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. 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. A ndo K, M i ya no T, Fu ji mot o T, et al . Sibl i ng oc c ur re nc e o f b il i- ary atresia and biliary 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 be- tween HLA and extrahepatic biliary atresia. J Pediatr Gastro- enterol Nutr 1993;16:114–17. 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. 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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 reg- istry, 1989 to 1994. Tohoku J Exp Med 1997;181:85–95. 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. [...]... 97–99, 120 bile/ bile duct leaks, 108 109 , 130 bile duct stones, 84, 101 , 102 – 110, 103 f biliary parasites, 102 103 chemical dissolution, 106 107 common bile duct, 107 108 , 108 f, 390–391 difficult extractions, 105 electrohydraulic lithotripsy, 105 extracorporeal shockwave lithotripsy, 106 , 106 f laser lithotripsy, 106 f mechanical lithotripsy, 105 , 105 f sphincterectomy, 104 , 104 f stenting, 107 , 107 f stone... 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 5 6 7 8 9 a, b, c a, c a b, d b a, b, c, d Chapter 5, Endoscopic diagnosis and treatment of disorders of the biliary tree and gallbladder 1 d 2 e (the fifth component is... 97–99 bile duct stones, 101 102 extrahepatic bile duct, 101 102 , 102 f “risk stratification,” 102 , 103 f 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 ... 2001;48:672–4 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 Answers Chapter 1, Anatomy and physiology of the biliary tree and gallbladder Chapter 4, Noninvasive imaging of the biliary system 1 b 2 c 1 a 2 e 3 b 4 d 3 d 4 e 5 d 6 c 5 a 6 d 7 a 8 b 7 a 8 e 9 b 10 b 9 c 10 b 11 c... Choledochal cyst and dilatation of the bile ducts in infancy and childhood Aust N Z J Surg 1972;42: 163–7 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 enzymes in the anomalous choledocho-pancreatico ductal junction J Pediatr Gastroenterol Nutr 1984;3:721–7 38 Spitz L The surgical... duplication of the gall bladder: review of the literature and report of a case Med J Malaya 1971; 25:305–6 107 Colombo C, Battezzati PM, Crosignani A, et al Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome Hepatology 2002;36:1374–82 124 Orava S, Leiviska T Hypoplasia and aplasia of the gall-bladder A report of two cases Acta Chir Scand 1972;138:420–4 108 Diwakar... cholecystectomy bile duct leaks, 108 109 bile duct stones, 107 108 , 108 f cholecystitis, 232–233, 235 complications, 177–178 contraindications, 175 ERCP vs., 107 – 110 gallstones, 225, 390 indications, 175 postsurgical biliary strictures, 108 f, 109 – 110, 110f technique, 175–177, 176f, 177f laparoscopic treatment, 174–181 autosomal dominant polycystic liver disease, 280 bile duct resection, 166, 167f, 168f bile duct... cholangitis, 103 cholecystitis, 233 endoscopic ultrasound see endoscopic ultrasound (EUS) endoscopy, 101 – 110 ERCP, 107 108 , 108 f 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... atresia and gall bladder hypoplasia: 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... drainage gallbladder, 9 liver, 4–6 viral hepatitis, cholestasis and, 366–367 vitamin K, osteoporosis prevention, 348 von Meyenburg complexes, 35–36, 36f, 41 W weight loss, gallstone risk, 59 X xanthelasma, primary biliary cirrhosis and, 347 xanthogranulomatous cholecystitis, 49, 234–235 CT Diseases of the Gallbladder and Bile Ducts: Diagnosis and Treatment, Second Edition Edited By Pierre-Alain Clavien, . 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 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. 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