pinto RD, et al The role of liver transplantation in patients with Caroli’s disease Hepatogas-troenterology 2001;48:672–4

Chapter 1, Anatomy and physiology of the biliary

tree and gallbladder

Chapter 2, Pathology of the intrahepatic and

extrahepatic bile ducts and gallbladder

Chapter 7, Radiation therapy for disease of the

biliary tree and gallbladder

Chapter 9, Laparoscopic treatment for diseases of

the gallbladder and biliary tree

Chapter 16, Acute cholangitis

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

1 c

2 d

3 cChapter 23, Biliary disease in infants and children

adriamycin, 5-fluorouracil with, 155

adult idiopathic ductopenia, 28–29, 29f, 41

alcohol, cholestasis and, 367

alcoholic foamy fatty disease, 367

alcoholic liver disease, 367

allergy, contrast agents, 98

acute acalculous cholecystitis, 234

acute calculous cholecystitis, 232percutaneous biliary imaging, 121anaplastic carcinoma, 158

anastomotic strictures, post-liver transplantation, 294fantiangiogenic therapy, bile duct tumors, 211

antibioticsacute acalculous cholecystitis, 234acute calculous cholecystitis, 232acute cholangitis, 268, 269, 269tbile leaks, post liver transplant, 296–297endoscopy prophylaxis, 98

nonanastomotic strictures, post liver transplant, 294, 296

surgery prophylaxis, 165

see also specifi c drugs

antihistamines, contrast allergy, 98antimitochondrial antibodies (AMA), primary biliary cirrhosis, 343, 346–347

antimitochondrial antibody negative primary biliary cirrhosis (PBC), 23–24

(AMA)-antisense oligonucleotides, 211apical sodium dependent bile acid transporter (ASBT), 358, 362apoptosis induction, bile duct tumors, 211appendectomy, primary sclerosing cholangitis and, 309, 311arachidonic acid (AA), gallbladder motility, 15

Ascariasis, 265

Ascaris lumbricoides, 265

ascites, percutaneous transhepatic cholangiography, 122–123atherosclerotic 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 gures: page numbers followed by ‘t’ indicate tables

Plates are indexed by number

autoimmune cholangitis, 23–24

autoimmune hepatitis see hepatitis,

autoimmuneautosomal dominant polycystic liver disease, 279–280

autosomal recessive polycystic kidney disease (ARPKD), 402congenital hepatic fibrosis and, 35, 400polycystic liver disease and, 36autosomal recessive polycystic liver disease, 280

azathioprine, 317B

bacterial cholangitis, 31, 60, 319bacterobilia, acute cholangitis, 266

“balloon sphincteroplasty,” 104–105Balthazar’s sign, 243, 244f

Banff Consensus Schema, 28, 28tbenign recurrent intrahepatic cholestasis (BRIC), 359, 364, 365–366, 387bile

canalicular excretion, 358–360composition, 12, 219, 221flow, 13, 355–356formation mechanisms, 355–360regulation, 360–363

functions, 11

leakage see bile leak(s)

nuclear transcription factor effects, 360–363, 361f, 361t

production, 11–13reabsorption, 12secretion, 11abnormalities in, 12–13intrahepatic bile ducts, 6–7sinusoidal membrane uptake, 357–358spillage in laparoscopic cholecystectomy, 178

transcellular movement, 358

Copyright © 2006 by Blackwell Publishing Ltd

bile acid, inborn errors of metabolism, 386

intrahepatic see intrahepatic bile ducts

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

gallbladder carcinoma and, 128, 129f

gallstone (biliary) pancreatitis, 102–103

endoscopy, 112fine-needle aspiration, 97, 113fluorescent in situ hybridization, 114forceps biopsy, 113, 114f

gene therapy, 211immunotherapy, 210–211

k-ras oncogene, 114

liver infiltration, 149management, 205–214molecular biology, 210, 211–212molecular markers, 114palliative care, 206, 209–210photodynamic therapy, 115positron emission tomography, 74, 74tradiation therapy, 205, 206

regional lymph node involvement, 149–150

signaling inhibitors, 211–212staging, 114

stenting, 114–115, 115ftelomerase, 114tissue sampling, 113–114TNM classifi cation, 114

bile fistula see biliary fistula(s)

bile leak(s), 128, 130–131biliary decompression, 135cholescintigraphy, 91f, 92cystic duct stump, 108, 109fdrainage, 130

ERCP, 108–109, 130laparoscopic cholecystectomy, 178percutaneous biliary imaging, 121–122percutaneous transhepatic

cholangiography, 108, 130–131post-liver transplantation, 296–297, 296fpostoperative/post-traumatic patients, 91f, 92

bile peritonitis, 122bile salt(s), 219, 355bile salt excretory peptide (BSEP), 359bile salt export pump disease, 387–388bilhemia, 241

biliary atresiachildren, 38–40, 40fcholestasis, 364classifi cation, 380, 380tclinical presentation, 378–379definition, 378

diagnostic tests, 378–379, 379fembryonic form, 378

epidemiology, 378etiology, 378

extrahepatic, 38–40, 40finfants, 378–381morphological features, 39–40, 40fpathology, 379, Plate 10, Plate 11perinatal form, 378

prognosis, 379–380, 381surgical management, 379–380biliary bypass, gallbladder carcinoma, 256biliary colic, 60, 101

biliary cystadenocarcinoma, 47, 48f, 285biliary cystadenoma, 42, 42f, 285biliary decompression

acute cholangitis, 268, 273bile leaks, 135

biliary diseasechildren, 38–41, 388–402infants, 378–384

see also specifi c diseases/disorders

biliary dyskinesia, 235, 393–394biliary–enteric bypass operations, 125, 125fbiliary–enteric fistulas, 239–241, 240tbiliary excreted contrast agents, 73biliary fistula(s), 239–242external, 242

internal, 239–242bilhemia, 241biliary obstruction, 241–242laparoscopic biliary injuries, 195orthotopic liver transplantation, 137percutaneous interventions, 133, 135, 136–137f, 137, 138f

see also specifi c types

biliary microhamartoma, 41–42biliary obstruction

biliary–vascular fistulas, 241–242cholangiocarcinoma and, 333cholangiography, 123cholestasis and, 363, 364large ducts, 30–31, 31fbiliary outflow reconstruction, 168–171cholangitis prevention, 168

end-to-side hepaticojejunostomy, 168–169, 169f, 170f

left common hepatic duct, 169, 171fLongmire procedure, 170

round ligament approach, 169–170, 171fbiliary parasites, bile duct stones, 102–103biliary perforation, spontaneous in infants, 381–382

biliary pressure, acute cholangitis, 266biliary reconstruction

liver transplantation, 289, 291fcholedochocholedochostomy, 289, 290–292, 291f, 292f

Roux-en-Y choledochojejunostomy,

289, 292–293, 293f

see also biliary outflow reconstruction

biliary sludge, 222–223, 222f, 297