Canadian Association for the Study of the Liver
Natural history of chronic Hepatitis B
The course of chronic hepatitis B is highly variable, characterized in some patients by exacerbations and remissions of inflammatory activity in the liver, in others by continuous active hepatitis of varying degrees of severity, and in yet others by trivial inflammation. The disease can be described by three phases (7). The first phase, the so-called immuno-tolerant phase, is characterized by high levels of virus in serum, and no or minimal hepatic inflammation (8). These patients are HBeAg-positive. This is followed by the “active” phase, during which there is intermittent or continuous hepatitis of varying degrees of severity (8,9,10,11). Seroconversion to anti-HBe-positive may occur during this phase (12), but cessation of inflammatory activity does not always follow. The third phase is the inactive phase during which viral concentrations are low, and there is minimal inflammatory activity in the liver (3). In general, patients who clear HBeAg have a better prognosis than patients who remain HBeAg-positive for prolonged periods of time do (14). About 1%/year of anti-HBe-positive patients will clear HBsAg (15). However these patients remain at risk for hepatocellular carcinoma. One of the major mechanisms by which seroconversion occurs (possibly the only mechanism) is by the development of the so-called “pre-core mutant” (16). This is a mutation which arises during the course of infection, and which results in inability of the virus to produce HBeAg. The virulence of this mutant is uncertain. Patients who are anti-HBe-positive with elevated ALT concentrations and detectable HBV DNA almost all carry the pre-core mutant. However, anti-HBe-positive patients with normal ALT levels and undetectable HBV DNA also frequently carry the mutant. It may be that virulence is determined by another related mutation in pre-core mutants.
Patients with hepatitis B-induced cirrhosis who are anti-HBe-positive
have a 97% 5-year survival, compared to a 72% survival for those who are
HBeAg-positive (17).
Once hepatic decompensation occurs in anti-HBe-positive patients, the survival
at 5 years is only 28%, whereas in HBeAg-positive patients the 4-year survival
is zero (18).
Factors predicting an adverse outcome include active hepatitis, bridging
necrosis on biopsy, older age, and persistent HBV DNA in serum (19).
Patients with chronic hepatitis B are at risk for the development of hepatocellular
carcinoma (20).
The relative
risk has been prospectively determined to be about 100, but that is
highly dependent on the population being studied. Studies in Asian
populations describe a much higher risk than Caucasian populations.
However, even in a Caucasian population the 10 year incidence of HCC may
be as high as 15% (17).