Liver injury in hepatitis B is produced largely by the immune response to infected hepatocytes rather than by the virus itself. The clearest evidence is that some patients carry an inactive hepatitis B virus (HBV) infection of the hepatocytes yet have normal liver histology: the virus is present, but without an immune attack the liver is not damaged.
The mechanism starts at the surface of the infected hepatocyte. The presence and co-expression of HBcAg, the core protein of the virus, and possibly HBeAg, beside the host cell’s own antigens on the cell membrane attracts cytotoxic T cells, the lymphocytes that kill infected cells, and these initiate the liver damage.
What decides the outcome
Whether infection with HBV resolves or becomes chronic, and how much damage it causes, depends on the immune response: on how broad and vigorous the cytotoxic T cell response is, on the level of HBV-specific T helper cells (the CD4+ cells that coordinate the response), on whether viral escape mutations let the virus evade the T cell response, and on the antiviral cytokines (signalling proteins) the T cells release.
During the acute phase of infection, more than 90% of the HBV DNA is eliminated, mainly by NK cells. This innate-immune phase is useful and even protective, because NK cells are able to dampen the effect of CD4+ and CD8+ T cells and so prevent out-of-control damage and cytotoxicity by cellular immunity.
Pre-core mutant HBV, a variant that does not produce HBeAg (described in the serologic markers note), however causes more severe, fulminant hepatitis that depends on the virus rather than on host immunity. It is therefore more accurate to say that the extent of liver damage depends mostly on the immune response and, to some degree, on the type of virus infecting the hepatocytes.
Infection in the newborn
Infection in neonates born to chronically infected mothers with highly replicative HBV, and a high level of circulating HBeAg, behaves differently. Studies show that passage of HBeAg into the circulation of the fetus leads to immune tolerance, a state in which the immune system does not respond to an antigen, for both HBcAg and HBeAg, so these infants mount no immune response to HBV while the virus replicates in their hepatocytes without robust immune-mediated damage. The result is the combination of immune tolerance, HBV replication and no robust liver damage. In patients infected during the neonatal period, immune tolerance predominates over immune intolerance in the first decades of life; in later decades immune intolerance tends to increase, but enough tolerance remains to prevent extensive liver damage even in the later stages of life.
Immune complex disease
Some of the damage in hepatitis B happens outside the liver and is mediated by immune complexes, clusters of viral antigen bound to antibody that lodge in tissues:
- in acute hepatitis B, complexes of HBsAg, anti-HBs and complement damage blood vessels;
- in chronic hepatitis B, complexes of HBsAg, anti-HBs and C3 complement deposit in the basement membrane of the nephrons, causing nephrotic syndrome and glomerulonephritis.