Delta Hepatitis and the Hepatitis Delta Virus

  • Jay H. Hoofnagle


Since its discovery in 1977 by Rizzetto and co-workers from Turin, Italy, the hepatitis delta virus (HDV) has become a focus of worldwide interest—interest almost equal to its worldwide importance.1, 2 The delta antigen, which first appeared to be a poorly explained finding of immunofluorescence staining in liver biopsies from Italian chronic hepatitis S surface antigen (HBsAg) carriers, has now been shown to be the nucleocapsid antigen of a startlingly unique and important viral agent. HDV is a “defective” RNA virus that can replicate only in the presence of HBsAg, the helper function provided by hepatitis S virus (HBV). For this reason, delta hepatitis occurs only in patients who have HBsAg in serum. Acute delta hepatitis occurs either as co-infection, simultaneous with acute hepatitis B, or as superinfection, in which acute delta hepatitis is superimposed on a chronic hepatitis S or an HBsAg carrier state. Delta superinfection commonly leads to chronic delta hepatitis, which ultimately leads to cirrhosis in more than 50% of cases.3 Delta hepatitis also has a peculiar epidemiology, commonly occurring in prolonged severe outbreaks in isolated communities.4 Delta hepatitis is most likely an old disease; indeed, the fulminant hepatitis syndromes known as Labrea fever and the hepatitis of Sierra Nevada de Santa Marta, described in South America for the past 50 years, probably present severe forms of acute delta hepatitis.5 This chapter summarizes recent advances made in the understanding of delta hepatitis and HDV.


Hepatitis Delta Virus Helper Virus HBsAg Carrier Hepatitis Delta Virus Infection Delta Antigen 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rizzetto M, Canese MG, Arico S, et al: Immunofluorescence detection of new antigen-antibody system (δ/anti-δ) associated to hepatitis S virus in liver and serum of HBsAg carriers. Gut 18:997–1003, 1977.PubMedCrossRefGoogle Scholar
  2. 2.
    Rizzetto M: The delta agent. Hepatology 3:729–737, 1984.CrossRefGoogle Scholar
  3. 3.
    Rizzetto M, Verme G, Recchia S, et al: Chronic HBsAg hepatitis with intrahepatic expression of delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 98:437–441, 1983.PubMedGoogle Scholar
  4. 4.
    Hadler SC, de Monzon M, Ponzetto A, et al: An epidemic of severe hepatitis due to delta virus infection in Yucpa Indians of Venezuela. Ann Intern Med 100:339–349, 1984.PubMedGoogle Scholar
  5. 5.
    Buitrago B, Popper H, Hadler SC, et al: Specific histologic features of Santa Marta hepatitis: A severe form of hepatitis delta-virus infection in northern South America. Hepatology 6:1285–1291, 1986.PubMedCrossRefGoogle Scholar
  6. 6.
    Rizzetto M, Hoyer B, Canese MG, et al: δ Agent: association of the δ antigen with hepatitis S surface antigen and RNA in serum of δ-infected chimpanzees. Proc Natl Acad Sci USA 77:6124–6128, 1981.CrossRefGoogle Scholar
  7. 7.
    Wang K-S, Choo Q-L, Weiner AJ, et al: Structure, sequence and expression of the hepatitis delta (δ) viral genome. Nature (Lond) 323:508–514, 1986.CrossRefGoogle Scholar
  8. 8.
    Chen PJ, Kalpana G, Goldberg J, et al.: Structure and replication of the genome of the hepatitis delta virus. Proc Natl Acad Sci USA 83:8774–8778, 1986.PubMedCrossRefGoogle Scholar
  9. 9.
    Makino S, Chang MF, Shieh CK, et al: Molecular cloning and sequencing of a human hepatitis delta virus RNA. Nature (Lond) 329:343–346, 1987.CrossRefGoogle Scholar
  10. 10.
    Branch AD, Robertson HD: A replication cycle for viroids and other small infectious RNAs. Science 223:450–458, 1984.PubMedCrossRefGoogle Scholar
  11. 11.
    Bergmann KF, Gerin JL: Antigens of hepatitis delta virus in the liver and serum of humans and animals. J Infect Dis 514:702–705, 1986.CrossRefGoogle Scholar
  12. 12.
    Pohl C, Baroudy BM, Bergmann KF, et al: A human monoclonal antibody that recognizes viral polypeptides and in vitro translation products of the genome of the hepatitis D virus. J Infect Dis 156:622–629,1987.PubMedCrossRefGoogle Scholar
  13. 13.
    Bonino F, Heermann KH, Rizzetto M, Gerlich WH: Hepatitis delta virus: Protein composition of delta antigen and its hepatitis S virus-derived envelope. J Virol 58:945–950, 1986.PubMedGoogle Scholar
  14. 14.
    Murant AF, Mayo MA: Satellites of plant viruses. Annu Rev Phytopathol 20:49–70, 1982.CrossRefGoogle Scholar
  15. 15.
    Diener TO: Autonomous and helper-dependent small pathogenic RNAs of plants: Viroids and satellites, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 3–18.Google Scholar
  16. 16.
    Rizzetto M, Canese MG, Gerin JL, et al: Transmission of the hepatitis S virus-associated delta antigen to chimpanzees. J Infect Dis 141:590–602, 1980.PubMedCrossRefGoogle Scholar
  17. 17.
    Fields HA, Govindarajan S, Margolis HS, et al: Experimental transmission of the delta virus to a hepatitis S chronic carrier chimpanzee with the development of persistent delta carriage. Am J Pathol 122:308–314, 1986.PubMedGoogle Scholar
  18. 18.
    Ponzetto A, Cote PJ, Popper H, et al: Transmission of the hepatitis S virus-associated δ agent to the eastern woodchuck. Proc Natl Acad Sci USA 81:2208–2212, 1984.PubMedCrossRefGoogle Scholar
  19. 19.
    Ponzetto A, Rapicetta M, Forzani B, et al: Hepatitis delta virus infection in Pékin ducks chronically infected by the duck hepatitis S virus in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 47–49.Google Scholar
  20. 20.
    Purcell RH, Satterfield WC, Bergmann KF, et al: Experimental hepatitis delta virus infection in the chimpanzee in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 27–36.Google Scholar
  21. 21.
    Caredda F, Antinori S, Re T, et al: Course and prognosis of acute HDV hepatitis in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 267–276.Google Scholar
  22. 22.
    De Cock KM, Govindarajan S, Chin KP, Redeker AG: Delta hepatitis in the Los Angeles area: A report of 126 cases. Ann Intern Med 105:108–114, 1986.PubMedGoogle Scholar
  23. 23.
    Bonino F, Negro F, Baldi M, et al: The natural history of chronic delta hepatitis in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 145–152.Google Scholar
  24. 24.
    Smedile A, Dentico P, Zanetti A, et al: Infection with the delta (δ) agent in chronic HBsAg carriers. Gastroenterology 81:992–997, 1981.PubMedGoogle Scholar
  25. 25.
    Farci P, Smedile A, Lavarini C, et al: Delta hepatitis in inapparent carriers of hepatitis S surface antigen. Gastroenterology 85:669–673, 1983.PubMedGoogle Scholar
  26. 26.
    Colombo M, Cambieri R, Rumi MG, et al: Long-term superinfection in HBsAg carriers and its relationship with the course of chronic hepatitis. Gastroenterology 85:235–239, 1983.PubMedGoogle Scholar
  27. 27.
    Fattovich G, Boscaro S, Noventa F, et al: Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis, type B. J Infect Dis 155:931–935, 1987.PubMedCrossRefGoogle Scholar
  28. 28.
    Verme G, Amoroso P, Lettier G, et al: Histological study of hepatitis delta virus liver disease. Hepatology 6:1303–1307, 1986.PubMedCrossRefGoogle Scholar
  29. 29.
    Aragona M, Macagno S, Caredda F, et al: IgM anti-HD in acute hepatitis D: Diagnostic and prognostic significance, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 243–248.Google Scholar
  30. 30.
    Farci P, Gerin JL, Aragona M, et al: Diagnostic and prognostic significance of the IgM antibody to the hepatitis delta virus. JAMA 255:1443–1446, 1986.PubMedCrossRefGoogle Scholar
  31. 31.
    Mushahwar IK, Gerin JL, Dienstag JL, et al: Interpretation of hepatitis S virus and hepatitis delta virus serologic profiles. Pathologist 38:648–650, 1984.Google Scholar
  32. 32.
    Buti M, Esteban R, Jardi R, et al: Clinical and serological outcome of acute delta infection. J Hepatol 5:59–64, 1987.PubMedCrossRefGoogle Scholar
  33. 33.
    Sjogren M, Hoofhagle JH: Immunoglobulin M antibody to the hepatitis S core antigen in patients with chronic type S hepatitis. Gastroenterology 89:252–258, 1985.PubMedGoogle Scholar
  34. 34.
    Denniston KJ, Hoyer BH, Smedile A, et al: Cloned fragment of the hepatitis delta virus RNA genome: Sequence and diagnostic application. Science 232:873–875, 1986.PubMedCrossRefGoogle Scholar
  35. 35.
    Smedile A, Rizzetto M, Denniston KJ, et al: Type D hepatitis: The clinical significance of hepatitis D virus RNA in serum as detected by a hybridization-based assay. Hepatology 6:1297–1302, 1986.PubMedCrossRefGoogle Scholar
  36. 36.
    Smedile A, Baroudy BM, Bergmann KF, Rizzetto M, et al: Clinical significance of HDV RNA in HDV disease, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 231–234.Google Scholar
  37. 37.
    Bortolotti F, Calzia R, Cadrobbi P, et al: Liver cirrhosis associated with chronic hepatitis S virus infection in childhood. J Pediatr 108:224–227, 1986.PubMedCrossRefGoogle Scholar
  38. 38.
    Hadziyannis SJ, Hatzakis A, Papaioannou C, et al: Endemic hepatitis delta virus infection in a Greek community, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 181–202.Google Scholar
  39. 39.
    Kojimo T, Callea F, Desmyter J, Desmet VJ: Immune electron microscopy of hepatitis delta-antigen in hepatocytes. Lab Invest 55:217–225, 1986.Google Scholar
  40. 40.
    Crivelli O, Lavarini C, Chiaberge E, et al: Microsomal autoantibodies in chronic infection with the HBsAg-associated delta agent. Clin Exp Immunol 54:232–238, 1983.PubMedGoogle Scholar
  41. 41.
    Caredda F, de Bartolo G, Zampini L, et al: Detection and further characterization of a newly described microsomal autoantibody associated with chronic delta infection. Digestion 33:181–188, 1986.PubMedCrossRefGoogle Scholar
  42. 42.
    Zauli D, Fusconi M, Crespi C, et al: Close association between basal cell layer antibodies and hepatitis S virus-associated chronic delta infection. Hepatology 4:1103–1106, 1984.PubMedCrossRefGoogle Scholar
  43. 43.
    Pisi E, Zauli D, Crespi C: Autoantibodies in chronic hepatitis delta virus infection, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 249–256.Google Scholar
  44. 44.
    Magnius LO, Lenkei R, Norder H, et al: Autoantibodies to thymic epithelial cells in hepatitis S virus-associated delta infection. J Infect Dis 152:232–236, 1985.PubMedCrossRefGoogle Scholar
  45. 45.
    Ponzetto A, Forzani B, Parravicini PP, et al: Epidemiology of delta virus (HDV) infection. Eur J Epidemiol 1:257–263, 1985.PubMedCrossRefGoogle Scholar
  46. 46.
    Nordenfeit E, Hansson BG, Al Nakib B, et al: Frequency of delta agent infections in Kuwait. J Infect Dis 143:768–769, 1984.Google Scholar
  47. 47.
    Chen DS, Lai MY, Sung JL: Delta agent infection in patients with chronic liver disease and hepatocellular carcinoma: An infrequent finding in Taiwan. Hepatology 4:502–503, 1984.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang DQ, Cheng HH, Minuk GY, et al: Delta hepatitis virus infection in China. Int J Epidemiol 16:79–83, 1987.PubMedCrossRefGoogle Scholar
  49. 49.
    Buitrago B, Hadler SC, Popper H, et al: Epidemiologic aspects of Santa Marta hepatitis over a 40-year period. Hepatology 6:1292–1296, 1986.PubMedCrossRefGoogle Scholar
  50. 50.
    Bensabath G, Hadler SC, Soares MC, et al: Hepatitis delta virus infection and Labrea hepatitis: Prevalence and role in fulminant hepatitis in the Amazon Basin. JAMA 258:479–483, 1987.PubMedCrossRefGoogle Scholar
  51. 51.
    Lesbordes JL, Ravisse P, Georges AJ, et al: Studies on the role of HDV in an outbreak of fulminant hepatitis in Bangui (Central African Republic), in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 451–459.Google Scholar
  52. 52.
    Lee SD, Wang JY, Wu JC, et al: Hepatitis S and D virus infection among drug abusers in Taiwan. J Med Virol 30:247–252, 1986.CrossRefGoogle Scholar
  53. 53.
    Liaw Y-F, Lin H-S, Chu C-M, et al: Hepatitis delta virus infection in Taiwan, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 479–483.Google Scholar
  54. 54.
    Hansson BG, Moestrup T, Widell A, Nordenfelt E: Infection with delta agent in Sweden: Introduction of a new hepatitis agent. J Infect Dis 146:472–478, 1982.PubMedCrossRefGoogle Scholar
  55. 55.
    Lattau LA, McCarthy JG, Smith MH, et al: Outbreak of severe hepatitis due to delta and hepatitis S viruses in parenteral drug abusers and their contacts. S Engl J Med 317:1256–1262, 1987.CrossRefGoogle Scholar
  56. 56.
    Rocca G, Poli G, Gerardo P, et al: Familial clustering of delta infection, in Verme G, Bonino F, Rizzetto M (eds): Viral Hepatitis and Delta Infection. Liss, New York, 1984, pp. 133–137.Google Scholar
  57. 57.
    Zanetti AR, Dentico P, Del Vecchio BC, et al: Multicenter tirai on the efficiacy of HBIG and vaccine in preventing perinatal hepatitis B. Final report. J Med Virol 18:327–334, 1986.PubMedCrossRefGoogle Scholar
  58. 58.
    Ponzetto A, Hoofnagle JH, Seeff LB: Antibody to the hepatitis S virus-associated delta agent in immune serum globulins. Gastroenterology 87:1213–1216, 1984.PubMedGoogle Scholar
  59. 59.
    Sagnelli E, Manzillo G: Clinical aspects of delta agent infection in southern Italy, in Verme G, Rizzetto M, Bonino F (eds): Viral Hepatitis and Delta Infection. Liss, New York, 1984, pp. 195–202.Google Scholar
  60. 60.
    Hoofnagle JH, Mullen K, Peters M, et al: Treatment of chronic delta hepatitis with recombinant human alpha interferon, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 291–298.Google Scholar
  61. 61.
    Thomas HC, Lever AML, Scully LJ, Pignatelli M: Approaches to the treatment of hepatitis S virus and delta-related liver disease. Semin Liver Disease 6:34–41, 1986.CrossRefGoogle Scholar
  62. 62.
    Rosina F, Saracco G, Lattore V, et al: Alpha 2 recombinant interferon in the treatment of chronic hepatitis delta virus (HDV) hepatitis, in Rizzetto M, Gerin JL, Purcell RH (eds): Hepatitis Delta Virus and Its Infection. Liss, New York, 1987, pp. 299–303.Google Scholar
  63. 63.
    Rizzetto M, Chiaberge E, Negro F, et al: Liver transplantation in hepatitis delta virus disease. Lancet 2:469–471, 1987.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1989

Authors and Affiliations

  • Jay H. Hoofnagle
    • 1
  1. 1.Liver Diseases Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA

Personalised recommendations