Overview of hepatitis A virus infection in adults

Catherine Petruff Cheney, MD

UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on April 24, 2006. The next version of UpToDate (14.3) will be released in October 2006. INTRODUCTION — Hepatitis A has plagued humankind for centuries by causing an acute hepatitis associated with significant morbidity and occasional mortality. Terms such as epidemic jaundice, acute catarrhal jaundice, and campaign jaundice have been used to describe this infection. Two distinct forms of hepatitis were recognized in 1947 and were designated hepatitis A and hepatitis B [ 1 ]; the hepatitis A virus (HAV) was identified in 1973 [ 2 ]. In recent years, extensive research has culminated in the development of vaccines that can prevent acute hepatitis A. ( See "Hepatitis A virus vaccination and postexposure prophylaxis" ). In addition, although most patients recover spontaneously, liver transplantation has revolutionized the treatment of fulminant hepatic failure resulting from infection. The epidemiology, major clinical manifestations, diagnosis, and treatment of HAV infection will be reviewed here. Atypical manifestations, such as cholestatic hepatitis, relapsing hepatitis, and extrahepatic manifestations, are discussed separately. ( See "Atypical manifestations of hepatitis A virus infection" ). GENOMIC ORGANIZATION — Hepatitis A is a 27 nm, nonenveloped, icosahedral, positive-stranded RNA virus classified in the Heparnavirus genus of the Picornaviridae. The hepatitis A viral genome is comprised of 7474 nucleotides divided into three regions: a 5' untranslated region (742 nucleotides); a single long open reading frame that encodes a 2227 amino acid polypeptide (6681 nucleotides); and a 3' noncoding region (63 nucleotides). The polypeptide encoded by the open reading frame is cotranslationally processed by a viral protease, resulting in four structural and seven nonstructural proteins ( show figure 1 ). Four distinct genotypes of HAV have been identified in humans, although they do not appear to have important biological differences [ 3 ]. All four genotypes belong to a single serotype. EPIDEMIOLOGY — Hepatitis A virus infection occurs worldwide ( show figure 2 ). The incidence in the United States has declined substantially since vaccination was recommended for persons at increased risk (in 1996) and children living in states with the highest incidence of HAV (in 1999) ( show figure 3 ) [ 4 ]. In 2003, the incidence was 2.6 per 100,000, 76 percent lower than previous nadirs in 1983 and 1992. The decline was most pronounced in states that routinely vaccinate compared to other states (a decline of 88 versus 53 percent). In 2003, cases from vaccinating states accounted for 33 percent of the national total versus 65 percent at baseline. The decline was greater among children ages 2 to 18 compared with older persons; the highest rates occurred in men aged 25 to 39. HAV is spread via the fecal-oral route, and is more prevalent in low socioeconomic areas in which a lack of adequate sanitation and poor hygienic practices facilitate spread of the infection ( show table 1 ). The majority of patients who acquire the illness have had personal contact with an infected person ( show figure 4 ). Maternal-fetal transmission has not been reported, and direct percutaneous inoculation or transfusion is not a major risk factor for transmission. Community outbreaks due to contaminated water or food have also been described. In one such report, HAV RNA could be detected in well water six months after the initial contamination [ 5 ]. HAV can be acquired from contaminated food, usually shellfish. Several outbreaks related to consumption of contaminated green onions have been described [ 6,7 ]. The largest included 601 patients whose infection could be traced to salsa prepared with green onions imported from Mexico [ 7 ]. The identified strain was similar to isolates from outbreaks in Tennessee, Georgia, and North Carolina all of which were related to green onions imported from Mexico. Hepatitis A can occur sporadically or in an epidemic form. However, some sporadic occurrences may be unrecognized cases from geographically distant regional outbreaks. In one report, for example, 213 cases of hepatitis A were detected from 23 schools in Michigan, and 29 cases from 13 schools in Maine; all were related to contaminated frozen strawberries [ 8 ]. The genetic sequence of the virus was identical to five cases reported in Wisconsin, seven in Arizona and two in Louisiana. These patients would have been considered sporadic cases had genetic sequencing of the virus and careful epidemiologic tracking not been performed. HAV is often transmitted within networks of persons with similar risk factors suggesting that some sporadic cases may be explainable [ 9 ]. Nevertheless, hepatitis A occurs sporadically in approximately 40 percent of cases in the United States [ 10 ]. Population immunity — The global epidemiology of the disease is changing, largely due to the improvement of living conditions in underdeveloped countries. As a result, fewer children are infected, leading to a larger population of adults who lack protective antibodies against HAV. The decrease in population immunity in endemic countries has resulted in an increasingly large group of adults who are at risk for outbreaks of infection. In one report in 1988, approximately 290,000 people in Shanghai China developed acute hepatitis A infection that was traced to a species of clam sold in large quantities in Shanghai markets (Anadara subcrenata lusche) [ 11 ]. PATHOGENESIS OF HEPATIC INJURY — Injury to the liver is secondary to the host's immune response. Replication of HAV occurs exclusively within the cytoplasm of the hepatocyte, where the virus causes a non cytopathic infection. Hepatocellular damage and destruction of infected hepatocytes is mediated by HLA-restricted, HAV-specific CD8+ T lymphocytes and natural killer cells [ 12-14 ]. Interferon gamma appears to have a central role in promoting clearance of infected hepatocytes [ 12 ]. An excessive host response (observable clinically by a marked degree of reduction of HAV RNA during acute infection) is associated with severe hepatitis [ 15 ]. CLINICAL MANIFESTATIONS — HAV infection usually results in an acute, self-limited illness and only rarely leads to fulminant hepatic failure. Fulminant hepatic failure occurs more commonly in patients with underlying liver disease, particularly chronic hepatitis C virus infection. This was illustrated in a study of 163 patients with chronic hepatitis B and 432 patients with chronic hepatitis C who were prospectively followed for seven years [ 16 ]. Hepatitis A superinfection occurred in 27 patients. An uncomplicated course occurred in 9 of the 10 patients with hepatitis B who acquired hepatitis A; one patient who also had preexisting cirrhosis developed marked cholestasis. In comparison, fulminant hepatic failure developed in 7 of the 17 patients with HCV who acquired hepatitis A; six of these patients died. The manifestations also vary with age. HAV infection is usually silent or subclinical in children. In contrast, infection in adults can vary in severity from a mild flu-like illness to fulminant hepatitis. The incubation period averages 30 days (range 15 to 49 days), after which the illness begins in symptomatic patients with the abrupt onset of prodromal symptoms including, fatigue, malaise, nausea, vomiting, anorexia, fever, and right upper quadrant pain [ 17 ]. Within a few days to one week, these patients note dark urine, acholic stool (light-colored stools lacking bilirubin pigment), jaundice, and pruritus. The prodromal symptoms usually diminish when jaundice appears; jaundice typically peaks within two weeks ( show figure 5 ). HAV is rarely associated with a relapsing or cholestatic clinical illness, and may serve as a trigger for autoimmune hepatitis in genetically susceptible individuals. ( See "Atypical manifestations of hepatitis A virus infection" ). The two most common physical examination findings are jaundice and hepatomegaly, which occur in 70 and 80 percent of symptomatic patients, respectively [ 18 ]. Less common findings include splenomegaly, cervical lymphadenopathy, evanescent rash, arthritis, and, rarely, a leukocytoclastic vasculitis. Laboratory findings in symptomatic patients are notable for marked elevations of serum aminotransferases (usually >1000 IU/dL), serum total and direct bilirubin, and alkaline phosphatase [ 18 ]. The serum alanine aminotransferase (ALT) is commonly higher than the serum aspartate aminotransferase (AST). The serum aminotransferase elevations precede the bilirubin elevation, with the peak bilirubin concentration occurring after the peak aminotransferase elevations. Serum bilirubin levels above 10 mg/dL are common. Other laboratory abnormalities include nonspecific elevations of acute phase reactants, elevated erythrocyte sedimentation rate, and increased immunoglobulins. A variety of extrahepatic manifestations have been associated with acute HAV infection including vasculitis, arthritis, optic neuritis, transverse myelitis, thrombocytopenia, aplastic anemia, and red cell aplasia [ 19 ]. These conditions are more likely in patients who have protracted illness. ( See "Atypical manifestations of hepatitis A virus infection" ). DIAGNOSIS — The diagnosis of acute HAV infection is made by the detection of anti-HAV antibodies in a patient with the typical clinical presentation. Serum IgM anti-HAV is the gold standard for the detection of acute illness. The presence of serum IgM anti-HAV antibodies in adults without clinical features of viral hepatitis does not necessarily indicate acute infection. Such patients may have previous HAV infection with prolonged presence of IgM anti-HAV, a false-positive result, or asymptomatic infection (which is much more common in children less than six compared with older children and adults) [ 20 ]. Anti-HAV is positive at the onset of symptoms, peaks during the acute or early convalescent phase of the disease, and remains positive for approximately four to six months ( show figure 4 ). The serologic detection of antibodies is simpler, easier, and less expensive than other techniques, such as HAV detection in stool and body fluids by electron microscopy and HAV RNA detection in stool, body fluids, serum, and liver tissue. IgG anti-HAV appears early in the convalescent phase of the disease, and remains detectable for decades. TREATMENT AND PROGNOSIS — Because the disease is usually self-limited, the treatment is supportive. Occasional patients require hospitalization (20 percent in the large outbreak described above [ 7 ]). Patients who develop fulminant infection require aggressive supportive therapy, and should be transferred to a center capable of performing liver transplantation. ( See "Fulminant hepatic failure: Definition; etiology; and prognostic indicators" ). Approximately 85 percent of individuals who are infected with hepatitis A have full clinical and biochemical recovery within three months, and nearly all have complete recovery by six months [ 21 ]. Serum aminotransferase concentrations decrease more rapidly than the serum bilirubin; the latter normalizes in more than 85 percent of individuals by three months. Fatalities due to hepatitis A are more common with advancing age and, as noted above, in patients with chronic hepatitis C [ 16 ]. Reported case fatality rates are 0.1 percent in infants and children, 0.4 percent between the ages of 15 and 39, and 1.1 percent in those over age 40 [ 22 ]. Pregnancy — Issues related to HAV during pregnancy are presented separately. ( See "Intercurrent hepatobiliary disease during pregnancy" ). PREVENTION — Since hepatitis A is transmitted predominantly by the fecal-oral route, prevention can be aided by improved sanitary conditions, adherence to sanitary practices such as handwashing, heating foods appropriately, and avoidance of water and foods from endemic areas. Handwashing is highly effective in preventing the transmission of the virus since hepatitis A virus may survive for up to four hours on the fingertips [ 23 ]. Chlorination and certain disinfecting solutions (household bleach 1:100 dilution) are sufficient to inactivate the virus. Preexposure prophylaxis — Passive immunization with polyclonal serum immune globulin prior to exposure has been available since the 1940s and can decrease the incidence of HAV infection by more than 90 percent [ 24-26 ]. Passive immunity lasts for up to six months depending upon the dose of immunoglobulin used, but is effective only if administered within two weeks of exposure [ 27 ]. However, several factors preclude widespread use of immunoglobulin prophylaxis. It is expensive, causes pain at the injection site, requires readministration every three to six months, and risks transmission of infectious agents due to the pooled, blood-derived source of the immunoglobulin preparation. As a result, immunoglobulin preexposure prophylaxis should be reserved for nonimmune individuals who are at risk for exposure hepatitis to A or who are allergic to the hepatitis A vaccine . ( See "Immunizations for travel" ). Postexposure prophylaxis — The issue of postexposure with immune serum globulin with or without HAV vaccination is discussed elsewhere. ( See "Hepatitis A virus vaccination and postexposure prophylaxis" ). Summarized briefly, treatment decisions regarding postexposure prophylaxis should be individualized:

• If the exposed individual falls into a high-risk group for repeated exposure, simultaneous administration of immune serum globulin and HAV vaccine may be warranted.

• If the individual has a single exposure with no identifiable risk for repeated exposure, a valid argument can be made for the administration of immune serum globulin alone.

Measurement of anti-HAV antibody titers prior to administration of postexposure prophylaxis is not recommended since it may delay treatment with immune serum globulin . Vaccination — Several highly effective and safe vaccines are now available for viral hepatitis A. Recommendations for vaccination are discussed in detail separately. ( See "Hepatitis A virus vaccination and postexposure prophylaxis" ).
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