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]

Overview

Intracellular hepatitis B virus is non-cytopathic and causes little or no damage to the cell.[1] During HBV infection, the host immune response causes both hepatocellular damage and viral clearance.

Pathogenesis

Immunopathogenesis

Life Cycle

Systematic Diagram of the Life Cycle of HBV Courtesy: World Health Organization[3]
  • The HBV virion binds to a receptor at the surface of the hepatocyte.[1]
  • Several cellular receptors have been identified, including the transferrin receptor, the asialoglycoprotien receptor molecule, and human liver endonexin. However, the mechanism of HBsAg binding to a specific receptor to enter cells has not been established yet. Viral nucleocapsids enter the cell and reach the nucleus, where the viral genome is delivered.[1][4][5]
  • 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 transcription of four viral RNAs that are 3.5, 2.4, 2.1, and 0.7 kb long.[6][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).[8][9]
  • The envelope proteins insert themselves as integral membrane proteins into the lipid membrane of the endoplasmic reticulum (ER). The 3.5 kb species, spanning the entire genome and termed pregenomic RNA (pgRNA), is packaged together with HBV polymerase and a protein kinase into core particles where it serves as a template for reverse transcription of negative-strand DNA. The RNA to DNA conversion takes place inside the particles.
  • The new, mature, viral nucleocapsids can then follow two different intracellular pathways, one of which leads to the formation and secretion of new virions, whereas the other leads to 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, from which they are secreted via the Golgi apparatus out of the cell.[1]

HBV and Antibody Nomenclature

Nomenclature Full Name Description
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

Associated Conditions

  • More than 85% of hepatocellular tumours examined harbor integrated HBV DNA, often multiple copies per cell. The viral DNA integrants are usually highly rearranged, with deletions, inversions, and sequence reiterations all commonly observed. Most of these rearrangements ablate viral gene expression, but the integrations alter the host DNA.[11][12][1]
  • Every cell in the tumour contains an identical complement of HBV insertions. This implies that the integration event(s) preceded the clonal expansion of the cells.
  • There is no similarity in the pattern of integration between different tumours, and variation is seen both in the integration site(s) and in the number of copies or partial copies of the viral genome.[1]

Microscopic Pathology

Immune complexes, such as surface antigen-antibody, are important in the pathogenesis of other disease syndromes characterized by severe damage of blood vessels:

  • Acute necrotizing vasculitis (polyarteritis nodosa)[1]

With high fever, anemia, leucocytosis, arthralgia, arthritis, renal disease, hypertension, heart disease, gastrointestinal disease, skin manifestations, neurologic disorders. Highly variable disease with mortality rate of 40% within 3 years unless treated. The diagnosis is established by angiography.[1]

  • Membranous glomerulonephritis:

Present in both adults and children. Remission of nephropathy occurs in 85 to 90% of cases over a period of 9 years and is associated with clearance of HBeAg from serum.[1]

  • Papular acrodermatitis of childhood (Gianotti-Crosti syndrome)

Distinctive disease of childhood. Skin lesions, lentil-sized, flat, erythematous, and papular eruptions localized to the face and extremities, last 15 to 20 days. The disease is accompanied by generalized lymphadenopathy, hepatomegaly, and acute anicteric hepatitis B of ayw subtype.[1]

Why only a small proportion of patients with circulating complexes develop vasculitis or polyarteritis is still not clear.[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 "Hepatitis B" (PDF).
  2. {{cite journal | author=Iannacone M. et al | title=Pathogenetic and antiviral immune responses against hepatitis B virus | journal=Future Virology | year=2006 | pages=189-196 | volume=1 | issue=2
  3. "http://www.who.int/en/". External link in |title= (help)
  4. Nathanson, Neal (1997). Viral pathogenesis. Philadelphia: Lippincott-Raven. ISBN 0781702976.
  5. 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 236947. PMID 8057429.
  6. Nathanson, Neal (1997). Viral pathogenesis. Philadelphia: Lippincott-Raven. ISBN 0781702976.
  7. Plotkin, Stanley (1999). Vaccines. Philadelphia: W.B. Saunders Co. ISBN 0721674437.
  8. Nathanson, Neal (1997). Viral pathogenesis. Philadelphia: Lippincott-Raven. ISBN 0781702976.
  9. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434.
  10. name="pmid791124">Petersen NJ, Barrett DH, Bond WW, Berquist KR, Favero MS, Bender TR, Maynard JE (1976). "Hepatitis B surface antigen in saliva, impetiginous lesions, and the environment in two remote Alaskan villages". Appl. Environ. Microbiol. 32 (4): 572–574. PMID 791124.
  11. Fields, Bernard (2007). Fields virology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 0781760607.
  12. Mandell, Gerald (2005). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. New York: Elsevier/Churchill Livingstone. ISBN 0443066434.

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