Hepatitis D

Virology

Talal Adhami, MD
William D. Carey, MD

Hepatitis D or delta virus (HDV) is a defective single-stranded RNA virus requiring the presence of hepatitis B virus (HBV) for its expression and replication. HDV is a 35- to 37-nm spherical particle enveloped by a lipoprotein coat derived from HBsAg. HDV-RNA consists of 1680 nucleotides, and replication is limited to hepatocytes. It is considered to be the smallest RNA genome among the animal viruses.

Prevalence

HDV has a worldwide distribution. It is endemic in the developing world, with a high prevalence in South America. HDV infection is limited to patients who have HBV infection and, like hepatitis B, is acquired parenterally. Worldwide, about 5% of HBV carriers are anti-HDV-positive. Delta hepatitis remains a common problem among intravenous drug users.

Pathophysiology

Patients may be infected with HDV at the same time that they acquire the hepatitis B virus (acute coinfection) or they can acquire the virus after infection with hepatitis B (superinfection). It is still not clear whether the virus is directly cytotoxic or whether an immune-mediated response is responsible for the pathology. An immune response may be the predominant mediator in chronic disease, whereas direct viral cytotoxicity can predominate in acute infection. Necroinflammatory activity is severe, but histologic features are nonspecific for chronic HDV infection.

Signs and Symptoms

Symptoms of HDV infection are nonspecific, and most patients have subclinical illness. Most patients who acquire HDV and HBV simultaneously clear the delta virus, whereas 70% to 90% of those superinfected develop chronic delta infection. Superinfection produces more-severe acute illness than HBV alone and carries a higher risk for fulminant hepatic failure, which occurs in 5% to 20% of cases.

Diagnosis

The diagnosis of delta hepatitis should only be considered if positive HBV infection is present. This is usually reflected by finding a positive serum HBsAg or HBV DNA, or both. Measuring antibodies to delta antigen using ELISA can make the diagnosis. However, it may be positive after viral clearance, especially in case of HBV-HDV coinfection. IgM antibodies are increased when there is liver damage and not just in the acute illness; they apparently disappear when the hepatitis resolves. Presence of HDV antigen in the serum confirms the diagnosis, as does HDV RNA, which is only available in a research setting. Anti-HDV antibody (IgG) can appear in high titers in chronic HDV infection, whereas lower titer may be detected after viral resolution.

Treatment

Delta hepatitis can be prevented by vaccination against hepatitis B. At this time, there is no effective vaccine to prevent delta hepatitis in chronic hepatitis B carriers. Delta hepatitis can be treated with high-dose interferon as high as 9 million U three times per week for 1 year. Although as many as 70% of patients clear the virus and normalize liver enzyme levels, almost all patients relapse at some point after therapy. Orthotopic liver transplantation is considered for decompensated patients. Interestingly, patients who have HDV and who receive a liver transplant have a higher chance of graft survival than those who receive a transplant for hepatitis B alone. This phenomenon may be a result of the inhibitory effect of HDV on HBV replication. Hepatitis B immunoglobulin is administered to these patients.

Outcomes

Coinfection with HDV and HBV can result in a severe fulminant hepatitis and liver failure or can persist as a chronic infection, resulting in cirrhosis or hepatocellular carcinoma. Chronic infection can persist in an inactive phase, and some patients go into complete remission. The chance of progression to cirrhosis is higher in patients with delta hepatitis than in patients solely infected with hepatitis B, as is the risk for hepatocellular carcinoma. Patients coinfected with human immunodeficiency virus or hepatitis C have a worse outcome.

Summary

• Hepatitis D or delta virus (HDV) is a defective single-stranded RNA virus requiring the presence of hepatitis B virus (HBV) for its expression and replication. HDV has a worldwide distribution. It is endemic in the developing world.
• HDV infection is limited to patients who have HBV infection and, like hepatitis B, is acquired parenterally.
• Infection with HDV produces more severe acute illness than HBV alone and carries a higher risk for fulminant hepatic failure, which occurs in 5% to 20% of cases.
• The chance of progression to cirrhosis is higher in patients with delta hepatitis than in patients solely with hepatitis B, as is the risk for hepatocellular carcinoma.
• Delta hepatitis can be prevented by vaccination against hepatitis B.

Suggested Reading

1. Polish LB, Gallagher M, Fields HA, Hadler SC. Delta hepatitis: Molecular biology and clinical and epidemiological features. Clin Microbiol Rev. 1993, 6: 211-229.
2. Chu CM, Yeh CT, Liaw YF. Viral superinfection in previously unrecognized chronic carriers of hepatitis B virus with superimposed acute fulminant versus nonfulminant hepatitis. J Clin Microbiol. 1999, 37: 235-237.
3. Huo TI, Wu JC, Lai CR, et al: Comparison of clinico-pathological features in hepatitis B virus–associated hepatocellular carcinoma with or without hepatitis D virus superinfection. J Hepatol. 1996, 25: 439-444.
4. Mendez L, Reddy KR, Di Prima RA, et al: Fulminant hepatic failure due to acute hepatitis B and delta co-infection: Probable bloodborne transmission associated with a spring-loaded fingerstick device. Am J Gastroenterol. 1991, 86: 895-897.