Pathogenesis and natural history
See Table 1. Hepatitis is an enveloped partially double-stranded DNA virus belonging to the Hepadnaviridae family. It is 100 times more infectious than HIV and can be transmitted by perinatal, percutaneous and sexual exposure.[10] Close person-to-person contact is an important form of transmission, most notably among children in highly endemic areas, such as in SA.[5,10]
Liver injury due to hepatitis B is mainly caused by cellular immune mediated mechanisms with cytotoxic T lymphocyte lysis of infected hepatocytes. The magnitude of the individual’s adaptive cellular immune response to HBV-related antigens determines the outcome of acute HBV infection, as well as the degree of liver injury. Chronically infected patients are unable to sustain an immune response to HBV and may experience intermittent episodes of hepatocyte destruction in an attempt to clear virally infected hepatocytes, in what can be termed ‘flares’. Note that, during the acute infection, hepatitis B does not appear to induce an intra-hepatic innate immune response. Instead, it acts as a ‘stealth’ virus early in the infection.[9]
Age is also an important host factor determining the risk of chronicity. Following acute exposure to HBV, 90% of neonates born to hepatitis B ‘e’ antigen (HBeAg)-positive mothers, 20 - 50% of infants and children under the age of 5 years, and <5% of adults will develop chronic hepatitis B infection.[11,12] Viral variants may also influence the course and outcome of the disease. In addition, and only rarely and in the setting of profound immune suppression, the virus can be directly cytopathic.
In choosing an appropriate management strategy, a clear understanding of the process of hepatitis B viral replication, as well as the natural history of chronic hepatitis B, is vital:
Following acute exposure, the HBV enters the hepatocyte and is imported into the nucleus. The partially doubled-stranded DNA is repaired to form a circular extra-chromosomal molecule called the covalently closed circular DNA (cccDNA),[13] which is the transcriptional template for the viral messenger RNAs (mRNAs). The RNA form of the genome is encapsidated together with the reverse transcriptase, and reverse transcription occurs within the cytoplasm. Cytoplasmic viral capsids containing mature viral DNA are either transported to the nucleus, thereby replenishing cccDNA, or bind to HBV surface antigens which have accumulated in the endoplasmic reticulum, bud through the cellular membranes and are secreted from the hepatocyte non-cytopathically, as virions.
Hence, even if the individual clears hepatitis B surface antigen (HBsAg), the hepatocyte still harbours cccDNA. This is the basis of occult HBV infection, which is defined as detectable HBV DNA in the liver and a very low level (<200 IU/ml) of HBV DNA in the blood of those previously exposed to HBV, viz. HBsAg negative and hepatitis B immunoglobulin G core antibody (anti- HBc IgG) positive. The clinical significance of occult HBV is that immunosuppression may lead to reactivation in these patients. HBV DNA can also integrate into the cellular genome during chronic infection, as a result of random insertion of viral DNA into the host genome, by host processes during failed repair of the partially double-stranded DNA. This integrated DNA plays no role in viral replication, but plays an important and ill-defined role in the development of HCC.
There are 5 phases of chronic infection which are not necessarily sequential and are of variable duration.[6,14]
1. The immune tolerant phase is characterised by HBeAg posi- tivity, high levels of viral replication (high serum HBV DNA), normal transaminases, minimal or no hepatic necroinflammation and no or slow progression to fibrosis. During this phase, the rate of spontaneous HBeAg loss is low. This phase, which is more common and more prolonged in individuals infected perinatally or under the age of 5 years, frequently persists into early adulthood and is frequent in SA.
2. The immune clearance phase (HBeAg-positive chronic hepatitis B) is characterised by HBeAg positivity, but lower levels of viral replication. The transaminases are elevated and histologically there is more severe necroinflammation and more rapid progression of fibrosis. This phase may last several weeks to years and, if successful, a sustained HBeAg seroconversion will occur with the development of anti-HBe. A successful HBeAg seroconversion is more likely to occur in individuals infected during adulthood.
3. The inactive HBV carrier or latency state (immune control phase) follows successful HBeAg to anti-HBe seroconversion and is characterised by very low (<2 000 IU/ml) or undetectable HBV DNA levels and normal transaminases. As a result of immunological control of the infection, these patients have a good prognosis, with a much lower risk of progression to cirrhosis or HCC. HBsAg loss and seroconversion to anti-HBs may occur spontaneously at a rate of 1 - 3% per year.
4. Five to 15% of individuals in the inactive HBV carrier state will develop HBeAg-negative chronic hepatitis B. This reactivation phase represents a later phase in the natural history of the disease and is more common in older men. Nucleotide substitutions in the precore and/or basal core promoter regions of the HBV genome result in HBV variants that are unable to express HBeAg, or which do so at very low levels. This phase is characterised by HBeAg negativity, fluctuating transaminases and HBV DNA levels, significant necroinflammation and progressive fibrosis. Low levels of hepatitis B immunoglobulin M core antibody (anti-HBc IgM) may be detected.
It is important, but often difficult, to distinguish this phase from the inactive HBV carrier state. Patients with HBeAg-negative chronic hepatitis B have a high risk of progression to cirrhosis, which may in turn lead to decompensation and the risk of HCC. At least 1 year follow-up, with 3 - 4-monthly monitoring of alanine transaminase (ALT) and HBV DNA levels, is required to confidently distinguish these two phases of the disease.[15-17]
Individuals in the inactive HBV carrier state may also revert back to HBeAg positivity and develop HBeAg-positive disease.
5. Occult HBV infection is the term used to describe those cases where patients have cleared surface antigen but have detectable plasma HBV DNA. Serologically they are HBsAg negative, hepatitis B surface antibody (HBsAb) positive and anti-HBc IgG positive, yet they are positive for HBV DNA, albeit at very low levels (invariably <200 IU/ml). While no liver disease is associated with occult infection, these individuals are at very high risk of reactivation of HBV with immune suppression, e.g. during use of rituximab (MabTheraR), and require prophylactic antiviral therapy.