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.

Figure 115-1 Normal anatomy of the hepatobiliary system.

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.

Figure 115-2 Esophageal varices as a result of portal hypertension.

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*

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
ECMO
CF	1.9
Ischemia secondary to congenital heart disease, asphyxia, cardiac surgery
Metabolic: AAT deficiency, fatty acid oxidation defect, urea cycle disorders	11.4
Intrahepatic cholestasis: PFIC 1, 2, and 3; Alagille’s syndrome	7.9
Idiopathic	4.8
Neonates and Infants
See All Ages
Biliary atresia	35.6
Endocrine (hypothyroidism, panhypopituitarism)
Metabolic: galactosemia, glycogen storage disease, hereditary fructose intolerance, tyrosinemia
Disorders of lipid metabolism: Wolman’s disease, Niemann-Pick disease, Gaucher’s disease
Bile acid synthesis defects
Idiopathic neonatal hepatitis
Mitochondrial disorders
Neonatal lupus erythematosus
Neonatal hemachromatosis
Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease	2.1
Peroxisomal disorders (Zellweger’s syndrome)
Young Children
See All Ages
Autoimmune hepatitis	2.6
Malignancy	3.5
Older Children and Adolescents
See All Ages and Young Children
Acetaminophen overdose
NAFLD
Primary sclerosing cholangitis (≈68% have IBD)	1.8
Wilson’s disease	1.1
Fatty liver disease of pregnancy

AAT, α-1-antitrypsin; CF, cystic fibrosis; CMV, cytomegalovirus; EBV, Epstein-Barr virus; ECMO, extracorporeal membrane oxygenation; IBD, inflammatory bowel disease; NAFLD, Nonalcoholic fatty liver disease; NANB, non-A, non-B; PFIC, progressive familial intrahepatic cholestasis; UTI, urinary tract infection.

* Percentages of total cases of liver transplant recipients (UNOS 1995–1999) identified as having the listed diagnosis are shown.

Neonates and Infants

Inborn errors of metabolism generally present in the neonatal period, as do congenital TORCH (toxoplasmosis or Toxoplasma gondii, other infections, rubella, CMV, and herpes simplex virus) infections. Urinary tract infections (UTIs) can cause cholestasis with conjugated hyperbilirubinemia. Neonatal hemachromatosis usually presents in the first few days of life with liver failure, cirrhosis, and splenomegaly. Patients with cystic fibrosis (CF) may have neonatal jaundice and benefit from early enzyme replacement therapy and nutritional intervention. Hereditary fructose intolerance can present in the infant after introduction of fruit juices, sucrose, or sorbitol.

BA is specific to neonates because it occurs only in the first several weeks of life. Although it is rare, early diagnosis and treatment are imperative to a good outcome. BA is a progressive, idiopathic, necroinflammatory process involving the biliary tree, which leads to obstruction of bile flow (Figure 115-3). At presentation, most infants are thriving and appear quite well despite being jaundiced. BA is treated surgically with hepatoportoenterostomy (see Figure 115-3). Despite this intervention, BA is still the most common reason for liver transplantation in children. To facilitate early detection of BA, it is very important that the evaluation of jaundiced infants beyond the first few days of life includes a fractionated bilirubin level. Any infant with a conjugated bilirubin greater than 2 mg/dL or more than 20% of the total bilirubin level requires a thorough evaluation (Figure 115-4).

Figure 115-3 Biliary atresia.

Figure 115-4 Evaluation of a newborn with jaundice.

Older Children and Adolescents

Infectious causes are the most common reason for liver disease in children beyond infancy. Autoimmune hepatitis can present as either acute fulminant hepatitis or chronic hepatitis. Cholecystitis and choledocholithiasis should be considered in any child presenting with acute right upper quadrant pain. Patients with hemolytic syndromes are at increased risk for gallstones. Because of the obesity epidemic, an increasing number of children are diagnosed with NAFLD. These patients typically present with mild elevation in their transaminases. Over time, NAFLD can lead to cirrhosis.

Use of various prescribed (isoniazid, valproate, other antiseizure medications) or recreational (cocaine, “Ecstasy”) drugs can lead to acute liver failure. Intentional or nonintentional overdose of acetaminophen is a common cause for acute liver failure in older children and adolescents. Acetaminophen overdose accounts for 21% of all patients 3 years and older who present with acute liver failure (see Chapter 9).

Wilson’s disease should be in the differential diagnosis of acute or chronic hepatitis in children and adolescents. The disease results from impaired biliary copper excretion that leads to progressive accumulation of copper in the liver. Over time, the liver becomes overloaded with copper, and copper begins to accumulate in the nervous system, corneas, and other organs. The presentation is variable; 25% of patients present with acute hepatitis, and a minority of patients present with acute liver failure, requiring liver transplantation. Some patients may first come to medical attention because of neuropsychiatric symptoms, such as fatigue and worsening school performance.

Evaluation

Although the laboratory evaluation of a child with suspected hepatobiliary disease can be quite extensive, there are studies that should be performed at the beginning of every evaluation (Table 115-2). A complete cell count may reveal a low platelet count or a low white blood cell (WBC) count, which may be seen with cirrhosis and hypersplenism. An elevated WBC count may indicate an infectious process. AST and ALT levels are usually elevated in liver disease, but in liver failure, the transaminases may decrease because of near-total hepatocyte loss. In this case, the synthetic function of liver is compromised, and the prothrombin time is prolonged. High GGT and ALP levels are seen with cholestatic processes, with the rare exception of some types of bile acid synthetic disorder or progressive familiar intrahepatic cholestasis. AAT deficiency can present at any age and can have a variable presentation, including neonatal cholestasis, asymptomatic hepatomegaly, or advanced liver disease. A low AAT level can be suggestive of AAT deficiency, but protease inhibitor (PI) typing is necessary to make the diagnosis of AAT deficiency. Abdominal ultrasonography is a noninvasive way to exclude anatomic abnormalities, such a choledochal cyst, choledocholithiasis, tumors, or vascular anomalies. Ultrasound is also useful in assessing hepatosplenomegaly, especially in patients with ascites in whom the physical examination may be difficult. Lack of visualization of the gallbladder may occur in diseases that involve the biliary system, such as BA and Alagille’s syndrome.

Table 115-2 Laboratory Evaluation of Hepatobiliary Disease

AAT, α-1-antitrypsin; ALP, aspartate aminotransferase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete cell count; CF, cystic fibrosis; GGT, γ-glutamyl transpeptidase; LDH, lactate dehydrogenase; PI, protease inhibitor; PT, prothrombin time; PTT, partial thromboplastin time.

Management

Many liver diseases are managed supportively and ultimately require liver transplantation. However, a number of hepatobiliary diseases may respond to specific therapies (Table 115-3).

Table 115-3 Examples of Specific Therapies for Liver Diseases

IFN, interferon; MP, mercaptopurine.

Only a few hepatobiliary diseases are treated with endoscopic intervention or surgically. Endoscopic retrograde cholangiopancreatography can be therapeutic in choledocholithiasis; these patients should undergo cholecystectomy. Patients with acute liver failure should be admitted to an intensive care unit for monitoring of fluids, glucose, electrolytes, coagulation abnormalities, and encephalopathy. N-acetylcysteine has been shown to improve survival in acetaminophen-induced liver injury.

Some of the complications associated with cirrhosis or portal hypertension are gastrointestinal bleeding, ascites, and hypersplenism. An esophageal variceal bleed can occur secondary to portal hypertension (see Figure 115-2). After they are hemodynamically stable, these patients usually undergo endoscopic intervention, such as sclerotherapy or banding. Diuretics are commonly used in the management of ascites. Abdominal paracentesis may be diagnostic (if spontaneous bacterial peritonitis is suspected) and therapeutic. β-Blockers and portosystemic shunts are sometimes used in pediatric patients with portal hypertension.

In the management of patients with cholestasis, the most commonly used choleretic agent is ursodeoxycholic acid. Some patients develop severe pruritus secondary to the accumulation of biliary salts. These patients may benefit from rifampin, phenobarbital, or surgical biliary diversion. The increased metabolic needs of chronic liver disease and malabsorption of fat secondary to cholestasis may lead to poor nutritional status in patients with liver disease. Growth and nutritional status should be monitored carefully. The levels of fat-soluble vitamins should be measured, and vitamins should be supplemented as needed.

Liver transplantation is the ultimate treatment for many hepatobiliary diseases. Children account for about 12% of all liver transplant recipients.

Future Directions

Currently, the outcomes of pediatric liver transplantation are quite good, although further improvements in antirejection therapies are needed. There is currently active research in the use of antifibrotic agents that may be useful in extending the time to transplant in patients with chronic liver disease. N-acetylcysteine is also currently being studied as a treatment in non-acetaminophen acute liver failure.