The incubation period of acute hepatitis B ranges from about 4 weeks to 6 months. Many childhood infections are sub-clinical, but most adults infected with HBV have some non-specific symptoms such as malaise and anorexia, or may experience jaundice. Myalgia and arthralgia can occur and a skin rash may develop. Acute hepatitis is usually self-limiting and benign. However, about one per cent of adults will develop a very severe infection resulting in the destruction of much of the liver, termed fulminant hepatitis, which can lead to fatal liver failure.

While it has been widely accepted that HBV is completely cleared in individuals who make a full recovery from acute hepatitis, it has recently been shown that low levels of HBV DNA can sometimes be detected in the blood many years later despite the presence of serum antibodies and HBV-specific cytotoxic T-lymphocytes. The results suggest that the immune system controls the virus lifelong in these individuals, although the infection is never eradicated. It may be that resolution of acute hepatitis B and progression to chronic disease represent the extremes of a spectrum of outcomes rather than discrete clinical entities. The likelihood of developing chronic hepatitis B is greatly affected by the age when infection occurs.Exposure to virus at birth almost invariably results in persistent infection. Infection between birth and the age of 2 years results in persistent infection in about 40 per cent of cases. However, for individuals infected from 2 years of age onwards, the risk of developing chronic hepatitis B is typically about 5 per cent. For immunocompromised individuals such as transplant recipients and those infected with human immunodeficiency virus (HIV), the risk of developing chronic infection is greatly increased. The natural course of chronic hepatitis B can be considered in three phases: a period of immune tolerance towards HBV is followed by active immune-mediated disease. Clearance of the virus coupled with resolution of disease may occur during this period. Finally, a transition to a phase of reduced viral replication occurs. At some stage during the course of chronic hepatitis B, the HBV genome becomes integrated into the hepatocyte DNA, but it is not understood how this affects subsequent disease progression.

Cirrhosis
A cirrhotic liver is degenerate and physically distorted as a result of fibrosis. The damage is permanent and serious because liver function is impaired, and may lead to liver failure. Patients in the early stages of liver failure experience malaise and fluid retention and have an enlarged liver and spleen. Pressure within the portal vein which serves the liver increases and can result in the rupture of the esophageal veins. Rapid and extensive blood loss can follow, requiring urgent medical treatment. Reduced levels of clotting factors in the blood increases the severity of this problem. During the final phase, the patient becomes jaundiced and may become mentally confused and eventually lapses into a coma and dies.

Hepatocellular carcinoma
Primary hepatocellular carcinoma is among the most common cancers in the world. The incidence of hepatocellular carcinoma shows geographical variation and is most common in Asia and Africa, where HBV infection is highly endemic and infection is usually acquired in early infancy. The association between HBV and hepatocellular carcinoma, which develops years after the initial infection, is now well-established. Chronic carriers are about 200 times more likely to develop hepatocellular carcinoma than uninfected individuals living in the same area. Approximately 20 per cent of patients with cirrhosis will develop hepatocellular carcinoma. When symptoms appear, the patient is already at the terminal stage and survival times are generally only a few months, depending on existing liver function at the time of diagnosis. Typically the development of hepatocellular carcinoma occurs 30-50 years after the time of infection; consequently hepatocellular carcinoma is far more likely to be seen in individuals exposed to HBV in early life rather than in adult life10. In areas where HBV infection is acquired in infancy, male carriers have a 40 per cent risk of dying from hepatocellular carcinoma compared with 15 per cent for females. This correlates with the observation that female patients with chronic hepatitis B are more likely to clear HBeAg than males11. For individuals infected with HBV as adults, the risk of developing hepatocellular carcinoma is less than one per cent.

Key points

Symptoms of acute HBV infection are non-specific, but may include malaise, anorexia or jaundice
Exposure to HBV perinatally or in early infancy usually leads to chronic infection
The natural course of chronic hepatitis B progresses through three stages: immune tolerance, active disease, and a late phase with reduced viral replication
Approximately 25 per cent of patients with chronic hepatitis B will develop cirrhosis, causing permanent and serious liver damage.
Chronic carriers of HBV are far more likely to develop hepatocellularcarcinoma than non-carriers
The course of hepatitis B is determined by many factors, including immune response, host genetic factors, and HBV mutations.