Page 183 - Read Online

In particular, exposure during childbirth from an HBV- with an occult HBV infection remain incompletely
infected mother is the leading global cause of HBV understood, although some evidence does suggest that
infections, with the potential of vertical transmission occult infections retain much of the same risk factors as
being as high as 90% in some parts of Asia. Additional chronic HBV infection. [218]
routes of exposure to bodily fluids from infected
individuals, such as sexual contact or sharing of needles, Clinically, a chronic HBV infection can be divided into
are also common routes of transmission. [11] multiple phases, [11,209,215,219] though not all patients
progress through each stage. The “immune tolerant”
The natural history of HBV has been divided into two phase is characterized by high titers of HBV DNA (>
types of infection [Figure 3]. For about 90-95% of HBV 100,000 copies/mL), the presence of HBeAg, and little
infections in adults, the result is “acute hepatitis” where liver disease. This phase can last decades, especially in
the infected individual resolves infection to the point of perinatally infected patients, but is typically short or
undetectable viral DNA and the presence of antibodies absent in childhood- and adult-acquired HBV.
against HBsAg. Symptomatic HBV-infected individuals
present with inflammation of the liver, which is known The “immune clearance” phase also has high levels of
as hepatitis, and associated nausea, jaundice, abdominal HBV, though usually less than is present in the immune
pain, and vomiting. For many cases of HBV infection, the tolerant phase, as well as HBeAg expression, but is
infected person is asymptomatic, and acute infections also characterized by more advanced liver disease with
are generally cleared within 6 months. In models of increased inflammation and progression of fibrosis. In
acute infection in WHV-infected woodchucks and HBV- addition, this phase is associated with spikes in levels of
infected chimpanzees, the first several weeks of infection aminotransferases, which are believed to be a result of an
are typically characterized by minimal innate [160,210] HBV-specific cytotoxic T-cell-mediated immune response
or adaptive [211] immune activation, with viral spread and destruction of HBV-infected hepatocytes. [220] This is
throughout the entire hepatocyte population. [145,211] important, as a longer duration of this phase and higher
Eventually, the activation of an effective antiviral frequency/severity of the HBV flares are associated with
response, including activation of cytotoxic T lymphocytes the development of cirrhosis and HCC. [221] Typically this
(CTLs), results in inflammation in the liver and killing of phase can last from several weeks to years and likely
the majority of HBV-infected hepatocytes over the length represents immunological attempts to control HBV levels.
of a few weeks. Interestingly, studies of integrated WHV Seroconversion from HBeAg to anti-HBe is considered
DNA in woodchucks treated with clevudine, a viral an important clinical outcome of the immune clearance
polymerase inhibitor, demonstrated that repopulation phase, with immune control of the virus leading to very
of the liver seems to occur from the population of
infected hepatocytes and not from a smaller population low or undetectable levels of serum HBV along with
of uninfected hepatocytes. [212] Clearance appears to be normal aminotransferase levels. Importantly, HBeAg
mostly mediated by antiviral cytokines, with CTLs directly seroconversion is associated with a favorable long-term
killing HBV-infected hepatocytes once the viral load has outcome and with decreased risk of developing cirrhosis
[37]
dropped below specific levels. [213,214] or HCC.
The “inactive HBsAg carrier” phase is characterized by
Approximately 5-10% of cases of HBV-infected adults, and
a significantly higher percentage of HBV-infected infants multiple changes to the disease state. Specifically, there is
and children, develop a chronic HBV infection [215] as a loss of HBeAg expression corresponding to an increased
indicated by continued, detectable expression of HBsAg presence of anti-HBe. Spontaneous seroconversion from
for at least 6 months after the initial infection. More HBsAg to anti-HBs and low to undetectable levels of serum
recently, the application of more sensitive detection HBV DNA are also hallmarks of this phase. Additionally,
techniques, such as polymerase chain reaction (PCR)- aminotransferase levels remain consistently normal; low
based methods that can detect < 250 HBV virions/mL, to mild hepatitis and fibrosis may be observed based
has also shown that many individuals who were believed on the length of the immune clearance phase. The
to be HBV-free following purported HBV clearance inactive carrier phase could potentially be maintained
(indicated by the absence of detectable levels of HBsAg indefinitely and is associated with a favorable clinical
expression) actually have low levels of detectable serum outcome; [215,219] however, some individuals in the inactive
and liver HBV DNA. In fact, low levels of HBV DNA can HBV carrier phase enter a “reactivation/HBeAg-negative
be detected in up to 30% of patients with liver disease chronic hepatitis B” phase during which HBV replication
of previously unknown etiology. [215-217] This result has led rebounds either spontaneously or as a result of immune
to the recognition of occult HBV infections, in which the suppression. These patients are HBeAg negative/anti-HBe
level of virus is persistently low and below the level of positive and have elevated liver enzymes with increased
detection by traditional HBsAg detection techniques. necroinflammation. Serum HBV DNA levels can reach
8
9
Because of the relatively recent identification of this group as high as 10 -10 copies/mL, though levels are typically
of HBV-infected individuals, the risk factors associated lower than in HBeAg-positive patients. [44,209,215,219]
174 Hepatoma Research | Volume 2 | July 1, 2016