Pathophysiology

After oral inoculation the virus is transported across the

intestinal epithelium by a poorly understood transport
mechanism. After travelling through the mesenteric veins to
the liver, the virus enters hepatocytes, where replication of
hepatitis A virus (HAV) occurs exclusively within the
cytoplasm via RNA-dependent polymerase. Exact mechanism
of injury is not proven, but there is evidence suggesting the
role of a cell-mediated immune response, as shown to be
mediated by HLA-restricted, HAV-specific CD8+ T
lymphocytes, and natural killer cells. [20] [21] [22] The role
of interferon gamma in promoting clearance of infected
hepatocytes has been described. [20] An excessive host
response (observable clinically by a marked degree of
reduction of HAV RNA during acute infection) is associated
with severe hepatitis. [23] HAV is then shed from the
hepatocyte to the sinusoids and bile canaliculi, and then to
the intestines through bile, whereby faecal excretion occurs.

Pathophysiology

The virus does not directly kill hepatocytes. [15] The host's
immune response to viral antigens is thought to be the
cause of the liver injury in HBV infection. [16] The cellular
immune response, rather than the humoral immune
response, seems to be primarily involved in disease
pathogenesis. Induction of antigen-specific T-lymphocyte
response is thought to occur when host T lymphocytes are
presented with viral epitopes by antigen-presenting cells in
lymphoid organs. These antigen-specific T cells mature and
expand and then migrate to the liver. In acute HBV infection,
most HBV DNA is cleared from hepatocytes through non-
cytocidal effects of inflammatory byproducts of CD8+ T
lymphocytes, stimulated by CD4+ T lymphocytes, notably
interferon-gamma and tumour necrosis factor-alfa. These
cause down-regulation of viral replication, and trigger direct
lysis of infected hepatocytes by HBV-specific CD8+ cytotoxic
T cells. [17] In contrast, people with chronic HBV infection
display weak, infrequent, and narrowly focused HBV-specific
T-cell responses, and the majority of mononuclear cells in
livers of chronic HBV-infected people are non-antigen-
specific. [18]

Life cycle of HBVFrom Ganem D, Prince AM. Hepatitis B virus infection - natural
history and clinical consequences. N Engl J Med. 2004; 350:1118-1129; used with
permission

Due to the presence of HBV in extrahepatic sites, as well as

the presence of covalently closed circular DNA (cccDNA)
within hepatocytes, eradication of the virus is an unrealistic
goal based on the currently available drugs. Covalently
closed circular DNA serves as a template for transcription of
pregenomic messenger RNA, a vital initial step in HBV
replication. [19] [20] [21] [22] The continued presence of
cccDNA within hepatocytes is considered as a marker of
viral persistence. Unfortunately, current therapies have not
been effective in eradicating cccDNA and are only able to
decrease levels. [23] [24] [25] [26] [27] [28] [29]Persistence
of even low levels of cccDNA in the hepatocyte nucleus has
been shown to correlate with viral rebound after
discontinuation of therapy. In addition, the integration of
HBV DNA to the hepatocyte nucleus during replication
process could explain increased risk for hepatocellular
carcinoma. Furthermore, co-infection with hepatitis C virus
(HCV) can synergistically increase the rate of fibrosis,
cirrhosis, and hepatocellular
cancer, [9] [30] [31] [32] because both HBV and HCV occupy
the same hepatocyte independently. [9] [33]

The natural history of HBV infection has been classified into

4 phases, [14] which are influenced by age of infection, host
genetic factors, presence of other viruses, HBV mutations,
and level of immunosuppression.

 In neonates with immature immune systems, 95% of

those infected become asymptomatic chronic HBV
carriers, compared with 30% of children infected over
the age of 6 years. [34]
 Most (70%) of primary infections with HBV in adults are
asymptomatic and self-limiting, with clearance of virus
 from the blood and liver, and lasting immunity to re-
infection.

 However, about 30% of adults with acute HBV may have

symptomatic icteric hepatitis. [34]

 Patients who develop chronic HBV have a 10% to 30%

risk of developing cirrhosis, particularly older patients
with high levels of HBV DNA, or patients with hepatitis
C, hepatitis D, or HIV co-infection. [35]

Pathophysiology

Following acute infection, up to 45% of young, healthy

patients may develop a vigorous antibody and cell-mediated
immune response, which leads to the spontaneous
eradication of the virus and lifelong immunity. [12] However,
the majority of infected patients fail to clear the virus. This
results in chronic infection and progressive liver damage.

Persistent viraemia is accompanied by variable degrees of

hepatic inflammation and fibrosis over time. Recent studies
suggest that 50% or more of hepatocytes may be infected
with hepatitis C virus (HCV). [13] Persistent infection
appears to be due to weak CD4+ and CD8+ T-cell responses
during acute infection, which fail to control viral
replication. [13] Acute HCV infection is characterised by co-
infection with multiple viral subtypes representing highly
diverse intra-patient genetic variability. [14]

When chronic infection is established, HCV may not be

cytopathic. Liver damage probably results from locally
driven immune responses, which are mainly non-specific.
Local inflammation triggers fibrogenesis, in which hepatic
stellate cells play a major role. Cirrhosis is facilitated by
factors such as chronic alcohol consumption, non-alcoholic
steatohepatitis, and coincidental viral infections. [13]