Hepatitis B Virus

Hepatitis B virus (HBV) is directly responsible for acute and chronic forms of hepatitis. Its significance lies in the fact that it is the only blood-borne viral infection which can be effectively prevented by vaccination. It was discovered by Blumberg in 1965 while studying serum lipoproteins of hemophiliacs who received multiple blood transfusions.

Classification and structure

Hepatitis B virus belongs to the family Hepadnaviridae and is approximately 42nm in size. It is an enveloped, double stranded DNA virus possessing a core protein of 27nm which encloses the viral genome and DNA polymerase enzyme. When visualized utilizing electron microscopy, sera of HBV infected patients show three types of particles. The first is a spherical 22nm particle found in abundance. The second, a tubular 22nm sized particle which was later found to be identical to the spherical particle, is actually the surface protein of the virus. The third is a double walled spherical structure which is 42nm in size and is representative of the complete virus. This is also known as the Dane particle as it was discovered by Dane in 1970.

The surface antigen of HBV was the first part of the virus to be discovered by Blumberg in an Australian Aboriginal hemophiliac. It was hence named
The Australia Antigen, but later was changed to the hepatitis B surface antigen (HBsAg). This is the first antigen discovered which can be detected in the serum post-infection. The surface antigen shows antigenic diversity with four major subtypes:

These subtypes do not play a significant role in immunity, but have distinct geographical distribution around the world and therefore can be utilized for epidemiological and outbreak surveillance.

The nucleocapsid antigen is also called the hepatitis B core antigen (HBcAg). This is frequently found to be concentrated in the liver and cannot be detected in the sera of positive patients. The envelope antigen (HBeAg) is another soluble non-particulate protein of the Hepatitis B virus.

The viral genome of HBV is unique in that it has two strands of linear DNA of which the plus strand is incomplete. The DNA polymerase of the virus is closely associated with the incomplete strand of the viral genome. This enzyme is required for repairing the viral genome and also for replication of the viral particles. Replication of this virus occurs primarily in the hepatocytes, therefore it primarily causes hepatitis.

HBV is a relatively heat stable virus and can remain viable at room temperature for extended periods of time. It can be deactivated using hypochlorite (10,000 ppm available chlorine) or 2% gluteraldehyde for at least 45 minutes.

Epidemiology

HBV is a blood borne pathogen transmitted by parenteral, sexual and perinatal routes. It occurs throughout the world without any seasonal distribution. The disease is frequently manifested in the third and fourth decade of life. According to the Centers for Disease Control and Prevention (CDC), approximately 1.25 million Americans are chronically infected with HBV and of these, about 20% to 30% acquired the infection in childhood. HBV infection has been associated with hospital outbreaks involving both patients and healthcare workers. The risk factors for acquiring HBV infection are:

intravenous drug abusers
repeated blood transfusions as in hemophiliacs and thallessemics, patients on haemodialysis
sexual promiscuity
mother to child transmission.

The blood of infected humans is the only source of infection. Following infection, approximately 5% to 10% of adults, 30 % of children and 90% of neonates become carriers. Carriers act as reservoirs of infection due to the fact that they remain asymptomatic. HBV carriers may either be super carriers, who are extremely infectious, or simple carriers, who have low infectivity. The most common source of infection is blood, however the virus is also present in other body fluids and excretions such as:

saliva
breast milk
semen
vaginal secretions
urine
bile
feces.

Feces, however, are not found to be infectious.

Clinical Spectrum of disease

As the virus has a predilection towards the hepatocytes, derangement of liver functions is frequently the first sign of infection in a patient with elevated risk factors. The clinical spectrum of the disease varies from asymptomatic infection to fulminant hepatitis, with liver cell failure, cirrhosis and even hepatocellular carcinoma. The incubation period is long and may extend from 1 to 6 months with approximately 30% of the patients being asymptomatic.

The symptoms of acute hepatitis are jaundice, fatigue, abdominal pain, loss of appetite and nausea. Rarely polyarthritis and glomerulonephritis may also be seen due to the circulating immune complexes in the body. Approximately 90% to 95% of these patients are likely to recover within 1 to 2 months. The virus is eliminated from the body within approximately 6 months following which they remain immune to the infection. Mortality in this stage is only about 0.5% to 2% which may increase in patients with a simultaneous delta viral infection related to to fulminant hepatitis.

The pathogenesis of disease is immune mediated. Therefore, carriers and chronically infected patients may have recurrent or chronic liver disease and cirrhosis with development of hepatocellular carcinoma many years after the infection.

Laboratory diagnosis

Various structural proteins of HBV are of diagnostic and prognostic significance after acquisition of infection. They are also helpful in determining the stage of the disease. Laboratory diagnosis of HBV infection can be done using enzyme assays or chromatography based methods to detect the antigens and antibodies. Viral load assays done by polymerase chain reactions assist in monitoring therapy.

The most frequently used test is the detection of HBsAg which is the first to appear after the infection. It appears within one week of infection and remains up to 24 weeks, after which its antibodies (anti- HBs) will persist throughout the course of infection. Anti- HBs antibodies are protective in nature.

The envelope antigen (HBeAg) appears at about 4 weeks and disappears by 20 weeks followed by the appearance of its antibody (Anti- HBe). HBeAg is significant because it indicates carrier status of the patients. If very high titers of HBeAg persist in blood, it is indicatative of high infectivity. The super carriers frequently have very high titers of HBsAg, HBeAg, DNA polymerase and HBV in circulation with elevated transaminases. On the other hand, simple carriers have HBsAg in blood and are negative for HBeAg, DNA polymerase and HBV.

The core antigen is never found in blood and can be detected utilizing fluorescent techniques on liver tissue. Its antibody (Anti- HBc) appears in blood by about the 4th week of infection and persists throughout the infection.

Prevention and treatment

Prevention is a critical aspect of HBV infection. This can be done by practicing safe sex and not sharing or reusing needles or personal care items such as blades or razors. Tattooing and body piercing also pose risks. Universal work precautions are a must for all healthcare workers.

Both active and passive immunization is available for HBV infection. Hyper immune hepatitis B immunoglobulin is prepared from human volunteers with high titers of anti-HBs. It is administered intramuscularly in doses of 300 to 500 IU soon after exposure to infection e.g. in healthcare workers or in neonates of infected mothers. Passive immunization will protect against illness and carrier status but not against the infection. Therefore, active immunization in the form of vaccination is equally important in such cases.

A vaccine is available, developed by recombinant engineering using the surface protein of HBV producing anti- HBs which is protective in nature. The dose is 0.5ml for children and 1ml for adults to be given at birth, 1 and 6 month intervals. In high risk individuals, it is essential to assess the antibody titers for the surface protein before administering the vaccine.