CURRENT Diagnosis and Treatment Pediatrics, (Current Pediatric Diagnosis & Treatment) 22nd Edition

22. Liver & Pancreas

Ronald J. Sokol, MD

Michael R. Narkewicz, MD

Shikha S. Sundaram, MD, MSCI

Cara L. Mack, MD

LIVER DISORDERS

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

Prolonged 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. Histologic examination of percutaneous liver biopsy specimens increases the accuracy of differentiation to 95% (Table 22–2).

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Elevated total and conjugated bilirubin.

 Hepatomegaly and dark urine.

 Patency of extrahepatic biliary tree.

 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% of cases. 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. It 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). 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 associated with neonatal intrahepatic cholestasis include herpes simplex virus, varicella virus, enteroviruses (coxsackievirus and echovirus), 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, enteroviruses) 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. Jaundice may be noted as early as the first 24 hours of life. 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 is present and splenomegaly is variably present. Macular, papular, vesicular, or petechial rashes may occur. In less severe cases, failure to thrive may be the primary problem. Unusual presentations include neonatal liver failure, hypoproteinemia, anasarca (nonhemolytic hydrops), and hemorrhagic disease of the newborn.

B. Diagnostic Studies

Neutropenia, thrombocytopenia, and signs of mild hemolysis are common. Mixed hyperbilirubinemia, elevated aminotransferases with near-normal alkaline phosphatase, 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 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. Careful ophthalmologic examination may be useful for diagnosis of herpes simplex virus, CMV, toxoplasmosis, and rubella.

A percutaneous liver biopsy is useful in distinguishing intrahepatic from extrahepatic 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 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 cordlike 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 dietary or drug therapy is available. These infants may also have concomitant bacteremia. α₁-antitrypsin deficiency, cystic fibrosis, bile acid synthesis defects, progressive familial intrahepatic cholestasis, mitochondrial respiratory chain disorders, and neonatal iron storage disease must also be considered. Specific physical features may suggest Alagille, arthrogryposis/renal dysfunction/cholestasis (ARC) syndrome or Zellweger syndrome. Idiopathic neonatal hepatitis can be indistinguishable from infectious causes.

Patients with intrahepatic cholestasis frequently appear ill, whereas infants with extrahepatic cholestasis do not typically appear ill, have stools that are usually completely acholic, and have an enlarged, firm liver. Histologic findings are described in Table 22–2.

 Treatment

Most forms of viral neonatal hepatitis are treated symptomatically. However, 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 need to be administered promptly. Fluids and adequate nutritional intake are encouraged. 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] or cholestyramine) are used if cholestasis persists. Corticosteroids are contraindicated.

 Prognosis

Multiple organ involvement is commonly associated with neonatal infectious hepatitis and has a poor outcome. Hepatic or cardiac failure, intractable acidosis, or intracranial hemorrhage may be fatal in herpesvirus, adenovirus, or enterovirus infections, and occasionally in CMV or rubella infection. HBV rarely causes fulminant neonatal hepatitis; most infected infants are immunotolerant to hepatitis B. Although persistent liver disease with any virus can result in mild chronic hepatitis, portal fibrosis, or cirrhosis, 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.

Brumbaugh D, Mack C: Conjugated hyperbilirubinemia in children. Pediatr Rev 2012 Jul;33(7):291–302 [PMID: 22753787].

2. Specific Infectious Agents

A. Neonatal Hepatitis B Virus Disease

Vertical transmission of HBV may occur at any time during perinatal life. Most cases of neonatal disease 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 hepatitis B surface antigen (HBsAg)–carrier mothers, neonatal acquisition risk is greatest if the mother (1) is also hepatitis B “e” antigen (HBeAg)–positive and hepatitis B “e” antibody (HBeAb)–negative, (2) has high serum levels of hepatitis B core antibody (HBcAb), or (3) has high blood levels of HBV DNA, indicating circulating infectious virus.

Neonatal HBV liver disease is extremely variable. 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 immunotolerant stage of HBV infection. Fulminant hepatic necrosis and liver failure rarely occur in infants. Other patients develop chronic hepatitis with focal hepatocyte necrosis and a mild portal inflammatory response. Cholestasis is intracellular and canalicular. Chronic hepatitis may persist for many years, with serologic evidence of persisting antigenemia (HBsAg) and mildly elevated or normal serum aminotransferases. Chronic hepatitis may rarely progress to cirrhosis within 1–2 years. 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 for a variable period of time and become an inactive carrier, develop chronic hepatitis or remain immune tolerant through childhood (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. HBIG can provide some protection when given as late as 72 hours after birth. If not given at birth it can be administered as late as 7 days postpartum as long as the infant has received the vaccine. Universal HBV immunization at birth, with two follow-up doses, is recommended for all infants regardless of maternal HBV status. Universal screening of pregnant women for HbsAg is conducted to determine which infants will need HBIG.

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 liver enlarges rapidly, and the histologic picture is that of diffuse hepatitis with or without microabscesses. 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. Bacterial hepatitis and neonatal liver abscesses require specific antibiotics in optimal doses and combinations and, rarely, surgical or radiologic interventional 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 mildly abnormal. Leukocytosis is 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.

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Tran TT: Hepatitis B: treatment to prevent perinatal transmission. Clin Obstet Gynecol 2012;55:541 [PMID: 22510637].

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

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

A. Enzyme Deficiencies and Other Inherited Disorders

Establishing the specific diagnosis as early as possible is important because dietary or pharmacologic treatment may be available (Table 22–5). Reversal of liver disease and clinical symptoms may be prompt and maintained in several disorders as long as the diet is maintained. As with other genetic disorders, 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 patients with galactosemia and cholestasis. Neonatal screening programs for galactosemia 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 of the gastrointestinal system are sometimes followed within 1–2 weeks by cholestasis. This occurs in preterm infants with respiratory distress, 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). Liver function studies reveal mixed hyperbilirubinemia, elevated alkaline phosphatase and γ-glutamyl transpeptidase (GGT) values, and variable elevation of the aminotransferases. 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 is present (eg, short gut syndrome or intestinal failure), resolution of the hepatic abnormalities is the rule, although this may take many weeks.

2. Prolonged parenteral nutrition—Cholestasis may develop after 1–2 weeks in premature newborns receiving parenteral nutrition. Even full-term infants with significant intestinal atresia, resections, or dysmotility may develop parenteral nutrition–associated cholestasis. Contributing factors include toxicity of intravenous lipid emulsions, diminished stimulation of bile flow from prolonged absence of feedings, frequent episodes of sepsis, small intestinal bacterial overgrowth with translocation of intestinal bacteria and their cell wall products, missing nutrients or antioxidants, photooxidation of amino acids, infusion of lipid hydroperoxides or plant sterols, and the “physiologic cholestatic” propensity of the premature infant. Activation of innate immune pathways in the liver appears to be involved. Histology of the liver may be identical to that of biliary atresia. Early introduction of feedings has reduced the frequency of this disorder. The prognosis is generally good; however, in infants with intestinal failure occasional cases progress to cirrhosis, liver failure, and 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. Intravenous fish oil–based lipid emulsions or reduction in soy-oil-based lipid emulsions may reverse features of cholestasis.

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 for more than 1–2 weeks requires further studies (ultrasonography, hepatobiliary iminodiacetic acid [HIDA] scanning, liver biopsy) with possible cholangiography. Irrigation of the common bile duct is sometimes necessary to dislodge the obstructing inspissated biliary material.

El Kasmi KC et al: Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. Hepatology 2012;55:1518 [PMID: 22120983].

Ng PC et al: High-dose oral erythromycin decreased the incidence of parenteral nutrition-associated cholestasis in preterm infants. Gastroenterology 2007;132:1726 [PMID: 17484870].

Rangel SJ et al: Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg 2012;47:225 [PMID: 22244423].

4. Idiopathic Neonatal Hepatitis (Giant-Cell Hepatitis)

This idiopathic type of cholestatic jaundice, which has a typical liver biopsy appearance, accounts for 20%–30% of cases of neonatal intrahepatic cholestasis but is decreasing in frequency as new causes of cholestasis are discovered. The degree of cholestasis is variable, and the disorder may be indistinguishable from extrahepatic causes in 10% of cases. Many cases of this disorder have been shown in recent years to have specific etiologies. Viral infections, α₁-antitrypsin deficiency, Alagille syndrome, Niemann-Pick type C disease (NPC), progressive familial intrahepatic cholestasis (PFIC), citrin deficiency, neonatal hemochromatosis, and bile acid synthesis defects may present with similar clinical and histologic features. 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.

Intrauterine growth retardation, prematurity, poor feeding, emesis, poor growth, and partially or intermittently acholic stools are characteristic of intrahepatic cholestasis. 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 surgical 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. Failure to detect patency of the biliary tree, nondiagnostic liver biopsy findings, or persisting complete cholestasis (acholic stools) are indications for minilaparotomy and intraoperative cholangiography performed by an experienced surgeon, ERCP, percutaneous cholecystography, or magnetic resonance cholangiopancreatography (MRCP). 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. 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.

Eighty percent 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 a yet to be defined underlying genetic/metabolic disorder. This may occur with either normal or diminished numbers of interlobular bile ducts (paucity of interlobular ducts). Liver transplantation has been successful when signs of hepatic decompensation are noted (rising bilirubin, coagulopathy, intractable ascites).

Guddat SS et al. Fatal spontaneous subdural bleeding due to neonatal giant cell hepatitis: a rare differential diagnosis of shaken baby syndrome. Forensic Sci Med Pathol 2011 Sep;7(3):294–297 [PMID: 21331818].

Torbenson M et al: Neonatal giant cell hepatitis: histological and etiological findings. Am J Surg Pathol 2010 Oct;34(10): 1498–1503 [PMID: 20871223].

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. The eyes are set deep and sometimes widely apart (hypertelorism). The chin is small and slightly pointed and projects forward. The ears are prominent. The stool color varies with the severity of cholestasis. Pruritus begins by age 3–6 months. Firm, smooth hepatomegaly may be present or the liver may be of normal size. Cardiac murmurs are present in 95% 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. Occasionally, early cholestasis is mild and not recognized or the patient presents with complex congenital heart disease (eg, tetralogy of Fallot).

Conjugated hyperbilirubinemia may be mild to severe (2–15 mg/dL). Serum alkaline phosphatase, GGT, and cholesterol are 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%) and renal abnormalities (dysplastic kidneys, renal tubular ectasia, single kidney, RTA, hematuria) are also characteristic and occur in about 40% of patients. Growth retardation with normal to increased levels of growth hormone (growth hormone resistance) is common. Some patients may rarely have pancreatic insufficiency that may contribute to the fat malabsorption. 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) eventually develop in many unsupplemented children and may be profound.

In the nonsyndromic form, paucity of interlobular bile ducts occurs in the absence of the extrahepatic malformations may also occur in conditions such as 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/d) of cholestyramine may control pruritus, lower cholesterol, and clear xanthomas. UDCA (15–20 mg/kg/d) appears to be more effective and causes fewer side effects than cholestyramine. Rifampicin may also reduce pruritus. Naltrexone (1 mg/kg/d) is occasionally required. Partial biliary diversion or ileal exclusion surgery may reduce pruritus in about half of severe cases. 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 30%–40% of patients have severe complications of disease, whereas over 70% of patients with nonsyndromic varieties progress to cirrhosis. Many of this latter group may have forms of PFIC. 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. Several patients have developed hepatocellular carcinoma. Hypogonadism has been noted; however, fertility is not obviously affected in most cases. 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, moya moya disease, or stroke may occur in up to 10%–12% of affected children.

Kamath BM et al: Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr 2010;50:580 [PMID: 20479679].

Kamath BM et al: Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl 2012;18:940 [PMID: 22454296].

Subramaniam P et al: Diagnosis of Alagille syndrome – 25 years of experience at King’s College Hospital. J Pediatr Gastroenterol Nutr 2011;52:84 [PMID: 21119543].

6. Progressive Familial Intrahepatic Cholestasis (PFIC; Byler Disease and 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 mutations in the gene coding FIC1, an aminophospholipid floppase, 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 diagnostic 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. 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 mutations in the bile salt export pump (BSEP) gene, which codes for 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 “giant cells.” There is an increased incidence of hepatocellular carcinoma in these patients with severe gene mutations. Treatment is similar to PFIC type I although close monitoring for hepatocellular carcinoma is essential. Following liver transplantation, recurrent disease has been described in patients who developed immune-mediated BSEP dysfunction.

PFIC type III is caused by mutations in the multiple drug resistance protein type 3 (MDR3) gene, which encodes 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.

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 and urine bile acid analysis may identify a synthesis defect. Treatment of bile acid synthesis defects is with oral cholic acid and UDCA. About 1/3 of PFIC patients have negative genotyping for the above genes and most likely have yet-to-be discovered genetic etiologies.

Arnell H et al: Follow-up in children with progressive familial intrahepatic cholestasis after partial external biliary diversion. J Pediatr Gastroenterol Nutr 2010;51:494 [PMID: 20683202].

Morotti RA et al: Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings. Semin Liver Dis 2011;31:3 [PMID: 21344347].

van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol 2010;24:541 [PMID: 20955958].

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 proved 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, and intrinsic or extrinsic obstruction of the common duct.

1. Biliary Atresia

 General Considerations

Biliary atresia is the progressive fibroinflammatory obliteration of the lumen of all, or part of, the extrahepatic biliary tree presenting within the first 3 months of life. Biliary atresia occurs in 1:6600 (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 at least two types of biliary atresia: the perinatal form (80% of cases), in which a perinatal insult, such as a virus infection, is believed to initiate inflammatory obstruction and fibrosis of the biliary tree, and the fetal-embryonic form (20% of cases), in which the extrahepatic biliary system did not develop normally. In the perinatal form, meconium and initial stools are usually normal in color, suggesting early patency of the ducts. Evidence obtained from surgically removed remnants of the extrahepatic biliary tree suggests an inflammatory sclerosing cholangiopathy. Recent research supports an autoimmune reaction that is responsible for progressive intrahepatic bile duct injury and fibrosis. In the fetal-embryonic type, the bile duct presumably did not develop normally and is associated with other nonhepatic congenital anomalies. The association of biliary atresia with the polysplenia syndrome (heterotaxia, preduodenal portal vein, interruption of the inferior vena cava, polysplenia, and midline liver) and asplenia syndrome supports an embryonic origin of biliary atresia in these cases.

 Clinical Findings

A. Symptoms and Signs

Jaundice may be noted in the newborn period or develops about age 2–3 weeks. Urine stains the diaper; and stools are often pale yellow, buff-colored, gray, or acholic. Seepage of bilirubin products across the intestinal mucosa may give some yellow coloration to the stools. Hepatomegaly is common, and the liver may feel firm to hard. By age 2–6 months, the growth curve reveals poor weight gain. Symptoms of portal hypertension (splenomegaly, ascites, variceal bleeding) may develop in the first year of life. Pruritus, digital clubbing, failure to thrive, bone fractures, and bleeding complications may also occur later in childhood.

B. Laboratory Findings and Imaging

No single laboratory test will consistently differentiate biliary atresia from other causes of complete obstructive jaundice. Although biliary atresia is suggested by persistent elevation of serum GGT or alkaline phosphatase levels, these findings have also been reported in severe neonatal hepatitis, α₁-antitrypsin deficiency, and bile duct paucity. Furthermore, these tests will not differentiate the location of the obstruction within the extrahepatic system. Generally, the aminotransferases are only modestly elevated in biliary atresia. Serum proteins and blood clotting factors are not affected early in the disease. Ultrasonography of the biliary system should be performed to exclude the presence of choledochal cyst and intra-abdominal anomalies; a triangular cord sign in the hepatic porta suggests biliary atresia. A HIDA scan showing lack of intestinal excretion is always present in biliary atresia, but may be seen with multiple other causes of intrahepatic cholestasis. Liver biopsy specimens (particularly if obtained after age 6–8 weeks) can differentiate intrahepatic causes of cholestasis from biliary atresia in over 90% of cases (see Table 22–2).

 Differential Diagnosis

The major diagnostic dilemma is distinguishing between this entity and bile duct paucity, metabolic liver disease (particularly α₁-antitrypsin deficiency), choledochal cyst, or intrinsic bile duct obstruction (stones, bile plugs). 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, and hepatomegaly is not found.

If the diagnosis of biliary atresia cannot be excluded by the diagnostic evaluation and percutaneous liver biopsy, surgical exploration should be performed as soon as possible. Laparotomy or laparoscopy must include liver biopsy and an operative cholangiogram if a gallbladder is present. The presence of yellow bile in the gallbladder implies patency of the proximal extrahepatic duct system. Radiographic visualization of cholangiographic contrast in the duodenum excludes obstruction to the distal extrahepatic ducts.

 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 diagnosis of biliary atresia is the hepatoportoenterostomy (Kasai procedure). Occasionally, portocholecystostomy (gallbladder Kasai procedure) may be performed if the gallbladder is present and the passage from it to the duodenum is patent. These procedures are best done in specialized centers where experienced surgical, pediatric, and nursing personnel are available. Surgery should be performed as early as possible (ideally before 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 now 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. The 3- to 5-year survival rate following liver transplantation for biliary atresia is at least 80%–90%. Biliary atresia is the leading indication for pediatric liver transplantation.

Whether or not the Kasai procedure is performed, supportive medical treatment consists of vitamin and caloric support (vitamins A, D, E, and K and formulas containing medium-chain triglycerides [Pregestimil or Alimentum]) (see Table 22–4). Monitoring of fat-soluble vitamin levels is essential to ensure adequate supplementation. Suspected bacterial infections (eg, ascending cholangitis) should be treated promptly with broad-spectrum antibiotics, and any bleeding tendency should be corrected with intramuscular vitamin K. Ascites can be managed initially with reduced sodium intake and spironolactone. Choleretics and bile acid–binding products (cholestyramine, aluminum hydroxide gel) are of little use. The value of UDCA remains to be determined. Antibiotic prophylaxis reduces the recurrence rate of cholangitis. The role of post-Kasai corticosteroids is controversial.

 Prognosis

When bile flow is sustained following portoenterostomy (serum total bilirubin < 2 mg/dL by 3 months of age), the 10-year survival rate without liver transplantation is up to 35%. 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 has dramatically changed the outlook for these patients.

Chiu CY et al: Taiwan infant stool color card study group. Biliary atresia in preterm infants in Taiwan: a nationwide survey. J Pediatr 2013 epub ahead of print [PMID: 23414661].

Mack CL et al: Clues to the etiology of bile duct injury in biliary atresia. Semin Liver Dis 2012;32:307 [PMID: 23414661].

Superina R et al: The anatomic pattern of biliary atresia identified at time of Kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival. Ann Surg 2011;254:577 [PMID: 21869674].

2. Choledochal Cyst

 ESSENTIALS OF DIAGNOSIS

 Abnormal abdominal ultrasound with cyst of the biliary tree.

 Clinical Features

A. Symptoms and Signs

Choledochal cysts are cystic lesions of all or part of the extrahepatic biliary system and in rare cases the cystic malformation can include the intrahepatic bile duct branches. In most cases, the clinical manifestations, basic laboratory findings, and histopathologic features on liver biopsy are indistinguishable from those associated with biliary atresia. In older children, choledochal cyst 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 choledochal cysts are at increased risk for developing bacterial cholangitis. Choledochal cysts cause only 2%–5% of cases of extrahepatic neonatal cholestasis; the incidence is higher in girls and patients of Asian descent. Neonatal symptomatic cysts may be associated with atresia of the distal common duct—accounting for the diagnostic dilemma—and may simply be part of the spectrum of biliary atresia.

B. Imaging Studies

Ultrasonography or magnetic resonance imaging (MRI) reveals the presence of a cyst.

 Treatment

Timely surgery is indicated for neonates once abnormalities in clotting factors have been corrected and bacterial cholangitis, if present, has been treated with intravenous antibiotics. Excision of the cyst and choledocho–Roux-en-Y jejunal anastomosis are recommended. In some cases, because of technical problems, only the mucosa of the cyst can be removed with jejunal anastomosis to the proximal bile duct. Anastomosis of cyst to jejunum or duodenum is not recommended due to the continued risks of cholangitis and bile duct carcinoma (cholangiocarcinoma).

 Prognosis

The prognosis depends on the presence or absence of associated evidence of atresia and the appearance of the intrahepatic ducts. If atresia is found, the prognosis is similar to that described in the preceding section. If an isolated extrahepatic cyst is encountered, the outcome is generally excellent, with resolution of the jaundice and return to normal liver architecture. 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; therefore, cystectomy or excision of cyst mucosa should be undertaken whenever possible.

Hung MH et al: Choledochal cysts in infants and children: experiences over a 20-year period at a single institution. Eur J Pediatr 2011;170:1179 [PMID: 21350805].

Tsai MS et al: Clinicopathological feature and surgical outcome of choledochal cyst in different age groups: the implication of surgical timing. J Gastrointest Surg 2008;12:2191 [PMID: 18677540].

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.

Pereira E et al: Conservative management of spontaneous bile duct perforation in infancy: case report and literature review. J Pediatr Surg 2012;47:1757 [PMID: 22974619].

Two other groups of disorders are associated with hyperbilirubinemia: (1) unconjugated hyperbilirubinemia, present in breast milk jaundice, Lucey-Driscoll syndrome, congenital hypothyroidism, upper intestinal obstruction, Gilbert disease, Crigler-Najjar syndrome, and drug-induced hyperbilirubinemia; and (2) conjugated noncholestatic hyperbilirubinemia, present in the Dubin-Johnson syndrome and Rotor syndrome.

1. Unconjugated Hyperbilirubinemia

A. Breast Milk Jaundice

Persistent elevation of the indirect bilirubin fraction (> 80% of total bilirubin) may occur in up to 36% of breast-fed infants. 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, 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.

Bhutani VK et al: Expert Committee for Severe Neonatal Hyperbilirubinemia; European Society for Pediatric Research; American Academy of Pediatrics: management of jaundice and prevention of severe neonatal hyperbilirubinemia in infants ≥ 35 weeks gestation. Neonatology 2008;94:63 [PMID: 18204221].

Fujiwara R et al: Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia. Gastroenterology 2012;142:109 [PMID: 21983082].

Preer GL, Philipp BL: Understanding and managing breast milk jaundice. Arch Dis Child Fetal Neonatal Ed 2011;96:F461 [PMID: 20688866].

B. Congenital Hypothyroidism

Although the differential diagnosis of indirect hyperbilirubinemia should always include congenital hypothyroidism, the diagnosis is usually suggested by clinical and physical clues or, more commonly, from the newborn screening results. The jaundice clears quickly with replacement thyroid hormone therapy, although the mechanism is unclear.

Tiker F: Congenital hypothyroidism and early severe hyperbilirubinemia. Clin Pediatr (Phila) 2003;42:365 [PMID: 12800733].

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.

Hua L et al: The role of UGT1A1∗28 mutation in jaundiced infants with hypertrophic pyloric stenosis. Pediatr Res 2005;58:881 [PMID: 16257926].

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/d), although this therapy is not justified.

The disease is inherited as an abnormality of the promoter region of uridine diphosphate-glucuronyl transferase-1 (UDGT1); 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/d) 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.

Bartlett MG, Gourley GR: Assessment of UGT polymorphisms and neonatal jaundice. Semin Perinatol 2011;35:127 [PMID: 21641485].

Claridge LC et al: Gilbert’s syndrome. BMJ 2011 Apr 19;342:d2293 [PMID: 21508045].

Kathemann S et al: Gilbert’s syndrome—a frequent cause of unconjugated hyperbilirubinemia in children after orthotopic liver transplantation. Pediatr Transplant 2012;16:20 [PMID: 22360405].

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). Consanguinity is often present. Prompt recognition of this entity and treatment with exchange transfusions are required, followed by phototherapy. Some patients have no neurologic signs until adolescence or early adulthood, at which time deterioration may occur suddenly. For diagnosis of this condition, it may be useful to obtain a duodenal bile specimen, which characteristically will be colorless and contain a predominance of unconjugated bilirubin, small amounts of monoconjugates, and only traces of unconjugated bilirubin. Phenobarbital administration does not significantly alter these findings, nor does it lower serum bilirubin levels. UGT genetic testing is available. The deficiency in UGT1A1 is inherited in an autosomal recessive pattern. A combination of aggressive phototherapy and cholestyramine may keep bilirubin levels below 25 mg/dL. The use of tin protoporphyrin or tin mesoporphyrin remains experimental. 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 is experimental and future gene therapy may be possible

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/d 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.

Bartlett MG, Gourley GR: Assessment of UGT polymorphisms and neonatal jaundice. Semin Perinatol 2011;35:127 [PMID: 21641485].

Kohli S et al: Novel human pathological mutations. Gene symbol: UGT1A1 Disease: Crigler-Najjar syndrome 1. Hum Genet 2010;127:485 [PMID: 21488310].

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 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 liver function tests 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 and OATP1B3 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 gall-bladder 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. Genotyping of MRP2 is available but for the Rotor syndrome this is only available on a research basis.

Choleretic agents (eg, UDCA) may help reduce the cholestasis in infants with Dubin-Johnson syndrome.

Jirsa M et al: Rotor syndrome. In: Pagon RA et al (eds): GeneReviews™ [Internet]. 2012 Dec 13 [PMID: 23236639].

Strassburg CP: Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol 2010;24:555 [PMID: 20955959].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Gastrointestinal upset (anorexia, vomiting, diarrhea).

 Jaundice.

 Liver tenderness and enlargement.

 Abnormal LFTs.

 Local epidemic of hepatitis A infection.

 Positive anti–hepatitis A virus (HAV) IgM antibody.

 Pathogenesis

Hepatitis A virus (HAV) infection occurs in both epidemic and sporadic fashion (Table 22–6). Fecal-oral route is the mode of transmission in epidemic outbreaks from contaminated food or water supplies, including by food handlers. HAV viral particles are found in stools during the acute phase of hepatitis A infection. 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 the 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 < 12 months old; over 40 years of age: anyone who is immunocompromised or who has chronic liver disease is recommended with immune globulin, 0.02 mL/kg intramuscularly. Illness is prevented in > 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 < 12 months old 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 currently recommended that all children 12–18 months of age receive HAV vaccination 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 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; 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.

 Prognosis

Ninety-nine percent of children recover without sequelae. Persons with underlying chronic liver disease have an increased risk of death. In rare cases of acute liver failure due to HAV hepatitis, the patient may die within days to weeks and requires 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; however, 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.

Dorell CG et al: Hepatitis A vaccination coverage among adolescents in the United States. Pediatrics 2012;129:213 [PMID: 22271690].

Erhart LM, Ernst KC: The changing epidemiology of hepatitis A in Arizona following intensive immunization programs (1988–2007). Vaccine 2012;30:6103 [PMID: 22835739].

Hepatitis A in Red Book: 2012 report of the committee on infectious diseases, 29th ed, Elk Grove Village, IL. American Academy of Pediatrics; 2012.

Marshall H et al: Long-term (5 year) antibody persistence following two- and three-dose regimens of a combined hepatitis A and B vaccine in children aged 1–11 years. Vaccine 2010;17:4411 [PMID: 20434544].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Gastrointestinal upset, anorexia, vomiting, diarrhea.

 Jaundice, tender hepatomegaly, abnormal LFTs.

 Serologic evidence of hepatitis B disease: HBsAg, HBeAg, anti-HBc IgM.

 History of parenteral, sexual, or household exposure or maternal HBsAg carriage.

 General Considerations

In contrast to HAV, hepatitis B virus (HBV) infection has a longer incubation period of 45–160 days (see Table 22–6). HBV is a DNA virus that 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. Transmission via blood products has been almost eliminated by donor-screening and donor blood testing protocols.

 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). The surface antigen in blood is termed HBsAg, which elicits an antibody (anti-HBs). The core antigen is termed HBcAg and its antibody is anti-HBc. Anti-HBc IgM antibody indicates recent viral infection. Another important antigen-antibody system associated with HBV disease is the “e” (envelope) antigen system. 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) and 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 born in the United States and of adolescents is now recommended, as it is in most other countries. 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 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.

 Clinical Findings

A. Symptoms and Signs

Most infants and young children are completely asymptomatic, especially if the infection is acquired vertically. Symptoms of acute HBV infection include slight fever (which may be absent), malaise, and mild gastrointestinal upset. Visible jaundice is usually the first significant finding and is accompanied by darkening of the urine and pale or clay-colored stools. Hepatomegaly is frequently present. Occasionally an antigen-antibody complex presentation antedates the appearance of icterus, and is characterized by macular rash, urticaria, and arthritis. HBV infection more rarely presents as a glomerulonephritis or nephrotic syndrome from immune complexes.

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. LFT results are similar to those discussed earlier for hepatitis A. Liver biopsy is most useful in chronic infection to determine the degree of fibrosis and inflammation. Renal involvement may be suspected on the basis of urinary findings suggesting glomerulonephritis or nephrotic syndrome. 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, an 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. The history may suggest a drug-induced hepatitis, especially if a serum sickness prodrome is reported. Autoimmune hepatitis Wilson disease, hemochromatosis, nonalcoholic fatty liver disease (NAFLD), α₁-antitrypsin deficiency, and drug-induced hepatitis should also be considered.

 Treatment

Supportive measures such as bed rest and a nutritious diet are used during the active symptomatic stage of acute HBV infection. Corticosteroids are contraindicated. No other treatment is needed for acute HBV infection. For acute infection complicated by acute liver failure, nucleos(t)ide therapy may be helpful. For patients with chronic infection who persist in the immunoactive phase for more than 6 months or with HBeAg-negative chronic hepatitis, there are currently two approved treatment options. Treatment with α-interferon (5–6 million U/m² of body surface area injected subcutaneously three times a week for 4–6 months) inhibits viral replication in 30%–40% of patients, normalizes the ALT level, and leads to the disappearance of HBeAg and the appearance of anti-HBe. Side effects are common. Younger children may respond better than older children. Orally administered nucleoside analog therapy (lamivudine 3 mg/kg/d up to 100 mg/d for children > 2 years old or adefovir 10 mg/d or tenofovir 300 mg/d for children > 12 years old and entecavir [0.5 mg once daily] or telbivudine [600 mg once daily] for children > 16 years old) leads to a successful response in 25% of treated children, with minimal side effects, but may require long-term treatment. However, resistant organisms can emerge, more frequently with lamivudine. Pegylated interferon, several oral antiviral agents (with much lower rates of resistance), and combination therapy are promising options being tested in children. Immunotolerant children and chronic carriers do not respond to therapy. Liver transplantation is successful in acute liver failure 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 acute liver failure (< 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. 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 yearly. Routine HBV vaccination of newborns in endemic countries has reduced the incidence of acute liver failure, chronic hepatitis, and hepatocellular carcinoma in children.

Haber BA et al: Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics 2009;124:183 [PMID: 19805457].

Jonas MM et al: Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology 2010;52:2192 [PMID: 20890947].

Ni YH: Natural history of hepatitis B virus infection: pediatric perspective. J Gastroenterol 2011;46:1 [PMID: 20812021].

 General Considerations

Hepatitis C virus (HCV) is the most common cause of non-B chronic hepatitis (see Table 22–6). 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. The risk from transfused blood products has diminished greatly (from 1–2:100 to < 1:100,000 units of blood) since the advent of blood testing for ALT and anti-HCV. In the past, children with hemophilia or on chronic hemodialysis were also at significant risk. Most cases in children are now associated with transmission from an infected mother (vertical transmission) or rarely from other household contacts. 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. Transmission of the virus from breast milk is very rare. HCV rarely causes fulminant hepatitis in children or adults in Western countries, but different serotypes do so in Asia.

HCV is a single-stranded RNA flavivirus. At least seven genotypes of HCV exist. Several well-defined HCV antigens are the basis for serologic antibody tests. The third-generation enzyme-linked immunosorbent assay (ELISA) test for anti-HCV is highly accurate. Anti-HCV is generally present when symptoms occur; however, test results may be negative in the first few months of infection. The presence of HCV RNA in serum indicates active 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. Breastfeeding does not promote HCV transmission from mother to infant. It is advised to avoid breastfeeding 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

Most 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 in chronic hepatitis. Ascites, clubbing, palmar erythema, or spider angiomas are rare and indicate progression to cirrhosis.

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 > 18 months of age 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 hepatitis. Fluctuating mild to moderate elevations of aminotransferases over long periods are characteristic of chronic HCV infection; however, normal aminotransferases are common in children.

Percutaneous liver biopsy should be considered in chronic cases. Histologic examination shows portal triaditis with chronic inflammatory cells, occasional lymphocyte nodules in portal tracts, mild macrovesicular steatosis, and variable bridging necrosis, fibrosis, and cirrhosis; most children have mild to moderate fibrosis on liver biopsy. 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 cirrhosis in children should be considered in cases of chronic illness, such as Wilson disease, α₁-antitrypsin deficiency, autoimmune hepatitis, drug-induced hepatitis, or steatohepatitis.

 Treatment

In 2012, triple therapy was implemented for adults with chronic HCV. Triple therapy includes pegylated interferon-α, ribavirin and a protease inhibitor (boceprevir or telaprevir). Triple therapy has been associated with successful eradication of virus in up to 80% of treatment-naïve genotype 1 cases. Indications for treatment of chronic infection in children are unclear, but generally include chronic hepatitis and fibrosis. The current approved therapy for treatment of children consists of pegylated interferon-α 2a or 2b (104 mcg/m² BSA weekly for 2a and 60 mcg/m² BSA weekly for 2b) and ribavirin (15 mg/kg/d). The sustained virological response rates of this double therapy are approximately 40% in genotype 1 (most common in United States) and approximately 80% for genotypes 2 and 3. Clinical trials of triple therapy for children with genotype 1 HCV are under investigation. End-stage liver disease secondary to HCV responds well to liver transplantation, although re-infection of the transplanted liver is very common and occasionally rapidly progressive. Pre- and post-transplant antiviral therapy may reduce the risk of reinfection.

 Prognosis

Following an acute infection with HCV, 70%–80% of adults and older children develop a chronic infection. Twenty percent 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 or after decades. The longer-term outcome in children is less well defined. 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. 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.

Goodman GD et al: Pathology of chronic hepatitis C in children: liver biopsy findings in the PEDS-C trial. Hepatology 2008;47:836 [PMID: 18167062].

Jacobson IM et al: Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405 [PMID: 21696307].

Mack CL et al: NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr 2012;54:838 [PMID: 22487950].

Schwarz KB et al: The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C. Gastroenterology 2011; 140:450 [PMID: 21036173].

The hepatitis D virus (HDV) is a 36-nm defective 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. 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 directed at therapy for HBV infection.

Hughes SA et al: Hepatitis delta virus. Lancet 2011;378:73 [PMID: 21511329].

Hepatitis E virus (HEV) infection is a cause of enterically transmitted, epidemic hepatitis (see Table 22–6). It is rare in the United States. HEV is a hepevirus that is transmitted via the fecal-oral route. It occurs predominantly in developing countries in association with waterborne epidemics, and has only a 3% secondary attack rate in household contacts. Areas reporting epidemics include Southeast Asia, China, the Indian subcontinent, the Middle East, northern and western Africa, Mexico, and Central America, with sporadic cases in the United States and Europe. Recent reports suggest zoonotic transmission occurs in low endemic regions. Its clinical manifestations resemble HAV infection except that symptomatic disease is rare in children, more common in adolescents and adults, and is associated with a high mortality (10%–20%) in pregnant women, particularly in the third trimester. HEV infection in individuals with chronic liver disease can cause acute deterioration. Zoonotic transmission from pigs, boars, and deer can lead to chronic infection and cirrhosis in immunocompromised individuals. Outside of these settings chronic disease is not reported. Diagnosis is established by detecting anti-HEV IgM antibody or by HEV PCR. A recombinant vaccine is being tested. There is no effective treatment.

Kamar N et al: Hepatitis E. Lancet 2012;379:2477 [PMID: 22549046].

Other undiscovered viruses may cause cases of acute liver failure (ALF)/severe hepatitis 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. Parvovirus has been associated with severe hepatitis; the prognosis is relatively good in children. Infectious mononucleosis (EBV) is commonly associated with acute hepatitis and rare cases of EBV-associated ALF have been reported. CMV, adenovirus, herpes simplex virus, HHV-6, HIV, brucella, Q-fever, and leptospirosis are other infectious causes of acute hepatitis.

Aydim M et al: Detection of human parvovirus B19 in children with acute hepatitis. Ann Trop Paediatr 2006;26:25 [PMID: 16494701].

Cacheux W et al: HHV-6-related acute liver failure in two immunocompetent adults: favourable outcome after liver transplantation and/or ganciclovir therapy. J Intern Med 2005;258:573 [PMID: 16313481].

Okano M, Gross TG. Acute or chronic life-threatening diseases associated with Epstein-Barr virus infection. Am J Med Sci 2012;343:483 [PMID: 22104426].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Acute hepatitis with deepening jaundice.

 Extreme elevation of AST and ALT.

 Prolonged PT and INR.

 Encephalopathy and cerebral edema.

 Asterixis and fetor hepaticus.

 General Considerations

Acute Liver Failure (ALF) is defined as acute liver dysfunction associated with significant hepatic synthetic dysfunction evidenced by a vitamin K–resistant coagulopathy (INR > 2.0) within 8 weeks after the onset of liver injury. This is often associated with encephalopathy, but in young children, encephalopathy may be difficult to detect or absent. Without liver transplantation, mortality is approximately 50% 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. Patients with immunologic deficiency diseases and those receiving immunosuppressive drugs are vulnerable to herpes viruses. In children with HIV infection, nucleoside reverse transcriptase inhibitors have triggered lactic acidosis and liver failure. In patients with underlying respiratory chain defects, valproic acid may trigger ALF.

 Clinical Findings

A. History

In some patients, ALF presents with the rapid development of deepening jaundice, bleeding, confusion, and progressive coma, 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. Signs of chronic liver disease (splenomegaly, spider hemangiomata) should suggest an underlying chronic liver disease. Hyper-reflexia and positive extensor plantar responses are seen before the onset of encephalopathy. Impairment of renal function, manifested by either oliguria or anuria, is an ominous sign.

C. Laboratory Findings

Characteristic findings include elevated serum bilirubin levels (usually > 15–20 mg/dL), sustained elevations of AST and ALT (> 3000 U/L), low serum albumin, hypoglycemia, and prolonged PT and INR. Blood ammonia levels become elevated, whereas blood urea nitrogen is often very low. 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. A high AST and ALT with normal bilirubin suggests acetaminophen toxicity or metabolic causes.

 Differential Diagnosis

Severe hepatitis, with or without coagulopathy, due to infections, metabolic disease, autoimmune hepatitis 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. Spontaneous survival may occur in up to 50% of patients. Liver transplant may be lifesaving in patients without signs of spontaneous recovery, with 60%–80% 1- to 3-year survival. 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. Living related donors may be required for transplantation in a timely fashion. The prognosis is better for acetaminophen ingestion, particularly when N-acetylcysteine treatment is given. Corticosteroids may be harmful, except in autoimmune hepatitis 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. Early signs of cerebral edema are treated with infusions of mannitol (0.5–1.0 g/kg). Comatose patients should be intubated, given mechanical ventilatory support, and monitored for signs of infection. Coagulopathy is treated with fresh-frozen plasma, recombinant factor VIIa, other clotting factor concentrates, platelet infusions, or exchange transfusion for bleeding or procedures. 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

The prognosis is primarily dependent on the etiology 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. Data from a recent large study suggest 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%.

Devictor D et al: Acute liver failure in neonates, infants and children. Expert Rev Gastroenterol Hepatol 2011;5:717 [PMID: 22017699].

Miloh T et al: Improved outcomes in pediatric liver transplantation for acute liver failure. Pediatr Transplant 2010;14:863 [PMID: 20609170].

Narkewicz MR et al: Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement. J Pediatr 2009;155:801 [PMID: 1963443].

Squires RH: Acute liver failure in children. Semin Liver Dis 2008;28:153 [PMID: 18452115].

Sundaram SS et al: Characterization and outcomes of young infants with acute liver failure. J Pediatr 2011;159:813 [PMID: 21621221].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Acute or chronic hepatitis.

 Hypergammaglobulinemia.

 Positive antinuclear antibodies (ANA), anti–smooth muscle antibodies (ASMA), anti–liver-kidney microsomal (LKM) antibodies, or anti–soluble liver antigen antibodies (SLA).

 Clinical Findings

A. History

Autoimmune hepatitis (AIH) is a progressive inflammatory disorder of unknown etiology. It is characterized histologically by portal tract inflammation that extends into the parenchyma; serologically by the presence of non-organ 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. Pediatric patients may complain of a gradual onset of jaundice that may be asymptomatic or associated with fever, malaise, and abdominal pain or distension. Other complaints at the time of presentation may include a recurrent rash, arthritis, chronic diarrhea or amenorrhea. A family history of autoimmune disease is often present and a high prevalence of seroimmunologic abnormalities has also been noted in relatives.

B. Symptoms and Signs

Asymptomatic hepatomegaly and/or splenomegaly may be found on examination, in association with elevated liver tests. 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). Occasionally patients present with acute liver failure (ALF)

C. Laboratory Findings

LFTs reveal moderate elevations of serum AST, ALT, and alkaline phosphatase. Serum bilirubin may be mildly elevated and albumin may be low. Serum IgG levels are generally elevated in the range of 2–6 g/dL. Two subtypes of disease have been described based on the autoantibodies present: type 1—ANA &/or ASMA (anti-actin); type 2—anti-LKM (anti–cytochrome P-450). Type 1 AIH is the most common form of AIH in the United States. Type 2 AIH 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) or HLA DR∗0701 (type 2). Liver biopsy reveals 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. Ten to fifteen percent of pediatric patients have an “overlap syndrome” of AIH and PSC. Anti-HCV antibodies can be falsely positive and should be confirmed by HCV PCR. Drug-induced (minocycline, isoniazid, methyldopa, pemoline) chronic hepatitis 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. Persistent malaise, fatigue, amenorrhea, and anorexia parallel disease activity. Bleeding from esophageal varices and development of ascites usually signal impending hepatic failure.

 Treatment

Corticosteroids (prednisone, 2 mg/kg/d maximum 60 mg) decrease the mortality rate during the early active phase of the disease. Recent data in adults suggests budesonide may be as efficacious as prednisone with less steroid side effects. Azathioprine or 6-mercaptopurine (6-MP), 1–2 mg/kg/d, is of value in decreasing the side effects of long-term corticosteroid therapy, but should not be used alone during the induction phase of treatment. Steroids are reduced over a 3- to 12-month period, and azathioprine is continued for at least 1–2 years if AST and ALT remain consistently normal. Whether a patient should be weaned completely off steroids is controversial. Liver biopsy is performed before stopping azathioprine or 6-MP therapy; if inflammation persists, then azathioprine or 6-MP is continued. Thiopurine methyltransferase activity in red blood cells should be assessed prior to starting azathioprine or 6-MP, to prevent extremely high blood levels and severe bone marrow toxicity. Relapses are treated with a course of steroids. Many patients require chronic azathioprine or 6-MP therapy. Cyclosporine, tacrolimus, or methotrexate may be helpful in poorly responsive cases. Mycophenolate mofetil can be substituted for azathioprine or 6-MP. Liver transplantation is indicated when disease progresses to decompensated cirrhosis despite therapy or in cases presenting in ALF that do not respond to steroid therapy.

 Prognosis

The overall prognosis for AIH is improved significantly with early therapy. Some studies report cures (normal histologic findings) in 15%–20% of patients. Relapses (seen clinically and histologically) occur in 40%–50% of patients after cessation of therapy; remissions follow repeat treatment. Survival for 10 years is common despite residual cirrhosis. Of children with AIH, 20%–50% eventually require liver transplantation. Complications of portal hypertension (bleeding varices, ascites, spontaneous bacterial peritonitis, and hepatopulmonary syndrome) require specific therapy. Liver transplantation is successful 70%–90% of the time. Disease recurs after transplantation 10%–50% of the time and is treated similarly to pretransplant disease.

Chai PF et al: Childhood autoimmune liver disease: indications and outcome of liver transplantation. J Pediatr Gastroenterol Nutr 2010;50:295 [PMID: 20118802].

Mieli-Vergani G, Vergani D: Autoimmune hepatitis. Nat Rev 2011;8:320 [PMID: 21537351].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Hepatomegaly in patient with BMI > 95th percentile.

 Elevated ALT > AST.

 Detection of fatty infiltration of the liver on ultrasound.

 Histologic evidence of fat in the liver.

 Insulin resistance.

Nonalcoholic fatty liver disease (NAFLD), a clinicopathologic condition of abnormal heptic fat deposition in the absence of alcohol, is the most common cause of abnormal liver function tests 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 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.

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 patient 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 > 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. There are no established reliable biochemical predictors of the degree of hepatic fibrosis, but new biomarkers, like patatin-like phospholipase domain-containing 3 polymorphisms and cytokeratin-18, show promise in research laboratories.

D. Imaging

Ultrasonography or CT scan can be used to confirm fatty infiltration of the liver. Ultrasound is the preferred methodology due to lower cost and lack of radiation exposure, though it may be insensitive in 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 is a research tool that shows promise in estimating hepatic 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, and insulin resistance 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.

Chalasani A et al: The diagnosis and management of nonalcoholic fatty liver disease; practice guidelines by the American Gastroenterological Association, American Association for the Study of Liver Diseases and American College of Gastroenterology. Gastroenterology 2012;143:503 [PMID: 22656328].

Lavine JE et al: Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011;27:1659 [PMID: 21521847].

Ovchinsky N. et al: A critical appraisal of advances in pediatric non-alcoholic fatty liver disease. Seminars in Liver Disease 2012;32:317 [PMID: 23397532].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Serum α₁-antitrypsin level < 50–80 mg/dL.

 Identification of a specific protease inhibitor (PI) phenotype (PIZZ, PISZ) or genotype.

 Detection of diastase-resistant glycoprotein deposits in periportal hepatocytes.

 Histologic evidence of liver disease.

 Family history of early-onset pulmonary disease or liver disease.

 General Considerations

The disease is caused by a deficiency in α₁-antitrypsin, a protease inhibitor (Pi) system, predisposing patients to chronic liver disease, and an early onset of pulmonary emphysema. It is most often associated with the Pi phenotypes ZZ and SZ. The accumulation of misfolded aggregates of α₁-antitrypsin protein in the liver causes the liver injury by unclear mechanisms.

 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 hepatosplenomegaly may be present. The family history may be positive for emphysema or cirrhosis.

The disease can also present in older children, where hepatomegaly or physical findings suggestive of cirrhosis and portal hypertension should lead to consideration of α₁-antitrypsin deficiency. Recurrent pulmonary disease (bronchitis, pneumonia) may be present in some older children. 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

Levels of the α₁-globulin fraction may be less than 0.2 g/dL. α₁-Antitrypsin level is low (< 50–80 mg/dL) in homozygotes (ZZ). Specific Pi phenotyping should be done to confirm the diagnosis. Genotyping is also available. 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. Occasionally, children develop paucity of interlobular bile ducts.

Early-onset pulmonary emphysema occurs in young adults (age 30–40 years), particularly in smokers. An increased susceptibility to hepatocellular carcinoma has been noted in cirrhosis associated with α₁-antitrypsin deficiency.

 Treatment

There is no specific treatment for the liver disease of this disorder. Replacement of the protein by transfusion therapy is used to prevent or treat pulmonary disease in affected adults. 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). UCDA 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 development of end-stage liver disease, cures the deficiency and prevents the development of pulmonary disease. Passive and active cigarette smoke exposure should be eliminated to help prevent pulmonary manifestations, and obesity should be avoided.

 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.

Hughes MG Jr et al: Long-term outcome in 42 pediatric liver transplant patients with alpha 1-antitrypsin deficiency: a single-center experience. Clin Transplant 2011;2:731 [PMID: 21077958].

Marciniuk DD et al: Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J 2012;19:109 [PMID: 22536580].

Teckman JH: Alpha 1-antitrypsin deficiency in childhood. Semin Liv Dis 2007;27:274 [PMID: 17682974].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Acute or chronic liver disease.

 Deteriorating neurologic status.

 Kayser-Fleischer rings.

 Elevated liver copper.

 Abnormalities in levels of ceruloplasmin and serum and urine copper.

 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 oxidant (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 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 acute liver failure, 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 considered after 3–4 years of age. 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 (measured by the oxidase method) 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 if immunoassays are 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/d; in Wilson disease, it is generally greater than 100 mcg/d although it can be as low as > 40 mcg/d. 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/d when characteristic liver histology is present.

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. NASH 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 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 may be 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 as part of the presentation of fulminant hepatitis.

 Treatment

Copper chelation with D-penicillamine or trientine hydrochloride, 750–1500 mg/d orally, is the treatment of choice, whether or not the patient is symptomatic. The target dose for children is 20 mg/kg/d; begin with 250 mg/d and increase the dose weekly by 250 mg increments. Strict dietary restriction of copper intake is not practical. 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. Tetrathiomolybdate is 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. 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. 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 (haplotype analysis or ATP7B genotyping) is available clinically if there is any doubt about the diagnosis and for family members.

Arnon R et al: Wilson disease in children: serum aminotransferases and urinary copper on triethylene tetramine dihydrochloride (trientine) treatment. J Pediatr Gastroenterol Nutr 2007;44:596 [PMID: 17460493].

Mizuochi T et al: Zinc monotherapy from time of diagnosis for young pediatric patients with presymptomatic Wilson disease. J Pediatr Gastroenterol Nutr 2011;53:365 [PMID: 21970993].

Roberts EA, Schilsky ML: American Association for Study of Liver Diseases (AASLD): diagnosis and treatment of Wilson disease: an update. Hepatology 2008;47:2089–2111 [PMID: 18506894].

Rosencrantz R, Schilsky M: Wilson disease: pathogenesis and clinical considerations in diagnosis and treatment. Semin Liver Dis 2011 Aug;31:245–259 [PMID: 21901655].

Weiss KH et al: Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology 2011 Apr;140:1189–1198 [PMID: 21185835].

 General Considerations

Drug-induced liver injury (DILI) may be predictable or and 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 in 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 detected because aminotransferases are performed for other reasons. If symptomatic, indicating more severe DILI, patients may have malaise, anorexia, nausea and vomiting, right upper quadrant pain, jaundice, acholic stools, and dark urine. Some may have severe pruritus. If the DILI is a hypersensitivity reaction, fever and rash may also occur.

 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, autoimmune hepatitis, and alcohol abuse.

 Treatment

Primary therapy is discontinuation of the offending drug, and avoiding re-exposure. This typically results in rapid and complete resolution of symptoms. However, DILI severe enough to cause acute liver failure has a poor prognosis without urgent liver transplant. Specific therapies for some DILI exist, such as N-acetylcysteine for acetaminophen poisoning. The use of ursodeoxycholic acid may speed resolution of jaundice. The use of corticosteroids for DILI remains controversial.

Liver Tox: Clinical and research information on drug-induced liver injury, http://www.livertox.nih.gov/.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Underlying liver disease.

 Nodular hard liver and splenomegaly.

 Nodular liver on abdominal imaging.

 Liver biopsy demonstrating cirrhosis.

 General Considerations

Cirrhosis is a histologically defined condition of the liver characterized by diffuse hepatocyte injury and regeneration, an increase in connective tissue (bridging fibrosis), and disorganization of the lobular and vascular architecture (regenerative nodules). 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, the two most common forms of cirrhosis are postnecrotic and biliary, each of which has different causes, symptoms, and treatments. Both forms can eventually 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 reportted. 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 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 may be detected as shifting dullness or a fluid wave. Gynecomastia may be noted in males. Digital clubbing occurs in 10%–15% of cases. Pretibial edema often occurs, reflecting underlying hypoproteinemia. In adolescent girls, irregularities of menstruation or/and amenorrhea may be early complaints.

In biliary cirrhosis, patients often have jaundice, dark urine, pruritus, hepatomegaly, and sometimes xanthomas, in addition to the previously mentioned clinical findings. Malnutrition and failure to thrive due to steatorrhea may be more apparent in this form of cirrhosis.

C. Laboratory Findings

Mild abnormalities of AST and ALT are often present, with a decreased level of albumin and a variable increase in the level of γ-globulins. 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, elevated 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.

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, postnecrotic cirrhosis is often a result of acute or chronic liver disease (eg, viral hepatitis [HBV, HCV], autoimmune or drug-induced hepatitis, idiopathic neonatal giant-cell hepatitis); more recently, NAFLD; or certain inborn errors of metabolism (see Table 22–5). The evolution to cirrhosis may be insidious, with no recognized icteric phase, as in some cases of HBV or HCV infection, autoimmune hepatitis, Wilson disease, or α₁-antitrypsin deficiency. 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. Most cases of biliary cirrhosis result from congenital abnormalities of the bile ducts (biliary atresia, choledochal cyst), tumors of the bile duct, Caroli disease, PFIC, PSC, paucity of the intrahepatic bile ducts, and cystic fibrosis. Occasionally, cirrhosis may follow a hypersensitivity reaction to certain drugs such as phenytoin. Parasites (Opisthorchis sinensis, Fasciola, and Ascaris) may be causative in children living in endemic areas.

 Complications

Major complications of cirrhosis in childhood include progressive nutritional disturbances, hormonal disturbances, and the evolution of portal hypertension and its complications. Hepatocellular carcinoma occurs with increased frequency in the cirrhotic liver, especially in patients with the chronic form of hereditary tyrosinemia or after longstanding HBV or HCV disease.

 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 may be reversed by successful antiviral therapy. Children with cirrhosis should receive the hepatitis A and B vaccines, and they should be monitored for the development of hepatocellular carcinoma with serial serum α-fetoprotein determinations annually and abdominal ultrasound for hepatic nodules at least 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

Postnecrotic 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%.

Hardy SC, Kleinman RE: Cirrhosis and chronic liver failure. In: Suchy FJ, Sokol RJ, Balistreri WF (eds): Liver Disease in Children. 3rd ed. Cambridge University Press; 2007:97–137.

Leonis MA, Balistreri WF: Evaluation and management of end-stage liver disease in children. Gastroenterology 2008;134:1741 [PMID: 18471551].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Splenomegaly.

 Recurrent ascites.

 Variceal hemorrhage.

 Hypersplenism.

 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 without cirrhosis 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 (pyelophlebitis), 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 probably 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 the 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 constant physical sign. Recurrent episodes of abdominal distention resulting from ascites may be noted. The usual presenting symptoms are hematemesis and melena.

The presence of prehepatic portal hypertension is suggested by the following: (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 tests with splenomegaly.

Most patients with suprahepatic portal hypertension present with abdominal pain, tender hepatomegaly of acute onset, and abdominal enlargement caused by 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 aminotransferases and PT are often present. Significant early increases in fibrinolytic parameters (especially plasminogen activator inhibitor 1) have been reported in veno-occlusive disease. Hypersplenism with mild leucopenia 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 with either portosystemic shunt or the mesorex (mesenterico–left portal bypass) shunt. When possible, the mesorex shunt is the preferred technique. Veno-occlusive disease may be prevented somewhat by the prophylactic use of UCDA 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.

The prognosis in patients treated by medical and supportive therapy may be better than in the surgically treated group, especially when surgery is performed at an early age, although no comparative study has been done. 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.

D’Antiga L: Medical management of esophageal varices and portal hypertension in children. Semin Pediatr Surg 2012;47:e5 [PMID: 22703824].

de Ville de Goyet J et al: Surgical management of portal hypertension in children. Semin Pediatr Surg 2012;21:219 [PMID: 22800975].

DeLeve LD et al: Vascular disorders of the liver. Hepatology 2009;49:1729 [PMID: 19399912].

Plessier A, Valla DC: Budd-Chiari syndrome. Semin Liver Dis 2008;28:259 [PMID: 18814079].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Episodic right upper quadrant abdominal pain.

 Elevated bilirubin, alkaline phosphatase, and GGT.

 Stones or sludge seen on abdominal ultrasound.

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. For some patients, gallbladder dysfunction is associated with biliary sludge formation, which may evolve into “sludge balls” or tumefaction bile and then into gallstones. The process is reversible in many 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 ampulla hepatopancreatica. 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 hyperalimentation 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.

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 ampulla hepatopancreatica.

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. Plain abdominal radiographs will show calculi with a high calcium content in the region of the gallbladder in up to 15% of patients. Lack of visualization of the gallbladder with hepatobiliary scintigraphy suggests chronic cholecystitis. 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. Acute distention and subsequent perforation of the gallbladder may occur when gallstones cause obstruction of the cystic duct. Stones impacted at the level of the ampulla hepatopancreatica often cause gallstone pancreatitis.

 Treatment

Symptomatic cholelithiasis is treated by laparoscopic cholecystectomy or open cholecystectomy in selected cases. Intraoperative cholangiography via the cystic duct is recommended so that the physician can be certain the biliary system is free of retained stones. Calculi in the extrahepatic bile ducts may be removed at 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 (UCDA) 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 cholecystectomy.

Ma MH et al: Risk factors associated with biliary pancreatitis in children. J Pediatr Gastroenterol Nutr 2012;54:651 [PMID: 22002481].

Svensson J et al: Gallstone disease in children. Semin Pediatr Surg 2012;21:255 [PMID: 22800978].

2. Primary Sclerosing Cholangitis

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Pruritus and jaundice.

 Elevated GGT.

 Associated with inflammatory bowel disease.

 Abnormal ERCP or MRCP.

 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 alteration 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, autoimmune hepatitis, IgG4 autoimmune pancreatitis, sicca syndromes, congenital and acquired immunodeficiency syndromes, and cystic fibrosis.

 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 and steatorrhea can occur. Physical findings include hepatomegaly, splenomegaly, and jaundice.

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. Patients with associated inflammatory bowel disease often test positive for perinuclear antineutrophil cytoplasmic antibodies. Other markers of autoimmune liver disease (ANA and ASMA) are often found, but are not specific for PSC. Sclerosing cholangitis due to cryptosporidia is common in immunodeficiency syndromes.

C. Imaging

Ultrasound may show saccular dilation of normal intrahepatic bile ducts with segmental strictures, described as “beads on a string.” MRCP is the diagnostic study of choice, demonstrating irregularities of the biliary tree. ERCP may be more sensitive for the diagnosis of irregularities of the intrahepatic biliary tree and allow for therapeutic interventions.

 Differential Diagnosis

The differential diagnosis includes infectious hepatitis, secondary cholangitis, AIH, metabolic liver disease, cystic fibrosis, choledochal cyst, or other anomalies of the biliary tree, including Caroli disease, choledochal cyst, and congenital hepatic fibrosis (see Table 22–10).

 Complications

Complications include secondary bacterial cholangitis, pancreatitis, biliary fibrosis, and cirrhosis. Slow progression to end-stage liver disease with liver failure is common, and patients are at increased risk of cholangiocarcinoma.

 Treatment

Treatment of PSC focuses on supportive care. Ursodeoxycholic acid is often used in pediatrics, though high doses may worsen disease in adults. Oral vancomycin has been used, though very little data support its use. Patients with autoimmune sclerosing cholangitis or IgG4 cholangitis may 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 10% after transplant.

 Prognosis

The majority of patients will eventually require liver transplantation, and PSC is the fifth leading indication for liver transplantation in the United States. The median duration from the time of diagnosis to end-stage liver disease is 12–15 years.

Ibrahim SH, Lindor KD: Current management of primary sclerosing cholangitis in pediatric patients. Pediatric Drugs 13:87 [PMID: 21351808].

Kerkar N, Miloh T: Sclerosing cholangitis: pediatric perspective. Curr Gastroenterol Rep 2010;12:195 [PMID: 20425475].

Mieli-Vergani G, Vergani D: Unique features of primary sclerosing cholangitis in children. Curr Opin Gastroenterol 2010;26:265 [PMID: 20393280].

Shneider BL: Diagnostic and therapeutic challenges in pediatric primary sclerosing cholangitis. Liver Transpl 2012;18:277 [PMID: 22140074].

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.

 Figure 22–1. Classification of cystic dilation of the bile ducts. Types I, II, and III are extrahepatic choledochal cysts. Type IVa is solely intrahepatic, and type IVb is both intrahepatic and extrahepatic.

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Fever and painful enlarged liver.

 Ultrasound of liver demonstrating an abscess.

 Positive serum ameba antibody or positive bacterial culture of abscess fluid.

 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 infective 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 (Mexico, Southeast Asia) 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. Early in the course, LFTs may suggest mild hepatitis. Blood cultures may be positive. The distinction between pyogenic and amebic abscesses 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 antiamebic therapy (metronidazole). Examination of material obtained by needle aspiration of the abscess using ultrasound guidance is often diagnostic.

D. Imaging

Ultrasound liver scan 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 with gallium or technetium sulfur colloid may be useful in differentiating tumor or hydatid cyst. Consolidation of the right lower lobe 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

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 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 promptly with oral metronidazole, 35–50 mg/kg/d, in three divided doses for 10 days. Intravenous metronidazole can be used for patients unable to take oral medication. Failure to improve after 72 hours of drug therapy suggests superimposed bacterial infection or an incorrect diagnosis. At this point, needle aspiration or surgical drainage is indicated. 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 15% for pyogenic liver abscess, especially with extrahepatic complications, and less than 1% for amebic abscess.

Mishra K et al: Liver abscess in children: an overview. World J Pediatr 2010;6:210 [PMID: 20706820].

Singh O et al: Comparative study of catheter drainage and needle aspiration in management of large liver abscesses. Indian J Gastroenterol 2009;28:88 [PMID: 19907956].

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Abdominal enlargement and pain, weight loss, anemia.

 Hepatomegaly with or without a definable mass.

 Mass lesion on imaging studies.

 Laparotomy and tissue biopsy.

 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 a symptomatic 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 grams) have a 15 times increased risk of hepatoblastoma, as compared to infants > 2500 grams. Pathologic differentiation from hepatocellular carcinoma, the other major malignant tumor of the liver, may be difficult.

Hepatocellular carcinoma most commonly occurs between the ages of 10–12 years and is more common in males. Children are more likely to be symptomatic, with abdominal distension, pain, and advanced disease, including anorexia and weight loss, at presentation. 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 also 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 all 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 be present if obstruction of the biliary tree occurs. Virilization has been reported as a consequence of gonadotropin 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 associated 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. However, evidence of virilization or feminization in prepubertal children may be noted.

C. Laboratory Findings

Normal LFTs are the rule. Anemia frequently occurs, especially in cases of hepatoblastoma. Cystathioninuria has been reported. 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 scintigraphic study of bone and chest CT are generally part of the pre-operative 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

Progressive enlargement of the tumor, abdominal discomfort, ascites, respiratory difficulty, and widespread metastases (especially to the lungs and the abdominal lymph nodes) are the rule. Rupture of the neoplastic liver and intraperitoneal hemorrhage has been reported. Progressive anemia and emaciation predispose the patient to an early septic death.

 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). Second-look celiotomy has, in some cases, allowed resection of the tumor, resulting in a reduced mortality rate. 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%.

Finegold MJ et al: Liver tumors: pediatric population. Liver Transpl 2008;14:1545 [PMID: 18975283].

Gupta AA et al: Critical review of controversial issues in the management of advanced pediatric liver tumors. Pediatr Blood Cancer 2011;56:1013 [PMID: 21488153].

Hadzic N et al: Liver neoplasia in children. Clin Liver Dis 2011;15:443 [PMID: 21689623].

Lopez-Terrada D: Current issues and controversies in the classification of pediatric hepatocellular tumors. Pediatric Blood Cancer 2012;59:780 [PMID: 22648939].

Orthotopic liver transplantation is indicated in children with end-stage liver disease, acute fulminant hepatic failure, 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 donation, all of which have expanded the potential donor pool. Lifetime immunosuppression therapy, using combinations of tacrolimus, cyclosporine, 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. Various protocols are being tested for prevention and treatment of lymphoproliferative disease.

Alonso EM, Sorensen LG: Cognitive development following pediatric solid organ transplantation. Curr Opin Organ Transplant 2009;14:522 [PMID: 19625964].

Anthony SJ et al: Quality of life after pediatric solid organ transplantation. Pediatr Clin North Am 2010;57:559 [PMID: 20371052].

Campbell KM et al: High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation. J Pediatr 2006;148:475 [PMID: 16647407].

Kamath BM, Olthoff KM: Liver transplantation in children: update 2010. Pediatr Clin North Am 2010;57:401 [PMID: 20371044].

PANCREATIC DISORDERS ACUTE PANCREATITIS

 ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES

 Epigastric abdominal pain radiating to the back.

 Nausea and vomiting.

 Elevated serum amylase and lipase.

 Evidence of pancreatic inflammation by CT or ultrasound.

 General Considerations

The rate of hospitalization for acute pancreatitis in children is 0.02–0.09/1000 US population. The incidence of pediatric acute pancreatitis seems to be increasing. 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 sulfasalazine, thiazides, valproic acid, azathioprine, mercaptopurine, asparaginase, antiretroviral drugs (especially didanosine), high-dose corticosteroids, and other drugs. It may also occur in cystic fibrosis, systemic lupus erythematosus, α₁-antitrypsin deficiency, diabetes mellitus, Crohn disease, glycogen storage disease type I, hyperlipidemia types I and V, 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 in families. Alcohol-induced pancreatitis should be considered in the teenage patient.

 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, and bowel sounds are diminished, suggesting peritoneal irritation. 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 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 amylase elevation. Leukocytosis, hyperglycemia (serum glucose > 300 mg/dL), hypocalcemia, falling hematocrit, rising blood urea nitrogen, hypoxemia, and acidosis may all occur in severe cases and imply a poor prognosis.

D. Imaging

Plain radiographic films of the abdomen may show a localized ileus (sentinel loop). Ultrasonography 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 is often difficult to image with ultrasound due to overlying gas. CT scanning images the pancreas more consistently and is better for detecting pancreatic phlegmon, pseudocyst, necrosis, or abscess formation. The computed tomography severity index (CTSI) is useful in identifying patients at increased risk for serious complications. 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

Other causes of acute upper abdominal pain include gastritis; peptic ulcer disease; duodenal ulcer; hepatitis; liver abscess; cholelithiasis; cholecystitis; choledocholithiasis; acute gastroenteritis or 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. The gastrointestinal, neurologic, musculoskeletal, hepatobiliary, dermatologic, and hematologic systems may also be involved. Early predictors of a more aggressive course include renal dysfunction, significant fluid requirements, and multisystem organ dysfunction and a high CTSI. Five to 20% of patients can develop a pseudocyst 1–4 weeks later that may be asymptomatic or present with recurrence of abdominal pain and rise in the serum amylase. 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. Most regress, but some require drainage. Infection may occur in this inflammatory mass. Pancreatic abscess formation, which is rare (3%–5%), develops 2–3 weeks after the initial insult. Fever, leukocytosis, and pain suggest this complication; diagnosis is made by ultrasound or CT scanning. Chronic pancreatitis, exocrine or endocrine pancreatic insufficiency, and pancreatic lithiasis are rare sequelae of acute pancreatitis.

 Treatment

Medical management includes careful attention to fluid, electrolytes, and respiratory status. Gastric decompression may be helpful if there is significant vomiting. Pain should be controlled with opioids. Acid suppression may be helpful. Nutrition is provided by the parenteral or enteral (jejunal or gastric) route. Broad-spectrum antibiotic coverage is useful only in necrotizing pancreatitis. Drugs known to produce acute pancreatitis should be discontinued. Surgical treatment is reserved for traumatic disruption of the gland, intraductal stone, other anatomic obstructive lesions, and unresolved or infected pseudocysts or abscesses. 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 surprisingly good with conservative management.

Dzakovic A, Superina R: Acute and chronic pancreatitis: surgical management. Semin Pediatr Surg 2012;21:266 [PMID: 22800979].

Lautz TB et al: Utility of the computed tomography severity index (Balthazar score) in children with acute pancreatitis. J Pediatr Surg 2012;47:1185 [PMID: 22703791].

Lowe ME, Greer JB: Pancreatitis in children and adolescents. Curr Gastroenterol Rep 2008;10:128 [PMID: 18342688].

Morinville VD et al: Increasing incidence of acute pancreatitis at an American pediatric tertiary care center: is greater awareness among physicians responsible? Pancreas 2010;39:5 [PMID: 19752770].

Chronic pancreatitis is differentiated from acute pancreatitis in that the pancreas remains structurally or functionally abnormal after an attack.

The causes are multiple and can be divided into toxic-metabolic (eg, alcohol, chronic renal failure, hypercalcemia), idiopathic, genetic (increasingly recognized in children and adolescents), autoimmune, recurrent and severe acute pancreatitis, and obstructive pancreatitis (eg, pancreas divisum, choledochal cyst).

 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 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. Mutations of the cationic trypsinogen gene, the pancreatic secretory trypsin inhibitor, the cystic fibrosis transmembrane conductance regulator gene (CFTR) and chymotrypsin C are associated with recurrent acute and chronic pancreatitis. Elevated blood glucose and glycohemoglobin levels and glycosuria frequently occur in protracted disease. Sweat chloride should be checked for cystic fibrosis, α₁-antitrypsin level or phenotype, and serum calcium for hyperparathyroidism.

D. Imaging

Radiographs of the abdomen may show pancreatic calcifications in up to 30% of patients. Ultrasound or CT examination demonstrates an abnormal gland (enlargement or atrophy), ductal dilation, and calculi in up to 80%. CT is the initial imaging procedure of choice. MRCP or ERCP can show ductal dilation, stones, strictures, or stenotic segments. Endoscopic ultrasound in the diagnosis and staging of chronic pancreatitis is being evaluated.

 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; α₁-antitrypsin deficiency; 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 by age 70.

 Treatment

Medical management of acute attacks is indicated (see section on Acute Pancreatitis, earlier). If ductal obstruction is strongly suspected, endoscopic therapy (balloon dilation, stenting, stone removal, or sphincterotomy) should be pursued. Relapses occur in most patients. Pancreatic enzyme therapy should be used in patients with pancreatic insufficiency. Antioxidant therapy is being investigated. Pseudocysts may be marsupialized to the surface or drained into the stomach or into a loop of jejunum if they fail to regress spontaneously. Lateral pancreaticojejunostomy or the Frey procedure can reduce pain in pediatric patients with a dilated pancreatic duct and may prevent or delay progression of functional pancreatic impairment. Pancreatectomy and islet cell autotransplantation has been used in selected cases of chronic pancreatitis.

 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.

Lal A, Lal DR: Hereditary pancreatitis. Pediatr Surg Int 2010;26:1193 [PMID: 20697897].

Sultan M et al: Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012;54:645 [PMID: 22094894].

Sutherland DE et al: Total pancreatectomy and islet autotransplantation for chronic pancreatitis. J Am Coll Surg 2012;214:409 [PMID: 22397977].

Yadav D et al: Incidence, prevalence, and survival of chronic pancreatitis: a population-based study. Am J Gastroenterol 2011;106:2192 [PMID: 21946280].

Cystic fibrosis is a disease with protean manifestations. Although pulmonary and pancreatic involvement dominate the clinical picture for most patients (see Chapter 19), 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.

Debray D et al: Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J Cyst Fibros 2011;10:S29 [PMID: 21658639].

Flass T, Narkewicz MR: Cirrhosis and other liver disease in cystic fibrosis. J Cyst Fibros 2013;12:116 [PMID: 23266093].

Gelfond D, Borowitz D: Gastrointestinal complications of cystic fibrosis. Clini Gastroenterol Hepatol 2013;11:333 [PMID: 23142604].

Munck A et al: Pancreatic enzyme replacement therapy for young cystic fibrosis patients. J Cyst Fibros 2009;8:14 [PMID: 18718819].

Several syndromes are associated with exocrine pancreatic insufficiency. Patients present with a history of failure to thrive, diarrhea, fatty stools, and an absence of respiratory symptoms. Laboratory findings include a normal sweat chloride; low fecal pancreatic elastase 1; and low to absent pancreatic lipase, amylase, and trypsin levels on duodenal intubation. 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. Bone marrow failure is seen in one third. 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 lessen with age. Intragastric lipolysis by lingual lipase may compensate in patients with low or absent pancreatic function. In Shwachman-Diamond syndrome, short stature and bony dysplasias are problematic. Increased numbers of infections may result from chronic neutropenia and the reduced neutrophil mobility that is present in many patients. 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. The prognosis appears to be good for those able to survive the increased number of bacterial infections early in life and lack severe associated defects.

Almashraki N, Abdulnabee MZ, Sukalo M, Alrajoudi A, Sharafadeen I, Zenker M: Johanson-Blizzard syndrome. World J Gastroenterol 2011;17:4247 [PMID: 22072859].

Chen R et al: Neonatal and late-onset diabetes mellitus caused by failure of pancreatic development: report of 4 more cases and a review of the literature. Pediatrics 2008;121:1541 [PMID: 18519458].

Dror Y et al: Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci 2011;1242:40 [PMID: 22191555].

Myers KC et al: Clinical and molecular pathophysiology of Shwachman-Diamond syndrome: an update. Hematol Oncol Clin North Am 2013;27:117 [PMID: 23351992].

Seneca S et al: Pearson marrow pancreas syndrome: a molecular study and clinical management. Clin Genet 1997;51:338 [PMID: 9212183].

Normal 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 into 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. 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, but do not have respiratory symptoms and have a normal sweat test. They respond to pancreatic enzyme replacement therapy and feeding formulas that contain a casein hydrolysate (eg, Nutramigen, Pregestimil).

Durie PR: Pancreatic aspects of cystic fibrosis and other inherited causes of pancreatic dysfunction. Med Clin North Am 2000;84:609 [PMID: 10872418].

McKenna LL: Pancreatic disorders in the newborn. Neonatal Netw 2000;19:13 [PMID: 11949098].

Stormon MO, Durie PR: Pathophysiologic basis of exocrine pancreatic dysfunction in childhood. J Pediatr Gastroenterol Nutr 2002;35:8 [PMID: 12142803].

Pancreatic tumors, whether benign or malignant, are rare. In the setting of malignancy, the majority of patients present with abdominal pain. Pancreatic tumors most often arise from ductal or acinar epithelium (malignant adenocarcinoma) or from islet (endocrine) components within the gland, such as the benign insulinoma (adenoma) derived from β cells. Other pancreatic tumors originate from these pluripotential endocrine cells (eg, gastrinoma, VIPoma, glucagonoma), and produce diverse symptoms, because they release biologically active polypeptides from this ectopic location. The clinical features of these tumors are summarized in Table 22–13. The differential diagnosis of pancreatic tumors includes Wilms tumor, neuroblastoma, and malignant lymphoma. In older children, endoscopic ultrasonography can aid in localizing these tumors.

Nissen NN et al: Pancreatic neuroendocrine tumors: presentation, management, and outcomes. Am Surg 2009;75:1025 [PMID: 19886158].

Rojas Y et al: Primary malignant pancreatic neoplasms in children and adolescents: a 20 year experience. J Pediatr Surg 2012;47:2199 [PMID: 23217876].

Yu DC et al: Childhood pancreatic tumors: a single institution experience. J Pediatr Surg 2009;44:2267 [PMID: 20006007].

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Kleinman R et al (eds): Walker’s Pediatric Gastrointestinal Disease: Physiology, Diagnosis, Management, 5th ed. BC Decker Inc; 2008.

Suchy FJ, Sokol RJ, Balistreri WF (eds): Liver Disease in Children, 4th ed. Cambridge University Press; 2014.

Wyllie R, Hyams JS (eds): Pediatric Gastrointestinal and Liver Disease, 4th ed. Elsevier; 2011.