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