Natural history

Hepatitis B virus can cause both acute and chronic infection. The outcome of HBV infection depends on the virus-host interaction and, in particular, the strength and persistence of the host immune response. The importance of the maturity of the immune system on the outcome of HBV infection is illustrated by the fact that 90% of adults clear acute HBV infection, as compared with 70–75% of those infected as children (ie under 5 years) and only 10% of those infected as neonates1 (Figure 1-3). Acute hepatitis B is asymptomatic or associated with mild, non-specific symptoms such as a rash, fatigue, nausea, malaise, fever and abdominal pain. Fulminant hepatic failure occurs in about 2% of cases. However, acute hepatitis B is usually mild and self-limiting, with clearance of virus from blood and liver and the development of lasting immunity, and does not generally require medical intervention.2

Figure 1-3. Spectrum of disease

Spectrum of disease

For patients who do not clear an active infection and then progress to chronic infection with HBV, the course of infection can be broadly divided into four phases: immunotolerant, immune clearance, low replicative and reactivation. (Figure 1-4)

In the immunotolerant phase, patients are positive for HBeAg and HBsAg and have high levels of serum HBV DNA but remain asymptomatic with normal levels of ALT and minimal liver damage. Patients infected perinatally or in early childhood generally remain in this phase until adolescence/adulthood due to the immaturity of their immune systems; this phase may not be seen in immunocompetent adults.

In the immune clearance phase, previously asymptomatic patients begin to have signs and symptoms of active hepatitis. During this phase, HBV infected hepatocytes are recognised and destroyed by the immune system. This results in elevated ALT levels reflecting ongoing liver damage and a decline in HBV DNA levels. HBeAg is present in serum. Most patients persist in this phase for many years and the continuous destruction of infected hepatocytes results in progressive liver damage. In some patients the defence mounted by the immune system against the virus can result in HBeAg seroconversion (HBeAg clearance and appearance of anti-HBe antibody; Figure 1-5). The mean annual rate of spontaneous HBeAg seroconversion generally ranges from 8–15% in children or adults with elevated ALT; however, it is considerably lower among Asian children.2 HBeAg seroconversion can not be considered as cure, but is rather an indicator of partial remission of the disease and has been associated with ALT normalisation, suppression of HBV DNA and, in the long term, HBsAg clearance, a reduction in HBV-related clinical complications and improved survival.3

Figure 1-4. Phases of chronic hepatitis B

Phases of chronic hepatitis B

Figure 1-5. Spontaneous HBeAg seroconversion

Spontaneous HBeAg seroconversion

The low replicative or inactive carrier phase is characterised by low HBV DNA levels and normal ALT levels. HBV DNA replication persists, but at low levels – being suppressed by the host immune response; patients are usually symptom free and the liver disease appears to be inactive. This phase may either last a lifetime or can result in one of the following outcomes:

This reactivation phase is characterised by high HBV DNA and ALT levels due to selection for replication-competent HBV variants with mutations in the pre-core or core promoter regions, which have an abolished or diminished ability to produce HBeAg. This form of the disease is called HBeAg-negative CHB.

1. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology 2004;39(3):857–61 and AASLD Practice Guidelines 2003: chronic hepatitis B. Accessed August 2008 at:
2. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis 2003;23(1):47-58.
3. Fattovich G, Rugge M, Brollo L, et al. Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B. Hepatology 1986;6(2):167-72.

Access the Hepatitis Knowledge Centre
Hepatitis Knowledge Centre

The Hepatitis Knowledge Centre contains comprehensive disease background, management and treatment information about both hepatitis B and hepatitis C.

This information is intended for healthcare professionals only. If you are not a healthcare professional please visit our patient website.