A. J. Zuckerman

FULMINANT HEPATIC FAILURE IN LEUKAEMIA AND CHORIOCARCINOMA RELATED TO WITHDRAWAL OF CYTOTOXIC DRUG THERAPY

In three patients with malignant disease HBsAg was detected in the serum at least 6 months before the development of acute hepatitis type B, which in each case followed a fulminant course to death. It is suggested that suppression of the normal immunological responses to hepatitis-B viral antigens by cytotoxic drug therapy permitted widespread infection of hepatocytes. Subsequently, upon withdrawal of these drugs, recovery of immunocompetence resulted in rapid destruction of all infected hepatocytes and massive liver damage. Screening for HBsAg before cytotoxic drug therapy, careful monitoring of liver function during its withdrawal, and prompt treatment with corticosteroids should abnormalities occur may prevent this unfortunate sequence of events.

Effect of Gamma Irradiation on the Human Immunodeficiency Virus and Human Coagulation Proteins

Abstract. The effect of gamma irradiation on HIV and plasma coagulation factors F VIII:C, F VIII:vWF and FIX was studied. Donor plasma was harvested from single donations, frozen and irradiated in the frozen state at target doses from 0 to 40 kGy (0–4 mRad). HIV was inoculated into human plasma and irradiated in a similar manner. A range of other viruses, not suspended in plasma, were also irradiated to establish viral inactivation. An inactivation rate of 0.164 TCID50 dose/ml/kGy was demonstrated for HIV compared to rates of 0.00173, 0.00526 and 0.00286 log10 units/ml/kGy for F VIII:C, F VIII:vWF and FIX respectively. The use of gamma irradiation to inactivate infectious agents present in human plasma may eliminate the need for any post‐production viral inactivation methods and provide a means of assuring the safety of as yet untreated products such as cryoprecipitate and fresh frozen plasma.

HEPATITIS B VIRUS INFECTION IN TWO GAMBIAN VILLAGES

The prevalence of hepatitis B virus infection was markedly different in two neighbouring Gambian villages. 62% of children in Manduar aged 2-4 years were infected whereas in Keneba, the other village, only 27% of this age-group were infected. However, in both villages few infants were infected--none under 6 months of age and only 2 of 58 between the ages of 6 and 12 months. Carriage of hepatitis B surface antigen (HBsAg) was high, reaching a peak of 36% in the 5-9 age-group in Manduar and 17.6% in the 2-4 age-group in Keneba. 86% of all the children under the age of five who were HBsAg-positive also carried hepatitis B e antigen (HBeAg). This proportion fell to 17.6% for children aged 10-14 years and to 12.9% for mothers. Infection clustered in families, transmission from sib to sib being of major importance. The chances of a child being an HBsAg carrier were approximately 42% if an elder sib carried the antigen, 27% if either mother or father was a carrier, and 15% if neither mother or father was a carrier. There were 4 HBeAg-positive mothers who were highly infectious, since 10 of 11 of their children became HBsAg carriers. Carriage of surface antigen lasted many years; 63% of those carrying the antigen in 1972 were still positive in late 1980. 4 cases of primary hepatocellular carcinoma out of 672 adults have been diagnosed in the past five years. All 4 were in HBsAg carriers.

HEPATITIS-B ANTIBODY IN POLYMYALGIA RHEUMATICA

Thirteen patients with polymyalgia rheumatica (P.M.R.) were examined for evidence of viral infection. Hepatitis-B surface antibody (HBsAb) was detected in nine out of twelve patients tested prior to therapy. The antibody persisted up to six months in four patients but reverted to negative in the other five. HBsAb was found in only one of twelve age-matched controls. Hepatitis-B surface antigen was not detected in any patient or control. No significant elevation of antibody titre was detected to a panel of twelve other organisms. Immunoglobulin levels were elevated prior to treatment in several patients. With steroid therapy the IgG and IgA levels fell serially but the IgM levels increased in six patients. These results suggest that hepatitis B is an important trigger for P.M.R. In view of the association with giant-cell arteritis, P.M.R. may represent an abnormal immunological response to infection in elderly patients.

DETECTION OF HEPATITIS-B ANTIGEN BY RADIOIMMUNOASSAY IN CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA IN GREAT BRITAIN

Abstract In a series of 264 patients with chronic liver disease or hepatocellular carcinoma, a sensitive radioimmunoassay technique showed 37 cases to be positive for HBAg. 20 of these 37 patients were HBAg negative by immunodiffusion and electrophoresis. In active chronic hepatitis 18% of the 94 patients were HBAg positive. Comparison of these cases with HBAg-negative cases showed a higher frequency of HBAg in males and those born overseas. There were no significant differences between HBAg positive and negative patients for clinical manifestations, immunoglobulins, autoantibodies (after allowing for differences in sex ratio), cell-mediated immunity, or prognosis, and in some cases the progression of tissue damage in this condition may be unrelated to the continued presence of circulating HBAg. HBAg was found in only 1 of 45 patients with primary biliary cirrhosis, and coincidental infection following blood-transfusion was a possibility in half of the HBAg-positive cases of cryptogenic cirrhosis. However, blood-transfusions could be implicated in only two of the six HBAg-positive patients with alcoholic cirrhosis. In primary hepatocellular carcinoma, 23 % of the 38 patients were positive, the frequency being higher in those born overseas (66% compared with 15%), showing that the reported geographical variation in this association cannot be due entirely to differences in technique for detecting HBAg.

Infusion of hepatitis-B antibody in antigen-positive active chronic hepatitis.

Abstract The effects of infusion of an immunoglobulin preparation with a high titre of antibody to hepatitis-B antigen (HBAg) have been investigated in six patients with active chronic hepatitis, in five of whom HBAg was persistently detected in the serum. The intravenous infusions were well tolerated and two patients only showed minor and transient evidence suggesting an immunecomplex reaction. Complexes containing HBAg were demonstrable after the infusion by electron microscopy in four cases, but in three of these complexes were also present beforehand. Complement levels and C3 conversion products were consistent with the presence of immune complexes. Clearance of antigen from the circulation for up to 9 days was achieved in the two cases with low initial titres of HBAg.

Australia Antigen as a Marker of Propagation of the Serum Hepatitis Virus in Liver Cultures

ATTEMPTS to isolate the human hepatitis viruses in tissue culture have resulted in a collection of “hepatitis-candidate” viruses, none of which has since been shown to be the causal agent of human hepatitis1. The discovery of Australia antigen provided a specific serological marker of infection with or carriage of the serum hepatitis virus, although the nature of the antigen remains unsettled2.

EXPOSURE AND IMMUNITY TO HEPATITIS-B VIRUS IN A LIVER UNIT

Abstract Using the leucocyte-migration test, cell-mediated immunity to hepatitis-B antigen (HBAg) was found in 12 (86%) of the 14 members of a liver-unit staff whose work involved frequent contact with purified antigen. In addition, 5 (36%) of them had hepatitis-B antibody (HBAb) detected by radioimmunoassay. Findings in the other 29 staff members were not significantly different from those in 43 age and sex matched factory-worker controls. 30% of the controls had evidence of cell-mediated immunity and 7% had HBAb. 6 patients recovering from acute HBAg-positive hepatitis also had both cell-mediated immunity and HBAb. However, only 1 of the 86 staff members and factory controls tested had ever had clinical hepatitis and liver-function tests were normal. It is suggested that frequent exposure to low-dose HBAg by the oral route may result in a primary immunological response in the gastrointestinal mucosa without viraemia or liver disease and that such immunity is likely to be protective.

Screening of antiviral drugs for hepadna virus infection in Pekin ducks: a review.

Acyclovir and suramin were examined for their efficacy alone and in combination, against duck hepatitis B virus (DHBV) in persistently infected Pekin ducks. The pharmacokinetics of acyclovir in ducks showed that the peak plasma concentration was reached 30 min after oral administration. Oral acyclovir and suramin administered intravenously suppressed the replication and production of infectious virions as measured by marked reduction of DNA polymerase activity during treatment. However, rebound of enzyme activity was observed soon after cessation of drug therapy. In contrast, sustained reduction of polymerase activity was attained by combined therapy of acyclovir followed by suramin, demonstrating a significant enhancement of anti-DHBV activity which requires confirmation in a larger experimental study. This report reviews the work with the duck model, demonstrating that it is ideal for screening antiviral compounds for treatment of infection with hepadna viruses.

Detection of hepatitis B virus DNA in hepatocellular carcinoma: methylation of integrated viral DNA.

In order to determine whether integrated hepatitis B virus DNA sequences in primary liver tumours are methylated we have analysed tumour DNA digested with either MspI or HpaII restriction endonuclease by Southern hybridization. Our results demonstrate methylation in 11 of 17 tumour DNA samples. Where possible, we have examined the tumour tissues for expression of HBsAg and HBcAg using the indirect immunoperoxidase technique. One tumour was positive for both HBsAg and HBcAg and a second was positive for HBsAg alone. Both of these tumours were in the group in which methylation of integrated HBV DNA sequences could not be detected. We postulate that methylation of integrated HBV DNA sequences may influence HBV gene expression in hepatocellular carcinoma.