Hepatobiliary Disease

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115 Hepatobiliary Disease

Hepatobiliary disease in children is relatively uncommon but accounts for significant morbidity. The liver is the most commonly transplanted solid organ in children. The diagnosis of many liver diseases in children can be difficult given their rarity. Data on the incidence of liver disease and the economic burden associated with liver disease are limited in children. In adults, liver disease is the second most costly digestive disease.

Normal Anatomy and Physiology

The liver arises from endoderm between the third and fourth weeks of gestation. The liver is important in the production of bile, synthesis of coagulation factors, metabolism of proteins and glucose, and biotransformation of drugs and toxins. It consists of four lobes: right, left, caudate, and quadrate. An understanding of the liver’s blood supply is useful when considering the consequences of portal hypertension (Figure 115-1). The portal vein and hepatic artery bring blood to the liver. The portal vein, which receives its supply from the splenic vein and mesenteric veins, carries about 75% of the liver’s blood supply. The hepatic artery receives its blood supply from the celiac axis. Blood exits the liver through the hepatic vein, which empties into the inferior vena cava. Bile exits the liver by way of the intrahepatic bile ducts that lead to the right and left hepatic ducts, which merge to form the common hepatic duct. The common hepatic duct merges with the cystic duct from the gallbladder to form the common bile duct, which allows drainage of bile into the duodenum.

Etiology and Pathogenesis

The most common pediatric liver diseases reflect infectious, metabolic, anatomic, autoimmune, and toxic etiologies. Metabolic liver diseases include Crigler-Najjar syndrome, galactosemia, tyrosinemia, hereditary fructose intolerance, urea cycle defects, bile acid synthetic disorders, and α-1-antitrypsin (AAT) deficiency. Anatomic liver diseases may be congenital (e.g., choledochal cysts, Alagille’s syndrome) or acquired (e.g., cholelithiasis, Budd-Chiari syndrome). Common infections include hepatitis A, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Toxins or medications that frequently injure the liver include acetaminophen, ethanol, chemotherapeutic agents, and total parenteral nutrition (TPN). The most common autoimmune diseases of the liver are autoimmune hepatitis and primary sclerosing cholangitis. Systemic processes, such as hypothyroidism or panhypopituitarism and obesity (and nonalcoholic fatty liver disease [NAFLD]) also may affect the liver.

Two common manifestations of hepatobiliary disease are elevations in liver transaminases and jaundice. Elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) arise from hepatocyte injury. Elevations of γ-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) result from impaired bile flow. Jaundice results from an elevation in conjugated or unconjugated bilirubin. Unconjugated hyperbilirubinemia occurs in about 60% of full-term infants and is most commonly physiologic jaundice partly caused by the immaturity of the bilirubin conjugation process (see Chapter 100). Unconjugated hyperbilirubinemia may also arise from hemolytic anemia (leading to overproduction of bilirubin) or abnormal bilirubin conjugation. Conjugated hyperbilirubinemia is always considered pathologic (see below).

Clinical Presentation

Hepatobiliary diseases can present as acute fulminant liver failure or can be quiescent with an insidious onset. A thorough history can be very helpful in narrowing down the differential diagnosis of liver disease. Knowledge of the time of onset of all symptoms, including jaundice, is helpful. Breast milk jaundice develops after the seventh day of life, in contrast to breastfeeding jaundice, which occurs in the first week of life. Both of these entities present with unconjugated hyperbilirubinemia. Infants who have conjugated hyperbilirubinemia from the first day of life most likely have a pathologic process. The medical provider should ask about medications taken by the child or the mother (in the case of a breastfed infant). Dark urine, abdominal enlargement, easy bruising, epistaxis, and pruritus may be reported in the history of a patient with liver disease. A patient with portal hypertension may present with hematemesis from an esophageal variceal bleed (Figure 115-2). It is important to ask about potential exposures to viral hepatitis and recent travel. Family history is important to address the possibility of hepatitis B or C transmission.

All patients should undergo a thorough physical examination focusing on some key features. Scleral icterus occurs secondary to hyperbilirubinemia (conjugated or unconjugated). Skin jaundice is sometimes difficult to ascertain in dark-skinned children; therefore, careful attention to the sclera is important. Evaluation of the skin may also reveal bruises secondary to coagulopathy in a patient in liver failure or petechiae secondary to thrombocytopenia resulting from portal hypertension and hypersplenism. Heart murmurs can occur secondary to persistent pulmonic stenosis, which occurs in Alagille’s disease. The lung examination may reveal signs of pleural effusions in a patient with liver disease who has significant ascites.

Abdominal inspection may reveal distension secondary to ascites or hepatosplenomegaly or prominent superficial abdominal veins in a patient with portal hypertension. Auscultation of the abdomen may reveal bruits in hepatic arteriovenous malformations. Hepatomegaly can be present, but a cirrhotic liver may actually be small in size. In the case of portal hypertension, the liver may be very firm or enlarged, and splenomegaly may be present. To get an accurate assessment of the size of the liver and spleen, it is important to palpate the abdomen from the pelvis toward the costal margins because hepatomegaly can be missed if palpation of the liver edge begins too high in the abdomen. Right upper quadrant tenderness may occur in cholecystitis, choledocholithiasis, or acute hepatitis.

Differential Diagnosis

The differential diagnosis is vast and can be divided by age (Table 115-1). The provider should always focus on quickly diagnosing diseases requiring urgent treatment. In the Pediatric Acute Liver Failure Registry, the most common diagnosis is indeterminate (49%); additionally, acetaminophen intoxication accounts for 14%, metabolic disease accounts for 10%, autoimmune hepatitis and infectious causes each account for 6%, and non-acetaminophen drug-induced liver disease accounts for 5% of cases. Data from the United Network for Organ Sharing show that the most common diagnoses in children who received a liver transplant from 1995 to 1999 were biliary atresia (BA; 35.6%), viral hepatitis (13%), metabolic liver disease (11.4%), intrahepatic cholestasis (7.9%), TPN (5.4%), and idiopathic cirrhosis (4.8%).

Table 115-1 Differential Diagnosis of Hepatobiliary Disease in Children*

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All Ages Patients (%)
Viral infection: EBV; CMV; hepatitis A, B, and C; herpes simplex virus, echovirus, enterovirus, rubella, parvovirus, adenovirus, toxoplasmosis, syphilis, HIV, varicella 12.0
Bacterial infection: sepsis, UTI, tuberculosis, Listeria, treponema pallidum  
Extrahepatic obstruction: choledochal cyst, bile duct stricture or tumor, cholelithiasis)  
Drugs (valproate, isoniazid, acetaminophen) 1.1
Parenteral nutrition 5.4
CF 1.9
Ischemia secondary to congenital heart disease, asphyxia, cardiac surgery  
Metabolic: AAT deficiency, fatty acid oxidation defect, urea cycle disorders 11.4