Natural history of chronic hepatitis B

The natural history of chronic hepatitis B can be divided into phases, each of which may last many years (1):

• immunotolerant phase
  • people who are affected at birth or in early childhood initially enter an 'immunotolerant' phase during which the immune system does not actively fight the virus
  • virus replicates rapidly during this immunotolerant phase - however the person usually has no symptoms
  • person is highly infectious, and may infect other members of the family and community
  • immunotolerant phase can last for many years before progressing to active disease
• incubation
  • incubation period for hepatitis B infection ranges from 40-160 days (average of 60-90 days)
• active chronic hepatitis B
  • first stage of active disease involves a period of increasing inflammatory hepatic necrosis as the immune system begins to fight the virus
  • characterised by elevated levels of viral DNA in the blood, persistently raised levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and evidence of hepatic necrosis and inflammation on biopsy
  • the liver damage caused by infection and inflammation may eventually cause cirrhosis of the liver
  • progression to cirrhosis occurs at an annual rate of 2-5.5% (cumulative 5-year rate of progression of 8-20%)
• HBeAg seroconversion
  • if infected with an HBeAg-positive form of the virus, the next stage of the infection occurs when inflammation becomes sufficiently intense to cause lysis of infected hepatocytes
  • produces a 'flare' of the disease with symptoms resembling acute hepatitis B, and leads to the development of antibodies against the 'e' antigen. This is referred to as 'HBeAg seroconversion'. The seroconverted disease state is associated with good quality of life and a relatively low risk of disease progression. It is referred to as the 'inactive HBsAg carrier state' because patients continue to express hepatitis B surface antigen (HBsAg)
    • spontaneous seroconversion rate is 5-10% per year, although this varies among populations
    • once seroconversion has taken place, most people remain in the inactive HBsAg carrier state. However, increasing viraemia and recurrent hepatitis after seroconversion indicate the emergence of the HBeAg-negative strain of the virus
      • HBeAg-negative chronic hepatitis B
        • a form of the virus that does not cause infected cells to secrete HBeAg has been discovered (sometimes called the 'precore mutant' strain)
        • people can be infected with the so-called HBeAg-negative form of the virus from the beginning, or the viral mutation can emerge later in the course of infection in people initially infected with the HBeAg-positive form of the virus
        • prevalence of HBeAg-negative hepatitis varies geographically; it is more common in Asia and the Mediterranean region than in Northern Europe
        • infection with HBeAg-negative chronic hepatitis B is associated with a fluctuating course and a poor prognosis. Active disease is associated with either persistent elevation of ALT or an erratic pattern of ALT changes with flare-ups resembling acute hepatitis B that can be severe or even fatal
        • few patients with HBeAg-negative chronic hepatitis B achieve a lasting remission. Progression to cirrhosis of the liver has been estimated to occur in 8-10% of people with HBeAg-negative chronic hepatitis B each year
• HBsAg seroconversion
  • development of antibodies against HBsAg, with clearance of HBsAg, occurs spontaneously in about 0.5-2% of people with chronic hepatitis B each year in western countries. In countries where hepatitis B is endemic, the rate is much lower - between 0.05 and 0.08% per year
  • clearance of HBsAg is most likely to occur in the year following HBeAg seroconversion
  • HBsAg seroconversion signifies resolution of the chronic infection. Variants of hepatitis B (known as 'occult hepatitis B') that are not associated with detectable HBsAg by current immunoassays have been recognised

Reference:

1. NICE (February 2006). Adefovir dipivoxil and peginterferon alfa-2a for the treatment of chronic hepatitis B