The enterically transmitted disease known first as "inlectious hepatitis," to distinguish it from "serum hepatitis" (hepatitis B), then as hepatitis A, was known for many years before its causal agent was identified unequivocally in 1973 by demonstration of a 27 nm icosahedral virus in patients' feces using immunoelectron microscopy (Fig. 23-6). Biophysical and biochemical studies later established hepatitis A virus as a member of the family Picornavtridae.
For a time hepatitis A virus (HAV) was classified as enterovirus type 72, but it was eventually accorded the status of a separate genus, Hepatovirus, on the basis of a number of differences from the enteroviruses, including stability of
Fig. 23.6 Hepatitis A virus. Negatively stained preparation of virions clumped by antibody as seen by immunoelectTon microscopy Bar, 100 ran (CoiiTtesy Drs J Marshall and I. D Gust )
the virion at 60°C, lack of reactivity with an enterovirus group-specific MAb, low percentage nucleotide homology with the genome of enteroviruses (in spite of having the same gene order), and certain differences in the replication cycle (see below).
Antigenically, HAV is highly conserved, there being only a single serotype in spite of the fact that four genotypes differing by around 20% in nucleotide sequence have been described; most human strains belong to genotypes I or III. An additional three genotypes have been isolated from monkeys. Most simian HAV strains are thought to be host-restricted and differ from human HAV in immunodominant antigenic sites, but at least one, the PA21 strain from Aotus monkeys, is very closely related antigenically to human HAV genotype Ifl.
Viral Replication. The replication of wild strains of HAV in cultured primate cells is slow and the yield of virus poor. Uncoating of the virion is inefficient. The 5' nontranslated region (NTR) contains an internal ribosomal entry site facilitating cap-independent initiation of translation. The processing of the PI polyprotein and assembly of the cleavage products into virions follows a different pathway from that of enteroviruses. Very little complementary (minus sense) RNA is detectable in infected cells; mosi of the newly synthesized plus strand RNA becomes rapidly encapsidated into new virions. Cellular protein synthesis is not inhibited, and ihere is little or no CPE; infection of cell lines is noncytocidal and persistent, with a restricted yield. After serial passage, rapidly replicating cytopathic variants emerge; they contain numerous mutations, including a 14 base reduplication in the 5' NTR HAV is resistant to several antiviral agents that inhibit the replication of enteroviruses.
Pathogenesis, Immunity, and Clinical Features
It is widely assumed that hepatitis A virus, known to enter the body by ingestion, multiplies first in intestinal epithelial cells before spreading via the blood stream to infect parenchymal cells in the liver, but this has yet to be formally proved. Virus is detectable (up to 108 virions per gram) in the feces, and in much lower titer in blood, saliva, and throat, during the week or two prior to the appearance of the cardinal sign, dark urine, and disappears soon after serum transaminase levels reach their peak. Hence the patient's feces are most likely to transmit infection before the onset of jaundice. The incubation period of hepatitis A is about 4 weeks (range 2-6 weeks).
The clinical features of hepatitis A closely resemble those already described for hepatitis B (see Chapter 22). The onset tends to be more abrupt and fever is more common, but the constitutional symptoms of malaise, anorexia, nausea, and lethargy which comprise the prodromal (preicteric) stage tend to be somewhat less debilitating and less prolonged. Hepatomegaly may produce pain in the right upper abdominal quadrant, followed by biliru-binuria, then pale Teces and jaundice. Most infections worldwide occur in children, in whom they are generally subclinical (i.e., asymptomatic) or anicteric (i.e., symptomatic but without jaundice). Severity increases with age, about two-thirds of all infections in adults being icteric. The case-fatality rate is 0.5% (0.1% of all infections), resulting from liver failure (fulminant hepatitis). The illness usually lasts about 4 weeks, but a minority relapse, typically after a premature bout of drinking or heavy exercise, and symptoms may continue for up to 6 months. Also, prolonged excretion of virus in feces has been observed in neonates nosocomially infected in an intensive care unit. However, in striking contrast to hepatitis B, all nonlethal infections resolve, with complete regeneration of damaged liver parenchyma, no long-term sequelae, and no chronic carrier state.
Liver pathology resembles that for hepatitis B. It is not striking until after viral replication has peaked and the immune response is underway, suggesting that hepatocellular injury is immunopathologically mediated. Natural killer (NK) cells are mobilized and activated, as are CD8^ cytotoxic T lymphocytes, known to secrete interferon y that up-regulates expression of class I MHC protein on hepatocytes, which normally display little of this antigen. The serum antibody response to HAV is lifelong, declining significantly only in old age. As there is only one known serotype of hepatitis A virus, infection leads to lifelong immunity, and second attacks of the disease are unknown.
Markedly elevated serum alanine and aspartate aminotransferase (ALT and AST) levels distinguish viral from nonviral hepatitis but do not discriminate among viral hepatitis A, B, C, D, and E. A single serological marker, anti-HAV IgM, is diagnostic for hepatitis A RIA or EIA are the methods of choice for detecting the fgM antibody, which is demonstrable from the time symptoms and signs appear until about 3-6 months later.
By the time the patient presents it is usually already too late to isolate virus; however, when it is necessary to do so for research purposes, virus can be recovered from feces in primary or continuous lines of primate ceils, derived from monkey kidney or from human fibroblasts or hepatoma. Amplification via the PCR is more sensitive and could perhaps be applied to the detection of trace amounts of hepatitis A virus in contaminated food or water.
Like poliovirus, hepatitis A virus is spread via the fecal-oral roule. As might be expected, therefore, the disease is hypereiidemic in the developing countries of Asia, Africa, and Central and South America where overcrowding, inadequate sanitation, and poor hygiene are rife. Where poverty and privation are extreme, infection, usually subclinical, is acquired in early childhood, so that virtually all adults have protective antibody. Most of the clinical cases are seen in children or young adults, and in visitors from the more developed countries. Direct person-to-person contact spread is most important, but contaminated food and water are also major vehicles of spread. Major common-source outbreaks may occur, particularly when wells or other communal water supplies become polluted with sewage.
In developed countries such as Sweden, in contrast, the epidemiologic picture is one of declining endemicity. The incidence of hepatitis A has been gradually declining for decades, such that only a minority of the population, notably the elderly, have antibody. Because primary infections tend to be more severe with increasing age, the peak incidence of clinical disease is in the 15-30 age group. Infection tends to be more prevalent in unsewered areas and in lower socioeconomic groups (e.g., American Indians and Hispanics in the southwestern United States where there has been a resurgence of hepatitis A in the past decade) as well as in particular high-risk occupational groups such as sewer workers and primate handlers, and in persons with high-risk behavior patterns, notably intravenous drug users and male homosexuals. In some Western nations today most sporadic cases are seen in travelers returning from Third World countries. Outbreaks, which can continue in the community for months or even years, frequently originate in communal living establishments with marginal standards of hygiene or special problems, such as children's day-care centers, homes for the mentally retarded, mental hospitals, prisons, army camps, and so forth. Infected handlers of food (especially uncooked or inadequately heated food such as salads, sandwiches, and berries) represent a particular danger in fast-food outlets, restaurants, etc. HAV can survive for months in water, hence sewage contamination of water supplies, swimming areas, or farms growing molluscs such as oysters and clams can also lead to explosive outbreaks. Special problems arise in times of war or natural disaster.
As hepatitis A is transmitted exclusively via the fecal-oral route, control rests on heightened standards of public and personal hygiene. Reticulated drinking water supplies and efficient modern methods of collection, treatment, and disposal of sewage (see Chapter 15) should be the objective of every municipal government. Where this is impracticable, as in remote rural areas, particular attention needs to be given to the siting, construction, maintenance, and operation of communal drinking water supplies such as wells; for example, these should not be downhill from pit latrines because of the risk of seepage, particularly after heavy rains. Public bathing and the cultivation of shellfish for human consumption should not be permitted near sewerage outlets
Those employed in the dispensing of food should be subject to special scrutiny and required to observe high standards of hygiene, especially hand washing after defecation. In so far as children often contract the infection at school, attention should be given to proper instruction of children in this matter. Especially difficult problems occur in day-care centers and homes for mentally retarded children. Routine precautions include separate diaper-changing areas and chemical disinfection of fecally contaminated surfaces and hands
Passive immunization against hepatitis A is a well-established procedure which has been in use for many years. For instance, during wars or other operations involving the mass movement of personnel into endemic areas of the tropics, it has been standard to immunize visitors with normal human immunoglobulin prior to arrival and every 4-6 months thereafter. Normal immune globulin (0 02 ml/kg) is also used postexposure to protect family and institutional contacts following outbreaks in creches, schools, and other institutions
The first hepatitis A vaccines were licensed in 1992. They are formalin-inactivated preparations of virions grown (following adaptation) in human fibroblasts or monkey kidney cell lines, adsorbed to alum as an adjuvant. Two doses injected 1 month apart, with or without a booster after 6 months, regularly elicit an excellent immune response in 99% of recipients that lasts for some years at least. Because the yield of virus from cultured cells is so low, the vaccine is expensive and hence is likely to remain a boutique vaccine targeted at small specialized markets until a live or recombinant vaccine perhaps eventually replaces it. High-risk cohorts to receive the inactivated vaccine should include travelers or long-term visitors to countries in which HAV is endemic, military personnel, sexually active homosexual men, intravenous drug users, sewage workers, primate handlers, workers in preschool day-care centers, certain staff and long-term residents of hospitals and institutions for the intellectually disabled, and workers engaged in food manufacturing and catering.
General vaccination of all infants worldwide should not be undertaken until it is clear that postvaccination immunity and/or immunologic memory are sufficient to protect for life, rather than simply to delay natural infection from childhood (when it is usually subclinical) to adulthood (when it usually causes disease). This consideration, as well as cost, argues for the development of an attenuated live virus vaccine for general use in infancy as part of the WHO Children's Vaccine Initiative. Candidate live vaccines, for parenteral not oral administration, are in the pipeline, but it has so far proved difficult to find the window of adequate attenuation without losing immunogenicity, perhaps because HAV replicates mainly or exclusively in hepatocytes.
Recopibinant DNA technology offers additional approaches. Cloning of the HAV genome in insect cells, or preferably in mammalian cells containing the necessary cellular proteases for cleavage of the polyprotein, may yield HAV procapsids or at least the pentameric capsomers within which the immunodominant epitopes retain their native conformation. Alternatively, the genome can be incorporated into vaccinia virus which could then be used either as a live attenuated vaccine or as a vector for expression of properly processed HAV proteins in cultured human cells.
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