Acute viral hepatitis is a systemic infection affecting the liver predominantly. Almost all cases of acute viral hepatitis are caused by one of five viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the HBV-associated delta agent or hepatitis D virus (HDV), and hepatitis E virus (HEV). Other transfusion-transmitted agents (e.g., “hepatitis G” virus and “TT” virus, have been identified but do not cause hepatitis). All these human hepatitis viruses are RNA viruses, except for hepatitis B, which is a DNA virus. Although these agents can be distinguished by their molecular and antigenic properties, all types of viral hepatitis produce clinically similar illnesses. These range from asymptomatic and inapparent to fulminant and fatal acute infections common to all types, on the one hand, and from subclinical persistent infections to rapidly progressive chronic liver disease with cirrhosis and even hepatocellular carcinoma, common to the bloodborne types (HBV, HCV, and HDV), on the other.
Hepatitis A virus is a nonenveloped 27-nm, heat-, acid-, and ether-resistant RNA virus in the Hepatovirus genus of the picornavirus family (Fig. 304-1). Its virion contains four capsid polypeptides, designated VP1 to VP4, which are cleaved posttranslationally from the polyprotein product of a 7500-nucleotide genome. Inactivation of viral activity can be achieved by boiling for 1 minute, by contact with formaldehyde and chlorine, or by ultraviolet irradiation. Despite nucleotide sequence variation of up to 20% among isolates of HAV, and despite the recognition of four genotypes affecting humans, all strains of this virus are immunologically indistinguishable and belong to one serotype. Hepatitis A has an incubation period of ∼4 weeks. Its replication is limited to the liver, but the virus is present in the liver, bile, stools, and blood during the late incubation period and acute preicteric phase of illness. Despite persistence of virus in the liver, viral shedding in feces, viremia, and infectivity diminish rapidly once jaundice becomes apparent. HAV can be cultivated reproducibly in vitro.
Electron micrographs of hepatitis A virus particles and serum from a patient with hepatitis B. Left: 27-nm hepatitis A virus particles purified from stool of a patient with acute hepatitis A and aggregated by antibody to hepatitis A virus. Right: Concentrated serum from a patient with hepatitis B, demonstrating the 42-nm virions, tubular forms, and spherical 22-nm particles of hepatitis B surface antigen. 132,000×. (Hepatitis D resembles 42-nm virions of hepatitis B but is smaller, 35–37 nm; hepatitis E resembles hepatitis A virus but is slightly larger, 32–34 nm; hepatitis C has been visualized as a 55-nm particle.)
Antibodies to HAV (anti-HAV) can be detected during acute illness when serum aminotransferase activity is elevated and fecal HAV shedding is still occurring. This early antibody response is predominantly of the IgM class and persists for several months, rarely for 6–12 months. During convalescence, however, anti-HAV of the IgG class becomes the predominant antibody (Fig. 304-2). Therefore, the diagnosis of hepatitis A is made during acute illness by demonstrating anti-HAV of the IgM class. After acute illness, anti-HAV of the IgG class remains detectable indefinitely, and patients with serum anti-HAV are immune to reinfection. Neutralizing antibody activity parallels the appearance of anti-HAV, and the IgG anti-HAV present in immune globulin accounts for the protection it affords against HAV infection.
Scheme of typical clinical and laboratory features of hepatitis A.
Hepatitis B virus is a DNA virus with a remarkably compact genomic structure; despite its small, circular, 3200-bp size, HBV DNA codes for four sets of viral products with a complex, multiparticle structure. HBV achieves its genomic economy by relying on an efficient strategy of encoding proteins from four overlapping genes: S, C, P, and X (Fig. 304-3), as detailed below. Once thought to be unique among viruses, HBV is now recognized as one of a family of animal viruses, hepadnaviruses (hepatotropic DNA viruses), and is classified as hepadnavirus type 1. Similar viruses infect certain species of woodchucks, ground and tree squirrels, and Pekin ducks, to mention the most carefully characterized. Like HBV, all have the same distinctive three morphologic forms, have counterparts to the envelope and nucleocapsid virus antigens of HBV, replicate in the liver but exist in extrahepatic sites, contain their own endogenous DNA polymerase, have partially double-strand and partially single-strand genomes, are associated with acute and chronic hepatitis and hepatocellular carcinoma, and rely on a replicative strategy unique among DNA viruses but typical of retroviruses. Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse transcription (effected by the DNA polymerase) of minus-strand DNA from a “pregenomic” RNA intermediate. Then plus-strand DNA is transcribed from the minus-strand DNA template by the DNA-dependent DNA polymerase and converted in the hepatocyte nucleus to a covalently closed circular DNA, which serves as a template for messenger RNA and pregenomic RNA. Viral proteins are translated by the messenger RNA, and the proteins and genome are packaged into virions and secreted from the hepatocyte. Although HBV is difficult to cultivate in vitro in the conventional sense from clinical material, several cell lines have been transfected with HBV DNA. Such transfected cells support in vitro replication of the intact virus and its component proteins.
Compact genomic structure of HBV. This structure, with overlapping genes, permits HBV to code for multiple proteins. The S gene codes for the “major” envelope protein, HBsAg. Pre-S1 and pre-S2, upstream of S, combine with S to code for two larger proteins, “middle” protein, the product of pre-S2 + S, and “large” ...
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