All the hepatotropic viruses can result in acute and chronic infection (with the exception of HAV), although these differ significantly in the propensity to develop chronicity. Typical manifestations of acute viral hepatitis include malaise, fever, abdominal pain, and jaundice. However, these symptoms are not specific and may even be missed altogether.
The incubation period for HAV is 15–50 days. Most children with HAV infection are asymptomatic. Approximately one-third of infected children have the abrupt onset of nonspecific findings such as fever, nausea, diarrhea, emesis, and abdominal pain. Mild hepatomegaly and splenomegaly are common in the symptomatic group. Most preschool-aged children do not develop jaundice, so this illness may be dismissed as an intercurrent viral illness. The illness is generally self-limited, and the severity of symptoms is worse with older age. Over the age of 14 years approximately 70% of individuals will present with jaundice. In children <6 years, jaundice, when it does occur, usually resolves in 2 weeks, but adolescents and adults may be symptomatic for weeks to months.
Fulminant hepatic failure associated with acute HAV is very rare, occurring in <1% of cases. It is more common in individuals with other underlying chronic liver disease. On occasion, HAV may present atypically with a relapsing hepatitis, or with extrahepatic manifestations (vasculitis, arthritis, transverse myelitis, and aplastic anemia). HAV does not progress to chronic infection.
Although HAV is never a chronic infection, the disease burden is real. Illness can be severe and protracted. Furthermore, people can remain reservoirs of infection long after the symptoms of infection have passed.
The incubation period for HBV is 50–180 days. Acute HBV infection in children varies from asymptomatic infection to fulminant illness. The typical course of acute HBV infection has three phases, namely prodromal, symptomatic, and convalescence. The prodromal phase is rarely associated with immune-mediated features such as membranous glomerulonephropathy and vasculitis. The symptomatic phase, which begins 2–3 weeks later, is characterized by fatigue, fever, nausea, jaundice, and abdominal pain. Fatigue may be prolonged, but most of the symptoms resolve after 1–3 months. In infants and young children, acute HBV infection may be associated with Gianotti–Crosti syndrome, which is manifested by papular acrodermatitis on the face, buttocks, and limbs and lymphadenopathy (this condition can also occur with infection by viruses other than HBV). Fulminant HBV infection occurs more often in older children and adolescents.
The likelihood of progressing to chronic HBV infection is inversely related to the age at which the infection is acquired. Up to 90% of neonates will progress to chronic infection compared with 25–50% of children infected between the ages of 1 and 5 years, 6–10% of school-age children, and 1–5% of adults.21 Most children with chronic HBV infection are asymptomatic and diagnosed during routine screening. Chronic HBV infection is rarely associated with membranous glomerulonephropathy and polyarteritis nodosa.
The natural history of chronic HBV in children is variable and also depends on age at acquisition. Perinatally acquired HBV infection is typically characterized by immunotolerance. These children remain HBeAg and HBsAg positive with very high serum HBV DNA; however, histologic injury is typically mild and they have minimally elevated serum aminotransferases. Few of these children spontaneously seroconvert (Table 40–2): only 2% per year of children younger than 3 years, and 4–5% per year of children older than 3 years.22,23 This group of children with perinatally acquired immunotolerant HBV infection are typically Asian and comprise approximately half the pediatric population with chronic HBV infection.24
Table 40–2. Hepatitis B: Definitions and Serology ||Download (.pdf)
Table 40–2. Hepatitis B: Definitions and Serology
Hepatitis B Disease State
Acute hepatitis B
Anti-HBc positive if immune as a result of resolved infection
HBsAg (>6 months duration)
High HBV DNA
Minimally elevated aminotransferases
Individuals who acquire HBV infection during childhood usually have lower HBV DNA but more evidence of hepatitis with elevated alanine transferase (ALT) levels. These children commonly seroconvert to anti-HBe during the second decade of life.25 After spontaneous HBeAg seroconversion, carriers have minimal HBV DNA, normal ALT, and minimal histologic changes on liver biopsy. Most children who achieve this inactive carrier state remain in this condition for years to decades.24,26 Lifelong follow-up is required to ascertain that the inactive carrier state is maintained.25
Hepatocellular carcinoma is a feared complication of chronic HBV infection and is reported in children.27,28 It is most likely to occur in the second decade of life. Many pediatric hepatologists perform annual serum alpha fetoprotein levels and surveillance abdominal ultrasonography for hepatocellular carcinoma; there are little data to support this practice.24
The incubation period for HCV is 2 weeks to 6 months but averages 6–7 weeks. Acute HCV infection largely goes undetected in the pediatric setting and is indistinguishable from acute HAV or HBV. The acute illness usually passes unnoticed, but if symptoms are present these usually occur approximately 2 months after exposure. Only 10% of cases of acute illness are associated with jaundice.
HCV has a high propensity to develop chronic infection, occurring in 80% or more of cases.29 The natural progression of chronic HCV infection in adults is somewhat defined—an adverse outcome in terms of risk of cirrhosis and hepatocellular carcinoma is associated with older age at acquisition of infection, presence of coinfection, alcoholic liver disease, and male gender. However, there is a paucity of data in children exploring the natural history of chronic HCV in the pediatric population. Chronic hepatitis and cirrhosis do occur in children with chronic HCV, although the disease is clearly more benign as compared to adults. There are very few reported cases of hepatocellular carcinoma in adolescents and young adults with childhood-acquired HCV.30 It should be noted that, like adults, children with normal biochemistry can have advanced liver histology. Liver disease in children with HCV also does not correlate with specific genotypes or HCV RNA levels.31
Studies reporting the rates of spontaneous clearance of HCV infection in children are contradictory.31–33 It appears that children with transfusion-acquired HCV have a higher chance of clearing the virus than those with vertical transmission.34 Infants with perinatally acquired infection who do clear HCV will likely do so in the first 2 years of life.9