By Datuk Dr M Jegathesan Former Clinical Consultant (Microbiology)
A Diagnostic and Prognostic Mainstay of Hepatitis B Infection
Hepatitis B is a common enough infection in this country and, with its potential sequelae of cirrhosis and hepatocellular carcinoma being well recognized, is a regular source of diagnostic requests for the laboratory.
It is the purpose of this paper to give a review of the current tests in use, their diagnostic value and their interpretation.
The diagnosis of Hepatitis B infection is essentially based on serological techniques, which look for either the antigens or the corresponding antibodies of the different constituents of the causative virus. A battery of tests have been developed which when viewed in tandem as well as in sequence allow not only diagnoses of present and past infection but also activity status, chronicity and transmissibility, and, by extension, potential for serious liver damage and possible carcinogenic outcome.
The cornerstone of this battery of tests is the Hepatitis B surface antigen, HBsAg, the very presence of which defines active hepatitis B infection, and which becomes detectable in the blood within four weeks of exposure.
In the normal course of events as the body mounts its immune response, the surface antigen will be destined to disappear from the blood within about four months since onset. Almost at the same time as this antigen disappears antibodies to it i.e. anti-HBs will begin to appear. Detection of the antigen and its corresponding antibody thus have an inverse relationship vis a vis the determination of activity status as well as immunity to subsequent infections. In most instances these are mutually exclusive although there are some circumstances in which they may co-exist. In short, absence of HBsAg with presence of anti-HBs indicates recovery and immunity from future infections, a picture also seen as a successful response to immunization.
In a proportion of cases, however, the surface antigen will not disappear in the expected four months and if this persists beyond six months it is deemed that the infection has progressed to a chronic state, the disease is still active with potential for lasting liver damage and that the patient is able to continuously transmit the disease to others and hence become a chronic carrier.
It is at this stage that the other tests in the battery of serological tests become useful as prognostic and diagnostic tools. The Hepatitis Be antigen and its antibody anti-HBe are particularly useful in this regard and generally they too have an inverse relationship. Meaning that, detection of the e antigen in hepatitis B surface Ag positive case connotes high disease activity status with the potential for high transmissibility whilst an absence of the e antigen but anti-HBe positive points to the converse, although both of these may coexist for a short period in the early stage of the acute infection.
Accordingly, if the HBsAg is persistently positive, the detection of HBe is not a good sign. While its absence especially if anti-HBe is present is comforting. However there is a circumstance in which HBe may be absent in the face of high viral activity and that is a condition called a pre core mutation where there is a genetic mutation that renders the virus incapable of producing the e antigen although it is actively replicating. (The arbiter under these circumstances that will indicate the true picture of viral replication is the Hepatitis B virus DNA test which will be positive).
Another component of the virus that can throw light on the activity status of the infection is the core antigen HBc and its antibody anti-HBc. Ongoing replication of the virus throws up large amounts of core antigen but this is only found in the liver and not in the blood and hence not useful in serology tests. However the antibody anti-HBc as it emerges can be detected in the blood and the IgM form is found during the acute infection and lasts for about 6 months whilst the IgG form appears later in the disease but persists for life. Hence it is the IgM anti-HBc which is a useful marker of acute infection. Unlike anti-HBs, anti-HBc is not seen as a response to immunization.
A test being requested with increasing frequency is the PCR (Polymerase Chain Reaction) test for hepatitis B virus DNA. It is mainly used to provide a quantitative estimate of viral load, evidence of viral replication, progress of the disease and response to therapy. In general a high count is reflective of increased viral replication and thus disease activity. Response to therapy is indicated by significant drops in levels.
Therapy with interferon or lavimudine is recommended for cases in which chronic hepatitis is associated with the presence of e antigen, or if there is evidence of viral replication through a DNA test. When to stop therapy once initiated is also important as premature cessation can lead to relapse. The measure of viral load through the PCR test is useful in making this decision.
*HBcAg - No blood test available (Histological marker)
Investigations for Chronic Hepatitis B
- HBeAg, Anti-HBe
- HBV DNA (requires 4 ml of blood in EDTA or minimum 1.5ml of frozen plasma to be sent)
- α fetoprotein
- Ultra sound liver
- s/c α Interferon (IF) - 3 times a week or PEG ylated IF - S/C Weekly
Problem of increasing resistance of HBV after 1 year.