Virchows Archiv B

, 45:301 | Cite as

Ultrastructural alterations in serial liver biopsy specimens from chimpanzees experimentally infected with a human non-A, non-B hepatitis agent

  • Zsuzsa Schaff
  • Edward Tabor
  • Daniel R. Jackson
  • Robert J. Gerety


Four chimpanzees experimentally infected with an agent of human non-A, non-B hepatitis were studied to determine the sequence of ultrastructural alterations in hepatocytes during infection. Three of the four types of cytoplasmic alterations previously described in association with non-A, non-B hepatitis were observed in the hepatocytes. Sponge-like cytoplasmic inclusions (designated C-I) were detected at or near the time of peak serum aminotransferase elevations in two of the four chimpanzees. Undulating membranes (designated C-II) were observed in all four chimpanzees, at the time of the first elevation of serum aminotransferase levels. Cytoplasmic tubules (designated C-III) were first observed four, eight, and twelve weeks, respectively, after inoculation in three of the chimpanzees. Four weeks after the peak of serum aminotransferase elevations, cytoplasmic alterations could no longer be detected in hepatocytes of the four chimpanzees.

Intranuclear inclusions consisting of 20–27 nm granules and vermicular particles were observed in hepatocytes from preinoculation liver biopsy specimens, as well as biopsies obtained during non-A, non-B hepatitis. The number of these particles was greatest near the time of peak elevation of serum aminotransferase levels, however. Tubulo-crystalline inclusions were noted as well in the endothelial cells from both preinoculated and infected chimpanzees.

Cytoplasmic alterations in hepatocytes of chimpanzees experimentally infected with an agent of non-A, non-B hepatitis appear characteristic of infection with this agent. In contrast, intranuclear particles were not specifically related to the non-A, non-B hepatitis infection.

Key words

Non-A, non-B hepatitis Chimpanzee Liver pathology Ultrastructure Endoplasmic reticulum 


  1. Alter HJ, Purcell RH, Holland PV, Popper H (1978) Transmissible agent in non-A, non-B hepatitis. Lancet 1:459–463PubMedCrossRefGoogle Scholar
  2. Bamber M, Murray A, Lewin J, Thomas HC, Sherlock S (1981) Ultrastructural features in chronic non-A, non-B (NANB) hepatitis: A controlled blind study. J Med Virol 8:267–275PubMedCrossRefGoogle Scholar
  3. Bedoya V, Rabson AS, Grimley PM (1968) Growth in vitro of herpes simplex virus in human lymphoma cell lines. J Natl Cancer Inst 41:635–652PubMedGoogle Scholar
  4. Bradley DW, Cook EH, Maynard JE, McCaustland KA, Ebert JW, Dolana GH, Petzel RA, Kantor RJ, Heilbrun A, Fields HA, Murphy BL (1979) Experimental infection of chimpanzees with antihemophilic (factor VIII) materials: recovery of virus-like particles associated with non-A, non-B hepatitis. J Med Virol 3:253–269PubMedCrossRefGoogle Scholar
  5. Bradley DW, Maynard JE, Cook EH, Ebert JW, Gravelle CR, Tsiquaye KN, Kessler H, Zuckerman AJ, Miller MF, Ling C-M, Overby LR (1980) Non-A, non-B hepatitis in experimentally infected chimpanzees: cross-challenge and electron microscopic studies. J Med Virol 6:185–201PubMedCrossRefGoogle Scholar
  6. Bradley DW, Maynard JE, Popper H, Ebert JW, Cook EH, Fields HA, Kemler (1981) Persistent non-A, non-B hepatitis in experimentally infected chimpanzees. J Infect Dis 143:210–218PubMedGoogle Scholar
  7. Bradley DW, Maynard JE, McCaustland KA, Murphy BL, Cook EH, Ebert JW (1983) Non-A, non-B hepatitis in chimpanzees: Interference with acute hepatitis A virus and chronic hepatitis B virus infections. J Med Virol 11:207–213PubMedCrossRefGoogle Scholar
  8. Brotman B, Prince AM, Huima T, Richardson L, van den Ende MC, Pfeifer U (1983) Interference between non-A, non-B and hepatitis B virus infection in chimpanzees. J Med Virol 11:191–205PubMedCrossRefGoogle Scholar
  9. Burk KH, Cabrai GA, Dreesman GR, Peters RL, Alter HJ (1981) Ultrastructural changes and virus-like particles localized in liver hepatocytes of chimpanzees infected with non-A, non-B hepatitis. J Med Virol 7:1–19PubMedCrossRefGoogle Scholar
  10. DeVos R, DeWolf-Peeters C, Desmet V, DeGroote G, Desmyter J (1981) Crystalline arrays and non-A, non-B hepatitis. Lancet 1:1364CrossRefGoogle Scholar
  11. DeVos R, DeWolf-Peeters C, Van Stapel MJ, Callea F, DeGroote G, Desmyter J, Mortelmans J, Fevery J, DeGroote J, Desmet VJ (1982) New ultrastructural marker in hepatocytes in non-A, non-B viral hepatitis. Liver 2:35–44Google Scholar
  12. DeWolf-Peeters C, DeVos R, Desmet V, Ray MB, Desmyter J, DeGroote G, Fevery J, Broeckaert L, DeGroote J (1981) Human non-A, non-B hepatitis: ultrastructural alterations in hepatocytes. Liver 1:50–55Google Scholar
  13. Gibo Y, Nagata A, Kiyosawa K, Sodeyama T, Wada S, Furuta S (1982) Intranuclear particles in the hepatocytes of patients with non-A, non-B hepatitis and acute intermittent porphyria. Gastroenterology 82:818–819PubMedGoogle Scholar
  14. Gmelin K, Kommerell B, Waldherr R, Ehrlich B (1980) Intracellular viruslike particles in a case of sporadic non-A, non-B hepatitis. J Med Virol 5:317–322PubMedCrossRefGoogle Scholar
  15. Grimley PM, Demsey A (1980) Functions and alterations of cell membrane during active virus infection. In: Trump BF, Arstila AV (eds) Pathobiology of cell membranes, vol II. Academic Press, New York, pp 74–173Google Scholar
  16. Grimley PM, Kang Y-H, Silverman RH, Davis G, Hoofnagle JH (1983) Blood lymphocyte inclusions associated with α-interferon. Lab Invest 48:30AGoogle Scholar
  17. Grimley PM, Schaff ZS (1976) Significance of tubuloreticular inclusions in the pathobiology of human diseases. In: Ioachim HL (ed) Pathobiol Ann Appleton-Century-Crofts, New York, pp 221–257Google Scholar
  18. Hollinger FB, Gitnick GL, Aach RD, Szmuness W, Mosley JW, Stevens CE, Peters RL, Weiner JM, Lerch JB, Lander JJ (1978) Non-A, non-B hepatitis transmission in chimpanzees: a project of the transfusion-transmitted viruses study group. Intervirology 10:60–68PubMedCrossRefGoogle Scholar
  19. Jackson DR, Tabor E, Gerety RJ (1979) Acute non-A, non-B hepatitis: specific ultrastructural alterations in endoplasmic reticulum of infected hepatocytes. Lancet 1:1249–1250PubMedCrossRefGoogle Scholar
  20. Karmen A (1955) A note on the spectrophotometric assay of glutamic-oxalacetic transaminase in human blood serum. J Clin Invest 34:131–133PubMedCrossRefGoogle Scholar
  21. McCaul TF, Tsiquaye KN, Tovey G, Duermeyer W, Zuckerman AJ (1982) Examination of crystalline arrays in non-A, non-B hepatitis. J Med Virol 9:185–188PubMedCrossRefGoogle Scholar
  22. McCaul TF, Tsiquaye KN, Tovey G, Hames C, Zuckerman AJ (1982) Application of electron microscopy to the study of structural changes in liver in non-A, non-B hepatitis. J Virol Meth 4:87–106CrossRefGoogle Scholar
  23. Nii S, Rosenkranz HS, Morgan C, Rose HM (1968) Electron microscopy of herpes simplex virus. III. Effect of hydroxyurea. J Virol 2:1163–1171PubMedGoogle Scholar
  24. Pfeifer U, Thomssen R, Legier K, Böttcher U, Gerlich W, Weinmann, Klinge O (1980) Experimental non-A, non-B hepatitis: four types of cytoplasmic alteration in hepatocytes of infected chimpanzees. Virchows Arch B [Cell Pathol] 33:233–243Google Scholar
  25. Prince AM, Brotman B, van den Ende MC, Richardson L, Kellner A (1978) Non-A/non-B hepatitis: Identification of a virus-specific antigen and antibody. A preliminary report. In: Vyas GN, Cohen SN, Schmid R (eds) Viral hepatitis. Franklin Inst. Press, Philadelphia, pp 633–640Google Scholar
  26. Rich SA (1981) Human lupus inclusions and interferon. Science 213:772–775PubMedCrossRefGoogle Scholar
  27. Sato S, Murphy GF, Harrist TJ (1982) The genesis of paired cisternae during the mitotic cycle. Am J Pathol 107:150–160PubMedGoogle Scholar
  28. Schaff ZS, Grimley PM, Michelitch HJ, Banfield W (1973) Spontaneous myxosarcoma in a cottontail rabbit (Sylvilagus floridanus): Observations of tumor cells. J Natl Cancer Inst 51:293–297PubMedGoogle Scholar
  29. Schaff ZS, Lapis K, Hollos I, Keresztury S, Kollath Z, Herics M (1981) Morphologische Aspekte der viralen, akuten und chronischen Hepatitis. HEK Forum 9:7Google Scholar
  30. Schaff ZS, Lapis K, Keresztury S, Kollath Z, Herics M, Hollos I (1982) Occurrence of tubuloreticular inclusions in acute viral hepatitis. Ultrastr Pathol 3:169–173CrossRefGoogle Scholar
  31. Schaff ZS, Tabor E, Jackson DR, Gerety RJ (1983) AIDS-associated ultrastructural changes. Lancet 1:1336PubMedCrossRefGoogle Scholar
  32. Shimizu YK, Feinstone SM, Purcell RH, Alter HJ, London WT (1979) Non-A, non-B hepatitis: ultrastructural evidence for two agents in experimentally infected chimpanzees. Science 205:197–200PubMedCrossRefGoogle Scholar
  33. Sidhu GS, Stahl RE, El-Sadr W, Zolla-Pazner S (1983) Ultrastructural markers of AIDS. Lancet 1:990–991PubMedCrossRefGoogle Scholar
  34. Tralka ST, Yee C, Trich TJ, Costa J, Dienes HP (1982) Unusual intranuclear inclusions in malignant fibrous histiocytoma: presence in primary tumor, metastases, and xenografts. Ultrastr Pathol 3:161–167CrossRefGoogle Scholar
  35. Swanson JL, Craighead JE, Reynold ES (1966) Electron microscopic observations on herpesvirus hominis (Herpes simplex virus) encephalitis in man. Lab Invest 15:1966–1981PubMedGoogle Scholar
  36. Tabor E (1981) Development and application of the chimpanzee animal model for human non-A, non-B hepatitis. In: Gerety RJ (ed) Non-A, non-B hepatitis. Academic Press, New York, pp 189–206Google Scholar
  37. Tabor E, Gerety RJ, Drucker JA, Seeff LB, Hoofnagle JH, Jackson DR, April M, Barker LF, Pineda-Tamondong (1978) Transmission of non-A, non-B hepatitis from man to chimpanzee. Lancet 1:463–66PubMedCrossRefGoogle Scholar
  38. Tabor E, Seeff LB, Gerety RJ (1980) Chronic non-A, non-B hepatitis carrier state: transmissible agent documented in one patient over a six year period. N Engl J Med 303:140–143PubMedGoogle Scholar
  39. Tabor E, Snoy P, Jackson DR, Schaff ZS, Blatt PM, Gerety RJ (1984) Additional evidence for more than one agent of human non-A, non-B hepatitis: transmission and passage studies in chimpanzees. Transfusion [in press]Google Scholar
  40. Thiery JZP (1967) Mise en evidence des polysaccharides sur coupes fines en microscopie electronique. J Microsc 6:987–992Google Scholar
  41. Tsiquaye KN, Amini S, Kessler H, Bird RG, Tovey G, Zuckerman AJ (1981) Ultrastructural changes in the liver in experimental non-A, non-B hepatitis. Br J Exp Pathol 62:41–51PubMedGoogle Scholar
  42. Tsiquaye KN, Bird RG, Tovey G, Wyke J, Williams R, Zuckerman AJ (1980) Further evidence of cellular changes associated with non-A, non-B hepatitis. J Med Virol 5:63–71PubMedCrossRefGoogle Scholar
  43. Tsiquaye KN, Portman B, Tovey G, Kessler H, Shanlian HU, Xiao-Zhen LU, Zuckerman AJ, Craske J, Williams R (1983) Non-A, non-B hepatitis in persistent carriers of hepatitis B virus. J Med Virol 11:179–189PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • Zsuzsa Schaff
    • 1
  • Edward Tabor
    • 1
  • Daniel R. Jackson
    • 1
  • Robert J. Gerety
    • 1
  1. 1.Hepatitis Branch, Division of Blood and Blood Products, Office of Biologies, National Center for Drugs and BiologicsFood and Drug AdministrationBethesdaUSA

Personalised recommendations