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Acute Viral Hepatitis

Chapter 350 | Harrison's 22e

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[PAGE 2643] Acute Viral Hepatitis 2643 CHAPTER 350 serotype. Human HAV can infect and cause hepatitis in chimpanzees, 350 Acute Viral Hepatitis tamarins (marmosets), and several monkey species. HAV-like hepa- toviruses have also been identified in small mammals, including bats Esperance A. K. Schaefer, and rodents. Hepatitis A has an incubation period of ~3–4 weeks. Its replication Raymond T. Chung, Jules L. Dienstag 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/ presymptomatic phase of illness. Despite slightly longer persistence Acute viral hepatitis is a systemic infection affecting the liver predomi- of virus in the liver, fecal shedding, viremia, and infectivity diminish nantly. Almost all cases of acute viral hepatitis are caused by one of five rapidly once jaundice becomes apparent. Detection of HAV RNA by viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis sensitive reverse transcription polymerase chain reaction assays has C virus (HCV), the HBV-associated delta agent or hepatitis D virus been reported to persist at low levels in stool, the liver, and serum for (HDV), and hepatitis E virus (HEV). All these human hepatitis viruses up to several months after acute illness; however, this does not cor- are RNA viruses, except for hepatitis B, which is a DNA virus but relate with persistent infectivity, probably because of the presence of replicates like a retrovirus. Although these agents can be distinguished neutralizing antibody. HAV can be cultivated reproducibly in vitro and by their molecular and antigenic properties, all types of viral hepatitis in primate models. produce clinically similar acute illnesses. These range from asymp- Antibodies to HAV (anti-HAV) can be detected during acute illness tomatic and inapparent to fulminant and fatal acute infections, which when serum aminotransferase activity is elevated and fecal HAV shed- can be observed in all types. On the other hand, the bloodborne types ding is still occurring. This early antibody response is predominantly (HBV, HCV, HDV) may also manifest a spectrum of chronic disease, of the IgM class and persists for several (~3) months, rarely for 6–12 from subclinical, persistent infections to rapidly progressive chronic months. During convalescence, however, anti-HAV of the IgG class liver disease with cirrhosis and even hepatocellular carcinoma. Rarely, becomes the predominant antibody (Fig. 350-2). Therefore, the diag- infections with other viruses (e.g., cytomegalovirus, Epstein-Barr virus, nosis of hepatitis A is made during acute illness by demonstrating anti- other herpes viruses, SARS-CoV-2) can be associated with mild or HAV of the IgM class. After acute illness, anti-HAV of the IgG class severe, even fulminant, hepatitis, more often in immunocompromised remains detectable indefinitely, and patients with serum anti-HAV hosts but also in otherwise healthy persons. In 2021 and 2022, after are immune to reinfection. Neutralizing antibody activity parallels the the peak years of the COVID-19 pandemic, multiple reports appeared appearance of anti-HAV, and the IgG anti-HAV present in immune globally of severe acute, often fulminant, hepatitis in previously globulin accounts for the protection it affords against HAV infection. healthy children. While these instances of severe acute hepatitis remain unexplained, links have been reported of infection with adenovirus Hepatitis B HBV is a DNA virus with a remarkably compact type 41 and adeno-associated virus 2, ordinarily not causes of liver genomic structure; despite its small, circular, 3200-bp size, HBV DNA injury. A reduction in circulating respiratory virus infections during codes for four sets of viral products with a complex, multiparticle the isolation of the COVID-19 pandemic has been postulated to have structure. HBV achieves its genomic economy by relying on an effi- accounted for the increased susceptibility to and severity of the acute cient strategy of encoding proteins from four overlapping genes: S, C, hepatitis associated with these nonhepatotropic viruses. P, and X (Fig. 350-3), as detailed below. Once thought to be unique among viruses, HBV is now recognized as one of a family of animal VIROLOGY AND ETIOLOGY viruses, hepadnaviruses (hepatotropic DNA viruses), and is classi- fied as hepadnavirus type 1. Similar viruses infect certain species of Hepatitis A HAV is a nonenveloped 27-nm, heat-, acid-, and ether- woodchucks, ground and tree squirrels, and Pekin ducks, to mention resistant, single-stranded, positive-sense RNA virus in the Hepatovirus the most carefully characterized; genetic evidence of ancient HBV-like genus of the picornavirus family (Fig. 350-1). Quasi-enveloped virus virus forbears has been found in fossils of ancient birds, and an HBV-like particles encased in host plasma membrane–derived membranous ves- virus has been identified in contemporary fish. Studies of ancient HBV icles circulate in the bloodstream. The virion contains four structural genomes date an association between HBV and human beings back capsid polypeptides, designated VP1–VP4, as well as six nonstructural as long as 21,000 years ago; primate HBV-like viruses date back mil- proteins, which are cleaved posttranslationally from the polyprotein lions of years, suggesting that HBV predated the emergence of modern product of a 7500-nucleotide genome. Inactivation of viral activity can humans. Like HBV, all have the same distinctive three morphologic be achieved by boiling for 1 min, by contact with formaldehyde and forms, have counterparts to the envelope and nucleocapsid virus anti- chlorine, or by ultraviolet irradiation. Despite nucleotide sequence gens of HBV, replicate in the liver but exist in extrahepatic sites, contain variation of up to 20% among isolates of HAV and despite the recog- their own endogenous DNA polymerase, have partially double-strand nition of six genotypes (three of which affect humans), all strains of and partially single-strand genomes, are associated with acute and this virus are immunologically indistinguishable and belong to one chronic hepatitis and hepatocellular car- cinoma, and rely on a replicative strategy unique among DNA viruses but typi- cal of retroviruses. Entry of HBV into hepatocytes is mediated by binding to the sodium taurocholate cotransporting polypeptide (NTCP) receptor. Instead of DNA replication directly from a DNA template, hepadnaviruses rely on reverse transcription (effected by the DNA poly- merase) of minus-strand DNA from a “pregenomic” RNA intermediate. Then, plus-strand DNA is transcribed from the minus-strand DNA template by the FIGURE 350-1 Electron micrographs of hepatitis A virus particles and serum from a patient with hepatitis B. Left: DNA-dependent DNA polymerase and 27-nm hepatitis A virus particles purified from stool of a patient with acute hepatitis A and aggregated by antibody to converted in the hepatocyte nucleus to hepatitis A virus. Right: Concentrated serum from a patient with hepatitis B, demonstrating the 42-nm virions, tubular a covalently closed circular DNA, which 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 serves as a template for messenger RNA has been visualized as a 55-nm particle.) and pregenomic RNA. Viral proteins [PAGE 2644] 2644 PART Disorders the Gastrointestinal System Jaundice HBsAg protein. Envelope HBsAg subdeterminants include a common group-reactive antigen, a, shared by all HBsAg isolates and one of ALT IgG Anti-HAV several subtype-specific antigens—d or y, w or r. Geographic distribu- IgM Anti-HAV tion of genotypes and subtypes varies; genotypes A (corresponding Fecal HAV to subtype adw) and D (ayw) predominate in the Unit