Hepatitis B 

In 1965, Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion.^[1] Since then, considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus. The image below depicts a liver biopsy specimen.

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population has been infected with the hepatitis B virus (HBV). Approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of HBV disease.

The hepatitis B virus (HBV) is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease or an asymptomatic disease. Patients may become immune to HBV, or they may develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC).^{[2, 3, 4, 5]}

Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates, liver transplantation currently seems to be the only viable treatment for the latest stages of hepatitis B.

See also Liver Disease in Pregnancy, Hepatitis A, Hepatitis C, Hepatitis D, and Hepatitis E, and Viral Hepatitis.

Hepatitis B virus (HBV) is a hepadnavirus.^{[6, 7, 8, 9, 10]} It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. HBV can survive when stored for 15 years at –20°C, for 24 months at –80°C, for 6 months at room temperatures, and for 7 days at 44°C.

Viral genome

The viral genome consists of a partially double-stranded, circular DNA of 3.2 kilobase (kb) pairs that encodes 4 overlapping open reading frames, as follows:

• S for the surface or envelope gene encoding the pre-S1, pre-S2, and the S protein
• C for the core gene, encoding for the core nucleocapsid protein and the e antigen
• X for the X gene encoding the X protein
• P for the polymerase gene encoding a large protein promoting priming RNA-dependent and DNA-dependent DNA polymerase and RNase H activities

An upstream region for the S (pre-S) and C (pre-C,) genes has been found. The structure of this virion is a 42-nm spherical, double-shelled particle consisting of small spheres and rods, with an average width of 22 nm.

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigen (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important. The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response. The e antigen, HBeAg, comes from the core gene and is a marker of active viral replication. Usually, HBeAg can be detected in patients with circulating serum HBV DNA.

The best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum.

The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.

Antibody production

The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to HBV. The immunoglobulin M (IgM) subtype is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state and one in which the antigen has been cleared.

Variant strains

With the newest PCR techniques, scientists are able to identify variations in the HBV genome (variant strains). Mutations of various nucleotides such as the 1896 (precore/core region) processing the production of the HBeAg have been identified (HBeAg negative strain). The prevalence of the HBeAg negative virus varies among different areas. Estimates indicate that 50-60% of the patients from Southern Europe, the Middle East, Asia, and Africa as well as 10-30% of patients in the United States and Europe who have chronic HBV infection have been infected by this strain.

Immune response

The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury. Activated CD4⁺ and CD8⁺ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.^{[11, 12]}

The final state of HBV disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop hepatocellular carcinoma (HCC).^{[2, 3, 4]} In the United States, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission).

Viral life cycle

Four different stages have been identified in the viral life cycle of hepatitis B and are briefly discussed below.

Stage 1

The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.

Stage 2

In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of HBV DNA is seen. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops.

Stage 3

In the third stage, the host can target the infected hepatocytes and HBV. Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.

Stage 4

In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and coinfection with other viruses.

Genotypes and disease progression

Eight different genotypes (A through H) representing a divergence of the viral DNA at around 8% have been identified.^[7] The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated, and the response to treatment with antiviral agents is less favorable for patients infected by genotype C compared with those infected by genotype B.

It is reported that the risk of HCC might be higher with an increasing level of HBV viral load and the presence of genotype C and common variants in the precore and basal core promoter regions.

Dong et al developed a novel in vitro 1.5X HBV replication system that was capable of consistently generating a high level of HBV. Although the investigators believed this system would help compare the replication capacity among the virus strains associated with high and low risk of HCC, there was no significant difference in the replication capacities among these strains in vitro.^[13] The investigators concluded that the HBV-1.5X system may be a useful platform in helping to establish stable cell lines and transgenic mice for the investigation of viral pathogenesis, particularly for the various strains of HBV.^[13]

An estimated 200,000 new cases of hepatitis B virus (HBV) infection occur annually in the United States, and 1-1.25 million people are carriers. The prevalence of the disease is higher among blacks and persons of Hispanic or Asian origin. In addition, a higher carrier rate exists among certain subpopulations such as the Alaskan Eskimos, Asian Pacific islanders, and Australian aborigines. HBV disease accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of hepatocellular carcinoma (HCC).

HBV is blamed for 5000 US deaths annually. The prevalence is low in persons younger than 12 years, but it increases in those older than 12 years—associated with the initiation of sexual contact (the major mode of transmission), the number of sexual partners, and an early age of first intercourse. Additional risk factors identified in the National Health and Nutrition Examination Survey (NHANES) III survey are non-Hispanic black ethnicity, cocaine use, high number of sexual partners, divorced or separated marital status, foreign birth, and low educational level.

Because of the implementation of routine vaccinations of infants in 1992 and adolescents in 1995, the prevalence of HBV infection is expected to decline further.

International statistics

The HBV carrier rate variation is 1-20% worldwide. This variation is related to differences in the mode of transmission and the patient's age at infection. The prevalence of the disease in different geographic areas can be characterized as follows:

• Low-prevalence areas (rate of 0.1-2%) include Canada, Western Europe, Australia, and New Zealand; in the areas of low prevalence, sexual transmission and percutaneous transmission during adulthood are the main modes of transmission
• Intermediate-prevalence areas (rate of 3-5%) include Eastern and Northern Europe, Japan, the Mediterranean basin, the Middle East, Latin and South America, and Central Asia; in areas of intermediate prevalence, sexual and percutaneous transmission and transmission during delivery are the major transmission routes
• High-prevalence areas (rate of 10-20%) include China, Indonesia, sub-Saharan Africa, the Pacific Islands, and Southeast Asia; in areas of high prevalence, the predominant mode of transmission is perinatal, and the disease is transmitted vertically during early childhood from the mother to the infant; vaccination programs implemented in highly endemic areas such as Taiwan seem to change the prevalence of HBV infection: In Taiwan, HBV seroprevalence declined from 10% in 1984 (before vaccination programs) to less than 1% in 1994 after the implementation of vaccination programs, and the incidence of HCC declined from 0.52% to 0.13% during the same period^[3]

Racial, sexual, and age-related differences in incidence

Black individuals have a higher prevalence of HBV disease than persons of Hispanic origin or white persons. More cases of HBV disease occur in males than in females.

The earlier the disease is acquired, the greater the chance of developing chronic hepatitis B infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and elderly persons have an approximately 20-30% chance of developing chronic disease.

Approximately 9% of patients in Western Europe who have cirrhosis develop hepatocellular carcinoma (HCC) due to hepatitis B infection at a mean follow-up of 73 months. The probability of HCC developing 5 years after the diagnosis of cirrhosis is established is 6%, and the probability of decompensation is 23%.

Significant risk factors for carcinogenesis include older age, liver firmness, and thrombocytopenia. Even the presence of hepatitis B surface antibody (HBsAb) in the absence of hepatitis B surface antigen (HBsAg) or hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC.

The annual incidence of this malignancy in patients with hepatitis B infection and cirrhosis reported in Taiwan is 2.8%. The US estimates for the annual incidence of HCC in patients infected with HBV is 818 cases per 100,000 persons. Familiar clustering of HCC has been described among families with hepatitis B infection in Africa, the Far East, and Alaska. The cumulative probability of survival is 84% at 5 years and 68% at 10 years.

Cox regression analysis has identified 6 variables that independently correlate with survival. These include age, albumin level, platelet count, splenomegaly, bilirubin level, and hepatitis B e antigen (HBeAg) positivity at the time of hepatitis B diagnosis. According to the contribution of each of these factors to the final model, a prognostic index has been constructed that allows calculation of the estimated survival probability. No difference in survival is observed in patients with hepatitis D (delta) virus (HDV) infection compared with those who are not infected.

The prevalence of HDV coinfection among patients infected with hepatitis B virus (HBV) varies worldwide from 0% to 20%. The speculation that HDV might promote hepatocarcinogenesis in these patients has been investigated, with controversial results. The prevalence of anti-delta among patients with cirrhosis with and without HCC is not significantly different, although HDV infection has been reported to increase the risk for HCC 3-fold and mortality rates 2-fold in patients with HBV cirrhosis.

An estimated 250,000 persons per year globally and 5000 persons per year in the United States die from chronic HBV disease.

The United States currently screens foreign-born residents for HBV infection if their country of origin has an HBV prevalence of 2% or greater. According to a model developed by Eckman et al, although this threshold for screening is cost-effective, a broader screening program with a threshold of 1.3% or even 0.3% country-of-origin prevalence would be cost-effective as well, suggesting a reconsideration of current policy.^[14]

Patients with acute and chronic HBV infections should be advised that this is a blood-borne disease that can be transmitted during sexual intercourse or at the time of childbirth. Prophylaxis is strongly advised. Family members born by the same parents should also be checked for HBV infection. The best preventative measurement is vaccination.^[15]

For patient education information, see Hepatitis A; Hepatitis B; Hepatitis C; Cirrhosis; Liver Cancer; Hepatitis in Pregnancy; Immunization Schedule, Adults; and Immunization Schedule, Children.