Natural history of chronic hepatitis B virus infection: An immunopathological study

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Abstract
Three clinicopathological phases of chronic hepatitis B virus (HBV) infection are identified. First, is immune tolerance of HBV. High levels of viraemia are associated with normal alanine aminotransferase (ALT) levels and minimal histological lesions. More than 30–40% of hepatocytes have the hepatitis B core antigen (HBcAg), predominantly in their nuclei. Maternally derived hepatitis B e antigen (HBeAg) crossing the placenta may result in the elimination of T helper cells responsive to HBeAg/HBcAg. This phase can last for periods ranging from a few weeks to 10 or more years until the immune tolerance is lost. Second, is the immune clearance of HBV. Intermediate levels of viraemia are associated with fluctuating ALT levels and active and ongoing hepatitis. Approximately 20–30% of hepatocytes have HBcAg, predominantly in their cytoplasm. Expression of pre‐core defective HBV mutants during chronic HBV infection may lead to a reduction in the secretion of HBeAg and may trigger the beginning of the immuno‐elimination phase. The mechanism of intrahepatic shift of HBcAg from the nucleus to the cytoplasm and the decreased levels of viraemia in this phase may be, at least in part, secondary to liver damage and regeneration. Third, is latent infection with residual integrated HBV. Undetectable viraemia is associated with normal ALT levels and no virus‐induced liver damage. With regard to hepatocyte expression of HBsAg in chronic HBV infection, membrane staining of HBsAg on hepatocytes has been shown to correlate well with the presence of viraemia. The degree of cytoplasmic hepatitis B surface antigen (HBsAg) expression inversely correlates with the level of viraemia. Therefore, HBsAg carriers with high levels of viraemia have low levels of cytoplasmic hepatitis B surface antigen (HBsAg) expression, while those with low levels of viraemia have high levels of cytoplasmic HBsAg expression. However, several exceptions have been identified. High levels of viraemia associated with high levels of cytoplasmic HBsAg expression were recognized in patients with fibrosing cholestatic hepatitis. In contrast, low levels of viraemia associated with low levels of cytoplasmic HBsAg expression were recognized in patients with hepatitis C virus but not hepatitis D virus superinfection.