Klin. Wschr. 53, 1081- 1082 (1975) - @) by Springer-Verlag 1975
Immunosuppressive Therapy and Virus-Cores in HBAg-Positive Chronic Hepatitis G. Kendrey, A. Szalka, B. Lfiszl6, L. Binder, and I. Hollds Central Municipal Hospital for Infectious Diseases of Budapest (L~tszl6-K6rh~tz) and National Institute of Hygiene, Budapest, Hungary Received April 23, 1975
Summary. Three liver biopsies were carried out in a case of chronic active hepatitis with persistent HB-antigenemia. Virus-cores could not be detected in the liver celt nuclei by electron microscopy before immunosuppressive therapy. Intranuclear, ring-shaped viruscores of 20 25 nm diameter appeared in almost every hepatocyte examined during immunosuppression. Key words: HBAg-positive chronic active hepatitis, virus-cores, immunosuppression.
The case presented here is basically similar to those of Huang [1] and Huang et al. [2], with the sole difference that immunosuppressive therapy was introduced due to the progressive and chronic nature of the liver disease and not because the patient bore a renal transplant. The particles found by the authors were morphologically similar to those observed in their renal transplant patients. Huang et al. [1, 2] suggested that the cores might be the virus responsible for viral hepatitis. Similar, mainly intranuclear particles, not associated with immunosuppressive therapy have been found in a case of chronic liver disease with HB-antigenemia [4] ; in the livers of persons - some of them HBsAg positive-who died of chronic aggressive hepatitis and post-necrotic cirrhosis [5] ; in the hepatocytes of HBAg-carriers either with normal liver [6], mild hepatitis [7] or with liver damage [3]; in one case of severe hepatitis [8]; and in HBsAg-seropositive persons deceased from various lymphoproliferative disorders, who had received cortico-steroids and antimitotic drugs [9]. Recently, in a case of chronic aggressive hepatitis with HB-antigenemia, viruslike particles of the same morphology have been found in the nuclei of liver cells in ultra-thin sections confirmed by immunofluorescent staining in the cytoplasm [10].
Huang [1] and Huang et al. [2] described predominantly intranuclear 2 1 ~ 5 nm spherical virus-like particles (i.e. virus-cores) in hepatocytes in liver biopsies from renal transplant patients who had developed HBAg-associated acute hepatitis and who showed rapid progression to chronic active hepatitis and posthepatitic cirrhosis while under immunosuppressive therapy. During September t 972, a 38-year-old woman developed acute HBsAg-positive viral hepatitis 3 months after receiving blood-transfusion during premature delivery of a child. A prolonged course of liver disease with relapses suggested chronic active hepatitis that did not respond to cortico-steroid therapy. Liver biopsy (February, 1973) revealed a typical chronic active hepatitis. Using a method similar to that of Tappet al. [3] no virus-like particles (virus-cores) were detected in the liver cells by electron microscopy. The HBantigenemia persisted for 6 months of immunosuppressive therapy (Imuran 50 mg/kg/day). A second liver biopsy (October, 1973) showed less striking inflammatory activity but liver damage was still marked. Ultra-thin sections showed numerous intranuclear and intranucleolar uniform, ring-shaped, single or clustered, non-coated virus-cores (Fig. 1) of 20-25 nm diameter and surface subunits of up to approximately 2-3 nm in diameter (Fig. 1, inset) in almost every hepatocyte examined. In spite of the fact that the patient's condition had improved under continuous immunosuppressive therapy, the HB-antigenemia remained constant. A third liver biopsy (November; 1974) showed the same changes in both the light microscope and the e.m. as the second one.
Fig. I. Portion of a liver celt nucleus with small group of virus-cores. x 76000. Inset: The cores show presence of subunits, x 166000 (Uranyl-acetate and lead-citrate)
Immunsiq~pressive Therapie und Virus-Cores bei HBAg-positiver chronischer Hepatitis. Zusammenfassung. Es wurden drei Leberbiopsien bei einem Fall yon chronisch-aggressiver Hepatitis mit dauernder HB-Antigen~imie vorgenommen. Elektronenmikroskopisch konnten keine Virus-Cores in den Leberzellkernen vor immunsuppressiver Therapie gefunden werden. Intranuclefire, ringf6rmige Virus-Cores im Durchmesser 2 0 - 25 nm sind in fast alien untersuchten Leberzellen im Laufe der immunsuppressiven Behandlung erschienen. Sehliisselwi4rter: HBAg-positive chronische Hepatitis, VirusCores, Imm unsuppressiva.
1082
Kurze wissenschaftliche Mitteilungen
It is noteworthy that non-coated virus-cores could not be detected in the first liver biopsy specimen of our patient, even though HB-antigenemia and chronic active hepatitis were already present and that they only appeared during immunosuppressive therapy.
References
1. Huang, S.N. : Hepatitis-associated antigen hepatitis. An electron microscopic study of virusqike particles in liver cells. Amer. J. Path. 64, 483 (1971) 2. Huang, S.N., Millman, I., O'Connel, A., Aronoff, A., Gault, H., Blumberg, B.S. : Virus-like particles in Australia antigen-associated hepatitis. An immunoelectron microscopic study of human liver. Amer. J. Path. 67, 453 (1972) 3. Tapp, E., Jones, D.M., Anfield, C., Whittaker, J.S., Woolf, I.L., Dymock, I.W.: Intranuclear particles in hepatocytes of HBAg-positive blood-donors. Lancet I, 934 (1974) 4. Scotto, J.M. etal. cir. Huang etal. 5. Krawczynski, K., Nazarevicz, T., Brzosko, W.J., Nowoslawski, A. : Cellular localization of hepatitis-associated antigen in livers of patients with different forms of hepatitis. J. Infect. Dis. 126, 372 (1972)
6. Caramia, F., De Bac, C., Ricci, G. : Virus-like particles within hepatocytes of Australia antigen carriers. Amer. J. Dis. Child. 123, 309 (1972) 7. Ricci, G., DeBac, C., Caramia, F. : Liver, disease in Australiaantigen carriers. Lancet I, 494 (1972) 8. Scotto, J.M., Homberg, J.C1., Caroli, J.: Electron microscopy studies of severe virus hepatitis. Amer. J. Dis. Child. 123, 311 (1972) 9. Nowoslawski, A., Brzosko, W.J., Madalinski, K., Krawczynski, K. : Cellular tocalisation of Australia antigen in the liver of patients with lymphoproliferative disorders. Lancet I, 494 (1970) 10. Ricci, G., DeBac, C., Turbessi, G , Caramia, F.: Intranuclear virusqike particles and cytoplasmic HbAg in chronic hepatitis. New Engl. J. Med. 289, 1144 (1973)
Dr. med. habil. G. Kendrey Abt. f. Pathologie Zentral-Infektionsspital d. Stadt Budapest/Ungarn Lfiszl6 k6rh~z
Immunosuppressive Therapy and Virus-Cores in HBAg-Positive Chronic Hepatitis G. Kendrey, A. Szalka, B. Lfiszl6, L. Binder, and I. Hollds Central Municipal Hospital for Infectious Diseases of Budapest (L~tszl6-K6rh~tz) and National Institute of Hygiene, Budapest, Hungary Received April 23, 1975
Summary. Three liver biopsies were carried out in a case of chronic active hepatitis with persistent HB-antigenemia. Virus-cores could not be detected in the liver celt nuclei by electron microscopy before immunosuppressive therapy. Intranuclear, ring-shaped viruscores of 20 25 nm diameter appeared in almost every hepatocyte examined during immunosuppression. Key words: HBAg-positive chronic active hepatitis, virus-cores, immunosuppression.
The case presented here is basically similar to those of Huang [1] and Huang et al. [2], with the sole difference that immunosuppressive therapy was introduced due to the progressive and chronic nature of the liver disease and not because the patient bore a renal transplant. The particles found by the authors were morphologically similar to those observed in their renal transplant patients. Huang et al. [1, 2] suggested that the cores might be the virus responsible for viral hepatitis. Similar, mainly intranuclear particles, not associated with immunosuppressive therapy have been found in a case of chronic liver disease with HB-antigenemia [4] ; in the livers of persons - some of them HBsAg positive-who died of chronic aggressive hepatitis and post-necrotic cirrhosis [5] ; in the hepatocytes of HBAg-carriers either with normal liver [6], mild hepatitis [7] or with liver damage [3]; in one case of severe hepatitis [8]; and in HBsAg-seropositive persons deceased from various lymphoproliferative disorders, who had received cortico-steroids and antimitotic drugs [9]. Recently, in a case of chronic aggressive hepatitis with HB-antigenemia, viruslike particles of the same morphology have been found in the nuclei of liver cells in ultra-thin sections confirmed by immunofluorescent staining in the cytoplasm [10].
Huang [1] and Huang et al. [2] described predominantly intranuclear 2 1 ~ 5 nm spherical virus-like particles (i.e. virus-cores) in hepatocytes in liver biopsies from renal transplant patients who had developed HBAg-associated acute hepatitis and who showed rapid progression to chronic active hepatitis and posthepatitic cirrhosis while under immunosuppressive therapy. During September t 972, a 38-year-old woman developed acute HBsAg-positive viral hepatitis 3 months after receiving blood-transfusion during premature delivery of a child. A prolonged course of liver disease with relapses suggested chronic active hepatitis that did not respond to cortico-steroid therapy. Liver biopsy (February, 1973) revealed a typical chronic active hepatitis. Using a method similar to that of Tappet al. [3] no virus-like particles (virus-cores) were detected in the liver cells by electron microscopy. The HBantigenemia persisted for 6 months of immunosuppressive therapy (Imuran 50 mg/kg/day). A second liver biopsy (October, 1973) showed less striking inflammatory activity but liver damage was still marked. Ultra-thin sections showed numerous intranuclear and intranucleolar uniform, ring-shaped, single or clustered, non-coated virus-cores (Fig. 1) of 20-25 nm diameter and surface subunits of up to approximately 2-3 nm in diameter (Fig. 1, inset) in almost every hepatocyte examined. In spite of the fact that the patient's condition had improved under continuous immunosuppressive therapy, the HB-antigenemia remained constant. A third liver biopsy (November; 1974) showed the same changes in both the light microscope and the e.m. as the second one.
Fig. I. Portion of a liver celt nucleus with small group of virus-cores. x 76000. Inset: The cores show presence of subunits, x 166000 (Uranyl-acetate and lead-citrate)
Immunsiq~pressive Therapie und Virus-Cores bei HBAg-positiver chronischer Hepatitis. Zusammenfassung. Es wurden drei Leberbiopsien bei einem Fall yon chronisch-aggressiver Hepatitis mit dauernder HB-Antigen~imie vorgenommen. Elektronenmikroskopisch konnten keine Virus-Cores in den Leberzellkernen vor immunsuppressiver Therapie gefunden werden. Intranuclefire, ringf6rmige Virus-Cores im Durchmesser 2 0 - 25 nm sind in fast alien untersuchten Leberzellen im Laufe der immunsuppressiven Behandlung erschienen. Sehliisselwi4rter: HBAg-positive chronische Hepatitis, VirusCores, Imm unsuppressiva.
1082
Kurze wissenschaftliche Mitteilungen
It is noteworthy that non-coated virus-cores could not be detected in the first liver biopsy specimen of our patient, even though HB-antigenemia and chronic active hepatitis were already present and that they only appeared during immunosuppressive therapy.
References
1. Huang, S.N. : Hepatitis-associated antigen hepatitis. An electron microscopic study of virusqike particles in liver cells. Amer. J. Path. 64, 483 (1971) 2. Huang, S.N., Millman, I., O'Connel, A., Aronoff, A., Gault, H., Blumberg, B.S. : Virus-like particles in Australia antigen-associated hepatitis. An immunoelectron microscopic study of human liver. Amer. J. Path. 67, 453 (1972) 3. Tapp, E., Jones, D.M., Anfield, C., Whittaker, J.S., Woolf, I.L., Dymock, I.W.: Intranuclear particles in hepatocytes of HBAg-positive blood-donors. Lancet I, 934 (1974) 4. Scotto, J.M. etal. cir. Huang etal. 5. Krawczynski, K., Nazarevicz, T., Brzosko, W.J., Nowoslawski, A. : Cellular localization of hepatitis-associated antigen in livers of patients with different forms of hepatitis. J. Infect. Dis. 126, 372 (1972)
6. Caramia, F., De Bac, C., Ricci, G. : Virus-like particles within hepatocytes of Australia antigen carriers. Amer. J. Dis. Child. 123, 309 (1972) 7. Ricci, G., DeBac, C., Caramia, F. : Liver, disease in Australiaantigen carriers. Lancet I, 494 (1972) 8. Scotto, J.M., Homberg, J.C1., Caroli, J.: Electron microscopy studies of severe virus hepatitis. Amer. J. Dis. Child. 123, 311 (1972) 9. Nowoslawski, A., Brzosko, W.J., Madalinski, K., Krawczynski, K. : Cellular tocalisation of Australia antigen in the liver of patients with lymphoproliferative disorders. Lancet I, 494 (1970) 10. Ricci, G., DeBac, C., Turbessi, G , Caramia, F.: Intranuclear virusqike particles and cytoplasmic HbAg in chronic hepatitis. New Engl. J. Med. 289, 1144 (1973)
Dr. med. habil. G. Kendrey Abt. f. Pathologie Zentral-Infektionsspital d. Stadt Budapest/Ungarn Lfiszl6 k6rh~z
