Chapter 22: Liver & Pancreas

NEONATAL CHOLESTATIC JAUNDICE

Key clinical features of disorders causing prolonged neonatal cholestasis are (1) jaundice with elevated serum conjugated (or direct) bilirubin fraction (> 1.0 mg/dL and > 20% of total bilirubin), (2) variably acholic stools, (3) dark urine, and (4) hepatomegaly.

Neonatal cholestasis (conditions with decreased bile flow) is caused by both intrahepatic and extrahepatic diseases. Specific clinical clues (Table 22–1) distinguish these two major categories of jaundice in 85% of cases. Patients with intrahepatic cholestasis frequently appear ill and are failing to thrive, whereas infants with extrahepatic cholestasis typically do not appear ill, have stools that are usually completely acholic, and have an enlarged, firm liver. Histologic examination of percutaneous liver biopsy specimens increases the accuracy of differentiation to 85%–95% (Table 22–2).

INTRAHEPATIC CHOLESTASIS

General Considerations

Intrahepatic cholestasis is characterized by impaired hepatocyte secretion of bile and patency of the extrahepatic biliary system. A specific cause can be identified in about 60%–80% of cases, the remainder being labeled as idiopathic neonatal hepatitis or transient neonatal cholestasis. Patency of the extrahepatic biliary tract is suggested by pigmented stools and lack of bile duct proliferation and portal tract bile plugs on liver biopsy. Bile duct patency can be confirmed least invasively by hepatobiliary scintigraphy using technetium-99m (^99mTc)-dimethyliminodiacetic acid (diethyl-IDA [DIDA]). Radioactivity in the bowel within 4–24 hours is evidence of bile duct patency, as is finding bilirubin in duodenal aspirates. However, these tests are rarely needed in the clinical setting. Patency can also be determined, when clinically indicated, by cholangiography carried out either intraoperatively, percutaneously by transhepatic cholecystography, or by endoscopic retrograde cholangiopancreatography (ERCP) using a pediatric-size side-viewing endoscope. Magnetic resonance cholangiopancreatography in infants is of limited use and highly dependent on the operator and equipment.

1. Perinatal or Neonatal Hepatitis Resulting From Infection

This diagnosis is considered in infants with jaundice, hepatomegaly, vomiting, lethargy, fever, and petechiae. It is important to identify perinatally acquired viral, bacterial, or protozoal infections (Table 22–3) as they may be treatable. Infection may occur transplacentally, by ascent through the cervix into amniotic fluid, from swallowed contaminated fluids (maternal blood, urine, vaginal secretions) during delivery, from blood transfusions administered in the early neonatal period, or from breast milk or environmental exposure. Infectious agents include herpes simplex virus, varicella virus, picornaviruses (enteroviruses and human parechoviruses), cytomegalovirus (CMV), rubella virus, adenovirus, parvovirus, human herpesvirus type 6 (HHV-6), hepatitis B virus (HBV), human immunodeficiency virus (HIV), Treponema pallidum, and Toxoplasma gondii. Although hepatitis C may be transmitted vertically, it rarely causes neonatal cholestasis. The degree of liver cell injury caused by these agents is variable, ranging from massive hepatic necrosis (herpes simplex, picornavirus) to focal necrosis and mild inflammation (CMV, HBV). Serum bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and bile acids are typically elevated. The infant is jaundiced, may have petechiae or rash, and generally appears ill.

Clinical Findings

A. Symptoms and Signs

Clinical symptoms typically present in the first 2 weeks of life, but may appear as late as age 2–3 months. Poor oral intake, poor sucking reflex, lethargy, hypotonia, and vomiting are frequent. Stools may be normal to pale in color, but are seldom acholic. Dark urine stains the diaper. Firm hepatomegaly may be present and splenomegaly is variably present. Macular, papular, vesicular, or petechial rashes may occur. Unusual presentations include neonatal liver failure, hypoproteinemia, anasarca (nonhemolytic hydrops), and hemorrhagic disease of the newborn.

B. Diagnostic Studies

Neutropenia, thrombocytopenia, and mild hemolysis are common. Mixed hyperbilirubinemia, elevated aminotransferases with near-normal alkaline phosphatase and gamma-glutamyl transpeptidase (GGT), prolongation of clotting studies, mild acidosis, and elevated cord serum IgM suggest congenital infection. Nasopharyngeal washings, urine, stool, serum, and cerebrospinal fluid (CSF) should be cultured for virus and/or tested for pathogen-specific nucleic acid. Specific IgM antibody may be useful, as are long-bone radiographs to determine the presence of “celery stalking” in the metaphyseal regions of the humeri, femurs, and tibias. When indicated, computed tomography (CT) scans can identify intracranial calcifications (especially with CMV and toxoplasmosis). Hepatobiliary scintigraphy shows decreased hepatic clearance of the circulating isotope with intact excretion into the gut. Gallbladder is present on ultrasonography. Careful ophthalmologic examination may be useful for diagnosis of herpes simplex virus, CMV, toxoplasmosis, and rubella.

A percutaneous liver biopsy may be useful in distinguishing infectious cholestasis, but may not identify a specific infectious agent (see Table 22–2). Exceptions are the typical inclusions of CMV in hepatocytes or bile duct epithelial cells, the presence of multinucleated giant cells and intranuclear acidophilic inclusions of herpes simplex or varicella-zoster virus, the presence of adenovirus basophilic intranuclear inclusions, or positive immunohistochemical stains for several viruses. Variable degrees of lobular disarray characterized by focal necrosis, multinucleated giant-cell transformation, and ballooned pale hepatocytes with loss of cord-like arrangement of liver cells are usual. Intrahepatocytic and canalicular cholestasis may be prominent. Portal changes are not striking, but modest neoductular proliferation and mild fibrosis may occur. Viral cultures, immunohistochemical stains, or polymerase chain reaction (PCR) testing of biopsy material may be helpful.

Differential Diagnosis

Great care must be taken to distinguish infectious causes of intrahepatic cholestasis from genetic or metabolic disorders because the clinical presentations are similar and may overlap. Galactosemia, hereditary fructose intolerance, and tyrosinemia must be investigated promptly, because specific therapy is available. These infants may also have concomitant gram-negative bacteremia. α₁-Antitrypsin deficiency, cystic fibrosis, bile acid synthesis defects, progressive familial intrahepatic cholestasis (PFIC), mitochondrial respiratory chain disorders, and neonatal iron storage disease must also be considered. Specific physical features may suggest Alagille syndrome, arthrogryposis/renal dysfunction/cholestasis (ARC) syndrome, or Zellweger syndrome. Idiopathic neonatal hepatitis (transient neonatal cholestasis) can be indistinguishable from infectious causes.

Treatment

Infections with herpes simplex virus, varicella, CMV, parvovirus, and toxoplasmosis have specific treatments (see Table 22–3). Penicillin for suspected syphilis, specific antiviral therapy, or antibiotics for bacterial hepatitis or urinary tract infections need to be administered promptly. Intravenous dextrose is needed if feedings are not well tolerated. The consequences of cholestasis are treated as indicated (Table 22–4). Vitamin K orally or by injection and vitamins D and E orally should be provided. Choleretics (ursodeoxycholic acid [UDCA]) are used if cholestasis persists. Corticosteroids are contraindicated.

Prognosis

Multiple organ involvement portends a poor outcome. Hepatic or cardiac failure, intractable acidosis, or intracranial hemorrhage is associated with fatal outcome in herpesvirus, adenovirus, or enterovirus infections, and occurs occasionally in CMV or rubella infection. HBV rarely causes fulminant neonatal hepatitis; most infected infants are immunotolerant to hepatitis B. The neonatal liver usually recovers without fibrosis after acute infections. Chronic cholestasis, although rare following infections, may lead to dental enamel hypoplasia, failure to thrive, biliary rickets, severe pruritus, and xanthoma.

2. Specific Infectious Agents

A. Neonatal Hepatitis B Virus Disease

Vertical transmission of HBV may occur at any time during perinatal life. Most cases are acquired from mothers who are asymptomatic carriers of HBV. Although HBV has been found in most body fluids, including breast milk, neonatal transmission occurs primarily from exposure to maternal blood at delivery and only occasionally transplacentally (< 5%–10% of cases). In chronic HB surface antigen (HBsAg)–carrier mothers, neonatal acquisition risk is greatest if the mother: (1) is also HB “e” antigen (HBeAg)–positive and HB “e” antibody (HBeAb)–negative, (2) has high serum levels of hepatitis B core antibody (HBcAb), or (3) has high blood levels of HBV DNA (> 10⁷ copies/mL). The infant has a 70%–90% chance of acquiring HBV at birth from an HBsAg/HBeAg-positive mother if the infant does not receive prophylaxis. Most infected infants develop a prolonged asymptomatic immune-tolerant phase of HBV infection. Fulminant hepatic necrosis and liver failure rarely occur in infants. Other patients develop immune active chronic hepatitis with focal hepatocyte necrosis and a mild portal inflammatory response. Chronic hepatitis may persist for years, with serologic evidence of persisting HBeAg and mildly elevated or normal serum aminotransferases. Most infected infants have only mild biochemical evidence, if any, of liver injury and do not appear ill. Most infants remain asymptomatic in an immune-tolerant state of HBV infection; 3%–5% per year develop acute or chronic hepatitis (see section on Hepatitis B).

To prevent perinatal transmission, all infants of mothers who are HBsAg-positive (regardless of HBeAg status) should receive hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine within the first 24 hours after birth and vaccine again at ages 1 and 6 months (see Chapter 10). This prevents HBV infection in 85%–95% of infants. If not given at birth, HBIG can be administered as late as 7 days postpartum as long as the infant has received the vaccine. Universal HBV immunization during infancy is recommended for all infants regardless of maternal HBV status. Universal screening of pregnant women for HBsAg is conducted to determine which infants will also need HBIG. Pregnant women with greater than 200,000 IU/mL of HBV DNA should be considered for third trimester anti-viral therapy to lower HBV levels and reduce risk for vertical transmission.

B. Neonatal Bacterial Hepatitis

Most bacterial liver infections in newborns are acquired by transplacental invasion from amnionitis with ascending spread from maternal vaginal or cervical infection. Onset is abrupt, usually within 48–72 hours after delivery, with signs of sepsis and often shock. Jaundice appears early with direct hyperbilirubinemia. The most common organisms involved are Escherichia coli, Listeria monocytogenes, and group B streptococci. Neonatal liver abscesses caused by E coli or Staphylococcus aureus may result from omphalitis or umbilical vein catheterization. These infections require specific antibiotics in optimal doses and combinations and, rarely, surgical or interventional radiologic drainage. Deaths are common, but survivors show no long-term consequences of liver disease.

C. Neonatal Jaundice With Urinary Tract Infection

Urinary tract infections typically present with cholestasis between the second and fourth weeks of life. Lethargy, fever, poor appetite, jaundice, and hepatomegaly may be present. Except for mixed hyperbilirubinemia, other liver function tests (LFTs) are only mildly abnormal. Leukocytosis is frequently present, and infection is confirmed by urine culture. The liver impairment is caused by the action of endotoxin and cytokines on bile secretion.

Treatment of the infection leads to resolution of the cholestasis without hepatic sequelae. Metabolic liver diseases, such as galactosemia and tyrosinemia, may present with gram-negative bacterial urinary tract infection and must be excluded.

3. Intrahepatic Cholestasis Resulting From Inborn Errors of Metabolism, Familial, & “Toxic” Causes

Cholestasis caused by specific enzyme deficiencies, other genetic disorders, or certain toxins share findings of intrahepatic cholestasis (jaundice, hepatomegaly, and normal to completely acholic stools). Specific clinical conditions have characteristic clinical signs.

A. Inborn Errors of Metabolism

Establishing the specific diagnosis as early as possible is important because dietary or pharmacologic treatment may be available (Table 22–5), and Parents of the affected infant should be offered genetic counseling. For some disorders, prenatal genetic diagnosis is available.

Cholestasis caused by metabolic diseases (eg, galactosemia, hereditary fructose intolerance, and tyrosinemia) is frequently accompanied by vomiting, lethargy, poor feeding, hypoglycemia, or irritability. The infants often appear septic; gram-negative bacteria can be cultured from blood in 25%–50% of symptomatic cases, especially in galactosemia with cholestasis. Neonatal screening programs for galactosemia and tyrosinemia usually detect the disorder before cholestasis develops. Other metabolic and genetic causes of neonatal intrahepatic cholestasis are outlined in Table 22–5. Treatment of these disorders is discussed in Chapter 36.

B. “Toxic” Causes of Neonatal Cholestasis

1. Neonatal ischemic-hypoxic conditions

Perinatal events that result in hypoperfusion or hypoxia of the gastrointestinal system are sometimes followed within 1–2 weeks by cholestasis. This occurs in infants with birth asphyxia, acute cardiac dysfunction, severe hypoxia, hypoglycemia, shock, and acidosis. When these perinatal conditions develop in association with gastrointestinal lesions, such as ruptured omphalocele, gastroschisis, or necrotizing enterocolitis, a subsequent cholestatic picture is common (25%–50% of cases). Mixed hyperbilirubinemia, elevated alkaline phosphatase and γ-glutamyl transpeptidase (GGT) values, and variable elevation of the aminotransferases are common. Stools are seldom persistently acholic.

The mainstays of treatment are choleretics (UDCA), introduction of enteral feedings using special formulas as soon as possible, and nutrient supplementation until the cholestasis resolves (see Table 22–4). As long as no severe intestinal problem or ongoing sepsis is present (eg, short gut syndrome or intestinal failure), resolution of the hepatic abnormalities is the rule, although this may take many weeks.

2. Parenteral nutrition-associated cholestasis (PNAC)

Cholestasis may develop after 1–2 weeks in premature newborns receiving parenteral nutrition, especially those with necrotizing enterocolitis. Even full-term infants with significant intestinal atresia, resections, congenital absorptive deficiencies, or dysmotility (intestinal failure) may develop PNAC, also called Intestinal Failure Associated Cholestasis when it occurs in term infants. Contributing factors include toxicity of intravenous soy lipid emulsions (eg, plant sterols), diminished stimulation of bile flow from prolonged absence of feedings, frequent episodes of bacterial or fungal infection, small intestinal bacterial overgrowth with translocation of intestinal bacteria and their cell wall products, missing nutrients or antioxidants, photooxidation of amino acids, and the “physiologic cholestatic” propensity of the infant. Activation of innate immune pathways in the liver by endotoxin and plant sterols appears to be involved. Histology of the liver may be identical to that of biliary atresia. Early introduction of feedings, surgical/medical therapies to induce intestinal adaptation, and modifications of intravenous lipid emulsions have reduced the frequency/severity of this disorder. The prognosis is generally good; however, in infants with intestinal failure cases may progress to cirrhosis, liver failure, or hepatoma. These infants may require liver and intestinal, or multivisceral transplantation. Oral erythromycin as a pro-motility agent may reduce the incidence of cholestasis in very-low-birth-weight infants. Substituting intravenous fish oil-based lipid emulsions or multiple constituent lipid emulsions, or reducing the amount of soy-oil-based lipid emulsions may reverse PNAC and prevent need for liver transplantation and delay the need for intestinal transplantation.

3. Inspissated bile syndrome

This syndrome is the result of accumulation of bile in canaliculi and in the small- and medium-sized bile ducts in hemolytic disease of the newborn (Rh, ABO) and in some infants receiving parenteral nutrition. The same mechanisms may cause intrinsic obstruction of the common bile duct. An ischemia-reperfusion injury may also contribute to cholestasis in Rh incompatibility. Stools may become acholic and levels of bilirubin, primarily conjugated, may reach 40 mg/dL. If inspissation of bile occurs within the extrahepatic biliary tree, differentiation from biliary atresia may be difficult. Although most cases improve slowly over 2–6 months, persistence of complete cholestasis (acholic stools) for more than 1–2 weeks requires further studies (ultrasonography, liver biopsy) with possible cholangiography. Irrigation of the common bile duct is sometimes necessary to dislodge the obstructing inspissated biliary material.

4. Idiopathic Neonatal Hepatitis (Transient Neonatal Cholestasis)

This idiopathic type of cholestatic jaundice, which has a typical liver biopsy appearance, accounts for up to 20%–30% of cases of neonatal intrahepatic cholestasis, but is decreasing in frequency as new genetic causes of cholestasis are discovered. The degree of cholestasis is variable, and the disorder may be indistinguishable from extrahepatic causes in 10% of cases. Viral infections, α₁-antitrypsin deficiency, Alagille syndrome, Niemann-Pick type C disease (NPC), PFIC disorders, citrin deficiency, neonatal hemochromatosis, mitochondrial disorders, and bile acid synthesis defects may present with similar clinical and histologic features and should be excluded. In idiopathic neonatal hepatitis, PFIC types I and II and ARC syndrome, and disease due to bile acid synthesis defects, the GGT levels are normal or low. Electron microscopy of the liver biopsy and genotyping will help distinguish NPC and PFIC. It is likely that a heterozygous state or mild missense mutations for known or yet to be discovered causative genes are responsible for the vast majority of idiopathic cases.

Intrauterine growth retardation, prematurity, poor feeding, emesis, poor growth, and partially or intermittently acholic stools are characteristic. Serious hemorrhage from vitamin K deficiency may also be present. Patients with neonatal lupus erythematosus may present with giant-cell hepatitis; however, thrombocytopenia, rash, or congenital heart block is usually also present.

In cases of suspected idiopathic neonatal hepatitis (diagnosed in the absence of infectious, known genetic, metabolic, and toxic causes), patency of the biliary tree may need to be verified to exclude extrahepatic disorders. HIDA scanning and ultrasonography may be helpful in this regard if stools are acholic. Liver biopsy findings are usually diagnostic after age 6–8 weeks (see Table 22–2), but may be misleading before age 6 weeks as there is overlap with biliary atresia histology. Failure to detect patency of the biliary tree, nondiagnostic liver biopsy findings, or persisting complete cholestasis (acholic stools) are indications for intraoperative cholangiography performed by an experienced surgeon, ERCP, or percutaneous cholecystography. Occasionally, a small but patent (hypoplastic) extrahepatic biliary tree is demonstrated (as in Alagille syndrome). It is probably the result, rather than the cause, of diminished bile flow, so surgical reconstruction of hypoplastic biliary trees in Alagille syndrome should not be attempted.

Therapy should include choleretics, a special formula with medium-chain triglycerides (eg, Pregestimil, Alimentum) or breast milk (if growth is adequate), and supplemental fat-soluble vitamins in water-soluble form (see Table 22–4). This therapy is continued as long as significant cholestasis remains (conjugated bilirubin > 1 mg/dL). Fat-soluble vitamin serum levels and INR should be monitored at regular intervals while supplements are given and repeated at least once after their discontinuation.

Around 80% of patients recover without significant hepatic fibrosis. However, failure to resolve the cholestatic picture by age 6–12 months is associated with progressive liver disease and evolving cirrhosis, most likely caused by known or yet to be defined underlying genetic/metabolic disorder. Liver transplantation has been successful when signs of hepatic decompensation are noted (rising bilirubin, coagulopathy, intractable ascites).

5. Paucity of Interlobular Bile Ducts

Forms of intrahepatic cholestasis caused by decreased numbers of interlobular bile ducts (< 0.5 bile ducts per portal tract) may be classified according to whether they are associated with other malformations. Alagille syndrome (syndromic paucity or arteriohepatic dysplasia) is caused by mutations in the gene JAGGED1, located on chromosome 20p, which codes for a ligand of the notch receptor, or more rarely in the gene NOTCH2. Alagille syndrome is recognized by the characteristic facies, which becomes more obvious with age. The forehead is prominent with deep-set eyes and sometimes hypertelorism. The chin is small and slightly pointed and ears are prominent. The stool color varies with the severity of cholestasis. Pruritus begins by age 6 months. Firm, smooth hepatomegaly may be present or the liver may be of normal size. Cardiac murmurs are present in 90% of patients, and butterfly vertebrae (incomplete fusion of the vertebral body or anterior arch) are present in 50%. Xanthomas develop as hypercholesterolemia becomes a problem.

Conjugated hyperbilirubinemia may be mild to severe (2–15 mg/dL). Serum alkaline phosphatase, GGT, and cholesterol may be markedly elevated, especially early in life. Serum bile acids are always elevated, aminotransferases are mildly increased, but clotting factors and other liver proteins are usually normal.

Cardiac involvement includes peripheral pulmonary artery, branch pulmonary artery, or pulmonary valvular stenoses, atrial septal defect, coarctation of the aorta, and tetralogy of Fallot. Up to 10%–15% of patients have intracranial vascular or cystic abnormalities or may develop intracranial hemorrhage or stroke early in childhood.

Eye findings (posterior embryotoxon or a prominent Schwalbe line in 90%) are common and renal abnormalities (dysplastic kidneys, renal tubular ectasia, single kidney, renal tubular acidosis, hematuria) may occur in 40% of patients. Growth retardation with normal to increased levels of growth hormone (growth hormone resistance) is common. Although variable, the intelligence quotient is frequently low. Hypogonadism with micropenis may be present. A weak, high-pitched voice may develop. Neurologic disorders resulting from vitamin E deficiency (areflexia, ataxia, ophthalmoplegia), which eventually develop in many unsupplemented children, may be profound.

In the nonsyndromic form, paucity of interlobular bile ducts occurs associated with α₁-antitrypsin deficiency, Zellweger syndrome, in association with lymphedema (Aagenaes syndrome), PFIC, cystic fibrosis, CMV or rubella infection, and inborn errors of bile acid metabolism.

High doses (250 mg/kg/day) of cholestyramine may control pruritus, lower cholesterol, and clear xanthomas. UDCA (15–20 mg/kg/day) appears to be more effective and causes fewer side effects than cholestyramine. Rifampicin may also reduce pruritus. Naltrexone (1 mg/kg/day) is occasionally required. Partial external or internal biliary diversion or ileal exclusion surgery may reduce pruritus in about half of severe cases as long as significant hepatic fibrosis is absent. Nutritional therapy to prevent wasting and deficiencies of fat-soluble vitamins is of particular importance because of the severity of cholestasis (see Table 22–4).

Prognosis is more favorable in the syndromic than in the nonsyndromic varieties. In the former, only 40%–50% of patients have significant complications of disease, whereas over 70% of patients with nonsyndromic varieties progress to cirrhosis. Many of this latter group likely have forms of PFIC that are yet to be categorized genetically. In Alagille syndrome, cholestasis may improve by age 2–4 years, with minimal residual hepatic fibrosis. Survival into adulthood despite raised serum bile acids, aminotransferases, and alkaline phosphatase occurs in about 50% of cases, however progressive portal hypertension may ensue. Several patients have developed hepatocellular carcinoma. Hypogonadism has been noted; however, fertility is not often affected. Cardiovascular anomalies and intracranial vascular lesions may shorten life expectancy. Some patients have persistent, severe cholestasis, rendering their quality of life poor. Recurrent bone fractures may result from metabolic bone disease. Liver transplantation has been successfully performed under these circumstances. Intracranial hemorrhage, moyamoya disease, or stroke may occur in up to 10%–12% of affected children. Blockers of the ileal bile acid transporter have shown promise as agents to reduce pruritus.

6. Progressive Familial Intrahepatic Cholestasis (Byler Disease & Byler Syndrome)

PFIC is a group of disorders presenting as pruritus, diarrhea, jaundice, fat-soluble vitamin deficiencies, and failure to thrive in the first 6–12 months of life. PFIC type I (Byler disease), caused by biallelic mutations in ATP8B1 coding FIC1, an aminophospholipid transporting ATPase is associated with low to normal serum levels of GGT and cholesterol and elevated levels of bilirubin, aminotransferases, and bile acids. Pancreatitis and hearing loss may develop. Liver biopsy demonstrates cellular cholestasis, sometimes with a paucity of interlobular bile ducts and centrilobular fibrosis that progresses to cirrhosis. Giant cells are absent. Electron microscopy shows characteristic granular “Byler bile” in canaliculi. Treatment includes administration of UDCA, partial biliary diversion or ileal exclusion if the condition is unresponsive to UDCA, and liver transplantation if unresponsive to these therapies. Ileal bile acid transporter blockers show promise as therapy in a subset of patients. With partial biliary diversion or ileal exclusion surgery, many patients show improved growth and liver histology, reduction in symptoms, and, thus, avoid liver transplantation. Following liver transplantation, chronic diarrhea and fatty liver may complicate recovery.

PFIC type II is caused by biallelic mutations in ABCB11 coding the bile salt export pump (BSEP), the adenosine triphosphate–dependent canalicular bile salt transport protein. These patients are clinically and biochemically similar to PFIC type I patients, but liver histology includes numerous multinucleated “giant cells” and they have higher elevations of AST and ALT. There is an increased incidence of hepatocellular carcinoma in patients with severe ABCB11 mutations. Treatment is similar to PFIC type I although close monitoring for hepatocellular carcinoma is essential. Ileal bile acid transporter blockers show promise as therapy in a subset of patients. Following liver transplantation, recurrent disease has been described in patients who developed autoantibody-mediated BSEP dysfunction.

PFIC type III is caused by mutations in ABCB4 coding the multiple drug resistance protein type 3 (MDR3), a canalicular protein that pumps phospholipid into bile. Serum GGT and bile acid levels are both elevated, bile duct proliferation and portal tract fibrosis are seen in liver biopsies (resembling biliary atresia), and bile phospholipid levels are low. Treatment is similar to that for other forms of PFIC except that partial biliary diversion is not recommended and liver transplantation is inevitable.

PFIC type 4 is a low GGT form of neonatal cholestasis caused by mutations in tight junction protein 2 (TJP2) with rapid progression to cirrhosis and need for liver transplantation in early childhood. PFIC type 5 (FXR deficiency) and type 6 (MYO5B deficiency) have recently been described and resemble clinically the other PFICs. About one-third of PFIC patients have negative genotyping for the above genes and likely have yet-to-be discovered genetic etiologies.

Bile acid synthesis defects are clinically similar to PFIC types I and II, with low serum levels of GGT and cholesterol; however, the serum level of total bile acids is inappropriately normal or low, pruritus is generally absent, and urine bile acid analysis may identify a synthesis defect. Milder defects cause fat-soluble vitamin deficiency without severe liver disease. Treatment of most bile acid synthesis defects is with oral cholic acid and for conjugation defects with oral glycocholic acid.

EXTRAHEPATIC NEONATAL CHOLESTASIS

Extrahepatic neonatal cholestasis is characterized by complete and persistent cholestasis (acholic stools) in the first 3 months of life; lack of patency of the extrahepatic biliary tree demonstrated by intraoperative, percutaneous, or endoscopic cholangiography; firm to hard hepatomegaly; and typical features on histologic examination of liver biopsy tissue (see Table 22–2). Causes include biliary atresia, choledochal cyst, spontaneous perforation of the extrahepatic ducts, neonatal sclerosing cholangitis, and intrinsic or extrinsic obstruction of the common duct.

1. Biliary Atresia

General Considerations

Biliary atresia (BA) is a progressive fibroinflammatory obliteration of the lumen of all, or part of, the extrahepatic biliary tree presenting within the first 3 months of life. BA occurs in 1:6,600 (Taiwan)–1:18,000 (Europe) births, and in the United States the incidence is approximately 1:12,000. The incidence is highest in Asians, African Americans, and preterm infants, and there is a slight female predominance. There are four types of BA: isolated BA (84% of cases), BA with at least one malformation but without laterality defects (6%; CV, GI, or GU defects), BA splenic malformation (BASM) syndrome associated with laterality defects and polysplenia or asplenia (4%–10%), and cystic BA which includes a hilar choledochal cyst. The etiology of BA is likely multifactorial, encompassing an initial viral, toxin or environmental injury to the bile duct epithelium, leading to inflammatory and autoimmune responses targeting the bile ducts in the genetically predisposed individual, and culminating in aggressive fibrosis of the biliary system.

Clinical Findings

A. Symptoms and Signs

All infants with BA will have jaundice that may be noted in the newborn period or by age 2–3 weeks. Therefore, all jaundiced infants ≥ 2 weeks of age should have conjugated bilirubin measured to identify cholestasis. Stools are pale yellow, gray, or acholic. Firm hepatomegaly is common at diagnosis and infants are at risk for failure to thrive due to fat malabsorption. Symptoms of portal hypertension (splenomegaly, ascites, variceal bleeding) may develop in the first year of life. Pruritus, digital clubbing, bone fractures, and variceal bleeding complications may occur later in childhood.

B. Laboratory Findings and Imaging

No single laboratory test will consistently differentiate BA from other causes of complete obstructive jaundice. Although BA is suggested by persistent elevation of serum GGT in addition to conjugated/direct bilirubin, these findings have also been reported in severe neonatal hepatitis, α₁-antitrypsin deficiency, cystic fibrosis, MDR3 deficiency, neonatal sclerosing cholangitis, and bile duct paucity. Furthermore, these tests will not differentiate the location of the obstruction within the extrahepatic system. Generally, the aminotransferases are only moderately elevated in BA and serum albumin and blood clotting factors are normal early in the disease. Ultrasonography of the biliary system should be performed to exclude the presence of choledochal cyst and identify intra-abdominal anomalies associated with BA. In the majority of cases of BA, the gallbladder is not visualized or is small; however, the presence of a normal gallbladder on ultrasound does not exclude BA.

Differential Diagnosis

The major diagnostic dilemma is distinguishing between this entity and bile duct paucity, genetic and metabolic liver diseases (particularly α₁-antitrypsin deficiency and PFIC), choledochal cyst, neonatal sclerosing cholangitis, or intrinsic bile duct obstruction (inspissated bile syndrome). Although spontaneous perforation of extrahepatic bile ducts leads to jaundice and acholic stools, the infants in such cases are usually quite ill with chemical peritonitis from biliary ascites.

The diagnosis of BA is suggested based on histologic findings of obstruction (bile duct plugs, bile duct proliferation, portal fibrosis). Once the diagnosis of α-1 antitrypsin deficiency and Alagille syndrome are excluded, a cholangiogram (intraoperative [IOC], endoscopic or transcholycystographic) to confirm the diagnosis of BA should be performed as soon as possible. Radiographic visualization of cholangiographic contrast in the duodenum excludes obstruction to the distal extrahepatic ducts. In the majority of cases of BA, the entire extrahepatic biliary system including the gall bladder is obstructed and no cholangiographic contrast will be visible within the biliary tree.

Treatment

In the absence of surgical correction or transplantation, biliary cirrhosis, hepatic failure, and death occur uniformly by age 18–24 months. The standard procedure at the time of IOC diagnosis of BA is the hepatoportoenterostomy (Kasai procedure) to achieve drainage of bile from liver to intestine. The Kasai procedure is best done in specialized centers where experienced surgical, pediatric, and nursing personnel are available. For best results, surgery should be performed as early as possible (ideally before 30–45 days of life); the Kasai procedure should generally not be undertaken in infants older than age 4 months because the likelihood of bile drainage at this age is very low. Orthotopic liver transplantation is indicated for patients who do not undergo the Kasai procedure, who fail to drain bile after the Kasai procedure, or who progress to end-stage biliary cirrhosis despite surgical treatment. Timing of liver transplant evaluation and care prior to transplant has recently been reviewed.

Supportive medical treatment consists of vitamin and caloric support (vitamins A, D, E, and K supplements and formulas containing high amounts of medium-chain triglycerides [Pregestimil or Alimentum]) (see Table 22–4). Nasogastric tube feedings or parenteral nutrition may be required in patients failing oral caloric supplementation. Monitoring of serum fat-soluble vitamin levels is essential to ensure adequate supplementation. UDCA as a choloretic agent is routinely given post-Kasai and continued up to 3 years of age. UDCA should not be used in the setting of a “failed Kasai” whereby bile flow is not established, as UDCA in this setting is potentially hepatotoxic. Suspected ascending cholangitis (based on fever, jaundice, acholic stools, abdominal pain, leukocytosis, elevated bilirubin and liver enzymes) should be treated promptly with antibiotics that treat gram-negative bacterial infections. Antibiotic prophylaxis may reduce the recurrence rate of cholangitis. Ascites can be managed initially with spironolactone; furosemide is added in severe or unresponsive cases. There is no therapy that prevents the progression of biliary disease and portal fibrosis that occurs in the majority of patients post-Kasai, including the use of corticosteroids.

Prognosis

In general, outcomes of post-Kasai include failure to reestablish bile flow in one-third and improvement in bile flow in up to two-thirds of patients. Approximately 50% of BA patients will require liver transplantation in the first 2 years of life, some despite achieving good bile drainage. The best predictor of the need for liver transplant in the first 2 years is the total serum bilirubin value at 3 months post-Kasai: if the total bilirubin is less than 2 mg/dL, then it is unlikely that child will need transplant in the first 2 years; if the bilirubin is greater than 6 mg/dL, then a liver transplant will likely be necessary in the first 2 years. Even in the setting of reestablished bile flow following Kasai surgery, the majority of patients will progress to biliary cirrhosis and need a liver transplantation at some point in childhood (~ 80% of all BA patients). Death is usually caused by liver failure, sepsis, intractable variceal bleeding, or respiratory failure secondary to intractable ascites. Esophageal variceal hemorrhage develops in 40% of patients, yet terminal hemorrhage is unusual. Occasional long-term survivors develop hepatopulmonary syndrome (intrapulmonary right to left shunting of blood resulting in hypoxia) or portopulmonary hypertension (pulmonary arterial hypertension in patients with portal hypertension). Liver transplantation is indicated for all of the above-noted complications and long-term survival post-transplant is ~ 80%–90%.

2. Choledochal Cyst

Clinical Features

A. Symptoms and Signs

Choledochal cysts (CDC) are cystic lesions of all or part of the extrahepatic biliary system, which in rare cases can include the intrahepatic bile duct branches. Abdominal ultrasound imaging will detect all cases of CDC. In most cases presenting in infancy, the clinical manifestations and basic laboratory findings are indistinguishable from those associated with biliary atresia. Furthermore, a rare form of biliary atresia, termed “cystic biliary atresia” can mimic a CDC in the neonatal period. Clues to the diagnosis of CDC (versus cystic biliary atresia) include the presence of intrahepatic biliary dilation and a normal or distended gallbladder. In older children, CDC presents as recurrent episodes of right upper quadrant abdominal pain, fevers, vomiting, obstructive jaundice, pancreatitis, or as a right abdominal mass. Infants and children with CDC are at increased risk for developing bacterial cholangitis. CDC represent only 2%–5% of cases of extrahepatic neonatal cholestasis; the incidence is higher in girls and patients of Asian descent.

B. Diagnosis and Treatment

Diagnosis

Ultrasonography is used to screen for CDC and an MRCP will confirm the diagnosis and the extent of the cystic lesion.

Treatment

Timely surgery is indicated once abnormalities in clotting factors have been corrected and bacterial cholangitis, if present, has been treated with intravenous antibiotics. Excision of the cyst and its mucosa and choledocho–Roux-en-Y jejunal anastomosis are recommended. Anastomosis of cyst to jejunum or duodenum is not recommended due to the continued risks of cholangitis and bile duct carcinoma (cholangiocarcinoma).

Prognosis

If an isolated extrahepatic cyst is encountered, the outcome is generally excellent, with resolution of the jaundice and return to normal liver architecture after cyst excision. However, bouts of ascending cholangitis may occur, particularly if intrahepatic cysts are present or stricture of the anastomotic site develops. The risk of cholangiocarcinoma developing within the cyst is about 5%–15% in adulthood.

3. Spontaneous Perforation of the Extrahepatic Bile Ducts

The sudden appearance of obstructive jaundice, acholic stools, and abdominal enlargement with ascites in a sick newborn is suggestive of this condition. The liver is usually normal in size, and a yellow-green discoloration can often be discerned under the umbilicus or in the scrotum. In 24% of cases, stones or sludge obstructs the common bile duct. HIDA scan or ERCP shows leakage from the biliary tree, and ultrasonography confirms ascites or fluid around the bile duct.

Treatment is surgical. Simple drainage, without attempts at oversewing the perforation, is sufficient in primary perforations. A diversion anastomosis is constructed in cases associated with choledochal cyst or stenosis. The prognosis is generally good.

OTHER NEONATAL HYPERBILIRUBINEMIC CONDITIONS (NONCHOLESTATIC NONHEMOLYTIC)

Two other groups of disorders are associated with hyperbilirubinemia: (1) unconjugated hyperbilirubinemia is characteristic of breast-feeding and breast milk jaundice, congenital hypothyroidism, red blood cell hemolysis, upper intestinal obstruction, Gilbert disease, Crigler-Najjar syndrome, and drug-induced hyperbilirubinemia; and (2) conjugated noncholestatic hyperbilirubinemia is characteristic of the Dubin-Johnson syndrome and Rotor syndrome.

1. Unconjugated Hyperbilirubinemia

A. Breast Milk Jaundice

Jaundice at 2 weeks of age is relatively common affecting up to 15% of newborns. Enhanced β-glucuronidase activity in breast milk is one factor that increases absorption of unconjugated bilirubin. Substances (eg, L-aspartic acid) in casein hydrolysate formulas inhibit this enzyme. The increased enterohepatic shunting of unconjugated bilirubin exceeds the normal conjugating capacity in the liver of these infants. The mutation for Gilbert syndrome (UDP-glucuronyltransferase 1A1 [UGT1A1]) predisposes to breast milk jaundice and to more prolonged jaundice. Neonates who carry the 211 and 388 variants in the UGT1A1 and OATP 2 genes, respectively, or the UGT1A1*6 allele and feed with breast milk, are at high risk to develop severe hyperbilirubinemia. Low volumes of ingested breast milk may also contribute to jaundice in the first week of life. Finally, breast milk may suppress UGT1A1 expression in the infant’s intestines which may also lead to unconjugated hyperbilirubinemia.

Hyperbilirubinemia does not usually exceed 20 mg/dL, with most cases in the range of 10–15 mg/dL. Jaundice is noticeable by the fifth to seventh day of breast-feeding. It may accentuate the underlying physiologic jaundice—especially early, when total fluid intake may be less than optimal. Except for jaundice, the physical examination is normal; urine does not stain the diaper, and the stools are golden yellow.

The jaundice peaks before the third week of life and clears before age 3 months in almost all infants, even when breast-feeding is continued. All infants who remain jaundiced past age 2–3 weeks should have measurement of conjugated bilirubin to exclude cholestasis and hepatobiliary disease.

Kernicterus has rarely been reported in association with this condition. In special situations, breast-feeding may be discontinued temporarily and replaced by formula feedings for 2–3 days until serum bilirubin decreases by 2–8 mg/dL. Cow’s milk formulas inhibit the intestinal reabsorption of unconjugated bilirubin. When breast-feeding is reinstituted, the serum bilirubin may increase slightly, but not to the previous level. Phototherapy is not indicated in the healthy full-term infant with this condition unless bilirubin levels meet high-risk levels as defined by the American Academy of Pediatrics.

B. Congenital Hypothyroidism

Although the differential diagnosis of indirect hyperbilirubinemia should always include congenital hypothyroidism, the diagnosis is usually identified by the newborn screening results or by clinical and physical clues. The jaundice clears quickly with replacement thyroid hormone therapy, although the mechanism is unclear. Hypopituitarism can also present with neonatal cholestasis and can be associated with septo-optic dysplasia, a congenital malformation syndrome featuring underdevelopment of the optic nerve, pituitary gland dysfunction, and absence of the septum pellucidum.

C. Upper Intestinal Obstruction

The association of indirect hyperbilirubinemia with high intestinal obstruction (eg, duodenal atresia, annular pancreas, pyloric stenosis) in the newborn has been observed repeatedly; the mechanism is unknown. Diminished levels of hepatic glucuronyl transferase are found on liver biopsy in pyloric stenosis, and genetic studies suggest that this indirect hyperbilirubinemia may be an early sign of Gilbert syndrome. Treatment is that of the underlying obstructive condition (usually surgical). Jaundice disappears once adequate nutrition is achieved.

D. Gilbert Syndrome

Gilbert syndrome is a common form of familial hyperbilirubinemia present in 3%–7% of the population. It is associated with a partial reduction of hepatic bilirubin uridine diphosphate-glucuronyl transferase activity. Affected infants may have more rapid increase in jaundice in the newborn period, accentuated breast milk jaundice, and jaundice with intestinal obstruction. During puberty and beyond, mild fluctuating jaundice, especially with illness and vague constitutional symptoms, is common. Shortened red blood cell survival in some patients is thought to be caused by reduced activity of enzymes involved in heme biosynthesis (protoporphyrinogen oxidase). Reduction of hyperbilirubinemia has been achieved in patients by administration of phenobarbital (5–8 mg/kg/day), although this therapy is not needed.

The disease is inherited as an abnormality of the promoter region of uridine diphosphate-glucuronyl transferase-1 (UDGT1) coded by UGT1A1; however, another factor appears to be necessary for disease expression. The homozygous (16%) and heterozygous states (40%) are common. Males are affected more often than females (4:1) for reasons that are not clear. Serum unconjugated bilirubin is generally less than 3–6 mg/dL, although unusual cases may exceed 8 mg/dL. The findings on liver biopsy and most LFTs are normal. An increase of 1.4 mg/dL or more in the level of unconjugated bilirubin after a 2-day fast (300 kcal/day) is consistent with the diagnosis of Gilbert syndrome. Gilbert syndrome, conferred by the donor liver, can occur following liver transplantation. Genetic testing is available but rarely needed. No treatment is necessary.

E. Crigler-Najjar Syndrome

Infants with type 1 Crigler-Najjar syndrome usually develop rapid severe unconjugated hyperbilirubinemia (> 30–40 mg/dL) with neurologic consequences (kernicterus). The deficiency in UGT1A1 is inherited in an autosomal recessive pattern. Consanguinity is often present. Genetic testing of UGT1A1 is definitive. Prompt recognition of this entity and treatment with exchange transfusions are required, followed by phototherapy. Phenobarbital administration does not significantly alter these findings, nor does it lower serum bilirubin levels. A combination of aggressive phototherapy and cholestyramine may keep bilirubin levels below 25 mg/dL. Orlistat therapy may decrease bilirubin in a subset of patients. Liver transplantation is curative and may prevent kernicterus if performed early. Auxiliary orthotopic transplantation also relieves the jaundice while the patient retains native liver. Hepatocyte transplantation through the portal vein has been tried in the past but is hampered by the requirement of multiple infusions of cells over time. Clinical trials using an adeno-associated virus vector to mediate gene therapy or using mesenchymal stem cells are underway.

A milder form (type 2) with both autosomal dominant and recessive inheritance is rarely associated with neurologic complications. Hyperbilirubinemia is less severe, and the bile is pigmented and contains small amounts of bilirubin monoglucuronide and diglucuronide. Patients with this form respond to phenobarbital (4 mg/kg/day in infants) with lowering of serum bilirubin levels. An increased proportion of monoconjugated and diconjugated bilirubin in the bile follows phenobarbital treatment. Liver biopsy findings and LFTs are consistently normal in both types.

F. Drug-Induced Hyperbilirubinemia

Vitamin K₃ (menadiol) may elevate indirect bilirubin levels by causing hemolysis. Vitamin K₁ (phytonadione) can be used safely in neonates. Carbamazepine can cause conjugated hyperbilirubinemia in infancy. Rifampin and antiretroviral protease inhibitors (atazanavir) may cause unconjugated hyperbilirubinemia. Pancuronium bromide and chloral hydrate have been implicated in causing neonatal jaundice. Other drugs (eg, ceftriaxone, sulfonamides) may displace bilirubin from albumin, potentially increasing the risk of kernicterus—especially in the sick premature infant.

2. Conjugated Noncholestatic Hyperbilirubinemia (Dubin-Johnson Syndrome & Rotor Syndrome)

These diagnoses are suspected when persistent or recurrent conjugated hyperbilirubinemia and jaundice occur and LFTs are normal. The basic defect in Dubin-Johnson syndrome is in the multiple organic anion transport protein 2 (MRP2) of the bile canaliculus, causing impaired hepatocyte excretion of conjugated bilirubin into bile. A variable degree of impairment in uptake and conjugation complicates the clinical picture. Transmission is autosomal recessive, so a positive family history is occasionally obtained. In Rotor syndrome, the defect lies in hepatic uptake and storage of bilirubin. OATP1B1 (coded by SLCO1B1) and OATP1B3 (SLCO1B3) are the two transporters that are deficient. Bile acids are metabolized normally, so that cholestasis does not occur. Bilirubin values range from 2 to 5 mg/dL, and other LFTs are normal.

In Rotor syndrome, the liver is normal; in Dubin-Johnson syndrome, it is darkly pigmented on gross inspection and may be enlarged. Microscopic examination reveals numerous dark-brown pigment granules consisting of polymers of epinephrine metabolites, especially in the centrilobular regions. However, the amount of pigment varies within families, and some jaundiced family members may have no demonstrable pigmentation in the liver. Otherwise, the liver is histologically normal. Oral cholecystography fails to visualize the gallbladder in Dubin-Johnson syndrome, but is normal in Rotor syndrome. Differences in the excretion patterns of bromosulfophthalein, in results of HIDA cholescintigraphy, in urinary coproporphyrin I and III levels, and in the serum pattern of monoglucuronide and diglucuronide conjugates of bilirubin can help distinguish between these two conditions. Clinical genotyping of MRP2, SLCO1B1, and SLCO1B3 is available. No treatment is needed for either condition. Choleretic agents (eg, UDCA) may help reduce the cholestasis in infants with Dubin-Johnson syndrome.

HEPATITIS A

Pathogenesis

Hepatitis A virus (HAV) infection occurs in both epidemic and sporadic fashion and is transmitted by the fecal-oral route (Table 22–6). HAV viral particles are found in stool during the acute phase of hepatitis A infection. Epidemic outbreaks are caused by contaminated food or water supplies, including by food handlers, while sporadic cases usually result from contact with an infected individual. Transmission through blood products obtained during the viremic phase is a rare event, although it has occurred in a newborn nursery.

Prevention

Isolation of an infected patient during initial phases of illness is indicated, although most patients with hepatitis A are noninfectious by the time the disease becomes overt. Stool, diapers, and other fecally stained clothing should be handled with care for 1 week after the appearance of jaundice.

Passive-active immunization of exposed susceptible persons younger than 12 months or older than 40 years: anyone who is immunocompromised or who has chronic liver disease is recommended with immune globulin, 0.02 mL/kg intramuscularly. Illness is prevented in more than 85% of individuals if immune globulin is given within 2 weeks of exposure. For individuals 12 months to 40 years old, HAV vaccine is recommended following exposure. Infants younger than 12 months traveling to endemic disease areas should receive HAV vaccine or 0.02 or 0.06 mL/kg (for trip > 3 months) of immune globulin as prophylaxis. Older individuals should receive the HAV vaccine. All children older than 12 months with chronic liver disease should receive two doses of HAV vaccine 6 months apart. It is also currently recommended that all children 12–18 months of age receive two doses of HAV vaccine in the United States. If an emigrant child from an endemic area is adopted, the immediate family members should be immunized. Lifelong immunity to HAV follows infection.

Antibody to HAV appears within 1–4 weeks of clinical symptoms. Although the great majority of children with infectious hepatitis are asymptomatic or have mild disease and recover completely, some will develop fulminant hepatitis leading to death or requiring liver transplantation.

Clinical Findings

A. History

Historical risk factors may include direct exposure to a previously jaundiced individual or recently arrived individual from a high-prevalence country, consumption of seafood, contaminated water or imported fruits or vegetables, attendance in a day care center, or recent travel to an area of endemic infection. Following an incubation period of 15–40 days, nonspecific symptoms usually precede the development of jaundice by 5–10 days. In developing countries, hepatitis A is common and most children are exposed to HAV by age 10 years, while only 20% are exposed by age 20 years in developed countries.

B. Symptoms and Signs

The overt form of the disease is easily recognized by the clinical manifestations. However, two-thirds of children are asymptomatic, and two-thirds of symptomatic children are anicteric. Therefore, the presenting symptoms in children with HAV often resemble gastroenteritis. Fever, anorexia, vomiting, headache, and abdominal pain are typical and dark urine precedes jaundice, which peaks in 1–2 weeks and then begins to subside. The stools may become light- or clay-colored. Clinical improvement can occur as jaundice develops. Tender hepatomegaly and jaundice are typically present in symptomatic children; splenomegaly is variable.

C. Laboratory Findings

Serum aminotransferases and conjugated and unconjugated bilirubin levels are elevated. Although unusual, hypoalbuminemia, hypoglycemia, and marked prolongation of PT (international normalized ratio [INR] > 2.0) are serious prognostic findings. Diagnosis is made by a positive anti-HAV IgM, whereas anti-HAV IgG persists after recovery.

Percutaneous liver biopsy is rarely indicated. “Balloon cells” and acidophilic bodies are characteristic histologic findings. Liver cell necrosis may be diffuse or focal, with accompanying infiltration of inflammatory cells containing polymorphonuclear leukocytes, lymphocytes, macrophages, and plasma cells, particularly in portal areas. Some bile duct proliferation may be seen in the perilobular portal areas alongside areas of bile stasis. Regenerative liver cells and proliferation of reticuloendothelial cells are present. Occasionally, massive hepatocyte necrosis portends a poor prognosis.

Differential Diagnosis

Before jaundice appears, the symptoms are those of nonspecific viral enteritis. Other diseases with somewhat similar onset include pancreatitis, infectious mononucleosis, leptospirosis, drug-induced hepatitis, Wilson disease, autoimmune hepatitis (AIH), and infection with other hepatitis viruses. Acquired CMV disease may also mimic HAV, although lymphadenopathy is usually present in the former.

Treatment

No specific treatment measures are required although bed rest is reasonable for the child who appears ill. Sedatives and corticosteroids should be avoided. During the icteric phase, lower-fat foods may diminish gastrointestinal symptoms but do not affect overall outcome. Drugs and elective surgery should be avoided. Hospitalization is recommended for children with coagulopathy, encephalopathy, or severe vomiting. Hospitalization rates for hepatitis A have decreased over the last decade, with those who require hospitalization being older adults or those with concurrent other liver disease and/or comorbid conditions.

Prognosis

Around 99% of children recover without sequelae. Persons with underlying chronic liver disease have an increased risk of death. In rare cases of acute liver failure (ALF) due to HAV hepatitis, the patient may die within days to weeks or require evaluation for liver transplantation. The prognosis is poor if hepatic coma or ascites develop; liver transplantation is indicated under these circumstances and is life-saving. Incomplete resolution can cause a prolonged hepatitis, but resolution invariably occurs without long-term hepatic sequelae. Rare cases of aplastic anemia following acute infectious hepatitis have been reported. A benign relapse of symptoms may occur in 10%–15% of cases after 6–10 weeks of apparent resolution.

HEPATITIS B

General Considerations

Hepatitis B virus (HBV) is a DNA virus whose infection has an incubation period of 45–160 days (see Table 22–6). HBV is either acquired perinatally from a carrier mother, or later in life from exposure to contaminated blood through shared needles, needle sticks, skin piercing, tattoos, or sexual transmission.

Pathophysiology

The HBV particle is composed of a core that is found in the nucleus of infected liver cells and a double outer shell (surface antigen or HBsAg). The nomenclature for the viral antigens and antibodies is found in the table of Hepatitis Virus Abbreviations provided above. HBeAg, a truncated soluble form of HBcAg, correlates with active virus replication. Persistence of HBeAg is a marker of infectivity, whereas the appearance of anti-HBe generally implies a lower level of viral replication. However, HBV mutant viruses (precore mutant) may replicate with negative HBeAg tests and positive tests for anti-HBe antibody (HBeAg-negative chronic hepatitis). Such cases are associated with a more virulent form of hepatitis. Circulating HBV DNA (measured by PCR) also indicates viral replication.

Prevention

HBV vaccination is the preferred method for prevention. Universal immunization of all infants is recommended. Other control methods include screening of blood donors and pregnant women, use of properly sterilized needles and surgical equipment, avoidance of sexual contact with carriers, general adoption of safe sex practices, and vaccination of household contacts, sexual partners, medical personnel, and those at high risk. For postexposure prophylaxis, HBV vaccine is given alone (see Chapter 10) or together with administration of hepatitis B immune globulin (HBIG) (0.06 mL/kg intramuscularly, given as soon as possible after exposure, up to 7 days). The risk of vertical transmission is dramatically reduced with the combination of newborn vaccination and HBIG administration. For infected pregnant women with high viral loads, use of oral antivirals in the last half of pregnancy combined with postdelivery prophylaxis can further reduce perinatal prophylaxis failures from 5% to 1.5%.

Clinical Findings

A. Symptoms and Signs

Most infants and young children are asymptomatic, especially if the infection is acquired vertically. Symptoms of acute HBV infection may include a slight fever, malaise, and mild gastrointestinal upset. Visible jaundice is usually the first significant finding and hepatomegaly is frequently present. Rare presentations include immune complex-mediated rash, arthritis, glomerulonephritis, or nephrotic syndrome.

B. Laboratory Findings

The diagnosis of acute HBV infection is confirmed by the presence of HBsAg and anti-HBc IgM. Recovery from acute infection is accompanied by HBsAg clearance and appearance of anti-HBs and anti-HBc IgG. Individuals who are immune by vaccination are positive for anti-HBs, but negative for anti-HBc IgG. Chronic infection is defined as the presence of HBsAg for at least 6 months. Vertical transmission to newborns is documented by positive HBsAg. The various phases of chronic HBV infection are shown in Table 22–7.

Differential Diagnosis

The differentiation between HAV and HBV disease is aided by a history of parenteral exposure, a HBsAg-positive parent, or an unusually long period of incubation. HBV and hepatitis C virus (HCV) infection or Epstein-Barr virus (EBV) infection are differentiated serologically. Other diseases to consider in the differential diagnosis include autoimmune hepatitis, Wilson disease, hemochromatosis, nonalcoholic fatty liver disease (NAFLD), or α₁-antitrypsin deficiency.

Treatment

There is no therapy that is highly curative for Hepatitis B. For children with vertically acquired HBV infection and normal LFTs and physical exam (immunotolerant phase), treatment is not recommended. For acute infection complicated by ALF, or for chronic infection with elevated LFTs for more than 6 months (immunoactive phase), nucleos(t)ide therapy may be helpful. Orally administered nucleoside analog therapy includes entecavir or tenofovir. A significant decrease in viral load with these nucleos(t)ide therapies can be seen in up to 75% of treated children, with minimal side effects, but may require long-term treatment. Resistant virus mutants rarely emerge. Liver transplantation is successful in ALF due to hepatitis B; however, reinfection is common following liver transplantation for chronic hepatitis B unless long-term HBIG or antivirals are used.

Prognosis

The prognosis for acute HBV infection is good in older children, although ALF (< 0.1%) or chronic hepatitis and cirrhosis (up to 10%) may supervene. The course of the acute disease is variable, but jaundice seldom persists for more than 2 weeks. HBsAg disappears in 95% of cases at the time of clinical recovery. Individuals who have cleared HBV (HBsAg negative, anti-HBcIgG positive) are at risk for reactivation of HBV infection with significant immunosuppression (eg, chemotherapy). Chronic infection is particularly common in children with vertical transmission, Down syndrome, or leukemia, and in those undergoing chronic hemodialysis. Persistence of neonatally acquired HBsAg occurs in 70%–90% of infants without immunoprophylaxis or vaccination. The presence of HBeAg in the HBsAg carrier indicates ongoing viral replication. However, 1%–2% of children infected at birth will show spontaneous seroconversion of HBeAg each year. If HBV infection is acquired later in childhood, HBV is cleared and recovery occurs in 90%–95% of patients. Chronic HBV disease predisposes the patient to development of hepatocellular carcinoma. Once chronic HBV infection is established, surveillance for development of hepatocellular carcinoma with serum α-fetoprotein is performed biannually and ultrasonography every 1–3 years. Routine HBV vaccination of newborns in endemic countries has reduced the incidence of ALF, chronic hepatitis, and hepatocellular carcinoma in children.

HEPATITIS C

General Considerations

Hepatitis C virus (HCV) is the most common cause of non-B chronic hepatitis (see Table 22–6). HCV is a single-stranded RNA flavivirus with at least seven genotypes. Risk factors in adults and adolescents include illicit use of intravenous drugs, occupational or sexual exposure, and a history of transfusion of blood products prior to 1992. Most cases in children are associated with transmission from an infected mother (vertical transmission) or rarely from other household contacts, and in adolescents from IV drug use or sexual contact. Vertical transmission from HCV-infected mothers occurs more commonly with mothers who are HIV-positive (15%–20%) compared with those who are HIV-negative (5%–6%). Approximately, 0.2% of children, 0.4% of adolescents, and 1.5% of adults in the United States have serologic evidence of infection.

Prevention

At present, the only effective means of prevention is avoidance of exposure through elimination of risk-taking behaviors such as illicit use of intravenous drugs. There is no effective prevention for vertical transmission, but avoidance of fetal scalp monitoring in infant of mothers with HCV has been suggested. Elective Caesarean section is not recommended for HCV-monoinfected women, as it confers no reduction in the rate of mother-to-infant HCV transmission. Breast-feeding does not promote HCV transmission from mother to infant. It is advised to avoid breast-feeding if the nipples are bleeding, if mastitis is present or if the mother is experiencing a flare of hepatitis with jaundice postpartum. There is no vaccine, and no benefit from using immune globulin in infants born to infected mothers.

Clinical Findings

A. Symptoms and Signs

The majority of childhood cases, especially those acquired vertically, are asymptomatic despite development of chronic hepatitis. The incubation period is 1–5 months, with insidious onset of symptoms. Flu-like prodromal symptoms and jaundice occur in less than 25% of cases. Hepatosplenomegaly may or may not be evident. Ascites, clubbing, palmar erythema, or spider angiomas are rare and indicate progression to cirrhosis. In adults, chronic HCV infection has been associated with mixed cryoglobulinemia, polyarteritis nodosa, a sicca-like syndrome, and membranoproliferative glomerulonephritis, as well as hepatocellular carcinoma.

B. Laboratory Findings

Since anti-HCV IgG crosses the placenta, testing anti-HCV IgG is not informative until the infant is 18 months old, at which time antibody testing should be performed. Patients older than 18 months with positive anti-HCV IgG should have subsequent testing for serum HCV RNA in order to determine active infection. Serum HCV RNA can be tested prior to 18 months of age, but should not be tested before 2 months old. If serum HCV RNA is positive in infancy, it should be rechecked when the infant is 12 months of age in order to determine presence of chronic infection. Fluctuating mild to moderate elevations of aminotransferases over long periods are characteristic of chronic HCV infection; however, normal aminotransferases are common in children. Cirrhosis in adults generally requires 20–30 years of chronic HCV infection, but it has occasionally developed sooner in children.

Differential Diagnosis

HCV disease should be distinguished from HAV and HBV disease by serologic testing. Other causes of chronic hepatitis in children should be considered, including Wilson disease, α₁-antitrypsin deficiency, AIH, primary sclerosing cholangitis, drug-induced hepatitis, or steatohepatitis.

Treatment

The treatment for chronic HCV has rapidly changed in the past decade, with the advent of direct-acting antiviral therapies (DAA), which when used for 12–24 weeks have resulted in HCV eradication rates of more than 90%. The use of subcutaneous injections of pegylated interferon-α and oral ribavirin is no longer recommended. In April of 2017, the FDA approved the combination of Sofosbuvir (400 mg) plus Ledipasvir (90 mg) (Harvoni) once daily for 12 weeks for the treatment of genotype 1, 4, 5, or 6 in children greater than 12 years of age, or 35 Kg in weight. For genotypes 2 and 3, 12 weeks of Sofosbuvir (400 mg daily, Sovaldi) plus Ribavirin (15 mg/kg in two divided doses), was approved for the treatment of children greater than 12 years of age, or 35 Kg in weight. Current clinical trials of Sofosbuvir plus Ledipasvir and Sofosbuvir plus Ribavirin are underway in children as young as 3 years of age. Most recently, in April of 2019, the FDA approved the DAA combination of Glecaprevir (GLE) and Pibrentasvir (PIB) to treat all six genotypes of HCV in children ages 12–17 (DORA Study, Part 1, ClinicalTrials.gov Identifier: NCT03067129). End-stage liver disease secondary to HCV responds well to liver transplantation, although reinfection of the transplanted liver is very common; the new DAA therapies appear to be effective at eradicating HCV post-liver transplant as well. A website provides up-to-date guidance for suggested therapies in this era of rapidly evolving approval of new drugs for HCV (http://www.hcvguidelines.org).

Prognosis

Following an acute infection with HCV, 70%–80% of adults and older children develop a chronic infection. Around 20% of adults with chronic HCV develop cirrhosis by 30 years. Infants infected by vertical transmission have a high rate of spontaneous resolution, approaching 25%–40%. Most have spontaneous resolution by 24 months of age, but some may have spontaneous resolution as late as 7 years after vertical infection. The majority of children with chronic HCV have mild inflammation and fibrosis on liver biopsy, although cirrhosis may develop rapidly in rare cases. Limited 30-year follow-up of infants exposed to HCV by transfusion suggests a lower rate of progression to cirrhosis compared to adults. The prognosis for infants infected at birth with concomitant HIV infection is unknown, but the course appears benign for the first 10 years of life.

HEPATITIS D (DELTA AGENT)

The hepatitis D virus (HDV) is a 36-nm virus that requires the presence of HBsAg to be infectious (see Table 22–6). Thus, HDV infection can occur only in the presence of HBV infection. Transmission is by parenteral exposure or intimate contact. HDV is rare in North America, but common in Africa, South America, Turkey, Mongolia, southern Italy, and Russia. HDV can infect simultaneously with HBV, causing acute hepatitis, or can superinfect a patient with chronic HBV infection, predisposing the individual to chronic hepatitis or fulminant hepatitis. In children, the association between chronic HDV coinfection with HBV and chronic hepatitis and cirrhosis is strong. Vertical HDV transmission is rare. HDV can be detected by anti-HDV IgG, which indicates active or previous infection; active infection is confirmed by detecting HDV RNA by PCR or by detecting HDV IgM antibody. Treatment is limited to interferon therapy but new treatments are being explored.

HEPATITIS E

Hepatitis E virus (HEV) infection causes acute hepatitis (see Table 22–6). The World Health Organization estimates that one-third of the world’s population has been exposed to HEV. Epidemics have occurred mainly in developing regions secondary to contamination of drinking water; however, recently HEV has increasingly been recognized as endemic in some developed regions where infections occur through zoonotic transmission or contaminated blood products. The routes of HEV transmission include fecal-oral (consumption of contaminated water and food), vertical, person-to-person, and, rarely, parenteral transmission. The majority of cases are asymptomatic; if symptomatic, the clinical manifestations resemble those of HAV infection. HEV infection in pregnancy is associated with a high mortality (10%–20%), particularly when acquired in the third trimester. HEV infection in individuals with chronic liver disease can cause acute deterioration. Immunocompromised individuals infected with HEV are at increased risk for the development of chronic infection, with higher rates of ALF and rapid onset of cirrhosis. Diagnosis is established by detecting anti-HEV IgM antibody or by HEV PCR. HEV is usually self-limited. Treatment is supportive care for healthy individuals and lowering of immunosuppressive medications and ribavirin in immunosuppressed individuals.

OTHER HEPATITIS VIRUSES

Other viruses including enterovirus, adenovirus, parvovirus, varicella, influenza, cytomegalovirus, herpes simplex virus, HHV-6, HIV, brucella, Q-fever, and leptospirosis may cause severe acute hepatitis or acute liver failure (ALF) in children, in some cases in association with aplastic anemia. Aplastic anemia occurs in a small proportion of patients recovering from hepatitis and in 10%–20% of those undergoing liver transplantation for ALF of unknown etiology. Infectious mononucleosis (EBV) is commonly associated with acute hepatitis and rare cases of EBV-associated ALF have been reported. Primary EBV infection in an immunocompromised solid organ transplant recipient may result in a lymphoproliferative disorder.

ACUTE LIVER FAILURE

General Considerations

Acute liver failure (ALF) is defined as acute liver dysfunction associated with significant hepatic synthetic dysfunction evidenced by vitamin K–resistant coagulopathy (INR > 2.0) within 8 weeks of onset of liver injury. This is often associated with encephalopathy, but in young children, encephalopathy may be difficult to detect. Without liver transplantation, mortality approaches 40% in children. In many cases, an identifiable cause is not found but is postulated to be an unusually virulent infectious agent or aggressive host immune response. Common identifiable causes of ALF are shown in Table 22–8.

Clinical Findings

A. History

In some patients, ALF presents with the rapid development of deepening jaundice, bleeding, confusion, and progressive encephalopathy, while others are asymptomatic at the onset and then suddenly become severely ill during the second week of the disease. Jaundice, fever, anorexia, vomiting, and abdominal pain are the most common symptoms. A careful history of drug and toxin exposure may identify a drug-induced cause.

B. Symptoms and Signs

Children may present with flu-like symptoms, including malaise, myalgias, jaundice, nausea, and vomiting. Tender hepatomegaly is common, which may be followed by progressive shrinking of the liver, often with worsening hepatic function. Other physical findings (splenomegaly, spider hemangiomata) should suggest an underlying chronic liver disease. Hyper-reflexia and positive extensor plantar responses are seen in the early stages of hepatic encephalopathy.

C. Laboratory Findings

Characteristic findings include elevated serum bilirubin levels (usually > 10 mg/dL), sustained elevations of AST and ALT (often > 3000 U/L), low serum albumin, hypoglycemia, and prolonged PT and INR. Blood ammonia levels may become elevated. Prolonged PT from disseminated intravascular coagulation (DIC) can be differentiated by determination of factor V (low in ALF and DIC) and VIII (normal to high in ALF and low in DIC). Rapid decreases in AST and ALT, together with shrinking hepatomegaly, due to massive necrosis and collapse, combined with worsening coagulopathy portend a poor prognosis.

Differential Diagnosis

Severe hepatitis, with or without coagulopathy, due to infections, metabolic disease, AIH or drug toxicity can initially mimic ALF. Acute leukemia, cardiomyopathy, and Budd-Chiari syndrome can mimic severe hepatitis. Patients with Reye syndrome or urea cycle defects are typically anicteric.

Complications

The development of renal failure and depth of hepatic coma are major prognostic factors. Patients in stage 4 coma (unresponsiveness to verbal stimuli, decorticate or decerebrate posturing) rarely survive without liver transplantation and may have residual central nervous system deficits even after transplant. Cerebral edema, which usually accompanies coma, is frequently the cause of death. Extreme prolongation of PT or INR greater than 3.5 predicts poor recovery, except with acetaminophen overdose. Sepsis, hemorrhage, renal failure, and cardiorespiratory arrest are common terminal events.

Treatment

Excellent critical care is paramount, including careful management of hypoglycemia, bleeding and coagulopathy, hyperammonemia, cerebral edema, and fluid balance, while systematically investigating for potentially treatable causes. Several therapies have failed to affect outcome, including exchange transfusion, plasmapheresis with plasma exchange, total body washout, charcoal hemoperfusion, and hemodialysis using a special high-permeability membrane. While spontaneous survival may occur in up to 50% of patients, liver transplant may be lifesaving in patients without signs of spontaneous recovery. Therefore, early transfer of patients in ALF to centers where liver transplantation can be performed is recommended. Criteria for deciding when to perform transplantation are not firmly established; however, serum bilirubin over 20 mg/dL, INR greater than 4, and factor V levels less than 20% indicate a poor prognosis. Prognosis is better for acetaminophen ingestion, particularly when N-acetylcysteine treatment is given. N-acetylcysteine is not recommended in non–acetaminophen-induced liver failure, as it does not improve survival and may, in fact, negatively impact survival in those younger than 2 years. Corticosteroids may be harmful, except in AIH for which steroids may reverse ALF. Acyclovir is essential in herpes simplex or varicella-zoster virus infection. For hyperammonemia, oral antibiotics such as neomycin or rifaximin, and lactulose (1–2 mL/kg three or four times daily) are used to reduce blood ammonia levels and trap ammonia in the colon.

Close monitoring of fluid and electrolytes is mandatory and requires a central venous line. Adequate dextrose should be infused (6–8 mg/kg/min) to maintain normal blood glucose and cellular metabolism. Diuretics, sedatives, and tranquilizers should be used sparingly. Comatose patients should be intubated, given mechanical ventilatory support, and monitored for signs of infection. Coagulopathy accompanied by bleeding and is treated with fresh-frozen plasma, recombinant factor VIIa, other clotting factor concentrates, platelet infusions. Hemodialysis may help stabilize a patient while awaiting liver transplantation. Monitoring for increased intracranial pressure (hepatic coma stages 3 and 4) in patients awaiting liver transplantation is advocated by some. Continuous venous-venous dialysis may be helpful to maintain fluid balance.

Prognosis

Prognosis is primarily dependent on the etiology of ALF and depth of coma. Only 20%–30% of children with stage 3 or 4 hepatic encephalopathy will have a spontaneous recovery. Children with acute acetaminophen toxicity have a high rate of spontaneous survival, while 40% of children with indeterminate ALF (of unknown etiology) will have a spontaneous recovery. A recent large study suggests that the spontaneous recovery rate is about 40%–50% when all causes of ALF are combined; 30% of patients will receive a liver transplant; and 20% will die without a transplant. Exchange transfusions or other modes of heroic therapy do not improve survival figures. Indeterminate ALF, non-acetaminophen drug-induced ALF, and ALF in infants are associated with a poorer prognosis. Acetaminophen and autoimmune hepatitis etiologies of ALF and rising levels of factors V and VII, coupled with rising levels of serum α-fetoprotein, may signify a more favorable prognosis. The 1-year survival rate in patients who undergo liver transplantation for ALF is 60%–85%.

AUTOIMMUNE HEPATITIS

Clinical Findings

A. History

Autoimmune hepatitis (AIH) is a progressive inflammatory disorder. It is characterized histologically by portal tract inflammation that extends into the parenchyma; serologically by the presence of nonorgan-specific autoantibodies; biochemically by elevated aminotransferases and serum IgG; and clinically by response to immunosuppressive treatment in the absence of other known causes of liver disease. A family history of autoimmune diseases is present in approximately 40% of cases.

B. Symptoms and Signs

Pediatric patients are often asymptomatic early in the disease process and come to medical attention based on an incidental finding of elevated liver tests. Lethargy as well as malaise are common symptoms, and patients may also complain of jaundice, recurrent fevers, abdominal pain, or distension. Other complaints at the time of presentation may include a recurrent rash, arthritis, chronic diarrhea, or amenorrhea. Hepatomegaly and/or splenomegaly may be found on examination. In more advanced cases, jaundice and ascites may develop. Cutaneous signs of chronic liver disease may be noted (eg, spider angiomas, palmar erythema, and digital clubbing). In ~ 10% of cases, AIH patients present with ALF.

C. Laboratory Findings

Liver tests reveal moderate elevations of serum AST, ALT, and variable elevations of alkaline phosphatase, bilirubin, and total IgG. Two subtypes of disease have been described based on the autoantibodies present: type 1 AIH—ANA and/or ASMA (anti-actin); type 2 AIH—anti-LKM (anti–liver-kidney microsomal). Type 1 AIH is the most common form of AIH in the United States. Type 2 AIH is more common in Europe, presents at a younger age, and is more likely to present with ALF compared to type 1. A genetic susceptibility to AIH is suggested by the increased incidence of the histocompatibility alleles HLA DR*0301 (type 1 AIH) or HLA DR*0701 (type 2 AIH). Liver biopsy remains the gold standard in diagnosis, revealing the typical histological picture of interface hepatitis: a dense infiltration of the portal tracts consisting mainly of lymphocytes and plasma cells that extends into the liver lobules with destruction of the hepatocytes at the periphery of the lobule and erosion of the limiting plate. There may be bridging fibrosis or cirrhosis evident as well.

Differential Diagnosis

Laboratory and histologic findings differentiate other types of chronic hepatitis (eg, HBV, HCV; steatohepatitis; Wilson disease; α₁-antitrypsin deficiency; primary sclerosing cholangitis [PSC]). PSC occasionally presents in a manner similar to AIH, including the presence of autoantibodies. Up to 30% of pediatric patients have an “overlap syndrome” of AIH and PSC. Drug-induced chronic hepatitis (minocycline, isoniazid, methyldopa, pemoline) should be ruled out. In addition, minocycline has been reported as a potential “trigger” of type 1 AIH.

Complications

Untreated disease that continues for months to years eventually results in cirrhosis, with complications of portal hypertension and liver synthetic dysfunction. Untreated AIH can also lead to ALF. Bleeding from esophageal varices and development of ascites usually signal impending hepatic failure.

Treatment

Corticosteroids (prednisone, 2 mg/kg/day; maximum 60 mg) as induction therapy decreases the mortality rate during the early active phase of the disease. Recent data suggests that oral budesonide may be as efficacious as prednisone at inducing remission with less steroid side effects. Budesonide, however, is not as potent an anti-inflammatory as prednisone and studies suggest that budesonide should be reserved for mild cases at presentation (ie, mild elevation of liver transaminases and minimal/no fibrosis on liver histology). Maintenance therapy with azathioprine or 6-mercaptopurine (6-MP), 1–2 mg/kg/day, is recommended in order to facilitate weaning off of steroids. Thiopurine methyltransferase activity in red blood cells or genotype should be assessed prior to starting azathioprine or 6-MP to prevent extremely high blood levels and severe bone marrow toxicity. Steroids are reduced over a 3- to 6-month period and azathioprine is continued for at least 2 years. At that point, if AST and ALT have been consistently normal, then one can consider a future wean off of therapy. A liver biopsy must be performed before stopping azathioprine or 6-MP therapy; if any inflammation persists, then azathioprine or 6-MP is continued. The majority of pediatric patients will require chronic azathioprine or 6-MP therapy, but up to 30% can be taken off of azathioprine or 6-MP eventually. Mycophenolate mofetil can be substituted for azathioprine or 6-MP if there is a contraindication or side effect from these medications. The calcineurin inhibitors, cyclosporine or tacrolimus, are highly effective in cases refractory to standard therapies. Liver transplantation is indicated when disease progresses to decompensated cirrhosis or in cases presenting in ALF that do not respond to steroid therapy.

Prognosis

The overall prognosis for AIH has improved significantly with early therapy; approximately 90% of patients with type 1 AIH will enter remission. Some studies report permanent remission (normal histologic findings) in up to 30% of patients. Relapses (seen clinically and histologically) occur in 40%–50% of patients after cessation of therapy; remissions follow repeat treatment. Complications of portal hypertension (bleeding varices, ascites, spontaneous bacterial peritonitis, and hepatopulmonary syndrome) require specific therapy or liver transplant. Disease recurs after transplantation in ~ 20% of cases and is treated by adding azathioprine or mycophenolate mofetil to the post-transplant immunosuppressant regimen.

NONALCOHOLIC FATTY LIVER DISEASE

Nonalcoholic fatty liver disease (NAFLD), a clinicopathologic condition of abnormal hepatic fat deposition in the absence of alcohol, is the most common cause of abnormal LFTs in the United States. NAFLD ranges from bland steatosis, to fat and inflammation, with or without scarring (also referred to as nonalcoholic steatohepatitis, NASH) to cirrhosis. Trends in NAFLD parallel trends in obesity, with up to 10% of all children, and 38% of obese children affected in the United States. Many children with NAFLD are also affected by type 2 diabetes mellitus, hypertension, hyperlipidemia, obstructive sleep apnea, and the metabolic syndrome. Most children are 11–13 years of age at diagnosis, with males (ratio of 2:1) and Hispanics at highest risk.

Prevention

The most effective therapy is prevention of the overweight or obese state.

Clinical Findings

A. History

Most patients with NAFLD are asymptomatic and discovered upon routine screening. Some may complain of fatigue or right-upper quadrant pain. Obesity and insulin resistance are known risk factors. Moderate sleep apnea is also common in children with NAFLD. NAFLD screening (using ALT) should be considered in children beginning at age 9–11 years if they are obese or overweight with additional risk factors.

B. Symptoms and Signs

Patients with NAFLD may present with asymptomatic soft hepatomegaly, though abdominal adiposity may make this difficult to assess. Physical findings of insulin resistance (acanthosis nigricans and a buffalo hump) are frequently present.

C. Laboratory Findings

Serum aminotransferases will not identify bland steatosis, so NAFLD patients may have completely normal AST and ALT. If elevated, the AST and ALT are typically elevated less than 1.5 times the upper limit of normal, with an ALT:AST ratio of greater than 1. Alkaline phosphatase and GGT may be mildly elevated, but bilirubin is normal. Hyperglycemia and hyperlipidemia are also common. If performed, the liver biopsy may show micro- or macrovesicular steatosis, hepatocyte ballooning, Mallory bodies, and lobular or portal inflammation. In addition, varying degrees of fibrosis from portal focused to cirrhosis may be present. Obstructive sleep apnea and hypoxia appear to contribute to NAFLD disease severity. There are no established reliable biochemical predictors of the degree of hepatic fibrosis. Currently, surrogate markers and scores developed to predict NAFLD are not accurate enough nor sufficiently validated to be used in the clinical setting.

D. Imaging

Ultrasonography, CT scan, or MRI can be used to confirm fatty infiltration of the liver. Ultrasound, however, is of lower cost and lacks radiation exposure, although it may be insensitive with severe central adiposity or if less than 30% steatosis is present. Currently, radiologic imaging cannot distinguish bland steatosis from the more severe NASH, nor reliably identify fibrosis. Transient elastography and MR elastography are increasingly available as clinical tools that show promise in accurately estimating both hepatic fat and fibrosis.

Differential Diagnosis

Steatohepatitis is also associated with Wilson disease, hereditary fructose intolerance, tyrosinemia, HCV hepatitis, cystic fibrosis, fatty acid oxidation defects, kwashiorkor, Reye syndrome, respiratory chain defects, total parenteral nutrition associated liver disease, and toxic hepatopathy (ethanol and others).

Complications

Untreated, NAFLD with hepatic inflammation can progress to cirrhosis with complications that include portal hypertension. Dyslipidemia, hypertension, insulin resistance, and obstructive sleep apnea are more common in children and adolescents with NAFLD.

Treatment

Multiple potential therapies, including metformin, UDCA, and lipid-lowering agents, have been tested without therapeutic success. Therefore, treatment is focused on lifestyle modifications, through both dietary changes and exercise, to induce slow weight loss. A 10% decrease in body weight can significantly improve NAFLD. Vitamin E, an antioxidant, has shown promise in clinical trials in improving histologically confirmed NASH.

Prognosis

Although untreated NAFLD can progress to cirrhosis and liver failure; there is a very high response rate to weight reduction. However, success in achieving long-term weight reduction is low in children and adults.

α₁-ANTITRYPSIN DEFICIENCY LIVER DISEASE

General Considerations

The disease is caused by a deficiency in α₁-antitrypsin, a protease inhibitor (Pi), predisposing patients to chronic liver disease, and an early onset of pulmonary emphysema. Liver disease is associated only with the Pi phenotypes ZZ and SZ. The accumulation of misfolded aggregates of α₁-antitrypsin protein in the liver causes liver injury by unclear mechanisms. α₁-Antitrypsin is a common genetic disorder affecting up to 1 in 1600 to 1 in 2000 live births, especially among those of Northern European heritage.

Clinical Findings

A. Symptoms and Signs

α₁-Antitrypsin deficiency should be considered in all infants with neonatal cholestasis. About 10%–20% of affected individuals present with neonatal cholestasis. Serum GGT is usually elevated. Jaundice, acholic stools, and malabsorption may also be present. Infants are often small for gestational age, and may have pruritus, hepatosplenomegaly, ascites and/or easy bleeding and bruising. The family history may be positive for emphysema or cirrhosis.

Toddlers and older children may present with signs of chronic liver disease, including failure to thrive, hepatosplenomegaly, gastrointestinal bleeding, or ascites. Very few children have significant pulmonary involvement. Most affected children are completely asymptomatic, with no laboratory or clinical evidence of liver or lung disease.

B. Laboratory Findings

Serum α₁-antitrypsin level is low (< 50–80 mg/dL) in homozygotes (PiZZ). Specific Pi phenotyping or genotyping should be done to confirm the diagnosis. LFTs often reflect underlying hepatic pathologic changes. Hyperbilirubinemia (mixed) and elevated aminotransferases, alkaline phosphatase, and GGT are present early. Hyperbilirubinemia generally resolves, while aminotransferase and GGT elevation may persist. Signs of cirrhosis and hypersplenism may develop even when LFTs are normal.

Liver biopsy findings after age 6 months show diastase resistant, periodic acid–Schiff staining intracellular globules, particularly in periportal zones. These may be absent prior to age 6 months, but when present are characteristic of α₁-antitrypsin deficiency.

Differential Diagnosis

In newborns, other specific causes of neonatal cholestasis need to be considered, including biliary atresia. In older children, other causes of insidious cirrhosis (eg, HBV or HCV infection, AIH, Wilson disease, cystic fibrosis, and glycogen storage disease) should be considered.

Complications

Of all infants with PiZZ α₁-antitrypsin deficiency, only 15%–20% develop liver disease in childhood, and many have clinical recovery. Thus, other genetic or environmental modifiers must be involved. An associated abnormality in the microsomal disposal of accumulated aggregates may contribute to the liver disease phenotype. The complications of portal hypertension, cirrhosis, and chronic cholestasis predominate in affected children. An increased susceptibility to hepatocellular carcinoma has been noted in cirrhosis associated with α₁-antitrypsin deficiency. α₁-Antitrypsin deficiency is the most common genetic cause of pediatric liver disease and the most frequent inherited indication for liver transplantation in the pediatric population.

Early-onset pulmonary emphysema occurs in young adults (age 30–40 years), particularly in smokers.

Treatment

There is no specific treatment for the liver disease of this disorder. The neonatal cholestatic condition is treated with choleretics, medium-chain triglyceride–containing formula, and water-soluble preparations of fat-soluble vitamins (see Table 22–4). UDCA may reduce AST, ALT, and GGT, but its effect on outcome is unknown. Portal hypertension, esophageal bleeding, ascites, and other complications are treated as described elsewhere. Hepatitis A and B vaccines should be given to children with α₁-antitrypsin deficiency. Genetic counseling is indicated when the diagnosis is made. Diagnosis by prenatal screening is possible. Liver transplantation, performed for end-stage liver disease cures the deficiency with excellent long-term survival and prevents the development of pulmonary disease. Pediatric patients should be referred to a pulmononologist by 18 years of age for education and to establish baseline pulmonary function tests (PFTs). Passive and active cigarette smoke exposure should be eliminated to help prevent pulmonary manifestations, and obesity should be avoided. Replacement of the protein by infusion therapy is used to prevent or treat pulmonary disease in affected adults. In the future, novel treatments including chemical chaperones, authophagy inducers, hepatocyte transplantation, and gene transfer therapy may be available.

Prognosis

Of those patients presenting with neonatal cholestasis, approximately 10%–25% will need liver transplantation in the first 5 years of life, 15%–25% during childhood or adolescence, and 50%–75% will survive into adulthood with variable degrees of liver fibrosis. A correlation between histologic patterns and clinical course has been documented in the infantile form of the disease. Liver failure can be expected 5–15 years after development of cirrhosis. Recurrence or persistence of hyperbilirubinemia along with worsening coagulation studies indicates the need for evaluation for liver transplantation. Decompensated cirrhosis caused by this disease is an indication for liver transplantation. Pulmonary involvement is prevented by liver transplantation. Heterozygotes may have a slightly higher incidence of liver disease. The exact relationship between low levels of serum α₁-antitrypsin and the development of liver disease is unclear. Emphysema develops because of a lack of inhibition of neutrophil elastase, which destroys pulmonary connective tissue.

WILSON DISEASE (HEPATOLENTICULAR DEGENERATION)

General Considerations

Wilson disease is caused by mutations in the gene ATP7B on chromosome 13 coding for a specific P-type adenosine triphosphatase involved in copper transport. This results in impaired bile excretion of copper and incorporation of copper into ceruloplasmin by the liver. The accumulated hepatic copper causes oxidative (free-radical) damage to the liver. Subsequently, copper accumulates in the basal ganglia and other tissues. The disease should be considered in all children older than age 1–2 years with evidence of liver disease (especially with hemolysis) or with suggestive neurologic signs. A family history is often present, and 25% of patients are identified by screening asymptomatic homozygous family members. The disease is autosomal recessive and occurs in 1:30,000 live births in all populations.

Clinical Findings

A. Symptoms and Signs

Hepatic involvement may present as ALF, acute hepatitis, chronic liver disease, cholelithiasis, fatty liver disease, or as cirrhosis with portal hypertension. Findings may include jaundice, hepatomegaly early in childhood, splenomegaly, and Kayser-Fleischer rings. The disease is generally considered after 3 years of age. However, liver involvement occurs early in life and may be present by age 1–2 years. The later onset of neurologic or psychiatric manifestations after age 10 years may include tremor, dysarthria, and drooling. Deterioration in school performance can be the earliest neurologic expression of disease. The Kayser-Fleischer ring is a brown band at the junction of the iris and cornea, generally requiring slit-lamp examination for detection. Absence of Kayser-Fleischer rings does not exclude this diagnosis.

B. Laboratory Findings

The laboratory diagnosis can be challenging. Plasma ceruloplasmin levels are usually less than 20 mg/dL. (Normal values are 23–43 mg/dL.) Low values, however, occur normally in infants younger than 3 months, and in at least 10%–20% of homozygotes the levels may be within the lower end of the normal range (20–30 mg/dL), particularly since immunoassays are commonly used to measure ceruloplasmin. Rare patients with higher ceruloplasmin levels have been reported. Serum copper levels are low, but the overlap with normal is too great for satisfactory discrimination. In acute fulminant Wilson disease, serum copper levels are elevated markedly, owing to hepatic necrosis and release of copper. The presence of anemia, hemolysis, very high serum bilirubin levels (> 20–30 mg/dL), low alkaline phosphatase, and low uric acid are characteristic of acute Wilson disease. Urine copper excretion in children older than 3 years is normally less than 30 mcg/day; in Wilson disease, it is generally greater than 100 mcg/day although it can be as low as > 40 mcg/day. Finally, the tissue content of copper from a liver biopsy, normally less than 40–50 mcg/g dry tissue, is greater than 250 mcg/g in most Wilson disease patients, but may be as low as > 75 mcg/day.

Glycosuria and aminoaciduria have been reported. Hemolysis and gallstones may be present; bone lesions simulating those of osteochondritis dissecans have also been found.

The coarse nodular cirrhosis, macrovesicular steatosis, and glycogenated nuclei in hepatocytes seen on liver biopsy may distinguish Wilson disease from other types of cirrhosis. Early in the disease, vacuolation of liver cells, steatosis, and lipofuscin granules can be seen, as well as Mallory bodies. The presence of Mallory bodies in a child is strongly suggestive of Wilson disease. Stains for copper may sometimes be negative despite high copper content in the liver. Therefore, quantitative liver copper levels must be determined biochemically on biopsy specimens. Electron microscopy findings of abnormal mitochondria may be helpful.

Differential Diagnosis

During the icteric phase, acute or chronic viral hepatitis, α₁-antitrypsin deficiency, AIH, and drug-induced hepatitis are the usual diagnostic possibilities. Nonalcoholic steatohepatitis may have similar histology and be confused with Wilson disease in overweight patients. Later, other causes of cirrhosis and portal hypertension require consideration. Laboratory testing for plasma ceruloplasmin, 24-hour urine copper excretion, liver quantitative copper concentration, and a slit-lamp examination of the cornea will help differentiate Wilson disease from the others. Urinary copper excretion during penicillamine challenge (500 mg twice a day in the older child or adult) may also be helpful. Genetic testing of ATP7B is available and is helpful if two disease-causing mutations are present. Other copper storage diseases that occur in early childhood include Indian childhood cirrhosis, Tyrolean childhood cirrhosis, and idiopathic copper toxicosis. However, ceruloplasmin concentrations are normal to elevated in these conditions.

Complications

Cirrhosis, hepatic coma, progressive neurologic degeneration, and death are the rule in the untreated patient. The complications of portal hypertension (variceal hemorrhage, ascites) may be present at diagnosis. Progressive central nervous system disease and terminal aspiration pneumonia were common in untreated older people. Acute hemolytic disease may result in acute renal failure and profound jaundice and coma as part of the presentation of fulminant hepatitis.

Treatment

Copper chelation with D-penicillamine or trientine hydrochloride, 750–1500 mg/day orally, is the treatment of choice, whether or not the patient is symptomatic. The target dose for children is 20 mg/kg/day; begin with 250 mg/day and increase the dose weekly by 250 mg increments. Strict dietary restriction of copper intake is not practical; however, selected high copper foods should be minimized. Supplementation with zinc acetate (25–50 mg orally, three times daily) may reduce copper absorption but must not be given at same time as copper chelators. Copper chelation or zinc therapy is continued for life, although doses of chelators may be reduced transiently at the time of surgery or early in pregnancy. Vitamin B₆ (25 mg) is given daily during therapy with penicillamine to prevent optic neuritis. In some countries, after a clinical response to penicillamine or trientine, zinc therapy is substituted and continued for life. Derivatives of tetrathiomolybdate are being tested as an alternative therapy. Noncompliance with any of the drug regimens (including zinc therapy) can lead to sudden fulminant liver failure and death.

Liver transplantation is indicated for all cases of acute fulminant disease (with hemolysis and renal failure), for progressive hepatic decompensation despite several months of therapy, and severe progressive hepatic insufficiency in patients who inadvisedly discontinue penicillamine, triene, or zinc therapy.

Prognosis

The prognosis of untreated Wilson disease is poor. The fulminant presentation is fatal without liver transplantation in almost all cases. Copper chelation reduces hepatic copper content, reverses many of the liver lesions, and can stabilize the clinical course of established cirrhosis. Neurologic symptoms generally respond to therapy and following liver transplantation. All siblings should be immediately screened and homozygotes given treatment with copper chelation or zinc acetate therapy, even if asymptomatic. Recent data suggest that zinc monotherapy may not be as effective for hepatic Wilson disease as copper chelation. Genetic testing (ATP7B genotyping) is available clinically if there is any doubt about the diagnosis and is particularly useful for screening family members.

DRUG-INDUCED LIVER DISEASES

General Considerations

Drug-induced liver injury (DILI) may be predictable or unpredictable. Predictable hepatotoxins cause liver injury in a dose-dependent manner. Unpredictable hepatotoxins cause liver injury in an idiosyncratic manner, which may be influenced by the genetic and environmental characteristics of particular individuals. DILI has been described with a wide variety of medications, including antihypertensives, acetaminophen, anabolic steroids, antibiotics, anticonvulsants, antidepressants, antituberculosis medications, antipsychotics, antivirals, herbals, dietary supplements, and weight loss agents.

Symptoms

Many people with DILI are asymptomatic and only detected because aminotransferases are performed for other reasons. If symptomatic, indicating more severe DILI, patients may have malaise, anorexia, pruritus, nausea and vomiting, right-upper quadrant pain, jaundice, acholic stools, and dark urine. If the DILI is a hypersensitivity reaction, fever and rash may also occur.

When submassive hepatic necrosis and fulminant failure occur, mortality can exceed 50%.

Diagnosis

No specific testing for DILI is available, with diagnosis requiring a causality assessment. This assessment should determine if the patient was exposed to the drug during a logical time period; if the drug has previously been reported to cause DILI; and if the symptom complex is consistent with DILI. In addition, other explanations for liver injury should be sought, including viral hepatitis, AIH, and alcohol use.

Treatment

Primary therapy is supportive care, discontinuation of the offending drug, and avoiding reexposure. This typically results in rapid and complete resolution of symptoms. However, DILI severe enough to cause ALF has a poor prognosis without urgent liver transplant. Specific therapies for some DILI etiologies include N-acetylcysteine for acetaminophen poisoning and L-carnitine for valproic acid hepatotoxicity. The use of ursodeoxycholic acid may speed resolution of jaundice. The use of corticosteroids for DILI remains controversial but may have a role in immune-mediated disease. An NIH-sponsored website provides up-to-date information about each drug and herbal substance associated with DILI (LiverTox).

CIRRHOSIS

General Considerations

Cirrhosis is defined by the World Health Organization as a diffuse process whereby the architecture of the liver has been replaced by structurally abnormal nodules due to fibrosis. It may be micronodular or macronodular in appearance. It is the vasculature distortion that leads to increased resistance to blood flow, producing portal hypertension, and its consequences.

Many liver diseases may progress to cirrhosis in children, including metabolic and genetic disorders, infectious diseases, autoimmune and inflammatory diseases, cholestatic diseases and biliary malformations, vascular lesions, and drugs/toxins. In the first year of life, biliary atresia and genetic-metabolic diseases are the most common cause of cirrhosis. In older children, cirrhosis is most commonly caused by chronic viral hepatitis, Wilson’s disease, primary sclerosing cholangitis, AIH, and α₁-antitrypsin deficiency. Regardless of etiology, cirrhosis can lead to liver failure and death.

Clinical Findings

A. History

Many children with cirrhosis may be asymptomatic early in the course. Malaise, loss of appetite, failure to thrive, and nausea are frequent complaints, especially in anicteric varieties. Easy bruising may be reported. Jaundice may or may not be present.

B. Symptoms and Signs

The first indication of underlying liver disease may be splenomegaly, ascites, gastrointestinal hemorrhage, or hepatic encephalopathy. Variable hepatomegaly, spider angiomas, warm skin, palmar erythema, or digital clubbing may be present. A small, shrunken liver may be present. Most often, the liver is enlarged slightly, especially in the subxiphoid region, where it has a firm to hard quality and an irregular edge. Splenomegaly generally precedes other complications of portal hypertension. Ascites, gynecomastia in males, digital clubbing, pretibial edema, and irregularities of menstruation in females may be present. In biliary cirrhosis, patients often also have jaundice, dark urine, pruritus, hepatomegaly, and sometimes xanthomas. Malnutrition and failure to thrive due to steatorrhea may be more apparent in biliary cirrhosis.

C. Laboratory Findings

Mild abnormalities of AST and ALT are often present, with a decreased level of albumin. PT is prolonged and may be unresponsive to vitamin K administration. Burr and target red cells may be noted on the peripheral blood smear. Anemia, thrombocytopenia, and leukopenia are present if hypersplenism exists. However, blood tests may be normal in patients with cirrhosis. In biliary cirrhosis, increased levels of conjugated bilirubin, bile acids, GGT, alkaline phosphatase, and cholesterol are common.

D. Imaging

Hepatic ultrasound, CT, or MRI examination may demonstrate abnormal hepatic texture and nodules. In biliary cirrhosis, abnormalities of the biliary tree may be apparent. Elastography and fibroscan will demonstrate increased liver stiffness.

E. Pathologic Findings

Liver biopsy findings of regenerating nodules and surrounding fibrosis are hallmarks of cirrhosis. Pathologic features of biliary cirrhosis also include canalicular and hepatocyte cholestasis, as well as plugging of bile ducts. The interlobular bile ducts may be increased or decreased, depending on the cause and the stage of the disease process.

Differential Diagnosis

In the pediatric population, multiple diseases can result in cirrhosis, including biliary obstruction (biliary atresia, choledochal cyst, bile duct stenosis), inborn errors of metabolism and genetic conditions (PFIC, α₁-antitrypsin deficiency, galactosemia, fructosemia, GSD type III and IV, cystic fibrosis, mitochondrial hepatopathies, Wilson’s disease), viral and parasitic infections (HBV, HCV, Opisthorchis sinensis, Fasciola, Schistosoma, and Ascaris), chronic drug and toxin exposure, AIH, primary sclerosising cholangitis, vascular alertations, and NAFLD. Most cases of biliary cirrhosis result from congenital abnormalities of the bile ducts (biliary atresia, choledochal cyst), tumors of the bile duct, Caroli disease, progressive familial intrahepatic cholangitis, primary sclerosing cholangitis, paucity of the intrahepatic bile ducts, and cystic fibrosis. The evolution to cirrhosis may be insidious, with no recognized icteric phase. At the time of diagnosis of cirrhosis, the underlying liver disease may be active, with abnormal LFTs; or it may be quiescent, with normal LFTs.

Complications

Major complications of cirrhosis in childhood include progressive nutritional disturbances, hormonal disturbances, infections, and the evolution of portal hypertension and its complications (GI bleeding, ascites, and encephalopathy). Hepatocellular carcinoma occurs with increased frequency in the cirrhotic liver, especially in patients with the chronic form of hereditary tyrosinemia or after long-standing HBV or HCV disease. Some children with cirrhosis may develop hepatopulmonary syndrome characterized by intrapulmonary vasodilation and hypoxia, portal-pulmonary hypertension, or hepatorenal syndrome characterized by progressive deterioration of renal function.

Treatment

At present, there is no proven medical treatment for cirrhosis, but whenever a treatable condition is identified (eg, Wilson disease, galactosemia, AIH) or an offending agent eliminated (HBV, HCV, drugs, toxins), disease progression can be altered; occasionally regression of fibrosis has been noted. Recent evidence suggests that cirrhosis from HCV and HBV may be reversed by successful antiviral therapy. Children with cirrhosis should receive the hepatitis A and B vaccines and be monitored for the development of hepatocellular carcinoma with serial serum α-fetoprotein determinations annually and abdominal ultrasound for hepatic nodules annually. Liver transplantation may be appropriate in patients with cirrhosis caused by a progressive disease; evidence of worsening hepatic synthetic function; or complications of cirrhosis that are no longer manageable.

Prognosis

Cirrhosis has an unpredictable course. Without transplantation, affected patients may die from liver failure within 10–15 years. Patients with a rising bilirubin, a vitamin K–resistant coagulopathy, or diuretic refractory ascites usually survive less than 1–2 years. The terminal event in some patients may be generalized hemorrhage, sepsis, or cardiorespiratory arrest. For patients with biliary cirrhosis, the prognosis is similar, except for those with surgically corrected lesions that result in regression or stabilization of the underlying liver condition. With liver transplantation, the long-term survival rate is 70%–90%.

PORTAL HYPERTENSION

General Considerations

Portal hypertension is defined as an increase in the portal venous pressure to more than 5 mm Hg greater than the inferior vena caval pressure. Portal hypertension is most commonly a result of cirrhosis. Portal hypertension may be divided into prehepatic, suprahepatic, and intrahepatic causes. Although the specific lesions vary somewhat in their clinical signs and symptoms, the consequences of portal hypertension are common to all.

A. Prehepatic Portal Hypertension

Prehepatic portal hypertension from acquired abnormalities of the portal and splenic veins accounts for 30%–50% of cases of variceal hemorrhage in children. A history of neonatal omphalitis, sepsis, dehydration, or umbilical vein catheterization may be present. Causes in older children include local trauma, peritonitis (pylephlebitis), hypercoagulable states, and pancreatitis. Symptoms may occur before age 1 year, but in most cases the diagnosis is not made until age 3–5 years. Patients with a positive neonatal history tend to be symptomatic earlier.

A variety of portal or splenic vein malformations, some of which may be congenital, have been described, including defects in valves and atretic segments. Cavernous transformation is the result of attempted collateralization around the thrombosed portal vein rather than a congenital malformation. The site of the venous obstruction may be anywhere from the hilum of the liver to the hilum of the spleen.

B. Suprahepatic Vein Occlusion or Thrombosis (Budd-Chiari Syndrome)

No cause can be demonstrated in most instances in children, while tumor, medications, and hypercoagulable states are common causes in adults. The occasional association of hepatic vein thrombosis in inflammatory bowel disease favors the presence of endogenous toxins traversing the liver. Vasculitis leading to endophlebitis of the hepatic veins has been described. In addition, hepatic vein obstruction may be secondary to tumor, abdominal trauma, hyperthermia, or sepsis, or it may occur following the repair of an omphalocele or gastroschisis. Congenital vena caval bands, webs, a membrane, or stricture above the hepatic veins are sometimes causative. Hepatic vein thrombosis may be a complication of oral contraceptive medications. Underlying thrombotic conditions (deficiency of antithrombin III, protein C or S, or factor V Leiden; antiphospholipid antibodies; or mutations of the prothrombin gene) are common in adults.

C. Intrahepatic Portal Hypertension

1. Cirrhosis

See previous section.

2. Veno-occlusive disease (acute stage)

This entity occurs most frequently in bone marrow or stem cell transplant recipients. Additional causes include high-dose thiopurines, ingestion of pyrrolizidine alkaloids (“bush tea”) or other herbal teas, and a familial form of the disease occurring in congenital immunodeficiency states. The acute form of the disease generally occurs in the first month after bone marrow transplantation and is heralded by the triad of weight gain (ascites), tender hepatomegaly, and jaundice.

3. Congenital hepatic fibrosis

This is a rare autosomal recessive cause of intrahepatic presinusoidal portal hypertension (see Table 22–10). Liver biopsy is generally diagnostic, demonstrating Von Meyenburg complexes (abnormal clusters of ectatic bile ducts). On angiography, the intrahepatic branches of the portal vein may be duplicated. Autosomal recessive polycystic kidney disease is frequently associated with this disorder.

4. Other rare causes

Hepatoportal sclerosis (idiopathic portal hypertension, noncirrhotic portal fibrosis), focal nodular regeneration of the liver, and schistosomal hepatic fibrosis are also rare causes of intrahepatic presinusoidal portal hypertension.

Clinical Findings

A. Symptoms and Signs

For prehepatic portal hypertension, splenomegaly in an otherwise well child is the most common physical sign. Ascites may be noted. The usual presenting symptoms are hematemesis and melena.

The presence of prehepatic portal hypertension is suggested by (1) an episode of severe infection in the newborn period or early infancy—especially omphalitis, sepsis, gastroenteritis, severe dehydration, or prolonged or difficult umbilical vein catheterizations; (2) no previous evidence of liver disease; (3) a history of well-being prior to onset or recognition of symptoms; and (4) normal liver size and liver tests with splenomegaly.

Most patients with suprahepatic portal hypertension present with abdominal pain, tender hepatomegaly of acute onset, and ascites. Jaundice is present in only 25% of patients. Vomiting, hematemesis, and diarrhea are less common. Cutaneous signs of chronic liver disease are often absent, as the obstruction is usually acute. Distended superficial veins on the back and the anterior abdomen, along with dependent edema, are seen when inferior vena cava obstruction affects hepatic vein outflow. Absence of hepatojugular reflux (jugular distention when pressure is applied to the liver) is a helpful clinical sign.

The symptoms and signs of intrahepatic portal hypertension are generally those of cirrhosis (see earlier section on Cirrhosis).

B. Laboratory Findings and Imaging

Most other common causes of splenomegaly or hepatosplenomegaly may be excluded by appropriate laboratory tests. Cultures, EBV and hepatitis serologies, blood smear examination, bone marrow studies, and LFTs may be necessary. In prehepatic portal hypertension, LFTs are generally normal. In Budd-Chiari syndrome and veno-occlusive disease, mild to moderate hyperbilirubinemia with modest elevations of AST, ALT, and PT/INR are often present. Significant early increases in fibrinolytic parameters (especially plasminogen activator inhibitor 1) have been reported in veno-occlusive disease. Hypersplenism with mild leukopenia and thrombocytopenia is often present. Upper endoscopy may reveal varices in symptomatic patients.

Doppler-assisted ultrasound scanning of the liver, portal vein, splenic vein, inferior vena cava, and hepatic veins may assist in defining the vascular anatomy. In prehepatic portal hypertension, abnormalities of the portal or splenic vein may be apparent, whereas the hepatic veins are normal. When noncirrhotic portal hypertension is suspected, angiography often is diagnostic. Selective arteriography of the superior mesenteric artery or MRI is recommended prior to surgical shunting to determine the patency of the superior mesenteric vein.

For suprahepatic portal hypertension, an inferior vena cavogram using catheters from above or below the suspected obstruction may reveal an intrinsic filling defect, an infiltrating tumor, or extrinsic compression of the inferior vena cava by an adjacent lesion. A large caudate lobe of the liver suggests Budd-Chiari syndrome. Care must be taken in interpreting extrinsic pressure defects of the subdiaphragmatic inferior vena cava if ascites is significant.

Simultaneous wedged hepatic vein pressure and hepatic venography are useful to demonstrate obstruction to major hepatic vein ostia and smaller vessels. In the absence of obstruction, reflux across the sinusoids into the portal vein branches can be accomplished. Pressures should also be taken from the right heart and supradiaphragmatic portion of the inferior vena cava to eliminate constrictive pericarditis and pulmonary hypertension from the differential diagnosis.

Differential Diagnosis

All causes of splenomegaly must be included in the differential diagnosis. The most common ones are infections, immune thrombocytopenic purpura, blood dyscrasias, lipidosis, reticuloendotheliosis, cirrhosis of the liver, and cysts or hemangiomas of the spleen. When hematemesis or melena occurs, other causes of gastrointestinal bleeding are possible, such as gastric or duodenal ulcers, tumors, duplications, and inflammatory bowel disease.

Because ascites is almost always present in suprahepatic portal hypertension, cirrhosis resulting from any cause must be excluded. Other suprahepatic (cardiac, pulmonary) causes of portal hypertension must also be ruled out. Although ascites may occur in prehepatic portal hypertension, it is uncommon.

Complications

The major manifestation and complication of portal hypertension is bleeding from esophageal varices. Fatal exsanguination is uncommon, but hypovolemic shock or resulting anemia may require prompt treatment. Hypersplenism with leukopenia and thrombocytopenia occurs, but seldom causes major symptoms.

Without treatment, complete and persistent hepatic vein obstruction in suprahepatic portal hypertension leads to liver failure, coma, and death. A nonportal type of cirrhosis may develop in the chronic form of hepatic veno-occlusive disease in which small- and medium-sized hepatic veins are affected. Death from renal failure may occur in rare cases of congenital hepatic fibrosis.

Treatment

Definitive treatment of noncirrhotic portal hypertension is generally lacking. Aggressive medical treatment of the complications of prehepatic portal hypertension is generally quite effective. Excellent results are also seen with either portosystemic shunt or the mesorex (mesenterico–left portal bypass) shunt. When possible (there must be an open left portal vein and no underlying liver disease on biopsy), the mesorex shunt is the preferred technique. Veno-occlusive disease may be prevented somewhat by the prophylactic use of UDCA or defibrotide prior to conditioning for bone marrow transplantation. Treatment with defibrotide and withdrawal of the suspected offending agent, if possible, may increase the chance of recovery. Transjugular intrahepatic portosystemic shunts have been successful in bridging to recovery in veno-occlusive disease. For suprahepatic portal hypertension, efforts should be directed at correcting the underlying cause, if possible. Either surgical or angiographic relief of obstruction should be attempted if a defined obstruction of the vessels is apparent. Liver transplantation, if not contraindicated, should be considered early if direct correction is not possible. In most cases, management of portal hypertension is directed at management of the complications (Table 22–9).

Prognosis

For prehepatic portal hypertension, the prognosis depends on the site of the block, the effectiveness of variceal eradication, the availability of suitable vessels for shunting procedures, and the experience of the surgeon. In patients treated by medical means, bleeding episodes seem to diminish with adolescence. Portacaval encephalopathy is unusual after shunting except when protein intake is excessive, but neurologic outcome may be better in patients who receive a mesorex shunt when compared with medical management alone.

The mortality rate of hepatic vein obstruction is very high (95%). In veno-occlusive disease, the prognosis is better, with complete recovery possible in 50% of acute forms and 5%–10% of subacute forms.

BILIARY TRACT DISEASE

1. Cholelithiasis

General Considerations

Gallstones may develop at all ages in the pediatric population and in utero. Gallstones may be divided into cholesterol stones (> 50% cholesterol) and pigment (black [sterile bile] and brown [infected bile]) stones. Pigment stones predominate in the first decade of life, while cholesterol stones account for up to 90% of gallstones in adolescence. The process is reversible in some patients.

Clinical Findings

A. History

Most symptomatic gallstones are associated with acute or recurrent episodes of moderate to severe, sharp right upper quadrant, or epigastric pain. The pain may radiate substernally or to the right shoulder. On rare occasions, the presentation may include a history of jaundice, back pain, or generalized abdominal discomfort, when it is associated with pancreatitis, suggesting stone impaction in the common duct or major ampulla. Nausea and vomiting may occur during attacks. Pain episodes often occur postprandially, especially after ingestion of fatty foods. The groups at risk for gallstones include patients with known or suspected hemolytic disease; females; teenagers with prior pregnancy; obese individuals; individuals with rapid weight loss; children with portal vein thrombosis; certain racial or ethnic groups, particularly Native Americans (Pima Indians) and Hispanics; infants and children with ileal disease (Crohn disease) or prior ileal resection; patients with cystic fibrosis or Wilson disease; infants on prolonged parenteral nutrition and those with bile acid transporter defects. Other, less certain risk factors include a positive family history, use of birth control pills, and diabetes mellitus.

B. Symptoms and Signs

During acute episodes of pain, tenderness is present in the right-upper quadrant or epigastrium, with a positive inspiratory arrest (Murphy sign), usually without peritoneal signs. While rarely present, scleral icterus is helpful. Evidence of underlying hemolytic disease in addition to icterus may include pallor (anemia), splenomegaly, tachycardia, and high-output cardiac murmur. Fever is unusual in uncomplicated cases and should raise concern for cholangitis or cholecystitis.

C. Laboratory Findings

Laboratory tests are usually normal unless calculi have lodged in the extrahepatic biliary system, in which case the serum bilirubin and GGT (or alkaline phosphatase) may be elevated. Amylase and lipase levels may be increased if stone obstruction occurs at the major papilla and causes gallstone pancreatitis.

D. Imaging

Ultrasound evaluation is the best imaging technique, showing abnormal intraluminal contents (stones, sludge) as well as anatomic alterations of the gallbladder or dilation of the biliary ductal system. The presence of an anechoic acoustic shadow differentiates calculi from intraluminal sludge or sludge balls. In selected cases, ERCP, MRCP, or endoscopic ultrasound may be helpful in defining subtle abnormalities of the bile ducts and locating intraductal stones.

Differential Diagnosis

Other abnormal conditions of the biliary system with similar presentation are summarized in Table 22–10. Liver disease (hepatitis, abscess, or tumor) can cause similar symptoms or signs. Peptic disease, reflux esophagitis, paraesophageal hiatal hernia, cardiac disease, and pneumomediastinum must be considered when the pain is epigastric or substernal in location. Renal or pancreatic disease is a possible explanation if the pain is localized to the right flank or mid back. Subcapsular or supracapsular lesions of the liver (abscess, tumor, or hematoma) or right-lower lobe infiltrate may also be a cause of nontraumatic right shoulder pain.

Complications

Major problems are related to stone impaction in either the cystic or common duct, which may lead to stricture formation or perforation and subsequent bile leak. Stones impacted at the level of the major ampulla often cause gallstone pancreatitis.

Treatment

Symptomatic cholelithiasis is treated by laparoscopic cholecystectomy or open cholecystectomy in selected cases. Intraoperative cholangiography via the cystic duct or preoperative endoscopic ultrasound can be considered in select patients so that the physician can be certain the biliary system is free of retained stones. Calculi in the extrahepatic bile ducts may be removed via ERCP.

Gallstones developing in premature infants on parenteral nutrition can be followed by ultrasound examination. Most of the infants are asymptomatic, and the stones will resolve in 3–36 months. Gallstone dissolution using cholelitholytics (UDCA) or mechanical means (lithotripsy) has not been approved for children. Asymptomatic gallstones do not usually require treatment, as less than 20% will eventually cause problems.

Prognosis

The prognosis is excellent in uncomplicated cases that come to standard or laparoscopic cholecystectomy.

2. Primary Sclerosing Cholangitis

General Considerations

Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by chronic inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts, leading to fibrotic strictures and saccular dilations of all or parts of the biliary tree. The etiology of PSC is likely multifactorial, including genetic predispositions, with alterations in innate and autoimmunity. PSC is more common in males, and has a strong relationship to inflammatory bowel disease, particularly ulcerative colitis. A PSC-like condition can also be seen with histiocytosis X, AIH, IgG4 autoimmune pancreatitis, sicca syndromes, congenital and acquired immunodeficiency syndromes, and cystic fibrosis. Sclerosing cholangitis due to Cryptosporidia may occur in immunodeficiency syndromes.

Clinical Findings

A. Symptoms and Signs

PSC often has an insidious onset and may be asymptomatic. Clinical symptoms may include abdominal pain, fatigue, pruritus, jaundice, and weight loss. Acholic stools, steatorrhea, hepatomegaly, and splenomegaly can occur.

B. Laboratory Findings

The earliest finding may be asymptomatic elevation of the GGT. Subsequent laboratory abnormalities include elevated levels of alkaline phosphatase and bile acids. Later, cholestatic jaundice and elevated AST and ALT may occur. Markers of autoimmune liver disease (ANA and ASMA) are often found, but are not specific for PSC and may actually be due to concurrent overlap with AIH (overlap syndrome or autoimmune cholangitis).

C. Diagnosis

Ultrasound is often normal in PSC, but may detect dilated bile ducts related to dominant biliary strictures. MRCP is the diagnostic study of choice for medium/large duct PSC, demonstrating irregularities of the biliary tree, including saccular dilation of normal intrahepatic bile ducts with segmental strictures (“beads on a string”), dominant strictures of large ducts, or “pruning” of the smaller bile duct branches. ERCP may be more sensitive for the diagnosis of irregularities of the intrahepatic biliary tree and allow for therapeutic interventions. In ~ 15% of cases, the MRCP will be normal and the disease manifests only in the small bile ducts (“small duct PSC”). Small duct PSC is diagnosed based on the liver histology finding of concentric fibrosis surrounding the bile ducts (“onion skinning”).

Differential Diagnosis

The differential diagnosis includes infectious hepatitis, secondary sclerosing cholangitis, AIH, progressive familial intrahepatic cholestasis type 3, cystic fibrosis, choledochal cyst, or other anomalies of the biliary tree, including Caroli disease (see Table 22–10).

Complications

Complications include refractory pruritus, bacterial cholangitis, biliary fibrosis, cirrhosis, and complications of portal hypertension. Slow progression to end-stage liver disease is likely, and patients are at increased risk of cholangiocarcinoma.

Treatment

Treatment of PSC focuses on supportive care. UDCA is often used in pediatrics, though high doses may worsen disease in adults. Pruritus may improve with UDCA, rifampin, or naltrexone. Patients with autoimmune sclerosing cholangitis or IgG4 cholangitis should benefit from treatment with corticosteroids and azathioprine. Antibiotic treatment of cholangitis and dilation and stenting of dominant bile duct strictures can reduce symptoms. Liver transplantation is effective for patients with end-stage complications, but the disease may recur in up to 20% after transplant.

Prognosis

The majority of patients will eventually require liver transplantation in adulthood. PSC is the fifth leading indication for liver transplantation in adults in the United States.

3. Other Biliary Tract Disorders

For a schematic representation of the various types of choledochal cysts, see Figure 22–1. For summary information on acute hydrops, choledochal cyst, acalculous cholecystitis, Caroli disease, biliary dyskinesia, and congenital hepatic fibrosis, see Table 22–10.

PYOGENIC & AMEBIC LIVER ABSCESS

General Considerations

Pyogenic liver abscesses are rare in developed countries, but remain a significant issue in developing countries. The most common cause is S aureus, with enteric bacteria less common; fungal abscesses also occur. The resulting lesion tends to be solitary and located in the right hepatic lobe. Unusual causes include omphalitis, subacute infectious endocarditis, pyelonephritis, Crohn disease, and perinephric abscess. In immunocompromised patients, S aureus, gram-negative organisms, and fungi may seed the liver from the arterial system. Multiple pyogenic liver abscesses are associated with severe sepsis. Children receiving anti-inflammatory and immunosuppressive agents and children with defects in white blood cell function (chronic granulomatous disease) are prone to pyogenic hepatic abscesses, especially those caused by S aureus.

Amebic liver abscess can occur when Entamoeba histolytica invasion occurs via the large bowel, although a history of diarrhea (colitis-like picture) is not always obtained.

Clinical Findings

A. History

With any liver abscess, nonspecific complaints of fever, chills, malaise, and abdominal pain are frequent. Amebic liver abscess is rare in children. An increased risk is associated with travel in areas of endemic infection within 5 months of presentation.

B. Symptoms and Signs

Weight loss is very common, especially when diagnosis is delayed. A few patients have shaking chills and jaundice. The dominant complaint is a constant dull pain over an enlarged liver that is tender to palpation. An elevated hemidiaphragm with reduced or absent respiratory excursion may be demonstrated on physical examination and confirmed by fluoroscopy.

Fever and abdominal pain are the two most common symptoms of amebic liver abscess. Abdominal tenderness and hepatomegaly are present in over 50%. An occasional prodrome may include cough, dyspnea, and shoulder pain when rupture of the abscess into the right chest occurs.

C. Laboratory Findings

Laboratory studies show leukocytosis and, at times, anemia. LFTs may be normal or reveal mild elevation of transaminases and alkaline phosphatase. Blood cultures may be positive. The distinction between pyogenic and amebic abscesses in developed countries is best made by indirect hemagglutination test for specific antibody (which is positive in more than 95% of patients with amebic liver disease) and the prompt clinical response of the latter to anti-amebic therapy (metronidazole). Examination of material obtained by needle aspiration of the abscess using ultrasound guidance is often diagnostic.

D. Imaging

Ultrasound is the most useful diagnostic aid in evaluating pyogenic and amebic abscesses, detecting lesions as small as 1–2 cm. MRI, CT, or nuclear scanning may be useful in differentiating tumor or hydatid cyst. Consolidation of the right lower lobe of the lung is common (10%–30% of patients) in amebic abscess.

Differential Diagnosis

Hepatitis, hepatoma, hydatid cyst, gallbladder disease, or biliary tract infections can mimic liver abscess. Subphrenic abscesses, empyema, and pneumonia may give a similar picture. Inflammatory disease of the intestines or of the biliary system may be complicated by liver abscess.

Complications

Spontaneous rupture of the abscess may occur with extension of infection into the subphrenic space, thorax, peritoneal cavity, and, occasionally, the pericardium. Bronchopleural fistula with large sputum production and hemoptysis can develop in severe cases. Simultaneously, the amebic liver abscess may be secondarily infected with bacteria (in 10%–20% of patients). Metastatic hematogenous spread to the lungs and the brain has been reported.

Treatment

Small bacterial liver abscesses (< 5 cm) or those with a solid appearance can be treated medically. Ultrasound- or CT-guided percutaneous needle aspiration for aerobic and anaerobic culture with simultaneous placement of a catheter for drainage, combined with appropriate antibiotic therapy, is the treatment of choice for solitary larger or liquid pyogenic liver abscess. Multiple liver abscesses may also be treated successfully by this method. Surgical intervention may be indicated if rupture occurs outside the capsule of the liver or if enterohepatic fistulae are suspected.

Amebic abscesses in uncomplicated cases should be treated with oral metronidazole, 35–50 mg/kg/day, in three divided doses for 10 days. Intravenous metronidazole can be used for patients unable to take oral medication. Needle aspiration or surgical drainage is indicated for failure of medical management or cysts greater than 10 cm. Once oral feedings can be tolerated, a luminal amebicide such as iodoquinol should be initiated. Resolution of the abscess cavity occurs over 3–6 months.

Prognosis

With drainage and antibiotics, the cure rate is about 90%. Mortality rates have improved, but remain at 4% for pyogenic liver abscess, especially with extrahepatic complications, and less than 1% for amebic abscess.

LIVER TUMORS

General Considerations

Primary neoplasms of the liver represent 0.3%–5% of all solid tumors in children. Of these, two-thirds are malignant, with hepatoblastoma being most common (79% of all pediatric liver cancers). Hepatoblastoma typically occurs in children ages 6 months to 3 years, with a male predominance. Most children present with an asymptomatic abdominal mass, though with more advanced disease, weight loss, anorexia, abdominal pain, and emesis may occur. Children with Beckwith-Wiedemann syndrome and familial adenomatosis polyposis coli are at increased risk of hepatoblastoma, and should undergo routine screening with α-fetoprotein determinations and abdominal ultrasound until the age of 5 years. In addition, low-birth-weight infants (< 1000 g) have a 15 times increased risk of hepatoblastoma, as compared to infants weighing more than 2500 g. Differentiation from hepatocellular carcinoma, the other major malignant tumor of the liver, may be difficult.

Hepatocellular carcinoma most commonly occurs between the ages of 10 and 12 years and is more common in males. Children are more likely to have advanced disease at presentation, and therefore be symptomatic, with abdominal distension, pain, anorexia, and weight loss. Patients with chronic HBV or HCV infection, cirrhosis, glycogen storage disease type I, tyrosinemia, and α₁-antitrypsin deficiency are at increased risk for developing hepatocellular carcinoma. The late development of hepatocellular carcinoma in patients receiving androgens for treatment of Fanconi syndrome and aplastic anemia must be kept in mind. The use of anabolic steroids by body-conscious adolescents poses a risk of hepatic neoplasia. In addition, Wilms tumors, neuroblastoma, and lymphoma may metastasize to the liver.

Clinical Findings

A. History

Noticeable abdominal distension, with or without pain, is the most constant feature. A parent may note a bulge in the upper abdomen or report feeling a hard mass. Constitutional symptoms (eg, anorexia, weight loss, fatigue, fever, and chills) may be present. Jaundice or pruritus may occur with obstruction of the biliary tree. Virilization has been reported as a consequence of gonadotropic activity of tumors. Feminization with bilateral gynecomastia may occur in association with high estradiol levels in the blood, the latter a consequence of increased aromatization of circulating androgens by the liver. Leydig cell hyperplasia without spermatogenesis has also been reported.

B. Symptoms and Signs

Weight loss, pallor, and abdominal pain in association with a large abdomen are common. Physical examination reveals hepatomegaly with or without a definite tumor mass, usually to the right of the midline. In the absence of cirrhosis, signs of chronic liver disease are usually absent.

C. Laboratory Findings

Normal LFTs are the rule. Anemia frequently occurs, especially in cases of hepatoblastoma. α-Fetoprotein levels are typically elevated, especially in hepatoblastoma. Estradiol levels are sometimes elevated. Tissue diagnosis is best obtained at laparotomy, although ultrasound- or CT-guided needle biopsy of the liver mass can be used.

D. Imaging

Ultrasonography, CT, and MRI are useful for diagnosis, staging, and following tumor response to therapy. A chest CT is generally part of the preoperative workup to evaluate metastatic disease.

Differential Diagnosis

In the absence of a palpable mass, the differential diagnosis is that of hepatomegaly with or without anemia or jaundice. Hematologic and nutritional conditions should be ruled out, as well as HBV and HCV infection, α₁-antitrypsin deficiency disease, lipid storage diseases, histiocytosis X, glycogen storage disease, tyrosinemia, congenital hepatic fibrosis, cysts, adenoma, focal nodular hyperplasia, and hemangiomas. If fever is present, hepatic abscess (pyogenic or amebic) must be considered. Veno-occlusive disease and hepatic vein thrombosis are rare possibilities. Tumors in the left lobe may be mistaken for pancreatic pseudocysts.

Complications

With progressive enlargement of the tumor, abdominal discomfort, ascites, respiratory difficulty, and widespread metastases (especially to the lungs and the abdominal lymph nodes) may occur. Rupture of the neoplastic liver and intraperitoneal hemorrhage have been reported.

Treatment

For tumors that are resectable, an aggressive surgical approach with complete resection of the lesion offers the only chance for cure. Individual lung metastases should also be surgically resected. Radiotherapy and chemotherapy have been disappointing in the treatment of hepatocellular carcinoma, although hepatoblastomas are generally more responsive. Chemotherapy may be used for initial cytoreduction of tumors (especially hepatoblastoma) found to be unresectable at the time of primary surgery (see Chapter 31 for additional discussion). Liver transplantation can be an option in hepatoblastoma with unresectable disease limited to the liver, with an 85% 10-year survival. For hepatocellular carcinoma, the survival rate is poor due to the typically advanced stage at diagnosis. The survival rate may be better for those patients in whom the tumor is incidental to another disorder (tyrosinemia, biliary atresia, cirrhosis) or is less than a total of 7 cm diameter without vascular invasion. In HBV-endemic areas, childhood HBV vaccination has reduced the incidence of hepatocellular carcinoma.

Prognosis

If the tumor is completely removed, the survival rate is 90% for hepatoblastoma and 33% for hepatocellular carcinoma. If metastases that cannot be surgically resected are present, survival is reduced to 40% for hepatoblastoma. In well-selected candidates with unresectable hepatoblastoma, survival after liver transplantation approaches 65%.

LIVER TRANSPLANTATION

Orthotopic liver transplantation is indicated in children with end-stage liver disease, acute fulminant hepatic failure, non-resectable liver tumors, or complications from metabolic liver disorders. Approximately 600 pediatric liver transplants are performed annually, with excellent 1-year (83%–91%) and 5-year (82%–84%) survival rates. The multitude of immunosuppression options, ability to individualize immunosuppression, improved candidate selection, refinements in surgical techniques, anticipatory monitoring for complications (eg, CMV and EBV infections, hypertension, renal dysfunction, and dyslipidemias), and experience in postoperative management have all contributed to improved outcomes over time. The major indications for childhood transplantation are shown in Table 22–11.

Children who are potential candidates for liver transplantation should be referred to a pediatric transplant center early for evaluation. In addition to full-sized cadaveric organs, children may also receive reduced segment or split cadaveric livers and live donor transplants, all of which have expanded the potential donor pool. Lifetime immunosuppression therapy, using combinations of tacrolimus, prednisone, azathioprine, mycophenolate mofetil, or sirolimus, with its incumbent risks, is generally necessary to prevent rejection. Small studies have examined the potential for complete immunosuppression withdrawal, with a more definitive multicenter study currently underway. Currently, the minimal amount of immunosuppression that will prevent allograft rejection should be chosen. The overall quality of life for children with a transplanted liver appears to be excellent. There is an increased risk (up to 25%) of renal dysfunction and low intelligence scores. The lifelong risk of EBV-induced lymphoproliferative disease, which is approximately 5%, is related to age and EBV exposure status at time of transplantation, and intensity of immunosuppression.

ACUTE PANCREATITIS

General Considerations

The incidence of acute pancreatitis in children is now about 1 per 10,000. Acute pancreatitis is defined as at least two of the following three: abdominal pain consistent with acute pancreatitis; amylase and/or lipase greater than three times the upper limit of normal; and US, CT, or MRI imaging consistent with acute pancreatitis. Most cases of acute pancreatitis are the result of drugs, viral infections, systemic diseases, abdominal trauma, or obstruction of pancreatic flow. More than 20% are idiopathic. Causes of pancreatic obstruction include stones, choledochal cyst, tumors of the duodenum, pancreas divisum, and ascariasis. Acute pancreatitis has been seen following treatment with many different medications, including sulfasalazine, thiazides, valproic acid, azathioprine, mercaptopurine, asparaginase, antiretroviral drugs, high-dose corticosteroids, and other drugs. It may also occur in cystic fibrosis, systemic lupus erythematosus, diabetes mellitus, Crohn disease, glycogen storage disease type I, hyperlipidemia, hyperparathyroidism, Henoch-Schönlein purpura, Reye syndrome, organic acidopathies, Kawasaki disease, or chronic renal failure; during rapid refeeding in cases of malnutrition; following spinal fusion surgery; and certain genetic mutations. Alcohol-induced pancreatitis should be considered in adolescents.

Clinical Findings

A. History

An acute onset of persistent (hours to days), moderate to severe upper abdominal and midabdominal pain occasionally referred to the back, frequently associated with vomiting, or nausea is the common presenting picture.

B. Symptoms and Signs

The abdomen is tender, but not rigid. Abdominal distention is common in infants and younger children, and classic symptoms of abdominal pain, tenderness, and nausea are less common in this age group. Jaundice is unusual. Ascites may be noted, and a left-sided pleural effusion is present in some patients. Periumbilical and flank bruising are rare and indicate hemorrhagic pancreatitis.

C. Laboratory Findings

An elevated serum amylase or lipase (more than three times normal) is the key laboratory finding. The elevated serum lipase persists longer than serum amylase. Infants younger than 6 months may not have an elevated amylase or lipase. In this setting, an elevated immunoreactive trypsinogen may be more sensitive. Pancreatic lipase can help differentiate nonpancreatic causes (eg, salivary, intestinal, or tuboovarian) of serum lipase elevation. Leukocytosis, hyperglycemia (serum glucose > 300 mg/dL), hypocalcemia, falling hematocrit, rising blood urea nitrogen, hypoxemia, and acidosis may occur in severe cases and imply a worse prognosis.

D. Imaging

Ultrasonography is the initial imaging of choice and is primarily used to assess for biliary tract disease leading to pancreatitis, but can show decreased echodensity of the pancreas in comparison with the left lobe of the liver. The pancreas (especially the body and tail) is often difficult to image with ultrasound due to overlying gas. CT scan images the pancreas more consistently and is better for detecting pancreatic phlegmon, pseudocyst, or necrosis. ERCP or MRCP may be useful in confirming patency of the main pancreatic duct in cases of abdominal trauma; in recurrent acute pancreatitis; or in revealing stones, ductal strictures, and pancreas divisum.

Differential Diagnosis

There are many other causes of acute upper abdominal pain include gastritis, peptic ulcer disease, duodenal ulcer, hepatitis, liver abscess, cholelithiasis, cholecystitis, choledocholithiasis, acute gastroenteritis, functional gastrointestinal disorders such as functional dyspepsia, atypical appendicitis, pneumonia, volvulus, intussusception, and nonaccidental trauma.

Complications

Early complications include shock, fluid and electrolyte disturbances, ileus, acute respiratory distress syndrome, and hypocalcemia. Hypervolemia due to renal insufficiency related to renal tubular necrosis may occur. Early predictors of a more aggressive course include renal dysfunction, significant fluid requirements, and multisystem organ dysfunction. Around 5%–20% of patients can develop pancreatic fluid collections (pseudocysts are completely fluid filled and walled off necrosis cavities contain fluid and solid necrotic debris) that may be asymptomatic or present with recurrence of abdominal pain, vomiting, or nausea. Up to 60%–70% of pseudocysts resolve spontaneously. Infection, hemorrhage, rupture, or fistulization may occur. Phlegmon formation is rare in children, but when present may extend from the gland into the retroperitoneum or into the lesser sac. Infection may occur in this inflammatory mass. Mature symptomatic fluid collections (pseudocyst or pancreatic walled-off necrosis) may be treated with endoscopic ultrasound-guided cystgastrostomy. Chronic pancreatitis and exocrine or endocrine pancreatic insufficiency are rare sequelae of acute pancreatitis.

Treatment

Medical management includes careful attention to fluid, electrolytes, and respiratory status. Data in adults suggest lactated ringers may be preferred for initial volume expansion in acute pancreatitis. Pain should be aggressively treated with opioid and non-opioid medications. Historically patients were kept NPO, but more recent studies have shown that early enteral nutrition by mouth decreases hospital length of stay in mild-moderate pediatric pancreatitis. Early supplemental enteral nutrition via nasogastric or nasojejunal tube has better outcomes than parenteral nutrition in severe pancreatitis. Broad-spectrum antibiotic coverage is only beneficial in necrotizing pancreatitis. Drugs known to produce acute pancreatitis should be discontinued. Surgical treatment is reserved for traumatic disruption of the gland, other anatomic obstructive lesions, and unresolved or infected pseudocysts or abscesses not amenable to endoscopic or radiographically-guided drainage. Early endoscopic decompression of the biliary system reduces the morbidity associated with pancreatitis caused by obstruction of the common bile duct.

Prognosis

In the pediatric age group, the prognosis is good with conservative management with mortality less than 0.4%. Up to 42% of children hospitalized with their initial episode of acute pancreatitis will have one or more subsequent admissions for pancreatitis.

CHRONIC PANCREATITIS

Chronic pancreatitis does not imply long-standing pancreatitis, but denotes that the pancreas has permanent parenchymal or ductal changes from inflammation.

The causes are similar to acute pancreatitis, but children with chronic pancreatitis are more likely to have underlying genetic or anatomic risk factors for pancreatitis.

Clinical Findings

A. History

The diagnosis often is delayed by the nonspecificity of symptoms and the lack of persistent laboratory abnormalities. There is usually a prolonged history of recurrent upper abdominal pain and/or nausea of variable severity. Radiation of the pain into the back is a frequent complaint.

B. Symptoms and Signs

Fever and vomiting are rare. Diarrhea, due to steatorrhea, and symptoms of diabetes may develop later in the course. Malnutrition due to acquired exocrine pancreatic insufficiency may also occur.

C. Laboratory Findings

Serum amylase and lipase levels are usually elevated during early acute attacks, but are often normal in the chronic phase. Pancreatic insufficiency may be diagnosed by demonstration of a low fecal pancreatic elastase 1. Increasingly, multiplex genetic testing panels are used to screen for the expanding number of identified genetic causes for chronic pancreatitis. Some identified genes include those for cationic trypsinogen (PRSS1), the pancreatic secretory trypsin inhibitor, the cystic fibrosis transmembrane conductance regulator (CFTR), carboxypeptidase A1, and chymotrypsin C. Screening for pancreatogenic (type 3c) diabetes should be considered. Sweat chloride should be checked for cystic fibrosis and serum calcium for hyperparathyroidism.

D. Imaging

Ultrasound or CT examination may demonstrate an abnormal gland (enlargement, atrophy or calcifications), ductal dilation, and/or calculi in up to 80% in advanced disease. MRCP or ERCP can show ductal dilation, stones, strictures, or stenotic segments. Endoscopic ultrasound may show early changes of chronic pancreatitis.

Differential Diagnosis

Other causes of recurrent abdominal pain must be considered. Specific causes of pancreatitis such as autoimmune pancreatitis, hyperparathyroidism, systemic lupus erythematosus, infectious disease, traumatic pancreatitis, and ductal obstruction by tumors, stones, or helminths must be excluded by appropriate tests.

Complications

Disabling abdominal pain, steatorrhea, malnutrition, pancreatic pseudocysts, and diabetes are the most frequent long-term complications. Pancreatic carcinoma occurs more frequently in patients with chronic pancreatitis, and in up to 40% of patients with hereditary pancreatitis (PRSS1 mutations) by age 70.

Treatment

Medical management of acute attacks is indicated (see section on Acute Pancreatitis). If ductal obstruction is strongly suspected, endoscopic therapy (balloon dilation, stenting, stone removal, or sphincterotomy) should be pursued. Relapses occur in most patients. There are no proven therapies which modify disease course of chronic pancreatitis. Pancreatic enzyme therapy should be used in patients with exocrine insufficiency. Mature fluid collections may be drained with endoscopic ultrasound-guided cystgastrostomy, or if this is unavailable, interventional radiology, or surgical approaches if they fail to regress spontaneously.

Surgical treatment includes pancreatic ductal decompression procedures as well as total pancreatectomy and islet cell autotransplantation (TPIAT). TPIAT is performed in specialized centers and is curative for the pancreatic inflammation, resolves risk of pancreatic cancer, and may significantly improve or resolve pain. However, it carries risks of surgical morbidity, causes lifelong exocrine insufficiency, and many patients progress to need lifelong insulin. Previous pancreatic surgery decreases the amount of islet cells which can be isolated from the pancreas and increases risk of diabetes after TPIAT.

Prognosis

In the absence of a correctable lesion, the prognosis is not good. Disabling episodes of pain, pancreatic insufficiency, diabetes, and pancreatic cancer may ensue. Narcotic addiction and suicide are risks in teenagers with disabling disease. TPIAT may significantly improve quality of life in pediatric patients with severe chronic pancreatitis pain. Given the complexity of chronic pancreatitis, a multidisciplinary approach is often beneficial, and referral to centers with expertise with management of pancreatic disorders should be considered.

GASTROINTESTINAL & HEPATOBILIARY MANIFESTATIONS OF CYSTIC FIBROSIS

Pulmonary and pancreatic involvement dominate the clinical picture for most patients with cystic fibrosis (see Chapter 19), however, various other organs can be involved. Table 22–12 lists the important gastrointestinal, pancreatic, and hepatobiliary conditions that may affect patients with cystic fibrosis along with their clinical findings, incidence, most useful diagnostic studies, and preferred treatment. In addition to the listed conditions, children with cystic fibrosis can develop functional gastrointestinal disorders like any other children.

SYNDROMES WITH PANCREATIC EXOCRINE INSUFFICIENCY

Several syndromes are associated with exocrine pancreatic insufficiency. Patients present with failure to thrive, diarrhea, fatty stools, and an absence of respiratory symptoms. Laboratory findings include low fecal pancreatic elastase 1; high fecal fat content with 72 hour fecal fat analysis using a standardized high-fat diet; and low to absent pancreatic lipase, amylase, and trypsin levels on endoscopic duodenal fluid aspiration. Each disorder has several associated clinical features that aid in the differential diagnosis. In Shwachman-Diamond syndrome, pancreatic exocrine hypoplasia with widespread fatty replacement of the glandular acinar tissue is associated with neutropenia because of maturational arrest of the granulocyte series. Metaphyseal dysostosis and an elevated fetal hemoglobin level are common; immunoglobulin deficiency and hepatic dysfunction are also reported. CT examination of the pancreas demonstrates the widespread fatty replacement. Genotyping of the SBDS gene is available. Serum immunoreactive trypsinogen levels are extremely low.

Other associations of exocrine pancreatic insufficiency include (1) aplastic alae, aplasia cutis, deafness (Johanson-Blizzard syndrome); (2) sideroblastic anemia, developmental delay, seizures, and liver dysfunction (Pearson bone marrow pancreas syndrome); (3) duodenal atresia or stenosis; (4) malnutrition; and (5) pancreatic hypoplasia or agenesis.

The complications and sequelae of exocrine pancreatic insufficiency are malnutrition, diarrhea, and growth failure. The degree of steatorrhea may vary by age and degree of pancreatic function. Intragastric lipolysis by lingual lipase may compensate in patients with low or absent pancreatic function. In Shwachman-Diamond syndrome, pancreatic exocrine insufficiency usually improves with age. Increased infections may result from chronic neutropenia and reduced neutrophil mobility. An increased incidence of leukemia has been noted in these patients; thus patients with myelodysplasia syndrome should be considered for hematopoietic stem cell transplantation.

Pancreatic enzyme and fat-soluble vitamin replacement are required therapy in most patients.

ISOLATED EXOCRINE PANCREATIC ENZYME DEFECT

Premature infants and most newborns produce little, if any, pancreatic amylase following meals or exogenous hormonal stimulation. This temporary physiologic insufficiency may persist for the first 3–6 months of life and be responsible for diarrhea when complex carbohydrates (cereals) are introduced early in the diet.

Congenital pancreatic lipase deficiency and congenital colipase deficiency are extremely rare disorders, causing diarrhea and variable malnutrition with malabsorption of dietary fat and fat-soluble vitamins. In these cases, the sweat chloride level is normal and neutropenia is absent. Treatment is oral replacement of pancreatic enzymes and a low-fat diet or formula containing medium-chain triglycerides.

Exocrine pancreatic insufficiency of proteolytic enzymes (eg, trypsinogen, trypsin, chymotrypsin) is caused by enterokinase deficiency, a duodenal mucosal enzyme required for activation of the pancreatic proenzymes. These patients present with malnutrition associated with hypoproteinemia and edema. Similar to lipase and colipase deficiencies, the sweat test and neutrophil counts are normal. Patients with enterokinase deficiency respond to pancreatic enzyme replacement therapy and feeding formulas that contain a casein hydrolysate (eg, Nutramigen, Pregestimil). Some patients may have transient exocrine pancreatic insufficiency which resolves with time.

PANCREATIC TUMORS

Pancreatic tumors, whether benign or malignant, are rare. The majority of patients with malignant tumors present with abdominal pain or are found incidentally. The most common pediatric pancreatic tumors are solid pseudopapillary tumors (found predominantly in adolescent females), and neuroendocrine tumors (NET) (insulinoma, gastrinoma, glucagonoma, VIPoma, and nonfunctioning NET). NET present in the pancreas in pediatric patients should prompt evaluation for MEN1 syndrome. NET can produce diverse symptoms if they are producing biologically active polypeptides or be asymptomatic. The clinical features of these tumors are summarized in Table 22–13. The differential diagnosis of pancreatic tumors includes Wilms tumor, neuroblastoma, pancreaticoblastoma, and lymphoma. Endoscopic ultrasonography with fine needle biopsy can aid in making definitive diagnoses and guiding surgical planning.