Hepatitis B

By Howard J. Worman, M. D. author of The Liver Disorders Resource Book.

The Hepatitis B Virus (HBV)

HBV is a mostly double-stranded DNA virus in the Hepadnaviridae family. HBV causes hepatitis in human and related virus in this family cause hepatitis in ducks, ground squirrels and woodchucks. The HBV genome has four genes: pol, env, pre-core and X that respectively encode the viral DNA-polymerase, envelope protein, pre-core protein (which is processed to viral capsid) and protein X. The function of protein X is not clear but it may be involved in the activation of host cell genes and the development of cancer.

Risk Factors for HBV Infection

Although relatively rare in the United States, hepatitis B is endemic in parts of Asia where hundreds of millions of individuals may be infected. HBV is transmitted horizontally by blood and blood products and sexual transmission. It is also transmitted vertically from mother to infant in the perinatal period which is a major mode of transmission in regions where hepatitis B is endemic.

The blood supply in developed countries has been screened for HBV for many years and at present transmission by blood transfusion is extremely rare. Major routes of transmission among adults in Western countries are intravenous drug use and sexual contact. The risk of HBV infection is notably high in promiscuous homosexual men but it is also transmitted sexually from men to women and women to men. Transmission is probably prevented by correct use of condoms. Health care workers and patients receiving hemodialysis are also at increased risk of infection.

Effective vaccines are available for the prevention of HBV infection. All individuals at risk for infection should be vaccinated. Post-exposure prophylaxis with hepatitis B immune globulin is also effective for non-immune individuals after a known exposure (e. g. needle stick).

Consequences of HBV Infection

HBV causes acute and chronic hepatitis. The chances of becoming chronically infected depends upon age. About 90% of infected neonates and 50% of infected young children will become chronically infected. In contrast, only about 5% to 10% of immunocompetent adults infected with HBV develop chronic hepatitis B. In some individuals who become chronically infected, especially neonates and children, the acute infection will not be clinically apparent.

Acute hepatitis B can range from subclinical disease to fulminant hepatic failure in about 2% of cases. Many acutely infected individuals develop clinically apparent acute hepatitis with loss of appetite, nausea, vomiting, fever, abdominal pain and jaundice. In cases of fulminant hepatic failure from acute HBV infection, orthotopic liver transplantation can be life-saving. About 90% to 95% of acutely infected adults recover without sequelae. About 5% to 10% of acutely infected adults become chronically infected.

The natural history of chronic HBV infection can vary dramatically between individuals. Some will develop a condition commonly referred to as a chronic carrier state. These patients, who are still potentially infectious, have no symptoms and no abnormalities on laboratory testing. Nonetheless, some of these patients will have evidence of hepatitis on liver biopsy.

Some individuals with chronic hepatitis B will have clinically insignificant or minimal liver disease and never develop complications. Others will have clinically apparent chronic hepatitis. Some will go on to develop cirrhosis. Individuals with chronic hepatitis B, especially those with cirrhosis but even so-called chronic carriers, are at an increased risk of developing hepatocellular carcinoma (primary liver cancer). Although this type of cancer is relatively rare in the United States, it is the leading cause of cancer death in the world, primarily because HBV infection is endemic in the East.

Chronic infection with HBV can be either "replicative" or "non-replicative." In non-replicative infection, the rate of viral replication in the liver is low and serum HBV DNA concentration is generally low and hepatitis Be antigen (HBeAg) is not detected. HBeAg is an alternatively processed protein of the pre-core gene that is only synthesized under conditions of high viral replication. In "replicative" infection, the patient usually has a relatively high serum concentration of viral DNA and detectable HBeAg. Patients with chronic hepatitis B and "replicative" infection defined by the presence of detectable HBeAg have a generally worse prognosis and a greater chance of developing cirrhosis and/or hepatocellular carcinoma than those without HBeAg. In rare strains of HBV with mutations in the pre-core gene, "replicative" infection can occur in the absence of detectable serum HBeAg.

Diagnosis

The diagnosis of HBV infection is generally made on the basis of serology. Virtually all individuals infected with HBV, either acutely or chronically, will have detectable serum hepatitis B surface antigen (HBsAg). In acute infection, HBsAg is detectable several weeks after infection and its appearance coincides with the onset of clinical symptoms. HBeAg is also detectable in acute infection which is characterized by a high rate of viral replication. At around the same time, IgM antibodies against core antigen are detectable in serum. Subsequently, IgG antibodies against core are produced. As acute infection resolves, IgG antibodies against core antigen persist and IgM antibodies and HBsAg become undetectable. Subjects who develop an immune response against HBV develop antibodies against HBsAg. Such antibodies are also produced by vaccination. Most people who have had acute infection that resolves continue to have IgG antibodies against core antigen for life. Some remain immune with antibodies against HBsAg but some lose these antibodies and may be susceptible to future infection.

Acutely infected individuals who do not clear HBV continue to have serum HBsAg. In most cases, the chronic infection becomes "non-replicative" and the subjects lose serum HBeAg and develop antibodies against HBeAg. In some cases, "replicative" infection persists along with detectable serum HBeAg. In chronically infected individuals, infection can switch from "non-replicative" to "replicative" and vice-versa. One goal of treatment (see below) is to convert patients with chronic hepatitis B from a "replicative" (HBeAg positive) to "non-replicative" (HBeAg negative) state.

Diagnosis of hepatitis B is confirmed, and prognosis is assessed, by liver biopsy. Most people who are chronic carriers (no symptoms, HBsAg positive and normal serum aminotransferase activities) generally have little or no inflammation on biopsy. In such patients, you can often see "ground glass cells" on liver biopsy which are liver cells in which large amounts of HBsAg is being synthesized. Other individuals with chronic hepatitis B will have various degrees of liver inflammation on biopsy. Others will have fibrosis or cirrhosis. The amount of inflammation, and the presence of fibrosis or cirrhosis, correlate with a worse prognosis.

In individuals suspected of having chronic hepatitis B, the appropriate screening test is for serum HBsAg. Individuals who may have chronic hepatitis B who should be considered for testing include:

• Those with symptoms of chronic liver disease
• Those with abnormal laboratory tests suggesting liver disease
• Individuals from countries where HBV infection is endemic (e. g. China)
• Those with risk factors such as past intravenous drug use or unprotected promiscuous sex
• Children of HBV infected parents or household contacts
• Health care workers
• Patients on hemodialysis

Individuals in the above groups who do not have chronic hepatitis B should be offered vaccination as most remain at increased risk of acquiring infection.

Cancer Screening

Individuals with chronic hepatitis B are at increased risk for the development of hepatocellular carcinoma. Although precise recommendations do not exist, it is reasonable for such individuals to undergo periodic screening for cancer. Screening procedures include measurement of serum alpha-fetoprotein (a tumor marker that is elevated in about 85% of individuals with hepatocellular carcinoma) and ultrasound examination. The optimal frequency of such screening examinations has not been determined.

Treatment

At the present time, alpha-interferons are the only drugs approved in the United States for the treatment of chronic hepatitis B. Treatment is recommended for individuals who have "replicative disease" (HBeAg positive). About 40% of such individuals will lose serum HBeAg after 16 weeks of treatment with interferon-alpha. Loss of HBeAg is correlated with an improved prognosis. A few treated patients (less than 10%) may even be cured as assessed by the loss of HBsAg. For additional information on interferon for the treatment of chronic viral hepatitis, click here.

Other promising treatment options for chronic hepatitis B include nucleoside analogues. One presently under investigation is lamivudine (3TC) which is also effective against HIV.

Howard J. Worman, M.D. <hjw14@columbia.edu> is the author of The Liver Disorders Resource Book.

©Copyright, 1995, 1998, Howard J. Worman, M. D. of Columbia University. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman. Reproduced on Comeunity with permission of the author.