The biliary tree includes the ducts that drain bile from the liver and coalesce into the right and left hepatic ducts, the cystic duct and gallbladder, and the common bile duct that drains bile from the gallbladder through the pancreas and into the duodenum. Biliary tract diseases can present at any age and have become increasingly recognized in pediatric practice as diagnostic tests have improved. Some diseases of the biliary system are associated with liver disease and others are specific to the biliary tract alone. In addition, some biliary diseases present at specific ages in children while others can develop at any time from early infancy through adulthood.

The primary pathologic processes of biliary tract disease fall into two categories, obstructive or inflammatory. Obstruction diminishes flow of bile from the liver into the duodenum with resultant pressure in the biliary system (leading to pain, jaundice, and potentially pancreatitis), fat malabsorption (from poor micelle formation in the gut), and potential infection (from gut flora contamination of the static bile fluid in the biliary tree). Hepatic inflammation and damage may result if biliary obstruction or inflammation is not relieved or treated.

Obstruction is most often from gallstones but may also occur as a result of anatomic abnormalities or scar formation. Chronic inflammation of the biliary tree, whether in the large ducts draining the liver and gallbladder or in the small ducts within the liver, can lead to scarring and obstruction of bile flow. Inflammatory processes are most often autoimmune in nature but can be due to chronic infections or genetic diseases. They are often insidious and unrecognized until significant biliary damage has occurred and large duct obstruction develops. Finally, the gallbladder itself can be poorly functional in storing and/or evacuating bile, which can lead to more subtle, subacute reductions in bile flow and chronic pain from gallbladder distention and inflammation.

Jaundice is the primary sign of biliary disease, indicating significant obstruction to bile flow. Jaundice typically prompts medical evaluation that leads to the diagnosis of biliary disease. Complete or near-complete obstruction of bile flow can result in acholic stools that are light yellow to clay in color. For infants in diapers, stools may occasionally have a hint of pigment on the exterior surface due to sloughing of enteric cells or staining from bile-pigmented urine. Once this layer is removed, however, the clay-colored stool inside is apparent.¹

Careful attention is required when evaluating jaundice in neonates as approximately 60% of term neonates and 80% of preterm infants develop physiologic jaundice in the first days of life.² This can lead to complacency and delays in diagnosing more serious liver and biliary diseases that present in early infancy. Any infant with new or persistent jaundice beyond the first 2 weeks of life requires further evaluation that includes measurement of fractionated serum bilirubin. Physiologic jaundice, breast milk jaundice, and hemolytic diseases are all associated with unconjugated hyperbilirubinemia; in contrast, extrahepatic biliary atresia (EHBA) and other cholestatic hepatobiliary diseases of the newborn result in an elevated conjugated bilirubin.^1,3 A conjugated or “direct” bilirubin >2.0 mg/dL or 20% of the total bilirubin is considered the threshold definition of cholestasis and requires prompt and aggressive evaluation and management in any young infant.^4,3

Biliary disease may present with poor growth and weight gain as a consequence of inadequate bile salts in the intestinal lumen, which leads to poor micelle formation and fat malabsorption. In addition, symptoms or physical findings indicative of fat-soluble vitamin deficiencies may be found. Specific findings include hemorrhage or hematoma (vitamin K deficiency), rickets (vitamin D deficiency), night blindness and corneal xerophthalmia (vitamin A deficiency), and peripheral neuropathy (vitamin E deficiency).⁵

While older children with biliary disease can present with jaundice, they often have other symptoms indicating biliary obstruction or inflammation, especially right upper quadrant to epigastric pain, right shoulder referred pain from diaphragmatic irritation, postprandial pain or nausea (particularly with high-fat foods), vomiting, light-colored stools, or dark urine. Fever, if present, may suggest superimposed infection. Signs of biliary disease include a positive Murphy sign (right upper quadrant tenderness during inspiration), scleral icterus and jaundice, epigastric tenderness if pancreatitis is present, and right upper quadrant mass. Subacute biliary disease such as acalculus cholangitis or biliary dyskinesia can present gradually with persistent and worsening right upper quadrant pain and tenderness and often nausea or vomiting with high-fat foods, but no fever or jaundice.

Systemic illnesses such as scarlet fever, Kawasaki disease, and leptospirosis can lead to hydrops of the gallbladder, with subsequent findings of right upper quadrant pain (93%) and mass (55%) along with evidence of broader acute systemic disease.⁶ In patients with infection of the biliary tree (cholangitis), Charcot’s triad of fever, right upper quadrant pain, and jaundice may be seen.^1,6 Bacterial cholangitis can progress to bacteremia and sepsis, especially if obstruction is present.

Hepatosplenomegaly is not typically associated with primary biliary tract conditions. However, the cholestasis of chronic biliary disease can result in hepatocellular injury, which may ultimately lead to liver fibrosis and portal hypertension. Thus the presence of hepatosplenomegaly in the context of biliary disease likely indicates the presence of advanced chronic disease and progressive liver dysfunction.

As with many diseases in pediatrics, the differential diagnosis of biliary disease in children is best categorized by age of presentation (Table 75-1). Metabolic, congenital endocrinologic, and genetic disorders are more likely to present in the neonatal and infant population, while gallbladder dysfunction and cholelithiasis are more typically found in older children and adolescents. Anatomic abnormalities often present in infancy, such as biliary atresia, which must be recognized within the first 2 months of life for optimal management, but may present later. Choledochal cysts, for example, can become apparent at any age, from birth to old age, with variable presentation from acute ascending cholangitis to chronic obstruction from biliary ductal carcinoma, a consequence of unresected choledochal cysts.⁷ Finally, biliary involvement of acute systemic processes such as Kawaski syndrome with gallbladder hydrops or graft-versus-host disease following bone marrow transplant must be considered within the specific context of the child’s health.

Although the evaluation for possible biliary tract disease should be tailored to the individual patient, the initial steps are usually similar (Table 75-2). Thereafter, certain studies may be selected on the basis of clinical suspicion, feasibility, and invasiveness. Evaluation of neonates and young infants with jaundice should be prompt and efficient, because timely intervention is required if biliary atresia is found. Management of conditions detected during diagnostic evaluation is addressed in the discussions of each specific diagnosis.

The first and most fundamental step in evaluating jaundice is the fractionation of the serum bilirubin.³ Biliary tract disease is associated with elevation of direct or conjugated bilirubin, as opposed to the elevated indirect or unconjugated bilirubin found in various hemolytic and abnormal liver conjugating conditions such as breast milk jaundice and Crigler-Najjar syndrome. An elevated conjugated bilirubin is associated with obstruction of bile flow through or from the liver due to either congenital or acquired lesions. Conditions of hepatic dysfunction can also be associated with elevated bilirubin without extrahepatic obstruction, such as occurs in viral hepatitis or gram-negative rod sepsis, which causes intracellular disruption of the bile flow. Various genetic and endocrinologic syndromes, such as progressive familial intrahepatic cholestasis or panhypopituitarism, may also interrupt or impede normal bile production and flow without involving frank ductal obstruction.

In addition to a fractionated bilirubin, a broader laboratory assessment of liver inflammation and function should be pursued in all patients with suspected biliary disease. These include alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, gamma-glutamyltransferase (GGT), total protein, and albumin levels and prothrombin time (PT)/INR. ALT and AST are markers of hepatocyte inflammation and breakdown and may be elevated if biliary tract disease is severe enough to generate secondary inflammation in the liver. Alkaline phosphatase and GGT are more specific for the biliary tract than are AST and ALT, and they are usually elevated, possibly 10 times normal or more, with acute obstruction or inflammation of the biliary tree.^8,9,10 Albumin and protime (PT) are indicators of liver synthetic function and are less likely to be abnormal in an acute biliary process. Although not common, liver failure can be seen with some biliary tract diseases, including biliary atresia and unrelieved acute obstruction such as untreated common bile duct cholelithiasis.^3,11 In patients with fever, a complete blood count and blood culture should be obtained, given the possibility of cholangitis and subsequent bacteremia.

Ultrasonography is the most useful imaging study for assessing biliary tract disease.^12,13 A carefully performed ultrasound study can detect stones in the gallbladder, common bile duct, or elsewhere in the biliary tree. Dilatation of bile ducts, either intra- or extrahepatic, can indicate obstruction. Congenital malformations of the biliary tree, primarily choledochal cysts, are typically detected by ultrasonography. Although biliary atresia cannot be definitely diagnosed by ultrasonography, an absent gallbladder or the presence of a “triangular cord” in the porta hepatitis is suggestive.^13-15 Conversely, it is important to note that the presence of a gallbladder does not rule out biliary atresia. Finally, abdominal ultrasonography allows the evaluation of other abdominal organs that can be affected by or associated with biliary disease, such as gallstone pancreatitis or polysplenia associated with the embryonic form of biliary atresia.

For a young infant presenting with cholestasis, the initial evaluation should include the blood work discussed earlier and ultrasonography. The presence of a choledochal cyst should lead to surgical consultation for repair. If such a definitive finding is absent, further investigation to rule out biliary atresia should be undertaken, particularly in patients with acholic stools. A hepatobiliary scintigram (HIDA scan) can be performed to look for excretion of the radioactive tracer from the liver into the gut, which would confirm the patency of the biliary tree.¹³ Lack of excretion into the gut may mean that biliary atresia is present. This study is not available at all institutions, however, and an abnormal study does not always distinguish extrahepatic obstruction from intrahepatic causes of cholestasis, such as Alagille syndrome or cystic fibrosis. A liver biopsy is helpful in these patients to distinguish among several causes of jaundice, including neonatal hepatitis, bile duct paucity syndromes such as Alagille, and extrahepatic biliary atresia (which is characterized by bile duct proliferation on biopsy).^1,3 Due to the possible overlap in the appearance of these cholestatic conditions on biopsy, if there is ongoing clinical concern for biliary atresia, surgical consultation for an intraoperative cholangiogram should be obtained. The cholangiogram is the most definitive study for biliary atresia. Some major pediatric centers have used endoscopic retrograde cholangiopancreatography (ERCP) to define biliary anatomy in neonates and infants with good results, but so far intraoperative cholangiogram remains the standard of care.¹⁶

A few other studies may be appropriate in selected patients. Since hypothyroidism, either alone or in conjunction with panhypopituitarism, can stunt intrahepatic bile duct formation, jaundiced infants should have thyroid function tests performed.^17,18 Infants with cystic fibrosis can also develop jaundice due to thick, inspissated bile plugging of both intra- and extrahepatic bile ducts, so patients in this age group should have their newborn screen tests for cystic fibrosis reviewed and a skin sweat test performed if there is any lingering question of cystic fibrosis.^19,20

Older children presenting with jaundice, abdominal pain, and elevated GGT or alkaline phosphatase are most likely to have acute obstruction of the biliary tree with gallstones, hematoma from trauma, or previously unrecognized anatomic abnormality such as a choledochal cyst. In the absence of gallstones or other obvious obstruction seen by ultrasound, the child may be suffering from primary sclerosing cholangitis, an autoimmune condition of the biliary tree. This condition requires imaging with either ERCP or magnetic resonance cholangiopancreatography (MRCP) to show the characteristic areas of alternating stricture and dilation, giving the intrahepatic and extrahepatic ducts a beaded appearance (Figure 75-1).^21,22 Characteristic findings are also present on liver biopsy. A history of inflammatory bowel disease, particularly ulcerative colitis, in the patient or the family should raise the suspicion for primary sclerosing cholangitis and lead to consultation with a pediatric gastroenterologist or hepatologist for a full evaluation.

This section discusses in greater depth the pathophysiology and management of those biliary diseases most likely to be encountered by the pediatric hospitalist. Biliary atresia and choledochal cysts are typically diagnosed in infancy, although the latter may rarely present in older children and adults. Cholelithiasis, cholangitis, biliary dyskinesia, gallbladder hydrops, and primary sclerosing cholangitis are more likely to be found in older children and adolescents, although infants may develop cholelithiasis, particularly if treated with parenteral nutrition in the neonatal period.

BILIARY ATRESIA

Biliary atresia is the most common cause of chronic cholestasis in infants, accounting for 40% to 50% of all cases of neonatal cholestasis, and occurring in 1 in 8000 to 12,000 births. It is the leading indication for pediatric liver transplantation worldwide.^23,3,24 In this condition, all or part of the extrahepatic bile ducts are destroyed or absent, leading to early cholestasis and rapidly progressive liver disease. Fifteen percent to 20% of cases are an embryonic form and thus usually associated with other congenital anomalies such as heterotaxy syndrome and polyspenia. The remaining 80% to 85% of cases are acquired, resulting from an inflammatory process in the intra-and extrahepatic bile ducts that destroys and scars the bile ducts. The etiology for this inflammation is still not fully understood, although it may be an autoimmune response to early viral infection in the infant.²⁵ Without surgical correction, death occurs in the first 1 to 2 years of life from liver failure; even with therapy, timing and surgical expertise are crucial to patient outcome.

Typical presenting symptoms of biliary atresia include prolonged neonatal jaundice and acholic stools; testing for biliary atresia should be considered for any infant with jaundice beyond the first 14 days of life. The physical examination reveals jaundice and possibly malnutrition due to fat malabsorption from inadequate bile secretion into the stools. Laboratory studies reveal an elevated conjugated bilirubin, and liver enzymes are often mildly elevated. The GGT and alkaline phosphatase are also often disproportionately elevated compared to the AST and ALT. Abdominal ultrasonography frequently fails to identify a gallbladder, although the presence of a gallbladder does not rule out biliary atresia. Radioisotope studies with technetium cholescintigraphy (HIDA scan) can be helpful in distinguishing between neonatal hepatitis and biliary atresia as causes of jaundice. Classically, tracer is taken up well by the liver but is not excreted into the bowel in biliary atresia, whereas the opposite is true in neonatal hepatitis and other nonobstructive lesions. Excretion of the tracer makes biliary atresia very unlikely, but other causes of chronic cholestasis, such as cystic fibrosis, Alagille syndrome, and α-1-antitrypsin deficiency, may also have non-excretion of tracer, so an abnormal study by itself is not diagnostic of biliary atresia.^1,3,13,12