Hepatitis B virus infection: Understanding its epidemiology, course, and diagnosis

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ABSTRACTAlthough hepatitis B virus (HBV) infection is not as common in the United States as in some countries, 5,000 Americans die from it every year. This number can be significantly decreased with proper screening and by vaccinating people at risk. Internists should be aware of the natural history of HBV infection, a vital prerequisite to correctly assessing disease severity and subsequently determining the need for antiviral therapy.


  • HBV infection is much more likely to persist and become chronic if it is acquired at birth or in early childhood rather than during adulthood.
  • Chronic HBV infection is defined as persistence of HBV surface antigen in the serum for more than 6 months.
  • Although many cases of chronic HBV infection resolve spontaneously, some progress to cirrhosis, hepatocellular carcinoma, and death.



Our knowledge about hepatitis B and related diseases has dramatically increased since the discovery of the causative virus, HBV, in 1963. Despite effective vaccination, hepatitis B still constitutes a major public health problem.

In two parts, this comprehensive review will highlight a practical clinical approach to HBV infection. In this first part, we discuss the epidemiology, natural history, and diagnosis of HBV infection. In the second part, to be published in the next issue of this journal, we will review the general principles of its management, its management in patients on immunosuppressant therapy and in pregnant women, and HBV vaccination.


More than 2 billion people—one-third of the world’s population—alive today have been infected with HBV at some time in their life, and of these, about 350 million remain infected.1 Every year, 1 million people die of HBV-related cirrhosis or hepatocellular carcinoma, which means that HBV takes a life every 30 seconds.2

World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services. Geneva: WHO; 2001. WHO/V AND B/01.31.
Figure 1. Global prevalence of hepatitis B virus (HBV) surface antigenemia.
HBV infection is highly prevalent in Asia, sub-Saharan Africa, and other parts of the developing world, but less so in the United States, except in Alaskan natives and immigrants from regions of high prevalence (Figure 1). By some estimates, 1.25 million carriers, defined as those positive for the HBV surface antigen for more than 6 months, live in the United States, and about half of them are Asian-American.3,4 Other estimates put the number as high as 2 million, taking into account the prevalence of HBV in immigrant populations.

The incidence of acute hepatitis B in the United States has declined from 8.5 per 100,000 population in 1990 to 2.1 per 100,000 population in 2004, with the greatest declines (94%) in children and adolescents, coincident with an increase in hepatitis B vaccination in these age groups.5 Despite these advances, HBV still causes a considerable number of cases of cirrhosis, cancer, and death—about 5,000 deaths each year in the United States.


HBV is a DNA virus of the Hepadnaviridae family. Its genome is double-stranded with four genes, each one encoding a specific structural protein or proteins6,7:

  • S gene, for the viral envelope (surface antigen)
  • C gene, for both the nucleocapsid (core) antigen and the pre-core (e) antigen
  • X gene, for two regulatory proteins required for HBV replication
  • P gene, for DNA polymerase.
Several clinically important mutations in the HBV genome are known (Table 1).7–12

Eight genotypes of HBV (labeled A though H) have been identified.13,14 All eight have been found in the United States, but genotype A accounts for 35% of cases, genotype B for 22%, and genotype C for 31%.15

The clinical significance of HBV genotypes is not as clear as that of hepatitis C virus genotypes. Although recent data have suggested that different HBV genotypes may be associated with different rates of progression of liver disease and different rates of response to interferon therapy,13 these data were not enough to recommend routine testing for HBV genotypes in clinical practice.16

In HBV infection, the virus itself does not injure liver cells. Rather, the damage of hepatitis is immune-mediated and begins to appear as the host’s immune system attempts to clear the virus.


Figure 2.
HBV produces several antigens that can be detected in the blood and that disappear as the body produces antibodies against them. The patterns of these and other markers provide clues to the phase of infection (Figure 2).

HBV surface antigen and HBV DNA are often the first detectable markers of acute infection, appearing before the onset of symptoms or before elevation of alanine aminotransferase (ALT) occurs. By definition, an HBV infection is chronic if surface antigen persists longer than 6 months.

HBV e antigen, derived from pre-core protein, is considered a marker of HBV replication and infectivity. In chronic infection, e antigen can persist for years or decades.

HBV core antigen cannot be detected in the serum, but antibodies against it can, first immunoglobulin M (IgM) and later immunoglobulin G (IgG).


Because HBV replicates profusely and produces high titers in the blood (108 to 1,010 virions/ mL), any parenteral or mucosal exposure to infected blood poses a high risk of HBV acquisition. The risk of HBV transmission from a single needlestick is 1% to 6% if the blood is positive for HBV surface antigen but negative for HBV e antigen, and 22% to 40% if positive for both antigens.17–19 Saliva, nasopharyngeal fluid, breast milk, semen, urine, and cervical secretions can also harbor HBV.20

Worldwide, perinatal (vertical) transmission is the predominant mode of HBV transmission, whereas intravenous drug abuse and unprotected sexual intercourse are the main routes of infection in areas of low prevalence, such as the United States. In sub-Saharan Africa, Alaska, and Mediterranean countries, transmission of HBV usually occurs horizontally during childhood, presumably via contact with nonintact skin.21–24 Saliva has also been thought to be the route of HBV transmission in sporadic cases through human bites.25

People at risk of HBV infection include:

  • Parenteral drug users
  • People with multiple sexual partners
  • Household contacts and sexual partners of people who are positive for HBV surface antigen
  • Infants born to HBV-infected mothers
  • Patients and staff in custodial institutions for the developmentally disabled
  • Recipients of certain plasma-derived products (including patients with congenital coagulation defects)
  • Hemodialysis patients
  • Health and public-safety workers who have contact with blood
  • People born in areas where HBV is endemic, and their children.

These people—as well as all pregnant women, patients infected with hepatitis C virus or human immunodeficiency virus, and patients with chronically elevated ALT or aspartate aminotransferase (AST) levels—should be screened for HBV infection with serologic markers.

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