Hepatitis A Virus: (Introduction, Structure, Replication, Pathogenesis, Clinical features, Lab Diagnosis, Treatment, Prevention & Control, and Epidemiology)

Hepatitis A Virus

• Hepatitis A Virus (HAV) belongs to the genus Heptovirus of family Picornaviridae.
• HAV is the causative agent of infectious non chronic hepatitis i.e inflammation of liver.
• It is commonly occurring water borne viral disease transmitted via faeco-oral route.
• It has high prevalence rate which rarely cause a fulminant disease.
• Also, it is not an oncogenic virus.
• Recently, it is found that this is the only hepatitis virus capable of growing in cell culture.
• HAV is highly resistant to environmental factors. It is stable at 60°C for 1 hour and 4°C for weeks. It can survive in acidic pH i.e. pH 1. It is resistant to inactivation by lipid solvents, action of detergents and drying.

Structure:

• HAV is a small, icosahedral, and non-enveloped virus that measures 23nm in diameter.
• It has 7.5Kb single-stranded positive-sense RNA genome.
• The core of the virus contains ssRNA genome which is surrounded by proteinous capsid.

Fig: A schematic diagram of Hepatitis A Virus.

• The Hepatitis A viral genome encodes for polyproteins which make up viral particle and helps in viral replication. The polyproteins are cleaved into structural and non-structural proteins.
• Viral RNA consists of 3 domain – 5′ UTR, a single ORF and 3′ UTR with Poly A tail. 5′ end consists of bound VPg protein which is assumed to be dissociated once the RNA is released into host cell. Also, 5′ UTR controls the replication and expression of these genes. ORF codes for polyproteins – P1, P2 and P3.

Fig: Hepatitis A Viral Genome

• P1 is a 4 segmented region which encodes for structural or viral proteins(VP) that together make up capsid. P2 has 3 segments that codes for non-structural(NS) proteins which have role in viral replication. P3 has 4 segments coding for 4 NS proteins.

Viral Replication:

• HAV specifically combines with a receptor expressed on liver cells and few other cells.
• Once inside the infected cell, it replicates in cytoplasm.
• The newly formed viruses are then released by exocytosis damaging those cells.

Pathogenesis:

• HAV infection is transmitted by the fecal–oral route.
• The pathogenicity is mainly associated with hepatic injury.
• Once inside the host body, the virus initially infects the gastrointestinal tract (GI). It replicates in the GI cells which then spread to liver via blood.
• The virus attaches to specific receptors on the hepatocytes and cause damage to the cells. However, the mechanism by which HAV causes cytopathic effect to hepatocytes is still not known.
• Virus replicates primarily within hepatocytes which cause secretion of virus into bile resulting in shedding of large quantity of virus in the faeces.
• Hepatocytes are damaged due to effect of cytotoxic T cells. After the infection is cleared and the cell damaged is repaired so no chronic disease occurs.
• The histopathological appearance shows mononuclear infiltration, hepatocellular necrosis, ballooning, liver cell degeneration, and acidophilic bodies.

Host Immunity:

• The HAV Infection is mildest in young children than adults. However, severity and fatal outcomes are higher in older age groups.
• Immunity is mediated primarily by circulating antibodies which confers lifelong immunity to HAV.
• The primary response to acute infection is characterized by the appearance of IgM anti-HAV whose titer increases in the initial stage of infection. But the IgM antibody disappears several months after jaundice.
• IgG antibody appears 1–3 weeks after appearance of IgM antibodies which is responsible to provide lifelong immunity against recurrent HAV infection.
• Cellular immune response to HAV infection is carried out by CD8 and cytotoxic T cells that lyses HAV infected cell.
• However the exact mechanism by which the HAV infection is cleared is not well defined. This process of may involve a combination of Ab-mediated neutralization of infection, Interferon mediated inhibition of viral replication and Cytotoxic T cell induction of cellular apoptosis.

Fig: Progression of HAV infection

• Infected individuals are contagious during the incubation period till about a week after jaundice appears.
• HAV is shed in the stool in high concentrations from two to three weeks before onset of clinical illness.
• The virus is seen in blood soon after inoculation which remains untill 7^th week. There is elevated serum transaminase levels from 3^rd to 5^th week.

Clinical Features:

• HAV causes Acute hepatitis A Infection. It does not cause chronic liver disease but debilitating symptoms and fulminant hepatitis may occur which is often fatal.
• Incubation period: 10–50 days (average 25–30)
• Route of infection: Predominantly fecal–oral
• The clinical manifestation of  from mild to severe. There is a prodrome of nausea, vomiting, anorexia, fever, malaise, and abdominal pain in right upper quadrant. Then dark coca cola like urine and pale clay coloured stools may also be observed within a few days to a week. Hepatomegaly and scleral icterus are the common signs of the infection.
• As these symptoms improve and disappear jaundice develops along with pruritus.
• HAV infection is usually a self-limiting mild disease which in most cases resolves spontaneously within 2–4 weeks. Sometimes the infection can relapse as well.
• Extrahepatic manifestations associated with HAV may occur which includes evanescent rash, arthralgias, leukocytoclastic vasculitis, arthritis, glomerulonephritis, myocarditis, thrombocytopenia, aplastic anemia, etc.
• Some complications associated with HAV infection are cholestatic hepatitis, relapsing hepatitis, and autoimmune hepatitis.

Lab Diagnosis:

• Specimen:
  • stool, blood, liver, bile for HAV antigen and genome
  • serum for antibody detection test
• Note: Rarely urine, saliva, and semen are also collected as a specimen for the detection of the infection.
• HAV is present in stool and blood 1- 2 weeks prior to the onset of jaundice. Hence, a virus can be demonstrated by using immunoelectron microscopy.
• DNA probes and polymerase chain reaction (PCR) are used to detect HAV genome in stool as well as in the serum of infected patients.
• Serodiagnosis of HAV infection can be done by the demonstration of specific antibodies in the serum. Usually, Enzyme-linked immunosorbent assay (ELISA) is performed for the detection of IgM and IgG antibodies. IgM-Ab appears first followed by IgG-Ab that usually increases as the IgM level decreases. A fourfold rise in IgG-Ab titers is also a diagnostic of infection.
• Liver function tests are also highly useful for the diagnosis of HAV infection. The test determines serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level which consistently increases during the infection.

Treatment:

• There is no antiviral treatment for HAV infection.
• However, there can be the administration of immunoglobin as passive protection when given within 1-2 weeks of exposure to HAV.
• Treatment is supportive that focuses to limit the liver damage.

Prevention & Control:

• The prevention of HAV infection mainly includes vaccination.
• Vaccination against this virus for adults and for children older than 2 years of age became available during the 1990s. Inactivated and live attenuated vaccine, both can be given.
• Active immunization can be done by vaccine containing formalin inactivated HAV. An initial dose followed by booster dose after 6-12 month is given for immunization.
• Recent vaccine formulations may combine hepatitis A and B antigens in the same vaccine.
• Control measures is to prevent feco-oral spread of infection. This involves maintenance of personal hygiene and proper sanitation.

Epidemiology:

• Occurrence:
  • HAV is widespread throughout the world. Approximately 1.5 million clinical cases of hepatitis A occur worldwide annually but the rate of infection is probably as much as ten times higher.
  • It is highly endemic in areas of Central and South America, Africa, the Middle East, Asia, and the Western Pacific.
  • The virus is prevalent in countries with poor sanitation practice, mainly in developing countries where nearly half of the population is infected.
  • Recurrent epidemics occur frequently as the infection result from fecal contamination of a single source.

• Reservoir:
  • The only natural reservoir of the virus is human.

• Transmission:
  • HAV infection is primarily acquired by the fecal-oral route via person-to-person contact or ingestion of contaminated food or water. Blood or blood product transmission is rare as viral titer is low in the blood.

• Risk Factors:
  • Groups at increased risk of acquiring hepatitis A are travelers to developing countries from developed countries, men who have sex with men, users of injection and non-injection drugs,  persons with clotting factor disorders,  and persons working with nonhuman primates.
  • Individuals with chronic liver disease are also at increased risk for fulminant hepatitis if HAV occurs.

References:

• https://www.cdc.gov/hepatitis/hav/index.htm
• https://www.webmd.com/hepatitis/digestive-diseases-hepatitis-a#1
• https://emedicine.medscape.com/article/177484-overview
• https://www.ncbi.nlm.nih.gov/books/NBK7864/