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Clinical Manifestations of Acute, Chronic & Viral Hepatitis
Clinical Manifestations Acute Infection
Patients infected with HCV are usually asymptomatic, or have non- specific
symptoms such as general fatigue and mild nausea. After an incubation
period of about 60 days, acutely infected patients develop elevated serum
alanine aminotransferase (ALT) enzyme levels with peak levels typically
averaging 600 U/L. Up to 25% of infected patients experience an icteric
illness.
Symptoms and signs, when they occur, are similar to those of other forms
of acute viral hepatitis, but are generally milder than those seen in
Hepatitis B infection.
Chronic State
From the available data it is estimated that a high proportion (greater
than 70%) of Hepatitis C infections lead to a chronic carrier state which
is asymptomatic in most cases. Symptoms, when present, may be non-specific
and therefore not obviously connected with the previous acute phase of
the illness.
Symptoms may include mild to severe fatigue and right upper quadrant abdominal
pain or discomfort. Jaundice, fever, chills or night sweats, malaise,
concentration problems, headaches and nausea may also occur.
Raised levels of liver enzymes (ALT, AST) are common and may persist for
years as acute infection enters a chronic phase. However, the levels of
these enzymes can fluctuate and may be within the normal range at times.
It is believed that the virus circulates in the bloodstream at a low level,
sometimes below the present levels of detection. Liver damage, as determined
by liver biopsy, does seem to gradually occur over the years but at any
one time ALT levels and virus detection in the serum may not reflect this.
It is estimated that 25-30% of individuals with chronic HCV infection
will develop cirrhosis over an average of twenty years, linking low level
replication of the virus with liver injury. Hepatocellular carcinoma and
liver failure may develop in a percentage of those that have cirrhosis.
†most people who contract HCV become chronic carriers
†many people who are HCV antibody positive will be asymptomatic
†chronic carriers are at a higher risk of developing liver damage
Detection Of HCV Infection Antibody Detection
The discovery of part of the genetic material of HCV in 1988 using molecular
recombinant technology has allowed the development of tests to detect
specific antibodies. The first enzyme immunoassay (EIA) test made available
in 1989 employed only a single recombinant protein to detect antibodies
and produced a significant proportion of both false positive and false
negative results.
The development of second generation antibody tests, incorporating a greater
range of antigens, has improved the sensitivity and specificity of antibody
detection, allowing detection of specific antibodies earlier in the course
of infection.
The time for seroconversion varies enormously but is usually eight to
twelve weeks after exposure and, in acute illness, antibodies may be detectable
one to six weeks after symptoms develop. In immunocompromised individuals
the antibody response may be weak or not develop at all.
Usually, the antibody response is long lasting. Whether Hepatitis C antibodies
provide immunity from further infection is not clear. Studies with chimpanzees
have shown that after resolution of an acute Hepatitis C infection, rechallenge
with the same strain of HCV causes reinfection.
As vaccine development will depend on stimulation of protective antibodies
these preliminary studies are not encouraging.
There are a number of HCV antibody detection kits available in Australia.
The ability of these tests to detect individuals who have been infected
with Hepatitis C is defined as the sensitivity and is about 90%. Some
positive individuals may be missed due to the window period between infection
and seroconversion.
The specificity of presently available assays, i.e. the ability to find
specimens non-reactive from individuals never infected with HCV, is about
99%.
HCV antibody indeterminate sera tend to give optical density readings
close to the cut-off values and may be attributed to non-specific interactions
with contaminants co- purified with the recombinant antigens or synthetic
proteins used in the tests.
HCV Antibody Indeterminants
Interpretation of these low reactive specimens has necessitated the development
of a diagnostic strategy to attempt to resolve their Hepatitis C status.
The medical history and examination findings are important components
of the diagnostic approach, especially the presence of a risk factor in
the clinical history.
At VIDRL the second generation Abbott EIA is presently used as the primary
screening assay. Low positive and high negative sera (approximately 6%
of all tested) are retested on a second independent EIA (Murex).
Those that are reactive in the Murex test are considered HCV antibody
positive and are reported as such. Specimens giving discordant results,
i.e. they are non-reactive in the Murex test, are interpreted by VIDRL
as indeterminate and a follow up specimen is requested. Individuals showing
such test results are dealt with on a case by case basis.
A proportion of repeat specimens may reveal a seroconversion to HCV thereby
clarifying the HCV infection status of the patient. Detection of HCV RNA
by PCR in serum from patients showing repeated HCV antibody indeterminate
status confirms HCV infection. However, if HCV RNA is not detected this
does not exclude infection.
Virus Detection By PCR
A positive antibody result does not distinguish a resolved infection
from a chronic carrier state. Development of the technique called polymerase
chain reaction (PCR) has allowed the detection of the HCV RNA in the serum
of infected patients.
The PCR test is a sensitive and specific test for detection of HCV gene
sequences in specimens; a short section of the HCV genome is amplified
thousands of times to levels that may easily be detected.
This process of PCR amplification requires many steps, is technically
complex and uses expensive reagents. However, the information obtained
from the test is very useful in the characterization and monitoring of
progression of HCV infections.
If HCV gene sequences are detected by PCR this means that the patient
has detectable levels of Hepatitis C virus in their blood.
If these gene sequences are not detected it can mean either that the patient
has cleared the virus from the body and a chronic carrier state has not
been established or that the level of virus in the blood is so low that
it is below the level of detectability by PCR.
Note that in the chronic carrier state, levels of HCV can fluctuate above
and below the level of detectability by HCV PCR. Persistent viraemia over
a period of six months is used to define the state of chronic Hepatitis
C and it appears that the majority of infected individuals do progress
to become chronic carriers.
This has important implications concerning prognosis and long-term management
for these patients.
Although PCR is not normally indicated for confirmation of the chronic
carrier state, it may be useful for:
†evaluation of antiviral therapy •investigation of modes of
transmission
†early diagnosis prior to serovconversion
†defining the status of hepatits C antibody indeterminates or problem
sera PCR has developed from being a research tool into a diagnostic test
at VIDRL (Fairfield Hospital). Both an in- house method and a commercially
available kit (Amplicor HCV test from Roche Diagnostic Systems) are used
routinely.
Liver Damage Detection
Serum levels of aminotransferase enzymes of liver origin, particularly
alanine aminotransferase (ALT), increase as a result of hepatocellular
damage. Regular testing of liver enzyme levels may be used to monitor
disease activity. However, liver damage may be occurring even when liver
enzyme levels are normal.
Specialist referral would be appropriate if the patient was to be considered
for alpha-interferon treatment, if the antibody test result was indeterminate,
if ALT levels were abnormal or the patient had signs of chronic liver
disease.
Specialist assessment may include liver biopsy which provides a more definite
assessment of liver damage than LFT testing.
†liver damage may be occurring even when liver enzyme levels are
normal
†liver biopsy may give a clearer indication of the extent of liver
damage
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