Hepatitis B pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2], Sara Mehrsefat, M.D. [3]

Overview

The intracellular hepatitis B virus is a non-cytopathic virus that causes little or no damage to the cell.[1] During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. The HBV virion binds to a receptor at the surface of the hepatocyte and enters the cell, where it uses the host's cell mechanisms to replicate its genome and proteins. Different viral antigens and antibodies may be detected in serum throughout the course of the disease, including HBsAg, HBcAg, HBeAg, anti-HBs, anti-HBC, and anti-HBe. Transmission occurs from exposure to infectious blood or body fluids. Hepatitis B is often associated with hepatocellular carcinoma. Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of hepatitis B.[2][3]

Pathogenesis

Immunopathogenesis

The host immune response is primarily responsible for both hepatocellular damage and viral clearance in patients with HBV infection. While the innate immune response does not play a significant role in these processes, the adaptive immune response (particularly virus-specific cytotoxic T lymphocytes) contributes to nearly all of the liver injury associated with HBV infection.[1][2][3]

Life Cycle

  • Several cellular receptors have been identified, including the transferrin receptor, the asialoglycoprotein receptor molecule, and the human liver endonexin. However, the mechanism by which HBsAg binds to a specific receptor to enter cells has not yet been established. Viral nucleocapsids enter the cell and reach the nucleus, where the viral genome is delivered.[1][4][5][6]
  • In the nucleus, second-strand DNA synthesis is completed and the gaps in both strands are repaired to yield a covalently closed circular (ccc) supercoiled DNA molecule that serves as a template for the transcription of four viral RNAs that are 3.5, 2.4, 2.1, and 0.7 kb long.[4][7]
  • These transcripts are polyadenylated and transported to the cytoplasm, where they are translated into the viral nucleocapsid and precore antigen (C, pre-C), polymerase (P), envelope L (large), M (medium), S (small)), and transcriptional transactivating proteins (X).[4][8]
  • The new, mature, viral nucleocapsids can then follow either of two different intracellular pathways. One of these pathways leads to the formation and secretion of new virions, while the other leads to the amplification of the viral genome inside the cell nucleus. In the virion assembly pathway, the nucleocapsids reach the ER, where they associate with the envelope proteins and bud into the lumen of the ER, at which point they are secreted via the Golgi apparatus out of the cell.[1]

HBV Antigens and Antibodies

Nomenclature Full Name Description[1]
HBV Hepatitis B Virus (complete infectious virion) The 42 nm, double-shelled particle, that consists of a 7 nm thick outer shell and a 27 nm inner core. The core contains a small, circular, partially double-stranded DNA molecule and an endogenous DNA polymerase. This is the prototype agent for the family epadnaviridae.
HBsAg Hepatitis B Surface Antigen (envelope antigen) The complex of antigenic determinants found on the surface of HBV and of 22 nm particles and tubular forms.
HBcAg Hepatitis B Core Antigen The antigenic specificity.
HBeAg Hepatitis B e Antigen The antigenic determinant that is closely associated with the nucleocapsid of HBV. It also circulates as a soluble protein in serum.
Anti-HBs
Anti-HBc
Anti-HBe
Antibody to HBsAg
Antibody to HBcAg
Antibody to HBeAg
Specific antibodies that are produced in response to their respective antigenic determinants.

Transmission

Coinfections

Hepatitis D

HIV

  • About 10% of people living with HIV in the United States are coinfected with HBV.[12]
  • HIV-positive patients who are coinfected with HBV are at increased risk for serious, life-threatening health complications. HIV/HBV coinfection can also complicate the management of HIV infection.[12]
  • Hepatitis B is preventable through vaccination. HBV vaccination is recommended for people who are at risk for or living with HIV and who have tested negative for HBV.
  • Persons infected with HIV are more likely to develop persistent infection with HBV.[1]
  • HIV infection is one of the factors that may reduce the immunogenicity of hepatitis vaccines, along with age (>40 years), gender, weight, genetics, hemodialysis, immunosuppression, and tobacco smoking.[1]

References

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 World Health Organization, Guidelines for the Prevention, Care, and Treatment of persons with chronic Hepatitis B Infection. (March 2015). http://apps.who.int/iris/bitstream/10665/154590/1/9789241549059_eng.pdf Accessed on October 4th, 2016
  2. 2.0 2.1 2.2 2.3 2.4 2.5 Zhang YY, Hu KQ (2015). "Rethinking the pathogenesis of hepatitis B virus (HBV) infection.". J Med Virol. 87 (12): 1989–99. PMID 25989114. doi:10.1002/jmv.24270. 
  3. 3.0 3.1 3.2 3.3 3.4 Chang KM, Liu M (2016). "Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics.". Curr Opin Pharmacol. 30: 93–105. PMID 27570126. doi:10.1016/j.coph.2016.07.013. 
  4. 4.0 4.1 4.2 Nathanson, Neal (1997). Viral pathogenesis. Philadelphia: Lippincott-Raven. ISBN 0781702976. 
  5. Plotkin, Stanley (1999). Vaccines. Philadelphia: W.B. Saunders Co. ISBN 0721674437. 
  6. Guidotti LG, Martinez V, Loh YT, Rogler CE, Chisari FV (1994). "Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice.". J Virol. 68 (9): 5469–75. PMC 236947Freely accessible. PMID 8057429. 
  7. Plotkin, Stanley (1999). Vaccines. Philadelphia: W.B. Saunders Co. ISBN 0721674437. 
  8. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434. 
  9. Petersen NJ, Barrett DH, Bond WW, Berquist KR, Favero MS, Bender TR; et al. (1976). "Hepatitis B surface antigen in saliva, impetiginous lesions, and the environment in two remote Alaskan villages.". Appl Environ Microbiol. 32 (4): 572–4. PMC 170308Freely accessible. PMID 791124. 
  10. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434. 
  11. Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399. 
  12. 12.0 12.1 AIDS. Hepatitis B and AIDS. (2015) https://www.aids.gov/hiv-aids-basics/staying-healthy-with-hiv-aids/potential-related-health-problems/hepatitis-b/ Accessed on October 5th, 2016

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