Scot. moo. J., 1975, 20: 99
HEPATITIS B ANTIGEN: PAST, PRESENT, FUTURE Australia antigen was discovered in 1963 by geneticists who were studying inherited variations in human plasma proteins. Soon it became apparent that it was in some way associated with hepatitis B virus: samples of blood or blood products which contained Australia antigen, when transfused to hospital patients or injected into volunteers, often gave rise to long incubation period 'serum' hepatitis, and in turn the antigen was present in the recipients' blood during the incubation period and clinical illness: it could not be found in epidemics of classical short incubation infectious (virus A) hepatitis which spread by non-parenteral routes. Of particular interest was the fact that the demonstration of Australia antigen (which has by now changed its name several, times) for the first time provided practical laboratory diagnostic tests for infection with hepatitis B virus. Most of these tests depend on serological reactions between the appropriate specific antibody and the abnormal antigen in the infected serum. It is important for the clinician to realise that the amount of Australia antigen in the serum varies greatly in different infected individuals and that radioimmunoassay, the latest and most expensive technique, is several thousand times more sensitive than gel diffusion, with immunoelectro osmophoresis, complement fixation and various agglutination tests occupying intermediate positions. There has been considerable difficulty in determining the precise nature of Australia antigen. Suggestions that it is merely a product of damaged liver cells have been disproved by the discovery of subtypes of Australia antigen which share the common 'a' antigen but differ from one another in having additional distinguishing antigenic groups termed d, y, rand w. In anyone epidemic of virus B hepatitis such as might occur in a renal dialysis unit all cases are of the same subtype showing that the properties of the Australia antigen are related to the infective agent rather than to the host liver cell. Electron microscopy of serum has revealed that the antigen consists of 20 nm. diameter spherical and cylindrical structures
which resemble virus particles but they consist mainly of protein and contain little or no nucleic acid; they cannot therefore be infective virus. It is now fairly certain that the larger 42 nm. diameter 'Dane' particles which occur in much smaller numbers in Australia antigen-positive sera are the hepatitis B virus. These particles have a core which is antigenically distinct (HBc antigen) and is also found in the nuclei of infected hepatocytes. The cores contain unique DNA and the enzyme DNA polymerase which is necessary for their reproduction. Australia antigen protein forms a coat on the Dane particle's surface and is now known as HBs antigen; it is produced in the cytoplasm of infected liver cells, frequently greatly in excess of that required for coating Dane particle cores, and in these circumstances it is released into the blood where it provides the basis for convenient diagnostic tests. Already our new found ability to diagnose virus B infection has practical advantages for the clinician. The screening of blood and blood products for HB s antigen has facilitated the recognition of symptom free hepatitis B carriers among blood donors and resulted in a diminished incidence of post-transfusion virus B hepatitis in several centres. In this issue of the journal, page 105, Dr Chaudhuri shows that this has happened in South West Scotland. It should be noted, however, that with improved diagnosis many clinically typical cases of post-transfusion hepatitis are not apparently due to hepatitis B virus. A second important application of tests for HBs antigen is in the prevention of hospital infection. Routine screening of all hospital patients is not yet attempted since it would be prohibitively expensive to provide for the general medical requirements of infected individuals in special isolation units, and given the rather low infectivity of such individuals in good hygienic circumstances, such extreme measures are scarcely required. On the other hand virus B hepatitis poses special problems for patients with impaired immunological responses and special measures should certainly be taken to exclude infected individuals from renal dialysis units where numerous epidemics with a substantial mortality rate have been recorded.
Leading Articles
As a world problem virus B infection is of enormous magnitude, especially in tropical countries. In Kenya, for example, 5 per cent of the general population are symptomless carriers, while 20 per cent of cases of cirrhosis and 40 per cent of cases of malignant hepatoma are reported to have HB s antigenaemia. Strong evidence that virus B infection may lead to chronic hepatitis in about 10 per cent of cases has been provided by serial studies of acute cases in Scandinavia and it is possible that the common occurrence of cirrhosis and malignant hepatoma in tropical countries may be largely due to virus B infection. In Scotland a sixth of cases of acute viral hepatitis admitted to hospital are due to virus B infection, the symptomless carrier rate being about I in 500; here only a minority of cases of chronic liver disease can be attributed to persisting virus B infection. The paper by Dr Chaudhuri on page 105 of this issue of the Scottish Medical Journal gives an account of
100
the findings in the acute disease in Scotland and this emphasises the difficulty in distinguishing it clinically from acute virus A infection in the majority of cases. It seems likely that further immigration from and increased travel in foreign countries will expand the reservoir of symptomless carriers in Scotland, while current trends in promiscuous sexual behaviour and intravenous narcotic addiction will lead to further spread of the acute disease and its sequelae. For the future perhaps the most important medical application of HBs antigen will be its role in the development of a vaccine. Preliminary studies show that immunisation with heated HB s antigen has some protective effect and in emergencies passive immunisation with HBs antibody may even be useful. Our final objective must be the eradication of virus B hepatitis. R. B. Gouma
HEPATITIS B ANTIGEN: PAST, PRESENT, FUTURE Australia antigen was discovered in 1963 by geneticists who were studying inherited variations in human plasma proteins. Soon it became apparent that it was in some way associated with hepatitis B virus: samples of blood or blood products which contained Australia antigen, when transfused to hospital patients or injected into volunteers, often gave rise to long incubation period 'serum' hepatitis, and in turn the antigen was present in the recipients' blood during the incubation period and clinical illness: it could not be found in epidemics of classical short incubation infectious (virus A) hepatitis which spread by non-parenteral routes. Of particular interest was the fact that the demonstration of Australia antigen (which has by now changed its name several, times) for the first time provided practical laboratory diagnostic tests for infection with hepatitis B virus. Most of these tests depend on serological reactions between the appropriate specific antibody and the abnormal antigen in the infected serum. It is important for the clinician to realise that the amount of Australia antigen in the serum varies greatly in different infected individuals and that radioimmunoassay, the latest and most expensive technique, is several thousand times more sensitive than gel diffusion, with immunoelectro osmophoresis, complement fixation and various agglutination tests occupying intermediate positions. There has been considerable difficulty in determining the precise nature of Australia antigen. Suggestions that it is merely a product of damaged liver cells have been disproved by the discovery of subtypes of Australia antigen which share the common 'a' antigen but differ from one another in having additional distinguishing antigenic groups termed d, y, rand w. In anyone epidemic of virus B hepatitis such as might occur in a renal dialysis unit all cases are of the same subtype showing that the properties of the Australia antigen are related to the infective agent rather than to the host liver cell. Electron microscopy of serum has revealed that the antigen consists of 20 nm. diameter spherical and cylindrical structures
which resemble virus particles but they consist mainly of protein and contain little or no nucleic acid; they cannot therefore be infective virus. It is now fairly certain that the larger 42 nm. diameter 'Dane' particles which occur in much smaller numbers in Australia antigen-positive sera are the hepatitis B virus. These particles have a core which is antigenically distinct (HBc antigen) and is also found in the nuclei of infected hepatocytes. The cores contain unique DNA and the enzyme DNA polymerase which is necessary for their reproduction. Australia antigen protein forms a coat on the Dane particle's surface and is now known as HBs antigen; it is produced in the cytoplasm of infected liver cells, frequently greatly in excess of that required for coating Dane particle cores, and in these circumstances it is released into the blood where it provides the basis for convenient diagnostic tests. Already our new found ability to diagnose virus B infection has practical advantages for the clinician. The screening of blood and blood products for HB s antigen has facilitated the recognition of symptom free hepatitis B carriers among blood donors and resulted in a diminished incidence of post-transfusion virus B hepatitis in several centres. In this issue of the journal, page 105, Dr Chaudhuri shows that this has happened in South West Scotland. It should be noted, however, that with improved diagnosis many clinically typical cases of post-transfusion hepatitis are not apparently due to hepatitis B virus. A second important application of tests for HBs antigen is in the prevention of hospital infection. Routine screening of all hospital patients is not yet attempted since it would be prohibitively expensive to provide for the general medical requirements of infected individuals in special isolation units, and given the rather low infectivity of such individuals in good hygienic circumstances, such extreme measures are scarcely required. On the other hand virus B hepatitis poses special problems for patients with impaired immunological responses and special measures should certainly be taken to exclude infected individuals from renal dialysis units where numerous epidemics with a substantial mortality rate have been recorded.
Leading Articles
As a world problem virus B infection is of enormous magnitude, especially in tropical countries. In Kenya, for example, 5 per cent of the general population are symptomless carriers, while 20 per cent of cases of cirrhosis and 40 per cent of cases of malignant hepatoma are reported to have HB s antigenaemia. Strong evidence that virus B infection may lead to chronic hepatitis in about 10 per cent of cases has been provided by serial studies of acute cases in Scandinavia and it is possible that the common occurrence of cirrhosis and malignant hepatoma in tropical countries may be largely due to virus B infection. In Scotland a sixth of cases of acute viral hepatitis admitted to hospital are due to virus B infection, the symptomless carrier rate being about I in 500; here only a minority of cases of chronic liver disease can be attributed to persisting virus B infection. The paper by Dr Chaudhuri on page 105 of this issue of the Scottish Medical Journal gives an account of
100
the findings in the acute disease in Scotland and this emphasises the difficulty in distinguishing it clinically from acute virus A infection in the majority of cases. It seems likely that further immigration from and increased travel in foreign countries will expand the reservoir of symptomless carriers in Scotland, while current trends in promiscuous sexual behaviour and intravenous narcotic addiction will lead to further spread of the acute disease and its sequelae. For the future perhaps the most important medical application of HBs antigen will be its role in the development of a vaccine. Preliminary studies show that immunisation with heated HB s antigen has some protective effect and in emergencies passive immunisation with HBs antibody may even be useful. Our final objective must be the eradication of virus B hepatitis. R. B. Gouma
