|HAV, hepatitis A virus; HBV, hepatitis B virus; HCV,
hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus; ssRNA,
single-stranded RNA; dsDNA, double-stranded DNA; kb, kilobase; Ag, antigen.|
- Hepatitis B. Infection with the hepatitis B virus (HBV)
may result in three different clinical states: acute hepatitis, chronic
hepatitis, and the asymptomatic carrier state. HBV causes much of the
morbidity and mortality from acute and chronic liver disease worldwide.
HBV is spread by the parenteral route and by intimate contact. In addition
to chronic liver disease, it is also implicated in the pathogenesis of
- HBV is a medium-sized DNA virus belonging to a new
class of animal viruses called hepadna viruses. These viruses are
hepatotropic, tend to cause persistent infections, and have been
associated with the development of hepatocellular carcinoma. HBV is
unique among human viruses in its genomic and antigenic structure and its
consists of an outer shell made up of a protein designated as the hepatitis B
surface antigen (HBsAg) and a complex inner core called the hepatitis B core
antigen (HBcAg). This core particle consists of a partially double-stranded
circular DNA molecule and a DNA polymerase (DNAP). The genome is composed of
circular DNA with a complete negative strand and an incomplete positive strand.
The negative strand contains overlapping genes that encode structural proteins
(surface proteins and their derivatives and core) and two replicative proteins
(polymerase and X). HBV is unique among DNA viruses in that it replicates in a
way similar to that of the RNA retroviruses such as the human immunodeficiency
virus (HIV) via an RNA intermediate. Following entry of HBV into a hepatocyte,
viral replication is initiated by the synthesis of an intermediary RNA molecule
using host enzymes. Viral genomic DNA is produced by reverse transcription
using DNA polymerase of the virus.
- Pathogenesis:- At the entry of HBV and its invasion of
hepatocytes, viral proteins are expressed on the hepatitis membrane.
These proteins are recognized by the host immune systems, both the
humoral and the cellular arms. If the host immune response to the
infected hepatocytes is strong enough to destroy all the involved cells,
hepatits is results in clearance of the virus. However, if the immune
response is inadequate to completely obliterate the infected hepatocytes,
an ongoing viral infection ensues with varying degrees of hepatic
- Serology:- Infection with HBV results in an overproduction of
HBsAg outnumbering the intact virus by 10 million to 1.
B e antigen (HBeAg) is an internal antigen of HBcAg particles that can be
detected in the serum of patients with high levels of circulating HBV. HBeAg is
found only in HBsAg-positive serum and signals active ongoing infection and
infectivity. HBcAg is found only within the infected hepatocytes
and not in the serum. The hepatitis B antibody (Ab) is described in the
- HBV infection. Infection with HBV can lead to several
outcomes. Approximately two thirds of the individuals infected with HBV
have a transient subclinical infection, followed by rapid clearance of
the virus with a strong immune response, production of high titers of
HBsAb, and permanent immunity. HBcAb is also produced in these
individuals but does not confer or suggest immunity.
- Acute hepatitis :- About one fourth of individuals with HBV infection
develop clinically apparent acute hepatitis. The incubation period, or
time between exposure and onset of symptoms, is 1 to 6 months. During
this time, there is active viral replication, and the patient's serum
becomes positive for HBsAg, DNA, and DNAP.
- Clinical presentation. Before
jaundice and typical clinical findings of hepatitis become apparent,
these patients may present with rash, neuralgia, arthralgia, arthritis,
glomerulonephritis, vasculitis, mixed cryoglobulinemia,
and aplastic anemia. These disease states are believed to result from circulating
- Laboratory tests
- As the patient becomes
symptomatic, there is a concomitant rise in serum ALT and AST (5-20
times normal) and a moderate elevation of the serum alkaline
phosphatase (2-10 times normal). These enzymes represent hepatocellular
damage. Serum bilirubin may reach very high levels (> 30 mg/dL).
time (PT) and partial thromboplastin time (PTT) levels may also become abnormal
depending on the severity of the liver disease.
- Serum DNA and DNAP become
undetectable in these patients within 1 to 8 weeks after the onset of
symptoms. HBcAg also disappears soon after the peak of serum
transaminase. HBsAg usually remains detectable in the serum throughout
the illness and may persist even into convalescence. This is because
the initial HBsAg titers are very high, and because HBsAg has a long
half-life of 8 days, it may take months to clear it to undetectable
- HBcAb is present in high
titers in the serum of infected patients with HBV when jaundice
appears. The initial antibody is of IgM type; with recovery, the IgM
type disappears, and the IgG HBcAb titers reach high levels and persist
- HBeAb appears when HBeAg
becomes negative and often disappears within a few months or years.
- HBsAg arises during recovery
after HBsAg has cleared. There is usually a window period between the
disappearance of HBsAg and the appearance of HBsAb. The only way to
make the diagnosis of acute
in these individuals is to show the presence of HBcAb (IgM type). A minority of
the patients (5%-15%) who clear HBV and recover normally never develop HBsAb.
However, most of these individuals have positive IgM HBcAb.
- In some patients (10%), HBV
clearance is very rapid, and HBsAg levels may be absent at the onset of
symptoms. These acutely ill patients have positive IgM HBcAb titers and
may have detectable HBeAg levels. These variations are more common in
both mild and fulminant disease.
- HBV DNA can be detected and
measured quantitatively with specific assays. The hybridization assay
measures replicating HSV DNA whereas the amplication assay performed
using the polymerase chain reaction (PCR) measures HBV DNA
- Prognosis:- In patients who can mount
a vigorous immune response, the virus is cleared, and recovery is within
a few months (1-6 months). A minority of the patients with acute
hepatitis (1%-5%) develop fulminant hepatic failure (FHF) due to massive
hepatic necrosis. The prognosis in these patients is poor and depends on
- Chronic HBsAg carrier state and chronic hepatitis
- Clinical course and serology.
About one tenth of patients infected with HBV do not clear the virus and
remain HBsAg-positive. Some of these patients develop chronic
progressive hepatitis, and others may remain in a
clinically quiescent carrier state.
- In patients who develop
chronic type B hepatitis, the initial pattern of HBV markers is similar
to that in patients with acute, self-limited hepatitis. However, in
patients with ongoing active disease, HBeAg, DNA, and DNAP persist and
accompany elevated serum transaminases even after 6 months of
- In most patients the initial
disease is mild, and some patients may be anicteric and symptomatic.
These patients may present with only nonspecific symptoms of anorexia
and fatigue and mild-to-moderate elevation of liver tests.
- IgM HBcAb levels remain
elevated in chronic active type B hepatitis. As the disease wanes, the
titers diminish with an increase in IgG HBcAb.
- Patients who remain
HBsAg-positive do not produce specific HBsAb. However, in 20% to 40% of
HBsAg carriers, there may be low levels of HBsAb directed toward HBsAg
subdeterminants not present in the serum.
- The course of chronic HBV
infection varies. The activity of the liver disease and the serologic
markers change over time. In approximately one half of these patients,
HBeAg disappears and is replaced by HBeAb. Concomitantly, there is a
flare of the hepatitis with elevated ALT and AST levels and loss of DNA
and DNAP from serum. This is followed by marked improvement of liver
histology and a decrease in serum transaminases. The transition from
the viral replicative phase, suggested by the presence of HBeAb, to the
nonreplicative phase, suggested by the presence of HBeAb, is marked by
an increased immune response of the patient to clear viral replication.
- HBsAg persists in the serum
of most of these patients even though there may be no evidence of viral
replication. These individuals are referred to as the healthy HBsAg carriers.
Integration of HBV DNA into the hepatocyte DNA occurs during chronic
HBV infection and persistent viral replication. This may be a necessary
step in the development of hepatocellular carcinoma in patients with
previous HBV infection.
- If the HBV infection has
occurred in adulthood, approximately 1% of the patients also clears the
HBsAg and becomes HBsAb-positive. Because previous liver damage has
occurred in these patients, they are usually left with some degree of
cirrhosis. These individuals account for some of the patients with
- In some patients, chronic
HBV infection remains in the viral replicative stage. This may be
continuous, with positive HBeAg titers; or intermittent or low grade,
with undetectable HBeAg. The latter pattern is more common in the Far
East and with HBV infection early in life.
- In 10% to 30% of the
patients with chronic HBV hepatitis, cirrhosis develops accompanied by
its complications of portal hypertension, esophageal varices, ascites,
and encephalopathy. The level of IgM HBcAb correlates with the activity
of the chronic hepatitis. High titers are found in severe
exacerbations, moderate titers in moderately active disease, and low
titers in mild cases. Patients who are healthy HBsAg carriers with no
evidence of active liver disease have no detectable IgM HBcAb titers.
- The determining factors for
development of chronic hepatitis after HBV infection are (a) the age of
the individual when initially infected, (b) the immune status of the
host, (c) gender, and (d) the severity of the acute infection.
ninety-five percent of infected neonates and about 30% of children but only 1%
to 10% of adults develop chronic disease. Women are less affected than men, and
the disease becomes chronic much more frequently in patients undergoing
hemodialysis and in other intrinsically or iatrogenically immunocompromised
patients. The severity of the initial disease appears to have little predictive
value when the age of onset and the host immune status are taken into account.
- Reactivation of quiescent
chronic HBV infection occurs spontaneously or, more frequently, in
individuals following the withdrawal of immunosuppressive drugs (e.g.,
chemotherapy, steroids, organ transplantation). In some patients,
reactivation may precipitate fulminant hepatic necrosis. Most
individuals with reactivation have positive HBsAg titers without
positive HBeAg titers. In some patients, if the prior presence of HBsAg
was not known due to subclinical acute disease, reactivation may be
regarded as the initial acute infection. In these individuals, HBeAg,
DNA, DNAP, and IgM HBcAb all may become positive. The initial loss of
HBeAg in the carrier does not necessarily represent resolution of the
infection, which suggests that HBV infection may become latent as the
herpesvirus infections do. Recent data suggest that HBV may infect and
reside quietly in the lymphocytes in the spleen of previously infected
- HBV mutants. HBV polymerase
is an RNA/DNA transcriptase that lacks a proofreading function. During
viral replication, it frequently transcribes its template incorrectly,
creating mutant viruses. Many of these mutants are incapable of forming
infectious virions. However, several infectious HBV mutants have been
identified by PCR. One of these mutants contains a point mutation in the
gene coding the surface protein in the highly antigenic a determinant of
HBsAg. This mutation alters the antigenic properties of the HBV,
allowing it to escape the protective effects of the HBV vaccine.
mutant of HBV has been identified in patients who have active hepatitis B but
lack HBcAg. These hepatitis B virions have a point mutation
in the precore gene. This mutation prevents the synthesis of the precore-core
protein and abolishes the formation of HBcAg, which modulates viral infection.
Lack of HBcAg expression on the infected hepatocytes prevents immunologic
recognition and destruction of these infected cells, resulting in chronic
- Superinfection. HBV carriers
may develop hepatic superinfections with other hepatotropic viruses.
Sudden increases in the serum transaminases may represent superinfection
with HAV, HCV, or HDV.
- HAV infection may be a
superinfection or simultaneous coinfection and is usually associated
with more severe and fulminant hepatitis.
- HCV superinfections may be
difficult to document accurately due to the delay of detectability of
HCAb in acute HCV infections. However, the diagnosis can be made in the
face of increased serum transaminases with reduction of HBsAg titers
due to viral interference, and negative tests for IgM HBcAb, IgM HAV,
and anti-HDV. HCAb titers should be measured again in ongoing
- HDV superinfection is
discussed in section V.
- Nonviral causes. It should
always be kept in mind that sudden increases in the serum transaminases
may result from nonviral causes, such as drug and alcohol
hepatotoxicity, shock, congestive heart failure, right ventricular
failure, and extrahepatic biliary obstruction.
- Primary hepatocellular
carcinoma (PHC). In the parts of the world where HBV infection is
endemic (e.g., Far East, sub-Saharan Africa), PHC is the leading cause
of death from cancer. It appears that persistent HBV infection is the
leading cause of PHC. This suggests that HBV is an oncogenic virus.
- Predisposing factors. Some
of the predisposing factors for development of PHC are race (e.g.,
Asians, Inuits), age at infection (especially infancy and early
childhood), chronic-persistent infection, and the presence of
environmental cocarcinogenic factors, such as ingestion of ethanol,
cigarette smoking, and possibly exposure to aflatoxin.
- Pathogenesis. It is thought
that the integration of HBV DNA into the DNA of the hepatocyte leads to
alterations in cellular gene expression and cellular transformation.
The resulting clones of transformed cells may become autonomous and
- Diagnosis. Early clinical
detection of PHC is difficult. However, determination of elevation of
serum alpha-fetoprotein (AFP) levels and
demonstration of a mass in the liver by ultrasonography (US), computed
tomography (CT) scanning, or magnetic resonance imaging (MRI) are currently
used with reasonable success. Tissue diagnosis can be made by needle biopsy of
the liver under US or CT guidance.
DIFFERENTIAL DIAGNOSIS OF HBsAG-POSITIVE
ACUTE VIRAL HEPATITIS
Acute hepatitis B
Acute delta hepatitis
IgM anti-HBc and anti-HDV
Chronic hepatitis B with
Acute hepatitis A
Delta hepatitis (superinfection)
Acute hepatitis C
Change in HBV markers
Other acute liver injury
Drug or alcohol history
Evidence of other liver disease
HBc, hepatitis B core; HDV,
hepatitis delta virus; HAV, hepatitis A virus; HCV, hepatitis C virus; HBV,
hepatitis B virus.