The first descriptions of hepatitis (epidemic jaundice) are attributed to Hippocrates. Outbreaks of jaundice, probably hepatitis A (HA), were reported in the 17th and 18th centuries, particularly in association with military campaigns. Despite such a long history, only in 1973 hepatitis A virus (HAV) was visualized by immune electron microscopy in suspensions of fecal samples collected from infected human volunteers [Feinstone et al., 1973]. HAV is a nonenveloped, spherical particle with a diameter of 27 nm, is classified as a member of the Hepatovirus genus within the Picornaviridae family.
The symptoms of HA develop, on average, around four weeks after becoming infected, although in many patients the disease is asymptomatic. The illness typically has an abrupt onset of fever, malaise, anorexia, nausea, abdominal discomfort, dark urine and jaundice. Clinical illness usually does not last longer than 2 months, although 10%–15% of persons have prolonged or relapsing signs and symptoms for up to 6 months.
The most important determinant influencing the severity of disease and the outcome of the infection appears to be the age of the patient. Asymptomatic (or at least anicteric) infection is common in very young children infected with HA. In contrast, up to 90% of young adults who are infected with HAV have symptoms, and as many as two-thirds become icteric. HA is particularly risky for elderly individuals, as age and the risk of developing fulminant hepatitis strongly correlate.
Once HAV reaches the liver, it replicates in hepatocytes and is released into the bloodstream. At the same time, the virus is present in the bile and shed in the feces. The titre of viraemia in blood is usually 100- to 1000-fold lower than the titre of virus shed in faeces.
Both faecal virus shedding and blood viraemia reach a maximum just prior to the onset of liver disease, i.e. at the end of the incubation period and at the beginning of the acute illness.
HAV infection is acquired primarily by the fecal-oral route by either person-to-person contact or ingestion of contaminated food or water. Since the virus is present in blood, HAV could be transmitted on rare occasions by transfusion or by injecting drugs.
Fecal-oral transmission is possible due to high resistance of HAV to degradation by environmental conditions as well as to several preservation methods used in the food industry. Resistance to acid pH and detergents also accounts for its ability to enter the host through the stomach, and to exit it via the biliary tract. These factors contribute significantly to the pathogenesis of HA.
Groups at increased risk for НA include international travelers to countries with high prevalence rates of HA, men who have sex with men, users of illegal drugs, and blood recipients.
Despite the considerable nucleotide sequence heterogeneity, HAV is antigenically conserved. A single serotype of HAV exists. Therefore, infection confers lifelong immunity.
Since the development of effective vaccines against HA in the 90th, the prevalence rates of HA are in decline. For example, in USA, around 30 000 annual cases were reported in the 90th, but only around 3500 cases in 2013. Still, 1,5 million clinical cases of HA are reported worldwide annually, mainly from parts of the world where standards of sanitation and food hygiene are generally poor. There is a wide variation in incidence rates—up to 1000-fold between the low rates in north-western Europe, USA and Canada and the highly endemic countries (Central and South America, the whole Africa, Asia excluding Japan). Immunological surveys indicated that in southern Europe and the Mediterranean, about 90% of the population had antibodies against HAV comparing to only 3% in Scandinavian countries; similarly, in South America over 90% of the low-income population had serological evidence of infection at the age of 18. In developed countries, most cases of HA are now restricted to high risk groups.
HAV typically causes persistent infections in cell cultures, but yet has not been shown to cause chronic infections in people. Unlike the situation with hepatitis C virus, the adaptive immune response to HAV is robust and extremely effective in eliminating the virus.
After infection via the gastrointestinal tract, HAV replicates asymptomatically within the liver for several weeks or more during the incubation period of the disease. By the end of this period, high titers of virus are present within liver tissue, bile, stool, and, to a lesser extent, blood. Despite this, there is little evidence of liver injury. Clinical manifestations of the infection appear only at the fourth or fifth week of the infection along with the first evidence of immune response to the virus. The early antibody response is composed largely of IgM, although IgG may also be present shortly after the onset of symptoms. Anti-HAV IgG reaches maximum at 4-6 month after infection, and then slowly decreases at rate of approximately 10% a year, persisting for life and conferring protection against reinfection. IgM antibody usually persists for 4- 6 months, but there are reports of its continued detection for more than a year following acute hepatitis A. Both secretory and serum anti-HAV IgA have been described, but the role of secretory immunity in protection against HAV infection appears to be very limited. Re-exposure of seropositive individuals may lead to increases in anti-HAV titer, but it does not cause liver disease.
HAV RNA genome is packaged within an icosahedral protein capsid composed of 60 copies of each of 3 major structural proteins, VP1, VP2, and VP3 (also known as 1D, 1B, and 1C). There are also 7 nonstructural proteins required for HAV RNA replication: 2B, 2C, 3A, 3B, 3Cpro (a cysteine protease responsible for most post-translational cleavage events within the polyprotein), and 3Dpol (the viral RNA-dependent, RNA polymerase).
Although there are attempts to study response against single surface proteins, considerable evidence suggests that the main antigenic epitopes of HAV are conformational structures formed by interactions of capsid proteins. The conformational nature of the immunodominant epitope of HAV has greatly hindered attempts to express an immunologically relevant antigen from recombinant DNA.
Currently, the main source of immunoreactive proteins for immunoassays is inactivated HAV derived from cell culture.
Isolation of HAV and detection of viral antigen or RNA are complicated, expensive, and not standardized. Consequently, detection of the virus is not useful for diagnosis. Fortunately, IgM anti-HAV antibodies are easily detectable by immunoassay; therefore, their detection is the reference standard of specific diagnosis of acute or recent HA. A wide variety of techniques have been used for the detection of antibodies to HAV. The most widely used methods for detection of antiboies to the virus are the competitive-inhibition RIA or EIA.
Immunoassays may be used:
a)To diagnose acute or recent HA - by IgM;
b)To determine the susceptibility (for example, before possible vaccination) - by IgG. The concentration of anti-HAV antibodies ≥20 mIU/mL, detectable by the standard HAV antibody assay, is regarded by the US Centers for Disease Control and Prevention as protective [Bovier et al., 2010].
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