Hepatitis A Virus- An Overview

Structure of Hepatitis A Virus

  • HAV (Hepatitis A Virus) is a distinct member of the picornavirus family, assigned to genus hepatovirus.
  • HAV is a 27 nm to 32 nm spherical particle with icosahedral symmetry containing a linear single-stranded RNA genome with a size of 7.5 kb and non-enveloped.
Structure of Hepatitis A Virus
Source: Dr. J. H. Hoofnagle and of Abbot Laboratories, Diagnostic Division, North Chicago, Illinois.
  • Hepatitis A virions have a primary buoyant density of 1.32 to 1.34 g/cc in CsCl and a sedimentation coefficient of 156S to 160S in neutral sucrose solutions.

Genome of Hepatitis A Virus

  • HAV can be divided into three parts
    • a 5′ noncoding region (NCR) that comprises approximately 10% of the genome, is uncapped, and is covalently linked at the 5′ terminus to viral protein VPg
    • a single open reading frame that appears to encode all of the viral proteins, with regions designated as P1 for capsid proteins and P2 and P3 for nonstructural proteins
    • a short 3′ NCR terminating in a polyA tail.
Genome of Hepatitis A Virus
Source: A Totsuka, Y Moritsugu, 1999. Hepatitis A virus proteins. Intervirology 426368.
  • The regions P1 contains four segments for structural proteins which make up the capsid protein; 1A-VP4, 1B- VP2, 1C-VP3, 1D-VP1.
  • P2 comprises of three non structural proteins; 2A, 2B, 2C which play a role in viral replication.
  • P3 makes up four non structural proteins
    • 3A- anchors the replication complex to cell membrane
    • 3B- it is VPg protein
    • 3C- it is cysteine protease that cleaves the protein from polypeptides
    • 3D- it is RNA dependent RNA Polymerase.

Epidemiology of Hepatitis A Virus

Epidemiology of Hepatitis A Virus
Source: http://virology-online.com/viruses/HepatitisA.htm
  • Hepatitis A occurs throughout the world.
  • It is highly endemic in some areas, particularly Central and South America, Africa, the Middle East, Asia, and the Western Pacific.

Transmission of Hepatitis A Virus

  • Transmission via fecal-oral route; ingestion of fecally contaminated food (eating uncooked shellfish harvested from sewage) or contaminated water.

Replication of Hepatitis A Virus

Replication of Hepatitis A Virus
Source: Kanda T et al. Direct-acting Antivirals and Host-targeting Agents against the Hepatitis A Virus. J Clin Transl Hepatol. 2015 Sep 28;3(3):205-10. doi: 10.14218/JCTH.2015.00016. Epub 2015 Sep 15.
  • HAV is spread primarily through the ingestion of fecally contaminated food or water.
  • Once HAV reaches the intestine, it is thought to be absorbed into the bloodstream and to reach the liver through the portal system.
  • Attachment of the virus to host cell receptors (HAV cr-1) mediates endocytosis of the virus into the host cell possibly by clathrin- dependent endocytosis.
  • Upon endosomal acidification, the capsid undergoes a conformational change and release VP4 that opens a pore in the host endosomal membrane and the viral genomic RNA penetrates into the host cell cytoplasm.
  • VPg protein is removed from the viral RNA, which is translated into a processed polyproten.
  • The IRES allows direct translation of the polyprotein.
  • A ds RNA genome is synthesized from the genomic ssRNA(+).
  • The dsRNA genome is transcribed thereby providing viral mRNAs/new ssRNA(+) genomes.
  • New genomic RNA is believed to be packaged into preassembled procapsids.
  • Cell lysis occurs and virus is released.

Pathogenesis of Hepatitis A Virus

  • Viral replication occurs primarily within hepatocytes and the secretion of virus into bile results in large quantities of virus being shed in the faeces.
  • During the incubation period, viremia is observed at about the same time that fecal shedding of HAV is occurring.
  • Viremia terminates shortly after hepatitis develops, whereas feces may remain infectious for another 1 to 2 weeks.
  • Acute hepatitis includes features like inflammatory cell infiltration, hepatocellualr necrosis and liver cell regeneration.
  • Portal infiltration by lymphocytes, plasma cells and periodic acid Schiff (PAS)-positive macrophages are prominent features in early biopsies.
  • Parenchymal cells undergo ballooning degeneration.
  • These hepatocytes are swollen and have indistinct plasma membranes, enlarged nuclei, and a featureless cytoplasm, except for some cytoplasmic remnants condensed around the nuclei.
  • Disruption of bile canaliculi may lead to bile retention after liver cell enlargement or necrosis.
  • In some cases, extension of the inflammatory infiltrate from the periportal region into the hepatic parenchyma with significant erosion of the limiting plate is seen.
  • HAV replication in the liver triggers a substantial immune response, both humoral and cell mediated.
  • CD8 +, cytotoxic T cells that are capable of lysing autologous HAV infected cells , but not of controlling uninfected cells, are present both in circulation and in the liver at the site of disease.
  • These virus specific T cells also produce interferon gamma and other cytokines at the site of infection that may be responsible for much of liver injury.
  • In addition to cell mediated immune response, there is vigorous antibody response to the virus during later stages of infection which are directed against conformational epitopes.
  • Neutralizing antiviral antibodies play an important role in clearance of the virus.
  • Serum antibody responses are first noted at onset of symptoms and include virus specific IgM as well as IgG and IgA.

Clinical Manifestations of Hepatitis A Virus

Clinical Manifestations of Hepatitis A Virus
Source: http://www.medicalindiatourism.com/
  • HAV causes an acute, self limiting infection that does not progress to chronic phase.
  • Following exposure, an incubation period of 15-45 days precedes the development of clinical symptoms.
  • Virus is present in blood and shed in stools within a few days of exposure.
  • Symptoms typically occurs abruptly, with liver injury heralded by fever, myalgia, nausea, anorexia and vomiting accompanied by right upper quadrant abdominal pain.
  • Disruption of hepatobilary metabolism results in passage of dark coca cola like urine, light gray coloured stool and frank icterus.
  • Appearance of biochemical abnormalities including abnormal elevation of liver derived enzymes like ALT- alanine aminotransferase, ALP- alkaline phosphatase, GGTP- gamma glutamyl transpeptidase and increased level of serum bilirubin.
  • The severity of infection is associated with age of patient indicating individuals over 50 years of age at increased risk.
  • They may developed fulminant hepatitis with clinical pictures including ascites, bleeding diathesis or hepatic coma.
  • Severe complication includes cholestatic hepatitis characterized by persistent jaundice associated with pruritis, anorexia and weight loss.

Lab Diagnosis of Hepatitis A Virus

Sample: blood, stool, bile, liver biopsy, serum

  1. Antigen detection
  • Detection using PCR and nucleic acid hybridization assay.
  1. Antibody detection
  • Demonstration of IgM antibodies to the virus, which are almost always present at the onset of symptoms and which persist for up to 6 months following infection.
  • IgG antibody usually persists for many years and is a useful indicator of immunity.
  • Antibody detection done by Enzyme linked immunsorbent assay (ELISA).
  1. Liver function test- detection of level of liver enzymes like ALT, ALP, GGTP, and serum bilirubin.

Treatment of Hepatitis A Virus

  • Supportive treatment to reduce other non specific symptoms
  • No antiviral therapy

Vaccination of Hepatitis A Virus

  • Inactivate or live attenuated vaccine confers 90% of prevention.
  • Formalin inactivated HAV vaccine given in two doses- an initial dose followed by booster dose after 6-12 months.
  • Two inactivated whole-virus hepatitis A vaccines are available: HAVRIX (GlaxoSmithKline) and VAQTA (Merck).

Prevention and control of Hepatitis A Virus

  • Persons exposed to HAV (e.g., those who have been served food by an HAV-infected food handler) can be offered administration of serum immune globulin.
  • If given soon after HAV exposure, the anti-HAV antibodies in serum immune globulin can prevent HAV infection or reduce its extent and severity.
  • This form of preventive intervention is known as postexposure prophylaxis.
  • Personnel hygiene and sanitation should be followed.

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