eMedicine Specialties > Gastroenterology > Liver

Hepatitis B

Author: Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Coauthor(s): K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
Contributor Information and Disclosures

Updated: Jun 19, 2009

Introduction

Background

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.

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 hepatitis B virus (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 the hepatitis B virus (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.

Liver biopsy specimen showing ground-glass appear...

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

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Liver biopsy specimen showing ground-glass appear...

Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.



Liver biopsy with trichrome stain showing stage 3...

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.

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Liver biopsy with trichrome stain showing stage 3...

Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.



Liver biopsy with hematoxylin stain showing stage...

Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.

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Liver biopsy with hematoxylin stain showing stage...

Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.


For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Hepatitis B, Immunization Schedule, Adults, and Immunization Schedule, Children.

Pathophysiology

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. Hepatitis B virus (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. 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: a, common to all HBsAg, and 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 hepatitis B virus (HBV) DNA.

The best indication of active viral replication is the presence of hepatitis B virus (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.

The production of antibodies against HBsAg confers protective immunity and can be detected in patients who have recovered from hepatitis B virus (HBV) infection or in those who have been vaccinated. Antibody to HBcAg is detected in almost every patient with previous exposure to hepatitis B virus (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.

With the newest PCR techniques, scientists are able to identify variations in the hepatitis B virus (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 hepatitis B virus (HBV) infection have been infected by this strain.

The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system. The latter attacks the hepatitis B virus (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 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 hepatitis B virus (HBV) disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop 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).

Four different stages have been identified in the viral life cycle of hepatitis B.

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.

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 hepatitis B virus (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.

In the third stage, the host can target the infected hepatocytes and the hepatitis B virus (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.

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.

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 hepatitis B virus (HBV) viral load and the presence of genotype C and common variants in the precore and basal core promoter regions.

Dong et al studied an in vitro 1.5X hepatitis B virus (HBV) replication system that could generate high level of such viruses, which the investigators believed would help compare the replication capacity among the virus strains associated with high and low risk of HCC.13   Four strains of hepatitis B virus (HBV) were isolated from 2 patients with HCC and 2 hepatitis B virus (HBV) carriers; then, 4 corresponding constructs, HBV-1.5Xs, were generated after molecular cloning. 

HepG2 cells were transfected with the HBV-1.5Xs, and the levels of HBsAg, HBeAg, and viral DNA were then detected in both the supernatant and the cells.13 After 24 and 48 hours of transfection, a high optical density value of HBsAg of 3.5 was observed in the supernatant as well as in some of the diluted cell lysate samples. The HBeAg level was relatively low in all strain samples of HBV. In addition, the log(10) values of viral loads were determined, with the cell lysate having a higher value (10-11 per mL) than that of the supernatant (6-7 per mL).13
 
Dong et al determined that the novel HBV-1.5X system was capable of generating a high level of hepatitis B virus (HBV) in a consistent manner, but there was no significant difference in the replication capacities among these strains in vitro. 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 hepatitis B virus (HBV).13

Frequency

United States

An estimated 200,000 new cases of hepatitis B virus (HBV) occur annually, 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. Hepatitis B virus (HBV) accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of HCC.

Hepatitis B virus (HBV) is blamed for 5000 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 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 hepatitis B virus (HBV) is expected to decline further.

International

The hepatitis B virus (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 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 hepatitis B virus (HBV) infection. In Taiwan, 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%.3

Mortality/Morbidity

An estimated 250,000 persons per year globally and 5000 persons per year in the United States die from chronic hepatitis B virus (HBV) infection.

Race

Black individuals have a higher prevalence of hepatitis B virus (HBV) disease than persons of Hispanic origin or white persons.

Sex

More cases of hepatitis B virus (HBV) disease occur in males than in females.

Age

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.

Clinical

History

The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase, and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC during the chronic phase.

  • Acute phase
    • The incubation period is 1-6 months.
    • Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis. Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis.
    • Icteric hepatitis is associated with a prodromal period, during which a serum sickness –like syndrome can occur. The symptomatology is more constitutional and includes the following:
      • Anorexia
      • Nausea
      • Vomiting
      • Low-grade fever
      • Myalgia
      • Fatigability
      • Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
      • Right upper quadrant and epigastric pain (intermittent, mild to moderate)
    • Patients with hyperacute, acute, and subacute hepatitis may present with the following:
      • Hepatic encephalopathy
      • Somnolence
      • Disturbances in sleep pattern
      • Mental confusion
      • Coma
  • Chronic phase
    • Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic.
    • Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:
      • Symptoms similar to those of acute hepatitis
      • Fatigue
      • Anorexia
      • Nausea
      • Mild upper quadrant pain or discomfort
      • Hepatic decompensation

Physical

The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease.

  • Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:
    • Low-grade fever
    • Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo)
    • Hepatomegaly (mildly enlarged soft liver)
    • Splenomegaly (5-15%)
    • Palmar erythema (rarely)
    • Spider nevi (rarely)
  • The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following:
    • Hepatomegaly
    • Palmar erythema
    • Spider angioma
  • Patients with cirrhosis may have the following symptoms:
    • Ascites
    • Jaundice
    • History of variceal bleeding
    • Peripheral edema
    • Gynecomastia
    • Testicular atrophy
    • Abdominal collateral veins (caput medusa)

More on Hepatitis B

Overview: Hepatitis B
Differential Diagnoses & Workup: Hepatitis B
Treatment & Medication: Hepatitis B
Follow-up: Hepatitis B
Multimedia: Hepatitis B
References
Further Reading
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Further Reading

Additional resources on hepatitis B are available at Medscape’s Hepatitis B Resource Center.

Related eMedicine Topics

Clinical Trials

National Guideline Clearinghouse

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Keywords

hepatitis B, hepatitis, HBV, hepatitis B infection, viral hepatitis, hepatitis B virus, chronic hepatitis, acute hepatitis, cirrhosis, fulminant hepatitis, hepatocellular carcinoma, HCC, extrahepatic manifestations, hepatitis D virus, HDV, delta virus, hepatitis C virus, HCV, hepatitis B surface antigen, HBsAg, Australia antigen, hepatitis B surface antibody, HBsAb, orthohepadnavirus, hepadnaviridae infection,

liver transplantation, liver transplant, OLT, interferon-alpha, IFN-a, peginterferon-alfa 2a, pegylated IFN-a 2a, lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir

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Contributor Information and Disclosures

Author

Nikolaos T Pyrsopoulos, MD, PhD, FACP, Chief of Hepatology, Medical Director of Liver Transplantation, Florida Hospital; Associate Professor of Medicine, University of Central Florida College of Medicine
Nikolaos T Pyrsopoulos, MD, PhD, FACP is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Liver Foundation, American Medical Association, American Society of Gastrointestinal Endoscopy, American Society of Transplantation, International Liver Transplantation Society, and Transplantation Society
Disclosure: Gilead Sciences Honoraria Speaking and teaching; Schering-Plough Honoraria Speaking and teaching; Roche Honoraria Speaking and teaching

Coauthor(s)

K Rajender Reddy, MD, FACP, FACG, Professor, Department of Medicine, Division of Hepatology, University of Miami School of Medicine
K Rajender Reddy, MD, FACP, FACG is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and Florida Medical Association
Disclosure: Nothing to disclose.

Medical Editor

George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine
George Y Wu, MD, PhD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, American Medical Association, American Society for Clinical Investigation, and Association of American Physicians
Disclosure: Humana Press Consulting fee Consulting; Novartis Consulting fee Review panel membership

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Oscar S Brann, MD, FACP, Associate Clinical Professor, Department of Medicine, University of California at San Diego; Consulting Staff, Mecklenburg Medical Group
Oscar S Brann, MD, FACP is a member of the following medical societies: American Gastroenterological Association
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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