Biliary tract disorders are responsible for the greatest number of cases of cirrhosis in the pediatric population; extrahepatic biliary atresia is most common (see also Chapter 367, Disorders of the Liver and Biliary System). Biliary atresia is a progressive inflammatory cholangiopathy that results in fibrosis and complete obstruction of the extrahepatic biliary tree.

Biliary atresia is the most common cause of cholestasis in nonpremature infants 0 to 3 months of age and is the single most common pediatric etiology requiring liver transplantation. The incidence of biliary atresia is 1 in 8,000 to 12,000 live births with a female-to-male ratio of 1.2:1.0. Approximately 10% of patients with biliary atresia have associated anomalies such as malrotation and polysplenia. Biliary atresia is the result of progressive obliteration of the extrahepatic biliary tree; it appears to be an acquired disorder rather than a consequence of abnormal development, as evidenced by the rare occurrence of biliary atresia in autopsied fetuses and premature newborns. Many theories regarding the etiology of biliary atresia have been proposed. For additional details about these theories, see Box 370.4.

Choledochal cysts are a relatively uncommon cause of cirrhosis; the incidence is 1 in 13,000 to 15,000 live births (see also Chapter 367). Females are affected four times more frequently than are males. Five major types of choledochal cysts are found. Type I is a congenital cystic dilation of the common bile duct and is the most common type of choledochal cyst. Type II choledochal cyst is a diverticular outpouching of the common bile duct. Type III is a choledochocele with an ampullary obstruction. Type IV has both extrahepatic and intrahepatic bile duct cystic dilations. Type V, or Caroli disease, consists of intrahepatic bile duct cysts. Although patients may present with a choledochal cyst at any age, approximately one-third of patients present in the first year of life and more than two-thirds in the first 6 years of life. The classic triad of abdominal pain, right upper quadrant mass, and jaundice is present in only 10% to 20% of patients. More commonly, patients with a choledochal cyst present with jaundice, abdominal pain, vomiting, acholic stools, or hepatomegaly. A choledochal cyst can be diagnosed with abdominal ultrasonography, which may reveal cystic dilations of the intrahepatic and extrahepatic biliary trees. A hepatobiliary scan can aid in the diagnosis by showing a rounded extrahepatic structure that retains the tracer and is distinguishable from the gallbladder. More recently, endoscopic retrograde cholangiopancreatography (ERCP) and magnetic retrograde cholangiopancreatography (MRCP) have been utilized to more specifically look at the biliary anatomy. If untreated, patients develop cirrhosis. A high incidence of cholangiocarcinoma is seen in this patient population. The incidence varies from 2% to 26% in patients who remain untreated and is up to 50% in those who had an enteric drainage procedure with the cyst still present. A higher incidence of cancer in the gallbladder also appears to exist. Treatment consists of excision of the cyst and performance of a choledochojejunostomy and a cholecystectomy.

Congenital segmental dilation of the intrahepatic biliary tree may progress to cirrhosis. Caroli disease, an autosomal recessive disorder, is characterized by hepatomegaly and dilated intrahepatic ducts that contain bile. A significant potential exists for the formation of stones within these dilated ducts and for the development of cholangitis. Although affected patients tend not to develop cirrhosis, a subset of patients has severe periportal fibrosis and do develop cirrhosis.

Intrahepatic bile duct paucity refers to a group of disorders characterized by a reduction or absence of bile ductules in the portal triads of the liver. Rather than the one to two bile ductules usually found per portal triad, the paucity syndromes are characterized by less than one-half bile duct per triad. This group of disorders can be subdivided into two major categories: syndromic and nonsyndromic. The syndromic form comprises Alagille syndrome (i.e., arteriohepatic dysplasia). The incidence of Alagille syndrome is 1:2,500 live births. In addition to the paucity of intrahepatic bile ducts, Alagille syndrome is associated with at least two of the four major associated abnormalities: abnormal facies (see Chapter 462), congenital heart disease, ocular abnormalities, and vertebral arch defects. The typical facial pattern is characterized by a broad forehead, mild hypertelorism, a straight nose, and a small, pointed chin. The most common congenital heart defect is pulmonary valve stenosis while peripheral pulmonic stenosis is the most common vascular disorder. Posterior embryotoxin in the anterior chamber of the eye is the most frequently noted ocular abnormality. Other potential associated anomalies include growth retardation, pancreatic insufficiency, mental retardation, hypogonadism, and renal abnormalities. Alagille syndrome is inherited in an autosomal dominant fashion, although a spontaneous mutation rate of 15% to 50% is seen. The gene responsible for this disorder, Jagged I, was identified in 1997. The clinical spectrum of this disorder is large. Some individuals will have mild liver disease while others will develop liver failure and require liver transplantation in the first year of life. Treatment is primarily supportive. Prognosis for patients with Alagille syndrome is variable. Survival in patients with their native liver is 51% and 38% at 10 and 20 years, respectively. Most patients die of liver disease, heart disease, or infections. Ten to twenty percent of these patients develop cirrhosis. It
has been estimated that 30% to 50% of patients require liver transplantation by 19 years of age due to cirrhosis, pruritus, or osteodystrophy. Patients with Alagille syndrome and cirrhosis are at increased risk for developing hepatic malignancy.

The nonsyndromic form comprises intrahepatic bile duct paucity that is not due to Alagille syndrome. This form includes bile duct paucity with and without an associated primary disorder. Disorders that may be associated with a decreased number of bile ducts include cystic fibrosis, alpha-1-antitrypsin deficiency, Down syndrome, hypopituitarism, inborn errors of bile acid metabolism, and graft-versus-host disease. The prognosis for these patients depends on the underlying disorder. Those with intrahepatic bile duct paucity but no associated disorder typically do not progress to severe liver disease; however, isolated reports have noted a rate of cirrhosis of up to 50% in such patients.

Congenital hepatic fibrosis is a rare autosomal recessive disorder characterized by the formation of multiple bands of fibrous tissue running throughout the liver and dysmorphic bile ducts within the fibrous tissue. The exact cause is unknown, but the condition is thought to be secondary to abnormal development of the bile ducts. Most patients have associated renal disease in the form of renal tubular ectasia or autosomal recessive polycystic kidney disease. The clinical manifestations are variable and age dependent; infants present primarily with renal disease and older patients present primarily with liver disease. Those with liver disease tend to show hepatosplenomegaly, especially of the left lobe, and portal hypertension. They may also develop cholangitis, biliary calculi, and intrahepatic abscesses. Therapy is supportive.

Cystic fibrosis is the most common lethal genetic disease affecting whites (see also Chapter 236). It is inherited in an autosomal recessive pattern and is found in approximately 1 in 2,000 live births. The lungs and pancreas are the primary organs affected, although multiple organ systems are involved. Hepatobiliary disorders occur in 20% to 60% of patients with cystic fibrosis, and the incidence increases with age. Ten to thirty-five percent of patients with cystic fibrosis will have asymptomatic elevation of their liver function tests. Hepatic steatosis is the most common liver abnormality, occurring in at least one-third of patients with cystic fibrosis. This complication is in part secondary to malnutrition, which is prevalent in these patients. Thirty percent of patients have microgallbladders, and 5% to 10% have cholelithiasis. Some infants with cystic fibrosis present with neonatal cholestasis secondary to sludge in the biliary tree. Patients with cystic fibrosis may develop focal biliary cirrhosis or multilobular cirrhosis, although cirrhosis rarely is the presenting manifestation of cystic fibrosis. Focal biliary cirrhosis occurs in 10% to 60% of patients with cystic fibrosis. Histologically, this lesion is characterized by inspissation of eosinophilic microprotein in the bile ducts, bile duct proliferation, chronic inflammation, and portal fibrosis. Focal biliary cirrhosis is of little clinical consequence. Multilobular cirrhosis, on the other hand, is very significant clinically and can lead to end-stage liver disease requiring liver transplantation. As with other liver diseases associated with cystic fibrosis, the incidence of multilobular cirrhosis increases with age; it is present in approximately 5% of patients older than 12 years and 10% to 15% of those older than 25 years. Due to the frequency of liver disease in patients with cystic fibrosis, it is recommended that all patients have liver blood tests performed on an annual basis.

Medical management is primarily supportive with nutritional therapy being the mainstay. Administration of ursodeoxycholic acid, 20 mg per kg per day in two divided doses, to patients with cystic fibrosis and liver disease has led to improvements in liver enzyme levels, but the long-term effect on the course of liver disease is still unknown.

Primary sclerosing cholangitis is a chronic inflammatory disease of unknown cause that rarely occurs in children. It is characterized by progressive fibrosis of the intrahepatic and extrahepatic biliary ducts. These ducts are best visualized by ERCP, which reveals multiple focal areas of stricture and irregularities. Three categories are identified, based on age of onset and the presence of associated disease states: primary sclerosing cholangitis of neonatal onset (27% of cases), that of postneonatal onset associated with a disease (55%), and that of postneonatal onset not associated with another disease (18%). Sclerosing cholangitis in the pediatric population is most commonly associated with inflammatory bowel disease (80%). Other disorders associated with primary sclerosing cholangitis include autoimmune thyroiditis, histiocytosis X, or immunodeficiency states. Patients commonly present with abdominal pain, fatigue, jaundice, and hepatosplenomegaly. Liver enzyme levels, in particular GGT, are almost always elevated. Two-thirds of individuals have hypergammaglobulinemia and in 70% antinuclear antibody (ANA) and anti-smooth muscle antibodies are present. Liver biopsy reveals portal fibrosis, ductular proliferation, and pericholangitis. The progression to frank cirrhosis is inevitable, although it tends to occur 5 to 10 years after diagnosis. Multiple medications have been used in an attempt to halt the progression of this disease; some, such as ursodeoxycholic acid, may result in improvement of liver enzyme levels, but they do not appear to alter the progression of the disease. Liver transplantation is the only life-extending therapeutic option for end-stage liver disease.

Alpha-1-antitrypsin deficiency (described in more detail in Chapter 367) is the prototypic genetic and metabolic disorder resulting in cirrhosis in pediatric patients. It is the most common genetic cause of liver disease in the pediatric population. In addition, this disorder is the most common inherited disorder for which liver transplantation is required. Alpha-1-antitrypsin is an acute-phase reactant that is synthesized in the liver and is the major antiproteolytic agent in the body. Alpha-1-antitrypsin deficiency is a disorder of glycoprotein metabolism with a prevalence of 1 in 1,600 to 1,800 persons. The gene responsible for the deficiency state resides on chromosome 14 and is associated with a single amino acid substitution resulting in the production of an abnormal protein. The liver disease associated with alpha-1-antitrypsin deficiency is believed to be the result of the accumulation of this abnormal protein, which undergoes polymerization that is concentration and temperature dependent. The diagnosis is made by determining the phenotype or Pi (protease inhibitor) type (Box 370.5).

The disorder can manifest in infancy, childhood, or adulthood. In infancy, patients present with cholestasis, bleeding (in the gastrointestinal tract or central nervous system, or from the umbilical stump), or transaminase elevation. In childhood or adulthood, patients present with chronic hepatitis, cirrhosis, or portal hypertension. A strong association also is seen between alpha-1-antitrypsin deficiency and the development of emphysema in young adults.

Treatment is primarily supportive unless severe liver disease ensues, in which case liver transplantation is curative. Intermittent intravenous infusion of purified alpha-1-antitrypsin from plasma has normalized serum alpha-1-antitrypsin levels and halted the progression of lung disease in adults. This therapy offers little benefit to those with liver disease because the liver pathology is secondary to the retained abnormal protein and is not due to the low serum levels of alpha-1-antitrypsin. The prognosis for pediatric patients with liver disease is more favorable than believed previously when the studies were hospital based. In a long-term study, Swedish children with alpha-1-antitrypsin deficiency and liver disease in infancy were followed from infancy to 18 years of age. Eleven percent died in infancy of liver disease; another 11% died as young children of other causes but at autopsy showed cirrhosis or fibrosis. The other 78% had no clinically demonstrable liver disease at 18 years of age; 13% of these had minimally elevated liver enzymes with normal procollagen, a marker of fibrogenesis in liver disease.

Wilson disease (i.e., hepatolenticular degeneration) is an inherited disorder of copper metabolism (see also Chapter 367). The prevalence of Wilson disease is approximately 1 in 30,000 to 100,000. Wilson disease is an autosomal recessive disorder; the gene responsible for the defect in copper metabolism is ATP7B located on chromosome 13. The defect in copper metabolism appears to result from decreased incorporation of copper into ceruloplasmin, thus limiting excretion of copper out of the hepatocyte as well as other cells. As a result, there is accumulation of copper in the cells of most organs, especially the liver, brain, and kidneys.

Wilson disease is usually detected in patients after 5 years of age; however, case reports are found of patients as young as 2 years. Many presentations are possible, although younger patients usually present with liver disease and older patients with neurologic symptoms. The liver disease can manifest as acute or chronic hepatitis, steatohepatitis, cholestasis, portal hypertension, cirrhosis, or liver failure. The neurologic symptoms range from deterioration in handwriting and personality changes to athetoid movements, Parkinson-like state, and psychosis. Patients with Wilson disease may have other extrahepatic manifestations, including hemolytic anemia, arrhythmias, arthropathy, osteomalacia and skeletal fractures, renal tubular acidosis, or Fanconi syndrome.

The diagnosis of Wilson disease is based on the physical examination (presence of Kayser-Fleischer rings), increased level of urinary copper excretion, and decreased serum copper and ceruloplasmin levels. The copper content of the liver is significantly elevated. Kayser-Fleischer rings result from the deposition of copper in Descemet membrane of the cornea. These rings increase in size with the duration of the disease and resolve over time with appropriate therapy. The finding of Kayser-Fleischer rings is essentially diagnostic. Genetic testing is also available for research purposes.

Therapy is directed toward achieving and maintaining a negative copper balance for life. Penicillamine, which chelates copper, is used when significant copper overload exists. It is not typically used in those with neurologic symptoms since it is associated with worsening of neurologic symptoms in 10% to 50% of cases. Triethylene tetramine (trientine hydrochloride) also chelates copper and is used in those who do not tolerate penicillamine. Maintenance therapy consists of a reduction in dietary copper and the use of zinc acetate to decrease absorption of dietary copper. A newer therapeutic alternative is ammonium tetrathiomolybdate, which has two anticopper mechanisms. Ammonium tetrathiomolybdate binds with dietary copper, limiting its absorption. In addition, it also complexes with copper and albumin, rendering copper unavailable for uptake by cells. Liver transplantation can be performed for end-stage liver disease and results in correction of the metabolic defect. Although the prognosis for untreated patients is dismal (i.e., early death is essentially universal), patients who are diagnosed early enough and treated appropriately have a normal life expectancy. If the diagnosis and appropriate therapy are delayed, permanent neurologic or hepatic damage can take place. In addition, siblings and offspring of patients with Wilson disease should be screened for this disorder with a complete physical examination, including slit lamp examination and measurement of liver enzymes, serum copper, and ceruloplasmin levels, and a 24-hour urine collection for copper.

Indian childhood cirrhosis (copper-associated liver disease in childhood), a rare disorder of copper metabolism once thought to be confined to India, has now been detected in other regions, including North America and Europe. The cause of the disorder is uncertain, but it is most likely due to increased dietary copper from water or cooking utensils. Some authors believe the condition is due to an inborn error of copper metabolism because an increased incidence is seen in families with an affected child. A family history of affected siblings is present in 30% of cases. The disorder affects children 1 month to 10 years of age, with a peak incidence between 1 and 3 years. Affected patients typically present with hepatosplenomegaly and hepatitis of unknown cause.

Early in the course of the disease, the liver histology is characterized by a diffuse inflammatory process with ballooning degeneration, Mallory bodies, and fibrosis. A large amount of copper is deposited in the liver, as in Wilson disease; however, patients with Indian childhood cirrhosis do not have low ceruloplasmin levels.

Therapy with penicillamine prior to the establishment of severe liver disease has been shown to improve clinical symptoms, reduce hepatic copper content, and improve liver histology. The use of penicillamine after the establishment of cirrhosis, however, has no beneficial effect, and liver transplant is necessary for long-term survival. Death frequently occurs within 8 months of onset of symptoms if no treatment is provided. Initiation of public health measures to reduce the copper consumption of infants and young children in India has resulted in a decreased incidence of this disorder.