Viral Hepatitis in Children

Introduction

Many viruses can infect the liver during childhood. Some, such as hepatitis A and B viruses, are largely hepatotropic, whereas others, such as adenovirus, can cause multisystem disease. Some, such as herpes viruses 1 and 2, only cause acute infection whereas others, such as hepatitis B virus, can cause acute hepatitis, with or without liver failure, or result in chronic infection. Some may cause very mild or asymptomatic disease such as cytomegalovirus (CMV), and some can cause acute liver failure, such as parvovirus B19. Finding evidence of viral infection in a patient with “hepatitis,” meaning elevation of serum aminotransferases, does not necessarily prove that the hepatitis is related causally to the viral infection.

Similarly, the presence of elevated serum aminotransferases in a child does not necessarily indicate viral infection of the liver. There is a long list of differential diagnoses depending on the age of the child, whether the child is cholestatic or not, and whether or not extrahepatic symptoms are present. These conditions include m etabolic, autoimmune, genetic, and nonviral infections, such as those secondary to bacteria, fungi, or parasites. Cholangiopathies, such as biliary atresia, sclerosing cholangitis, or autoimmune cholangitis, are usually accompanied by elevation of serum aminotransferases. Drug-induced liver disease is increasingly diagnosed in children. As many as one quarter of children with gluten-sensitive enteropathy may exhibit elevated aminotransferases. Furthermore, a child with marked elevations of serum aminotransferases may have suffered nonaccidental trauma from child abuse and abdominal battering. Such children often have very high elevation of serum aminotransferases, up to 20,000 IU/L with prompt return to normal values over just a few days, a pattern which is not typical of viral hepatitis. Myopathies such as Duchenne muscular dystrophy are often accompanied by elevation of serum aminotransferases of muscular origin. In such children, serum creatine phosphokinase is usually dramatically elevated, whereas in viral hepatitis it is in the normal range. Nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease have now become the most common liver diseases of children. Thus, when an obese child presents with clinical signs and symptoms of an infection such as fever, accompanied by elevation of serum aminotransferases, it may be a challenge to determine if the patient has viral hepatitis or underlying NASH, or both.

This chapter on viral hepatitis in children is organized according to the major clinical presentations of viral infections of the liver in childhood: acute hepatitis with possible progression to pediatric acute liver failure (PALF) and chronic hepatitis.

Individual Viruses

The diagnostic tests for these agents are described in Table 65-1 and possible treatments are shown in Table 65-4 .

TABLE 65-4

Agents of Acute Viral Hepatitis and Suggested Therapies

Virus	Agent	Comments
Adenovirus	Cidofovir (not FDA-approved for adenovirus but the expert's choice)	Usually used only in immunosuppressed individuals
Cytomegalovirus	Gancyclovir, valgancyclovir Broad spectrum T cells in the immunosuppressed host	For use after reactivation after hematopoietic stem cell transplant
Epstein-Barr virus	Broad spectrum T cells	For use after reactivation after hematopoietic stem cell transplant
Enterovirus	Intravenous Immune Globulin	Effective for severe neonatal infection when given within 3 days of symptom onset
Hepatitis A virus	None
Hepatitis E virus	Ribavirin	May be effective in solid-organ transplant recipients if reduction of immunosuppression is ineffective
Human herpes virus 6	Broad spectrum T cells
Parvovirus B19	Intravenous immune globulin	May be effective in some cases but have a paradoxical exacerbating effect in others
Varicella-zoster	Acyclovir

Adenovirus

Adenovirus (AD) is a ubiquitous DNA virus which most often causes mild multisystem disease with a predilection towards the lung. Children who are immunocompromised are particularly vulnerable. On rare occasions AD can cause PALF, most often in immunosuppressed individuals such as bone marrow transplant recipients. Fig. 65-1 demonstrates characteristic hepatic histopathology with the arrows indicating intranuclear inclusion bodies. Cidofovir is considered the drug of choice for severe AD infections, but not all patients require treatment.

Cytomegalovirus

Congenital cytomegalovirus (CMV) infection is often asymptomatic, but a minority of infected newborns will develop hepatitis, hepatosplenomegaly, conjugated hyperbilirubinemia, and/or thrombocytopenia and neurologic involvement. The diagnosis of CMV infection may be made by liver biopsy, urine CMV culture, or IgM antibody to CMV. CMV does not cause chronic infection in immunocompetent children. Acute CMV hepatitis is usually not a disorder of healthy children or adolescents, but a common disease in immunocompromised hosts. Treatment with ganciclovir or valganciclovir is indicated.

Enterovirus

Enteroviruses such as coxsackie B virus or echovirus 11 may cause PALF in infants less than 7 months of age, as well as myocarditis and meningoencephalitis. The infectious signs and symptoms in older children are usually much milder and gastrointestinal symptoms predominate. The age-related difference in pathogenesis may be related to the age-related decline in the coxsackie virus-adenovirus receptor. Antibodies to this receptor have been shown to abrogate the severe hepatitis in mice infected with coxsackie B virus. Early intravenous immunoglobulin (IVIG) therapy may be effective for severe neonatal infection when given within 3 days of symptom onset.

Epstein-Barr Virus

Clinical symptoms of infectious mononucleosis caused by Epstein-Barr virus (EBV) infection include fever, pharyngitis, lymphadenopathy, splenomegaly, and hepatitis with jaundice. Abnormal aminotransferases are present in up to 80% of patients. Acute liver failure and EBV-associated hemophagocytic syndrome are rare complications. Serum IgM to the EB viral capsid antigen (VCA) and/or EBV DNA by polymerase chain reaction (PCR) are the diagnostic tests of choice. Hepatitis associated with infectious mononucleosis usually resolves spontaneously and fully over 2 to 3 weeks.

Hepatitis A Virus

Hepatitis A virus (HAV) is an RNA virus which causes acute hepatitis and, rarely, acute liver failure in children and young adults. The infection is spread by the fecal-oral route. It has an incubation period of 15 to 40 days followed by an abrupt onset of symptoms, often gastrointestinal in nature. Anorexia is severe. Seldom, the infected child may suffer from arthritis, arthralgias, or skin rash. The illness usually lasts weeks and, in the rare cases of relapsing HAV, the symptoms can last months. However, the infection is always self-limited. Postinfectious immunity is life-long. Postexposure prophylaxis is with the active vaccine and passive (immune serum globulin) immunization. Children with HAV can be completely asymptomatic and thus serve as an infectious reservoir. HAV is a vaccine preventable disease and the American Academy of Pediatrics (AAP) recommends HAV vaccine at 12 to 23 months of age. There are two vaccines approved for use in children: Havrix (Glaxo Smith Kline) and Vaqta (Merck). Twinrix (Glaxo Smith Kline) vaccine is approved for age 18 years and older and protects recipients against both HAV and HBV. Other indications for HAV vaccine include catch-up immunization of unimmunized children 2 to 18 years of age, travelers to endemic areas, close contacts of newly arrived international adoptees, patients with chronic liver disease or clotting factor disorders, and users of injections and illicit drugs. Preexposure prophylaxis for travelers to endemic areas is via immune serum globulin for infants younger than 12 months of age and active vaccine for children older than 12 months of age, providing the immunization is given 1 month or more before travel. Household and other close contacts should receive immunoprophylaxis (active vaccine if within 8 days of exposure or passive immune serum globulin within 2 weeks of exposure). Fecal shedding usually decreases rapidly after the onset of jaundice and for this reason the child may return to school soon after becoming jaundiced, provided he or she feels well. There is no specific treatment.

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