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PATHOPHYSIOLOGY

The virus does not directly kill hepatocytes. The host's immune response to viral antigens is thought to be the cause of the liver injury in HBV infection. The cellular immune response, rather than the humoral immune response, seems to be primarily involved in disease pathogenesis. Induction of antigen-specific T-lymphocyte response is thought to occur when host T lymphocytes are presented with viral epitopes by antigen-presenting cells in lymphoid organs. These antigen-specific T cells mature and expand and then migrate to the liver. In acute HBV infection, CD4+ T (helper T) lymphocytes are stimulated by the MHC-2, which then stimulates the CD8+ (cytotoxic T) lymphocytes, together with the interferon-gamma and tumour necrosis factor-alfa to clear the viral DNA from hepatocytes.These cause down-regulation of viral replication, and trigger direct lysis of infected hepatocytes. In contrast, the clearance mechanism in people with chronic HBV infection are mainly by the non-antigen specific(or natural immune response) ways rather than specific one.

Four different stages have been identified in the viral life cycle of hepatitis B.

• The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.
• In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of hepatitis B virus (HBV) DNA is seen. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops.
• In the third stage, the host can target the infected hepatocytes and the hepatitis B virus (HBV). Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.
• In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and coinfection with other viruses.

The natural history of HBV infection has been classified into 4 phases, which are influenced by age of infection, host genetic factors, presence of other viruses, HBV mutations, and level of immunosuppression.

1. • Immunocompetent adult (70%) are asymptomatic and self-limiting, with clearance of virus from the blood and liver, and lasting immunity to re-infection.
2. • Immunoincompetent (due to immature liver) 95% of those infected become asymptomatic chronic HBV carriers
3. • Patients who develop chronic HBV have a 10% to 30% risk of developing cirrhosis, particularly older patients with high levels of HBV DNA, or patients with hepatitis C, hepatitis D, or HIV co-infection.

In summary, during HBV infection, the host immune response causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, particularly virus-specific cytotoxic T lymphocytes, contributes to most of the liver injury associated with HBV infection. Most of the infected person will be asymptomatic or resolved by themselves, yet, some may progress into chronic carrier or superinfection with other disease.