Pathogenesis, epidemiology, natural history, and clinical manifestations of hepatitis D virus infection
- Francesco Negro, MD
Francesco Negro, MD
- Professor of Gastroenterology and hepatology
- University Hospitals, Geneva, Switzerland
- Anna SF Lok, MD
Anna SF Lok, MD
- Professor of Medicine
- University of Michigan Medical School
Hepatitis D is caused by a defective virus: the hepatitis D virus (HDV). HDV is often referred to as hepatitis delta virus or delta agent. However, the term HDV is preferred.
HDV infection is closely associated with hepatitis B virus (HBV) infection. Although HDV can replicate autonomously , the simultaneous presence of HBV is required for complete virion assembly and secretion (see 'Virion structure' below). As a result, individuals with hepatitis D are always dually infected with HDV and HBV. Due to interference mechanisms that are not well understood, HBV replication is suppressed in most HDV-infected individuals.
This topic review will provide general information concerning the HDV structure and replication strategy, the nature of its strict association with HBV, and the epidemiology, pathogenesis, and clinical features of HDV infection. Issues related to diagnosis, treatment, prevention, and liver transplantation are discussed separately. (See "Diagnosis of hepatitis D virus infection" and "Treatment and prevention of hepatitis D virus infection".)
The HD virion comprises an RNA genome, a single HDV encoded antigen, and a lipoprotein envelope provided by HBV (figure 1).
HDV genome — The HDV genome is a small RNA molecule (1676 to 1683 nucleotides in size) bearing some structural analogies with plant viroids and virusoids . HDV RNA is a single-stranded circle, with a high degree of self-complementarity and G+C content causing the circle to collapse as a rod-like structure . Significant sequence heterogeneity (as high as 39 percent) exists among the different HDV isolates that have been sequenced, and a classification into eight HDV genotypes has been proposed .To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Bichko V, Netter HJ, Wu TT, Taylor J. Pathogenesis associated with replication of hepatitis delta virus. Infect Agents Dis 1994; 3:94.
- Le Gal F, Gault E, Ripault MP, et al. Eighth major clade for hepatitis delta virus. Emerg Infect Dis 2006; 12:1447.
- Polson AG, Bass BL, Casey JL. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature 1996; 380:454.
- Bonino F, Heermann KH, Rizzetto M, Gerlich WH. Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J Virol 1986; 58:945.
- Negro F, Korba BE, Forzani B, et al. Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks. J Virol 1989; 63:1612.
- Ni Y, Lempp FA, Mehrle S, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 2014; 146:1070.
- Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 2012; 3.
- Lo K, Hwang SB, Duncan R, et al. Characterization of mRNA for hepatitis delta antigen: exclusion of the full-length antigenomic RNA as an mRNA. Virology 1998; 250:94.
- Yamaguchi Y, Filipovska J, Yano K, et al. Stimulation of RNA polymerase II elongation by hepatitis delta antigen. Science 2001; 293:124.
- Modahl LE, Macnaughton TB, Zhu N, et al. RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol Cell Biol 2000; 20:6030.
- Chang J, Nie X, Chang HE, et al. Transcription of hepatitis delta virus RNA by RNA polymerase II. J Virol 2008; 82:1118.
- Smedile A, Farci P, Verme G, et al. Influence of delta infection on severity of hepatitis B. Lancet 1982; 2:945.
- Caredda F, d'Arminio Monforte A, Rossi E, et al. Prospective study of epidemic delta infection in drug addicts. Prog Clin Biol Res 1983; 143:245.
- Smedile A, Dentico P, Zanetti A, et al. Infection with the delta agent in chronic HBsAg carriers. Gastroenterology 1981; 81:992.
- Casey JL, Brown TL, Colan EJ, et al. A genotype of hepatitis D virus that occurs in northern South America. Proc Natl Acad Sci U S A 1993; 90:9016.
- Tang JR, Hantz O, Vitvitski L, et al. Discovery of a novel point mutation changing the HDAg expression of a hepatitis delta virus isolate from Central African Republic. J Gen Virol 1993; 74 ( Pt 9):1827.
- Smedile A, Rosina F, Saracco G, et al. Hepatitis B virus replication modulates pathogenesis of hepatitis D virus in chronic hepatitis D. Hepatology 1991; 13:413.
- Romeo R, Del Ninno E, Rumi M, et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 2009; 136:1629.
- Wu JC, Choo KB, Chen CM, et al. Genotyping of hepatitis D virus by restriction-fragment length polymorphism and relation to outcome of hepatitis D. Lancet 1995; 346:939.
- Niro GA, Smedile A, Andriulli A, et al. The predominance of hepatitis delta virus genotype I among chronically infected Italian patients. Hepatology 1997; 25:728.
- Wu JC, Huang IA, Huang YH, et al. Mixed genotypes infection with hepatitis D virus. J Med Virol 1999; 57:64.
- Rizzetto M, Verme G, Recchia S, et al. Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98:437.
- Govindarajan S, De Cock KM, Redeker AG. Natural course of delta superinfection in chronic hepatitis B virus-infected patients: histopathologic study with multiple liver biopsies. Hepatology 1986; 6:640.
- Bonino F, Negro F, Baldi M, et al. The natural history of chronic delta hepatitis. Prog Clin Biol Res 1987; 234:145.
- Hadziyannis SJ, Papaioannou C, Alexopoulou A. The role of the hepatitis delta virus in acute hepatitis and in chronic liver disease in Greece. Prog Clin Biol Res 1991; 364:51.
- Rosina F, Conoscitore P, Cuppone R, et al. Changing pattern of chronic hepatitis D in Southern Europe. Gastroenterology 1999; 117:161.
- Fattovich G, Giustina G, Christensen E, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut 2000; 46:420.
- Wu JC, Chen TZ, Huang YS, et al. Natural history of hepatitis D viral superinfection: significance of viremia detected by polymerase chain reaction. Gastroenterology 1995; 108:796.
- Hadler SC, Alcala de Monzon M, Rivero D, et al. Epidemiology and long-term consequences of hepatitis delta virus infection in the Yucpa Indians of Venezuela. Am J Epidemiol 1992; 136:1507.
- Popper H, Thung SN, Gerber MA, et al. Histologic studies of severe delta agent infection in Venezuelan Indians. Hepatology 1983; 3:906.
- 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 1987; 258:479.
- Dény P. Hepatitis delta virus genetic variability: from genotypes I, II, III to eight major clades? Curr Top Microbiol Immunol 2006; 307:151.
- Rizzetto M, Ponzetto A, Forzani I. Epidemiology of hepatitis delta virus: overview. Prog Clin Biol Res 1991; 364:1.
- Gaeta GB, Stroffolini T, Chiaramonte M, et al. Chronic hepatitis D: a vanishing Disease? An Italian multicenter study. Hepatology 2000; 32:824.
- Liaw YF, Chiu KW, Chu CM, et al. Heterosexual transmission of hepatitis delta virus in the general population of an area endemic for hepatitis B virus infection: a prospective study. J Infect Dis 1990; 162:1170.
- Lok AS, Wong A, Sporton S, et al. Hepatitis D virus superinfection remains a rare occurrence in non-drug abusers in Hong Kong. J Hepatol 1992; 14:332.
- Weisfuse IB, Hadler SC, Fields HA, et al. Delta hepatitis in homosexual men in the United States. Hepatology 1989; 9:872.
- Gaeta GB, Stroffolini T, Smedile A, et al. Hepatitis delta in Europe: vanishing or refreshing? Hepatology 2007; 46:1312.
- Wedemeyer H, Heidrich B, Manns MP. Hepatitis D virus infection--not a vanishing disease in Europe! Hepatology 2007; 45:1331.
- VIRION STRUCTURE
- HDV genome
- Hepatitis D antigen
- Lipoprotein envelope of HDV
- HDV LIFE CYCLE
- HDV INFECTION
- Pathogenesis of HDV-induced hepatitis
- NATURAL HISTORY OF CHRONIC HEPATITIS D
- Genotype 1
- Genotype 2
- Genotype 3
- Other genotypes
- EPIDEMIOLOGY OF HDV INFECTION
- The Mediterranean basin
- The Far East
- Western countries