Overview: An additional mechanism for liver cell injury in some cases during HBV infection is coinfection with a second cytopathic virus, the hepatitis delta virus (HDV). Delta antigen was discovered by immunofluorescent staining as a nuclear antigen distinct from HBsAg, HBcAg, and HB_e Ag in hepatocytes of some HBsAg carriers in Italy, which is the area with the highest prevalence of delta antigen. Most patients with delta antigen in liver have antibody to delta antigen (anti-delta) in their sera. There is a high prevalence of anti-delta in Italians residing in southern Italy and in other Mediterranean populations, and it is particularly high in residents of North Africa. Epidemics have been reported in parts of South America. In the United States, the prevalence is low in the general population but high in some groups such as certain intravenous drug users and multiply transfused HBsAg carriers. Although delta antigen has not been found in HBsAg-negative patients, anti-delta is found in low prevalence in multiply transfused HBsAg-negative patients, but only in those with anti-HBs.

The virus: Delta antigen is contained in a 68,000-Da protein encoded by the HDV genome, which is a small single-stranded circular RNA with features of viroids. Virions of HDV consist of a core of delta antigen and RNA enclosed in an HBsAg-containing envelope. Research trials in which an inoculation of HDV-containing sera was given to chimpanzees who are HBsAg carriers but who do not have delta antigen in the liver, resulted in the appearance of delta antigen in the hepatocyte nuclei of these animals, along with the disappearance of HBc Ag detected by immunofluorescent staining in the liver, and a rise in serum alanine aminotransferase. Thus, HDV appears to be a defective virus, and its replication requires coinfection with HBV.

Clinical manifestations: There is a higher incidence of HDV infection in HBsAg-positive patients with acute and chronic hepatitis compared with asymptomatic carriers. Simultaneous infection with HBV and HDV may lead to severe or fulminant hepatitis more often than do infections with HBV alone. In countries with a low prevalence of HDV infection such as the United States and Ireland, delta antigen appears to be present in only a small fraction of fulminant hepatitis B cases, and thus delta agent probably plays no role in most cases. HDV may play a more prominent role in chronic liver disease, especially in geographic areas where it is common, such as in Italy where 32% of HBsAg carriers with chronic active hepatitis and 52% with cirrhosis were found to be delta antigen-positive. This is compared with HBsAg carriers with no liver disease, none of whom had detectable delta antigen. Exacerbations of hepatitis may occur in HBsAg carriers when they subsequently acquire HDV infection, but how often this mechanism accounts for exacerbations and the precise impact of HDV on the severity of acute and chronic hepatitis B in the United States remain to be determined.

Diagnosis: A diagnosis of acute viral hepatitis can usually be made from clinical findings, and the responsible viral agent can often be suspected from the epidemiologic setting and features such as the incubation period; however, only virus-specific tests can conclusively identify the infecting virus. Highly sensitive and specific tests are commercially available for HBsAg, anti-HBs, anti-HBc , anti-HB_c IgM, HB_e Ag, anti-HB_e, and anti-HDAg, and are of great diagnostic use. Tests specific for Dane particles or DNA and DNA polymerase-containing virions, and for HDAg and HDV RNA in liver and serum are available only in research laboratories.

Rizzetto M, Purcell RH, Gerin JL. Epidemiology of HBV-associated data agent: Geographical distribution of anti-delta and prevalence of polytransfused HBsAg carriers. Lancet. 1980;1:1215.

Smedile A, Farci P, Verme G. Influence of delta infection on severity of hepatitis B. Lancet. 1982;2:945.