Acute viral hepatitis is one of the commonest infectious diseases and hepatitis A is the most common form of acute viral hepatitis in much of the world

Seminar Hepatitis A

Acute viral hepatitis is one of the commonest infectious diseases and hepatitis A is the most common form of acute viral hepatitis in much of the world. Outbreaks of hepatitis A have been recognised as a concomitant of warfare for centuries, affecting both military and civilian populations. No specific drug treatment is available. Usually, hepatitis A affects children without producing symptoms, but in adults it causes clinically apparent disease, often with jaundice. Acute liver failure due to severe hepatitis A is well-documented in young children, but is more frequent in middle-aged and older people, and those with underlying chronic liver disease; it is also a rare complication of hepatitis A during pregnancy. As a result of the increased severity of hepatitis A with increasing age, its economic impact is greatest in adults; nonetheless, few studies of the costs of illness are currently available. Hepatitis A is not linked to chronic liver disease and it does not result in persistent viraemia or an intestinal carrier state. Infection is maintained in nature by serial transmission from acutely infected individuals to those who are susceptible. Although transmission from recently infected non-human primates to human beings has been described, there is no evidence that hepatitis A is a zoonotic disease or that there is a reservoir of infection other than in human beings.

Virology

The hepatitis A virus (HAV) is a small, non-enveloped, spherical particle with cubic symmetry (panel). The virus is thermostable and acid-resistant. For some time after its identification, HAV was thought to be an enterovirus; in 1991, it was subclassified into its own unique genus (hepatovirus).¹ Only one human HAV serotype has been identified. The four human genotypes that have been identified are stable² and can be used to trace transmission. HAV vaccine prepared from any human HAV genotype will provide protection against infection by all strains.

The precise oral infective dose of HAV in human beings remains ill-defined. After oral inoculation HAV is thought to be transported across the intestinal epithelium by a vectorial transport process that is poorly understood,³ and is taken up by hepatocytes. Whether specific receptors are involved remains uncertain, although a novel glycoprotein has been identified as a cellular receptor for HAV in one cell line.⁴ The liver is the only target organ of injury, and HAV genomic replication occurs exclusively in the cytoplasm of the infected hepatocyte by a mechanism involving an RNA-dependent RNA polymerase. From the liver, HAV is transported

Lancet 1998; 341: 1643–49

Department of Medicine, MetroWest Medical Center, Framingham

Union Campus, 115 Lincoln Street, Framingham, MA 01702, USA

(Raymond S Koff MD) 

through the biliary tree to the intestine; its resistance to inactivation by bile and intestinal proteolytic enzymes allows it to be shed in the faeces and facilitates faecal-oral transmission.

HAVRNA genome

Direct intrahepatic inoculation of HAV RNA transcribed from HAV cDNA clones induces acute hepatitis in nonhuman primates.⁵ The HAV genome is a single-stranded, linear, 7·5 kb RNA molecule, with positive polarity. The genome consists of a 5' non-translated region of about 735 nucleotides, which contains an internal ribosomal entry site, followed by structural (P1) and non-structural protein-encoding regions (P2 and P3), and, finally, a 3' non-translated region about 63 nucleotides in length with a terminal poly(A) tract. Nucleotide substitution in the 5' non-translated region has been linked with virulence,⁶ but this link remains to be confirmed. Immunodominant HAV neutralisation epitopes occur at a site on the structural capsid proteins of the virus, of which there are four, although only three of these have been definitively demonstrated. The P3 region encodes the RNAdependent RNA polymerase and the 3C viral proteinase. The RNA genome acts as an mRNA, directing the synthesis of a single, long polyprotein that is processed by the 3C viral proteinase to produce the viral structural and non-structural proteins. The 3C proteinase, thought to be the only proteolytic enzyme present in HAV, may also serve a replicative function.⁷ Inhibitors of the RNA polymerase and 3C proteinase may have therapeutic application.

HAV propagation in cell culture

Slow growth, with low viral yields, absence of cytopathic effects, and rapid establishment of persistent, non-lytic infection, have characterised the propagation of HAV in cell lines originating from non-human primates or human beings. The 5' non-translated region appears to have a variable influence