Chapter 427. The Biliary Tract

In the human embryo the first anlage of the bile ducts and liver is the hepatic diverticulum from the proximal gastrointestinal tract, as described in Chapter 418. The caudal part of this bud, known as the pars cystica, grows in length and forms the gallbladder, cystic duct and common bile duct. At about the eighth week of gestation, the hepatic precursor cells that lie adjacent to the hilar portal vein vessels form a sleeve-like double layer of cells that extends toward the periphery along the smaller intrahepatic portal vein branches. These hepatoblasts strongly expresses biliary specific cytokeratins and can be considered biliary precursor cells, that then form a continuous single-layered ring around the portal mesenchyme, known as the ductal plate.1 Beginning at 12 weeks of gestation and extending into the postnatal period, the ductal plate undergoes progressive remodeling. As new ductules form they are incorporated into the periportal mesenchyme that surrounds the portal vein branches. Thus, during successive periods of fetal life, ductal plate remodeling leads to the formation of the intrahepatic biliary tree. The largest ducts are formed first, followed by segmental, interlobular, and, finally, the smallest bile ductules. Arrest or derangement in remodeling leads to the persistence of primitive bile duct configurations termed ductal plate malformations. The occurrence of ductal plate malformations at different generations of the developing biliary tree gives rise to different clinicopathologic entities, such as congenital hepatic fibrosis and Caroli syndrome.

Congenital Gallbladder Abnormalities

A variety of structural abnormalities of the gallbladder have been described. Congenital absence of the gallbladder occurs in one of 7500 to 10,000 people. Failed development of the pars cystica is the likely etiology. As an isolated abnormality this is often of little clinical significance, although symptoms of abdominal pain, nausea and fatty food intolerance may develop because calculi form in the ductal system. In these patients gallbladder agenesis is frequently misinterpreted as cholecystitis with cystic duct obstruction.2 In addition to extrahepatic biliary atresia, which may accompany agenesis of the gallbladder, other associations with an absent gallbladder include imperforate anus, genitourinary anomalies, anencephaly, bicuspid aortic valve, and cerebral aneurysms. Hypoplasia of the gallbladder has also been described in association with neonatal diabetes, hypoplastic pancreas, and intestinal atresia.3 There is also an association with trisomy 18. The incidence of double gallbladder is 0.1 to 0.75 per 1000. The two cystic ducts may converge into a single duct, forming a Y-shaped structure. The accessory gallbladder may lie under the left lobe of the liver, draining into the left hepatic duct. A “floating gallbladder” is an anatomic variant observed in up to 5% of individuals. The gallbladder lacks a peritoneal coat or supporting membrane, making the pendulous gallbladder susceptible to torsion. This presents clinically as acute, severe right upper quadrant pain with nausea and vomiting. Often symptoms follow rapid movements that generate centrifugal forces causing gallbladder torsion and volvulus. Symptoms are consistent with an acute cholecystitis requiring operative intervention.4

Congenital Hepatic Fibrosis

Congenital hepatic fibrosis (CHF) is the most common ductal plate malformation. It is most commonly associated with autosomal-recessive polycystic kidney disease (ARPKD) and occurs with an incidence of one in 6000 to 40,000 births (see Chapter 470).5 A large number of mutations in the PKHD1 gene associated with ARPKD and CHF have been identified but the pathogenicity of the defects has as yet not predicted the clinical phenotype.6 Congenital hepatic fibrosis may also be frequently associated with von Myenburg complexes (bile duct microhamartomas), and autosomal-dominant polycystic kidney disease. Less frequently it can be associated with renal dysplasia, nephronophthisis, asphyxiating thoracic dystrophy (Jeune syndrome), Bardet-Biedl syndromes and congenital disorder of glycosylation, type 1b (phosphomannose isomerase deficiency).

Clinical Features

Hematemesis or melena is the presenting sign in 30 to 70% of patients. It may occur as early as 1 year but more typically at 5 to 13 years of age. Gastrointestinal bleeding is a consequence of portal hypertension caused by fibrosis of the liver. Physical examination reveals abdominal distention with a firm, enlarged liver, often with a prominent left lobe, and splenomegaly. Many patients have enlarged palpable kidneys. In most patients the biochemical parameters of hepatic synthetic function are normal, and there is occasionally a mild elevation of aminotransferase values. Irregular bile ducts resulting from the ductal plate malformation present a risk of ascending cholangitis, which significantly contributes to morbidity and mortality. Abnormal portal flow can cause clot in the portal vein and result in development of the cavernous transformation of the portal vein. Patients with cavernous transformation of the portal vein appear to be at higher risk for more severe portal hypertension and complications of variceal bleeding.7

Due to association with ARPKD many patients with CHF will have arterial hypertension or uremia. In neonates or infants who present with CHF-ARPKD complications of the renal disease dominate clinical picture, whereas those who present later in childhood or in adulthood have a predominance of hepatic complications.

Diagnosis and Treatment

Diagnosis is confirmed by liver biopsy. The hepatic lesions are fairly uniform and rarely give rise to macroscopically visible cysts. Microscopically characteristic dysmorphic cystic structures lined with columnar biliary epithelium in the portal zones, surrounded by dense fibrous deposits are found. These correspond to incompletely remodeled ductal plates. The portal tracts often lack normal interlobular ducts in the center. The abnormal dilated branching bile duct structures are in continuity with the rest of the biliary system.

Treatment is similar to that of other chronic liver disorders and includes nutritional management, including administration of fat soluble vitamins, and management of complications of cirrhosis if required. Variceal bleeding is treated with either variceal band ligation or sclerotherapy. Beta blockers, variceal band ligation, sclerotherapy or portosystemic shunting can be used as a prophylaxis of the variceal bleeding. Aggressive antibiotic therapy should be administered for cholangitis. In patients with chronic cholangitis and/or progressive hepatic dysfunction, liver transplantation may be the best treatment option. In isolated congenital hepatic fibrosis, the prognosis is good, given the excellent preservation of parenchymal and renal function in most patients.

Caroli Syndrome

Caroli disease is a congenital ductal plate disorder associated with congenital dilatation of the larger, segmental intrahepatic bile ducts. When this lesion is combined with the changes of congenital hepatic fibrosis, as is typically the case, the disorder is termed Caroli syndrome.8 Inheritance patterns are consistent with an autosomal-recessive disease. Both occur with an incidence of less than 1 per 100,000. A genetic cause is likely. Mutations in the APRKD gene, PKHD1, have been found in some but not all patients with Caroli disease.

Clinical Features

Caroli disease may present at any age but is most frequently recognized in adolescents or young adults with recurrent bouts of cholangitis and abscesses caused by bile stasis and gallstone formation within cysts, including fever, pruritus, jaundice, a tender liver, and modest elevations in serum bilirubin, alkaline phosphatase, and aminotransferase. Patients with Caroli syndrome may also have hepatic fibrosis, as seen in congenital hepatic fibrosis. Both Caroli disease and Caroli syndrome are associated with a 100-fold increased risk of cholangiocarcinoma compared to the general population.

Diagnosis and Treatment

Liver biopsy may reveal the changes of congenital hepatic fibrosis. Diagnosis traditionally has been made by ultrasonography, computed tomography, percutaneous transhepatic cholangiography, or ERCP but MR cholangiography is emerging as the method of choice.9 Saccular and cystic dilation of the intrahepatic bile ducts and enlargement of the major intra- and extrahepatic biliary passages are evident (Fig. 427-1). Ursodeoxycholic acid therapy may enhance biliary flow and decrease the frequency of cholangitis episodes.10 Cholangitis should be treated with broad spectrum antibiotics, including anaerobic coverage. Partial hepatectomy may be helpful when disease is primarily confined to a single lobe.11 These measures are only partially successful in most patients with continuing problems of sepsis, cholangiocarcinoma, and amyloidosis. Liver transplantation is reported to be curative in patients with recurrent cholangitis, sepsis, or cholangiocarcinoma.12

Choledochal Cysts

The incidence of choledochal cysts has been estimated between one in 13,000 and one in 2,000,000 live births, and they are found in girls four times more frequently than in boys. Choledochal cysts are more prevalent in Asians, specifically the Japanese. The etiology of cyst formation is unclear, although there is growing evidence that the dilatation results from an anomalous junction of the common bile duct and the pancreatic duct, resulting in a common channel that is as long as 3.5 cm, versus a normal of 5 mm. This long common channel may allow for the reflux of pancreatic proteases into the extrahepatic biliary tree, resulting in cholangitis and stenosis.13 This hypothesis is supported by the measurement of high levels of amylase within the cysts, but the documentation of prenatal choledochal cysts suggests alternative abnormalities in the process of morphogenesis.

Clinical Features

Jaundice is the most common presentation of choledochal cysts in infants, being diagnosed in about 2% of infants presenting with cholestasis. In older children and adults abdominal pain is as common a presenting symptom as jaundice.14,15 Eighty percent of patients are female. Most patients present within the first decade of life, with the diagnosis made in 38% in the first year of life, 34% between ages 1 and 6 years, and 28% thereafter. The classic triad of abdominal pain, jaundice, and palpable right upper quadrant mass occurs in some patients, but in recent years the diagnosis is more commonly made during abdominal imaging for non-specific pain symptoms.16 Other common symptoms are fever, nausea, and vomiting, with or without associated pancreatitis.

Diagnosis and Treatment

Children with choledochal cysts may have abnormal aminotransferase, bilirubin, and pancreatic enzyme values. Early treatment is required to prevent hepatic complications including fibrosis.16 Ultrasound is the most valuable screening test, as it can demonstrate both intrahepatic and extrahepatic dilatation of the biliary tree. Radionuclide scanning may demonstrate the accumulation of tracer within the cyst. Endoscopic retrograde cholangiopancreatography provides better delineation of the biliary anatomy. On occasion, impacted biliary calculi within the distal biliary tree are removed, resulting in resolution of the biliary dilatation. The location of the cyst allows classification into one of five anatomic types, as described by Todani (Fig. 427-2).18 The overwhelming majority of choledochal cysts are of type I, with diffuse enlargement of the common bile duct. Complications consist of perforations, liver abscesses, stone formation, secondary biliary cirrhosis, pancreatitis, amyloidosis and carcinoma of the biliary tree. Co-existing biliary anomalies including double common bile duct, double gallbladder, absent gallbladder, annular pancreas, biliary atreisa or stenosis are found in up to 25% of cases. Choledochal cysts vary in size with some of the larger ones containing 5-10 liters of bile.

The most worrisome complication of choledochal cyst is the high incidence of associated malignancy. In Japan, and incidence of 2.5 to 17.5% is reported. The majority of tumors are adenocarcinomas, detected at a mean age of 35 years.18 The cause of the malignant transformation is unclear but may relate to the chronic reflux of pancreatic proteases as well as the mutagenic potential of secondary bile acids in a stagnant environment. This has led to the recommendation that cysts be completely excised with concurrent removal of the gallbladder because of the risk of neoplasia. The approach to biliary reconstruction varies depending on the cyst type, anatomy, and surgical preference; the most common procedures are hepaticoduodenostomy, hepaticojejunostomy, or jejunal interposition.

Bile duct paucity syndromes are divided into those that are syndromatic or nonsyndromatic. Nonsyndromatic bile duct paucity is relatively rare compared to the syndromic form known as Alagille syndrome. Paucity of the intrahepatic bile ducts is a histologic finding defined as a ratio of interlobular ducts to portal tracts less than 0.9. However, since the remodeling of the intrahepatic bile ducts in the most peripheral (smallest) portal tracts is not complete until approximately 6 weeks of age, defining the ‘‘normal’’ bile duct-to-portal tract ratio to estimate the degree of ductopenia in the liver is problematic in the premature infant, where a ratio lower than 0.9 may be normal.19

Alagille Syndrome

Pathophysiology and Genetics

Alagille syndrome is a multisystem, inherited disorder with highly variable clinical features even within affected families. The incidence is about 1 in 70,000 live births. Mutations of the JAG1 gene, that encodes protein ligands for NOTCH1, are detected in over 88% of individuals with Alagille syndrome.20 Fluorescence in situ hybridization (FISH) detects a microdeletion of 20p12, including the entire JAG1 gene, in approximately 7% of affected individuals. Mutations in NOTCH2 are observed in fewer than 1% of individuals with Alagille syndrome. The NOTCH proteins play a role in determining cell fate during differentiation, especially in tissues where epithelial-mesenchymal interactions are important. The disorder is inherited in an autosomal dominant manner. Approximately 30%-50% of individuals have an inherited mutation and about 50%-70% have a de novo mutation. The offspring of an individual with Alagille syndrome have a 50% chance of having Alagille syndrome. Prenatal testing is possible if the JAG1 disease-causing mutation or a deletion detected by FISH is identified in an affected family member. However, although genetic testing can determine whether or not the fetus has inherited the JAG1 disease-causing mutation or deletion, it cannot predict the occurrence or severity of clinical manifestations.

Clinical Features

Alagille syndrome was initially described as an association of congenital heart disease and neonatal cholestasis. The most frequent cardiovascular findings are peripheral pulmonary artery stenosis but more severe hypoplasia of the pulmonary artery branches may occur. Complex congenital heart disease such as tetralogy of Fallot has been found. Other common clinical features include skeletal abnormalities and a typical facies. The characteristic facies in the infant or child has the shape of an inverted triangle. The forehead is broad, and eyes are deep-set with mild hypertelorism; the nose is small and straight, and the chin is small and pointed. The facies may not be evident in the first months of life. The classic childhood appearance differs from its adult form, which may have somewhat coarse facial features, often with a long face, deep-set eyes, and prominent forehead.

Butterfly vertebrae, from failure of the anterior arches of the vertebral body to fuse, are most commonly detected in the thoracic spine. Other vertebral abnormalities have been described such as abnormalities of the interpedicular distance in the lumbar spine and spina bifida occulta. Very short distal phalanges and a short ulna have also been reported. Eye findings include posterior embryotoxon, optic disc drusen, retinal abnormalities (including abnormal pigmentation but not functional retinal degeneration), strabismus, ectopic pupil, and hypotrophic optic discs.

Renal disease associated with Alagille syndrome is highly variable. Structural abnormalities include symmetrically small kidneys or congenital single kidney. Several reports document renal cystic disease associated with Alagille syndrome. Histologic examination of kidneys in Alagille syndrome has revealed a membranous nephropathy in some cases, but the most frequent finding is lipid accumulation in the kidney (mesangiolipidosis). Nonspecific changes include azotemia, defects in concentrating urine, and nephrolithiasis.

Other abnormalities include small birth size and/or poor growth, delayed puberty or hypogonadism, abnormal cry/voice (“high-pitched”), and mental retardation, learning difficulties, or antisocial behavior. Associated vascular abnormalities have been noted including decreased intrahepatic portal vein radicals, moyamoya disease, coarctation of the aorta, and anomalies of other large arterial vessels. Neurologic abnormalities, especially peripheral neuropathies, described in early reports probably were not part of the syndrome itself but due instead to vitamin E deficiency from severe chronic cholestasis. Hypothyroidism and pancreatic insufficiency have also been observed in association with Alagille syndrome.

Diagnosis

In most cases a clinical diagnosis is made based upon findings of bile duct paucity on a liver biopsy that is performed as part of the evaluation of neonatal cholestasis. Although considered to be the most important and constant feature of Alagille syndrome, bile duct paucity is present in only 90% of infants with the disorder. A normal ratio of portal tracts to bile ducts, bile duct proliferation, or a picture suggestive of neonatal hepatitis may be observed. Surgical biopsy is usually required to examine at least 20 portal tracts, the recommended sample number for definitive diagnosis. However, many experts believe that visualization of as few as five portal tracts in a percutaneous biopsy may be sufficient for diagnosis in the appropriate clinical setting.22 In addition to bile duct paucity, three other features including cholestasis, cardiac defects, skeletal abnormalities, characteristic facies or ophthalmologic abnormalities are required for diagnosis. Evaluation otherwise includes an echocardiogram to evaluate for cardiac anomalies and peripheral pulmonic stenosis, AP and lateral chest radiographs to allow evaluation for the presence of butterfly vertebrae, ophthalmologic examination to identify anterior chamber involvement, renal ultrasound and renal function testing to identify renal complications, and screening for early identification of any developmental delays. Confirmation of the diagnosis by genetic testing for JAG1 mutations is desirable. Given the medical problems of this condition and their variability, it is appropriate to assess first-degree relatives for manifestations of the disorder. If a JAG1 mutation has been identified in a proband, at-risk relatives can be evaluated using genetic testing. If no JAG1 mutation has been identified, at-risk relatives are best assessed with measurement of liver enzymes, cardiac examination, eye examination, skeletal x-rays, and evaluation of facial features.

Treatment and Outcomes

Alagille syndrome has a variable course. Patients with Alagille’s syndrome should not undergo Kasai portoenterostomy since it will not improve bile flow. Close monitoring of plasma concentration of fat-soluble vitamins, nutritional optimization, and therapy with vitamins A, D, E, and K prevent fat soluble vitamin deficiency. Zinc deficiency may also occur and require replacement therapy. The cholestasis usually improves or resolves over the first year of life. If this occurs the patients generally do not develop cirrhosis. In about 15% of Alagille syndrome patients the liver disease progresses to cirrhosis with eventual liver failure that requires liver transplantation. Comparatively minor head trauma may cause significant intracranial bleeding in infants and toddlers with Alagille syndrome; mortality is significant, even in the absence of coagulopathy.

Pruritus can be very severe and disabling. Pruritus can be treated with rifampin or naltrexone.23 Hyperlipidemia and hypercholesterolemia can be very problematic with resultant xanthomas. The hyperlipidemia has been treated with cholestyramine but efficacy of such therapy is uncertain. Xanthomas have been successfully treated with choloretic agents (ursodeoxycholic acid) cholestyramine or partial external biliary diversion. Liver transplantation for end-stage liver disease has an 80.4% five-year survival rate, and results in improved liver function and some catch-up growth in 90% of affected individuals.24

Conservative estimates put overall mortality at 20 to 25% from cardiac disease, intercurrent infection, or progressive liver disease. Neurovascular accidents have also been reported with rates as high as 15% and account for up to a third of the mortality in Alagille syndrome.25 Renal failure is another potential long term complication from Alagille syndrome. Hepatic malignancy has been reported in both children and adults.

Non-Syndromatic Bile Duct Paucity

Paucity of the bile ducts has been described in association with a wide variety of conditions including Down syndrome, Turner syndrome, hypopituitarism, cystic fibrosis, alpha-1-antitrypsin deficiency, congenital infections such as cytomegalovirus, rubella, and syphilis, hepatitis B, graft-versus-host disease, chronic hepatic allograft rejection, primary sclerosing cholangitis, Zellweger syndrome, and Ivemark syndrome. Treatment of the liver disease is similar to that of syndromatic bile duct paucity. Other manifestations of the associated disorders are treated accordingly.

Approximately 1/3 of infants presenting with neonatal cholestasis are diagnosed with extrahepatic biliary atresia (EHBA), a fibro-obliterative cholangiopathy resulting in obstruction of the common bile duct as its central component. Two subtypes of the disorder have been described based upon clinical characteristics. The most common acquire or non-syndromatic form presents with cholestatic jaundice between 1 and 2 months of age and is not associated with congenital anomalies. The syndromatic form is associated with other anomalies including situs inversus, polysplenia/asplenia, intestinal malrotation, portal vein anomalies, annular pancreas and congenital cardiac malformations. The incidence of EHBA is variable worldwide. An incidence of 1 in 5000 births occur is reported in Asia, 1 in 12, 000 in the United States and 1 in 17,000 in Europe.26 About 10 to 15% of patients diagnosed with EHBA are of the syndromatic form.

Pathophysiology and Genetics

The pathogenic mechanisms of both the acquired and syndromatic forms of biliary atresia are unknown. The presence a T-helper type 1 lymphocytic infiltrate has led to a theory that an insult such as a virus triggers an inflammatory process directed against a bile duct specific antigen. A variety of candidate viral infectious triggers have been proposed including cytomegalovirus, human herpes virus, human papillomavirus, rotavirus and reovirus but none of these has been confirmed. It is possible that the virus triggers an immune response against a bile duct antigen that persists following viral clearance due to molecular mimicry. A murine model of EHBA triggered by rhesus rotavirus supports this possible pathogenic mechanism but a specific infectious agent or antigen has not been identified in the human.27

Monozygotic twins are usually discordant suggesting that in most cases a gene defect is not causative. However, some HLA classes or genes may increase the susceptibility to other causative insults. A causative genetic defect seems more likely to be associated with the less common syndromatic form of EHBA. One mouse model with a recessive deletion of the inversin gene manifests with situs inversus with extrahepatic biliary obstruction but no specific gene defect has been identified in the human.28

Clinical Features

Prolonged neonatal jaundice extending beyond the age of 2 weeks should raise suspicion and prompt initiate evaluation for conditions associated with neonatal conjugated hyperbilirubinemia (see Chapter 418). Infants with EHBA usually are of normal birth weight and gestational age, while, infants with the syndromic form present with dark urine and acholic stools at between 2 and 4 weeks of age. Infants with the syndromatic form have an earlier onset of cholestasis, and an absence of a jaundice-free period after physiologic jaundice subsides. In patients not diagnosed early, further progression of biliary cirrhosis presents with splenomegaly, ascites, and bleeding or easy bruising from an underlying coagulopathy. Infants with EHBA usually have a mixed hyperbilirubinemia, acholic stools, with elevated serum alkaline phosphatase, GGT, and aminotransferase values. The absence of a gallbladder on sonography should raise suspicion of BA, although some affected infants will have a gallbladder.

Several surgical classification systems of biliary atresia have been proposed that define the anatomic segments involved. The French classification29 describes Type 1 as atresia limited to the common bile duct; Type 2 as a cyst in the liver hilum communicating with dystrophic intrahepatic bile ducts; Type 3 as having a patent gallbladder, cystic duct and common bile duct with the atresia of the ducts occurring above the cystic duct; and Type 4 being complete atresia of the entire extrahepatic biliary tree. The incidence of each type is about 3, 6, 19, and 72%, respectively.

Diagnosis

In infants with possible biliary atresia it is important to make a diagnosis promptly since the success of surgical intervention decreases with age. Previously, it was believed that the outcome of surgery was optimal if performed by 60 days. However, a recent retrospective review demonstrated that 65% of affected infants that underwent operation prior to 45 days of age had their native liver at 2 years age, compared to 58% of those that underwent operation before 60 days, and 42% if after 90 days.30 Thus, diagnosis and operation by 45 days is now considered optimal, although challenging. A new strategy using a “stool color card” to identify infants with biliary atresia has proven surprisingly effective in Taiwan.31 This simple approach had a sensitivity of over 97%. It has not yet been applied in other countries but deserves consideration.

Diagnostic approaches for the infant with cholestasis are outlined in Chapter 418. Ultrasound has been considered to be important for ruling out other anatomic causes of cholestasis such as a choledochal cyst. Recent data demonstrate that findings of a “triangular cord sign” and hepatic subcapsular flow on color Doppler ultrasound has a sensitivity of 100% and specificity of 86% for diagnosing biliary atresia.32 Further confirmation will be required before this approach might replace other diagnostic methods. Hepatobiliary scintigraphy has traditionally been used to demonstrate an absence of bile secretion into the intestinal lumen. However, the lack of sensitivity and specificity, combined with a delay in diagnosis required for phenobarbital priming has reduced the use of this technique for evaluation of neonatal cholestasis. Endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) have been used for diagnosis but limited data is available to support this approach and the equipment and expertise required are not uniformly available.

Liver biopsy is often considered the gold standard for diagnosis of biliary atresia and remains the most valuable test for discrimination of biliary atresia from other causes of infant cholestasis. However, because there are no pathognomonic histological changes it is critical that the biopsy be interpreted by a pediatric pathologist with experience in pediatric liver disease. If such expertise is applied, biopsy has been reported to have a diagnostic accuracy of up to 97%, compared to 91% scintigraphy, 71% for MRCP and 65% for ultrasound without Doppler.33,34 Common histologic findings include fibrous portal expansion, an increased number of intralobular bile ducts, and ductal proliferation. Portal inflammation is visible, as well as intrahepatic cholestasis or bile plugging. The portal fibrosis varies from portal expansion to cirrhosis.

Treatment and Outcomes

As described in the above section on diagnosis, surgical treatment before 45 days of age has the best outcome. After 3 months of age, the liver injury may be severe enough to make portoenterostomy less likely to be of value. The Kasai hepatoportoenterostomy consists of mobilizing the extrahepatic biliary tree and anastomosing a jejunal Roux en-Y loop to the liver hilum. If successful, any patent intrahepatic bile ducts will drain into the roux limb, relieving the obstruction. Various interventions have been attempted to promote post-operative establishment of bile drainage including the use of ursodeoxycholic acid, phenobarbital and high dose corticosteroids. A randomized controlled study of corticosteroid use demonstrated no improvement in native liver survival.35 Children that have a bilirubin of less than 2 three months after portoenterostomy have a 90% chance of having their native liver for at least 2 years, whereas if the bilirubin is greater than 6 there is a high likelihood that liver transplant will be required in the next 2 years. About 40% of EHBA patients will survive to adulthood with their native live but the majority have cirrhosis, and some will require transplantation as adults.

In about one-third of infants treated with portoenterostomy, jaundice never resolves, and hepatic injury progresses rapidly. In approximately another one-third, jaundice resolves over several months, but cirrhosis is already established or develops over the next several years. In these children, liver transplantation is the only other treatment option, although supportive measure such as fat-soluble vitamins, choleretic agents, and nutritional therapy are useful before transplantation as poor nutrition is a leading cause of complications associated with liver transplant. Between 45 and 60% of children that have undergone a Kasai procedure will have episodes of cholangitis, with most occurring within the first year of surgery. The frequency of episodes usually decreases with age but episodic cholangitis occurs through adulthood in many patients. Prompt therapy with intravenous antibiotics is required in these patients if they have fever associated with increasing jaundice or other indications of worsening liver disease.

Cholelithiasis and Choledocholithiasis

Cholelithiasis is the word used to describe the presence of gallstones within the gallbladder or bile ducts, whereas choledocholithiasis is the presence of gallstones in the common bile duct. Cholelithiasis, or gallstones, is increasingly recognized in children. This most likely can be attributed to the pediatric obesity epidemic or to the increased use of imaging techniques, especially abdominal ultrasound.

Epidemiology

The incidence currently is reported to be 0.1% to 0.2% in children. In comparison, gallstones are found in approximately 10% of adults. Associated conditions leading to gallstone formation in children differ by age group (Table 427-1).36 In infants, the most common causes are prematurity, parenteral nutrition, infection, and a history of intestinal surgery (including short bowel syndrome); in children ages 1 to 5 years, hepatobiliary disease, a history of abdominal surgery, and congenital heart disease; and in children ages 6 to 21 years, pregnancy, hemolytic disease, and obesity.37 Other conditions associated with gallstone formation include malabsorptive diseases (ie, Crohn disease), a history of heart transplantation, prior abdominal trauma, and bronchopulmonary dysplasia. Patients with cystic fibrosis have an increased incidence of gallstones along with other hepatobiliary findings. Gallstones are relatively uncommon in African Americans (except in sickle cell disease), exceptionally common in select groups of Native Americans and Hispanics, and a frequent occurrence in Caucasians.

Pathophysiology

The three most common types of stones include cholesterol stones, black pigmented stones, and brown pigmented stones. Cholesterol stones are composed of cholesterol crystals and mucin (Fig. 427-3). Black pigmented stones are composed of calcium salts and bilirubin, and brown pigmented stones are made of calcium bilirubinate, calcium phosphate, calcium palmitate, cholesterol, and other residues (eFig. 427.1). Stones may form as a result of abnormalities in cholesterol and lecithin concentrations, mucin secretion, gallbladder motility, enterohepatic circulation of bile salts, or hydrolysis of bilirubin by bacteria.38,39

Clinical Features and Evaluation

The differential diagnosis of gallbladder disease includes: acute and chronic hepatitis, malignancy, pneumonia, pelvic inflammatory disease (including Fitz-Hugh-Curtis perihepatitis), pancreatitis, esophagitis, gastritis, duodenitis, nephrolithiasis, and urinary tract infection.

In children with cholelithiasis the most common symptoms include vomiting and abdominal pain, typically in the right upper quadrant or epigastric region. Biliary colic usually lasts between 15 to 30 minutes and 6 hours. These symptoms can be caused by a stone that is obstructing the neck of the gallbladder or is within the cystic duct. In large series, 40% to 60% of children under the age of 5 years with cholelithiasis presented with jaundice, even in the absence of common duct stones. This is less common in older children. Physical examination may demonstrate a child with right upper quadrant tenderness, or guarding. Rarely, a mass is palpable in the right upper quadrant or epigastrium. Laboratory abnormalities may include mild elevation in serum aminotransferases, GGT, or 5'-nucleotidase. Both conjugated and unconjugated bilirubin may be elevated.40,41 Abdominal radiographs may reveal calcium stones; gallstones are most commonly visualized by abdominal ultrasound (Fig. 427-4). Computerized tomography (CT) scan, magnetic resonance cholangiography (MRCP), endoscopic ultrasound (EUS), or endoscopic retrograde cholangiopancreatography (ERCP) may also demonstrate stones (eFig. 427.2).

With choledocholithiasis, stones may be found within either the intra- or extrahepatic bile ducts. The majority of stones come from the gallbladder, because primary bile duct stones occur rarely in childhood, most often in hemolytic disease or associated with abnormal ducts due to genetic or inflammatory disorders. The clinical presentation of bile duct stones is similar to that of cholelithiasis; however, abdominal pain, nausea, and jaundice are more prominent symptoms. Physical exam findings include jaundice and right upper quadrant tenderness. Common bile duct stones are most commonly visualized by abdominal ultrasound, but more specific imaging modalities include MRCP, EUS, ERCP, or intraoperative cholangiogram. In a subset of patients, stones are not visualized, but the common bile duct is dilated (normal adult size is 5 mm), suggesting a distally obstructing stone.

Treatment

Asymptomatic patients found to have stones may be followed with conservative management. However, in certain conditions such as sickle cell anemia, elective cholecystemy is recommended. Similarly, in patients with hereditary spherocytosis, cholecystectomy is recommended at the time of splenectomy if gallstones are present. The use of ursodiol and lithotripsy are not well studied in children and are not beneficial for pigmented stones. In symptomatic patients with gallstones, laparascopic cholecystectomy, with or without intraoperative cholangiogram (IOC), is the procedure of choice. The timing of surgery is dependent on clinical status, comorbidities, and presence of complications.42 Endoscopic retrograde cholangiopancreatography (ERCP) may also be done pre- or postoperatively for retained stones or if IOC does not demonstrate stone clearance. Percutaneous cholecystostomy can be performed in patients that are not surgical candidates. ERCP is performed for patients with gallstone disease when they have persistent jaundice or pain from an obstructing common bile duct stone, imaging abnormality, cholangitis, or gallstone pancreatitis.

Complications

Complications of cholelithiasis and choledocholithiasis include cholecystitis, cholangitis, and bile duct perforation. Pancreatitis is common secondary to obstruction of the nearby pancreatic duct. Stones passing through the sphincter of Oddi may cause scarring and stenosis of the distal common bile duct. More than 80% of older children with gallstones may have evidence of chronic cholecystitis.41 Acute histologic evidence of cholecystitis in patients with gallstones occurs in less than 10% of cases.

Cholecystitis and Cholangitis

Inflammation of the gallbladder may manifest as either acute or chronic cholecystitis. Cholecystitis is frequently caused by obstruction of the neck of the gallbladder or cystic duct by a stone, referred to as calculous cholecystitis. Acalculous cholecystitis occurs in the absence of stones and is frequently related to systemic illness. Cholangitis is inflammation of the biliary tree.

Calculous Cholecystitis

The acute form of calculous cholecystitis presents in children with right upper quadrant pain (biliary colic in older children), nausea, vomiting, jaundice (in up to 50%), and fever. Exam findings are notable for tenderness over the affected area. A Murphy sign, which is pain on inspiration, may be elicited. Laboratory evaluation is notable for an elevated white blood count, as well as moderate elevations in aminotransferases and GGT.40 Ultrasound findings include a thickened, anechoic gallbladder wall, with sludge, or gallstones. Ten to twenty percent of patients may also have common bile duct stones.

Thickened gallbladder walls may also be seen in patients with hypoalbuminemia and ascites, and in those who have recently eaten a meal.43 A hepatobiliary iminodiacetic acid (HIDA) scan may show lack of uptake in the gallbladder. The majority of patients can be managed conservatively by administering intravenous fluids, maintaining no oral intake, and providing opioid analgesics. Surgical consultation should be obtained early in the course of the illness. Antibiotics are not necessary unless there is persistent fever, signs of sepsis, or other biliary complications. Selection of antimicrobials should include coverage for gram-negative bacteria and enteric anaerobes.

Unless there are emergent indications, cholecystectomy is the definitive treatment once the initial infection and complications have resolved. Open or percutaneous cholecystostomy can be performed in high-risk patients if necessary. Intraoperative cholangiogram and common bile duct exploration can evaluate whether there are retained common bile duct stones.37 The most common complications of acute cholecystitis include perforation, empyema, and pericholecystic abscess.

Chronic calculous cholecystitis is more common in children than the acute form. It presents with a series of acute episodes. Pain is often associated with eating, specifically eating fatty meals. Laboratory findings may be normal or have mild perturbations in aminotransferases and GGT. Ultrasound may show thickened gallbladder wall and stones.43 The treatment is also cholecystectomy.

Acalculous Cholecystitis

Acalculous cholecystitis is an inflammatory condition seen in the absence of gallstones. There are two forms: acute, which is less than 1 month’s duration and chronic, which is greater than 3 months’ duration.44 Acalculous cholecystitis most commonly occurs in association with infection or systemic illness. The most common infections include group A beta-hemolytic streptococcus and gram-negative enterics (ie, salmonella, shigella, and E coli). Parasitic infections have been described in patients with cryptosporidiosis, giardiasis, and ascariasis. Leptospirosis is a spirochetal infection described in a large US midwestern outbreak in patients who developed acalculous cholecystitis.45 Hemolytic uremic syndrome, cystic fibrosis, and systemic vasculitides (systemic lupus erythematosus, polyarteritis nososum, Kawasaki disease) may also cause acalculous cholecystitis. Risk factors for acute acalculous cholecystitis include prolonged fasting, total parenteral nutrition (TPN), shock, intravenous opiate use, history of transfusion, and sepsis.

Most patients with the acute form will have fever, right upper quadrant pain, and vomiting. Jaundice and palpable mass may be present.46 Laboratory evaluation is notable for an elevated white blood count, abnormal aminotransferases, abnormal GGT, and elevated bilirubin. Children with chronic acalculous cholecystitis have right upper quadrant pain with nausea or vomiting, but typically have a normal complete blood count (CBC) and liver panel. Abdominal ultrasound in acute and chronic acalculous cholecystitis will show a thickened gallbladder wall without stones, but some patients will have sludge. A hepatobiliary iminodiacetic acid (HIDA) scan will not demonstrate gallbladder filling. Treatment of the underlying illness should be initiated, and cholecystectomy is performed in most patients.

Cholangitis

Infection of the biliary tree is rare, but most frequently seen in the setting of obstruction. Cholecystitis, choledocholithiasis, sclerosing cholangitis, and biliary cystic disorders (Caroli’s) may be complicated by cholangitis. Patients at greatest risk are those patients with biliary atresia or choledochal cyst who have had hepatoportoenterostomy. Most patients have fever and jaundice or may have acholic stools. Charcot triad, which includes fever, right upper quadrant pain, and jaundice, is commonly described in adults. Laboratory abnormalities include an elevated conjugated bilirubin, elevated GGT, and serum aminotransferases. Blood cultures are frequently positive and the most commonly isolated organisms are E coli, enterococci, and Klebsiella. Ultrasound, magnetic resonance imaging (MRI), or hepatobiliary iminodiacetic acid (HIDA) scan may show evidence of obstruction. Acute therapy includes fluid management, treatment of the underlying condition, and broad-spectrum antibiotics. Antimicrobial selection should incorporate therapy to achieve appropriate biliary and serum coverage. Combination therapy is necessary and may include piperacillin/tazobactam and gentamicin. Biliary decompression with percutaneous drainage or endoscopic retrograde cholangiopancreatography (ERCP) may be necessary to restore flow. In patients with negative blood cultures, liver biopsy may help identify an organism. Complications of cholangitis include liver abscess, biliary stricture, biloma, and acute perforation. Frequent episodes of cholangitis can lead to acute and chronic worsening of underlying liver disease.

Hydrops of the Gallbladder

Acute distention of the gallbladder wall without stones or evidence of local inflammation is the hallmark of gallbladder hydrops. The pathogenesis is unknown and may affect children at any age. This condition is most commonly associated with Kawasaki syndrome, but has been described as the sequelae of group A beta-hemolytic streptococccal and leptospiral infection. Hydrops has also been associated with Henoch-Schönlein purpura.

Common presenting symptoms of gallbladder hydrops include abdominal pain, nausea, and vomiting. Some patients may have fever and jaundice, and often have abdominal distention and right upper quadrant pain on physical examination. A distended gallbladder may be palpable. Laboratory investigations are often unrevealing and may be indistinguishable from cholecystitis, but may include mild elevations in aminotransferases, alkaline phosphatase, or GGT.40

Diagnosis is usually by ultrasound, which shows a thin-walled and distended gallbladder without gallstones, radiographic evidence of common bile duct enlargement, or inflammatory changes in the gallbladder mucosa. Treatment is usually conservative and surgical intervention is reserved for complicated illness or progression with ischemia or gangrenous changes. Therapeutic intervention may include percutaneous cholecystostomy, open cholecystostomy, or cholecystectomy.

Gallbladder and Sphincter Dysfunction

A spectrum of functional biliary disorders including functional gallbladder disease (biliary dyskinesia) and sphincter of Oddi dysfunction have been described. In adults, diagnostic criteria for this disorder include (1) pain that is localized to the epigastric and/or right upper quadrant region and lasts 30 minutes or longer; (2) recurrent pain that occurs at different intervals, builds to a steady level, and is severe enough to interrupt daily activities or lead to an emergency room visit; and (3) pain that is not relieved by bowel movements or postural change, and not relieved by antacids. Associated symptoms include nausea, vomiting, radiation of pain to the back, and pain that wakens patient from sleep. Laboratory testing may show elevation of aminotransferases, alkaline phosphatase, GGT, or bilirubin during pain episodes. Abdominal ultrasound and magnetic resonance cholangiography (MRCP) studies are usually normal.

Biliary dyskinesia is likely a form of chronic cholecystitis. Hepatobiliary scintigraphy using a hepatobiliary iminodiacetic acid (HIDA) scan is often abnormal. A cholecystokinin (CCK) analog (sincalide) is given by intravenous (IV) infusion, which may mimic symptoms and cause nausea, pain, or vomiting and may be suggestive of gallbladder dysfunction. A fatty meal or Lipomul can be given to stimulate the gallbladder.47 Although an ejection fraction of HIDA greater than 35% is considered normal, values of less than 35% should be taken in the clinical context. False-positive reading (poor emptying) may occur during acute illness, pancreatitis, prolonged fasting, stress, or opiate use. Patients with markedly abnormal studies may benefit from cholecystectomy; however, more than 20% may still have pain, so conservative management may be appropriate.

Patients with sphincter of Oddi dysfunction (SOD) have biliary colic symptoms but may have elevated serum aminotransferases, alkaline phosphatase, or bilirubin temporarily associated with pain episodes. These patients may also have bile duct dilation. The physiology of SOD is likely the result of stenosis of the papilla or dysmotility of the biliary ducts and papilla. Endoscopic retrograde cholangiopancreatography (ERCP) with biliary manometry has been used for diagnosis; however, no pediatric normal values are available. For patients with normal sphincter pressures, medications to treat hyperalgesia (ie, antidepressants or antispasmodics) may be effective. In the presence of laboratory and/or imaging abnormalities, ERCP with stenting or sphincterotomy may be curative but patient selection for these treatment approaches remains somewhat controversial.48