Hepatitis B pathophysiology: Difference between revisions

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__NOTOC__
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{{Hepatitis B}}
{{Hepatitis B}}
{{CMG}}; {{AE}} {{JS}}
{{CMG}}; {{AE}} {{JS}}, {{SaraM}}


==Overview==
==Overview==
The intracellular [[hepatitis B virus]] is a non-cytopathic virus that causes little or no damage to the cell.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref> 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]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref> Different viral [[antigens]] and [[antibodies]] are detected in serum throughout the course of the disease, such as: [[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.
The intracellular [[hepatitis B virus]] is a non-cytopathic virus that causes little or no damage to the cell.<ref name=WHO-Guideline-Hepatitis-B> 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</ref> 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.<ref name="pmid25989114">{{cite journal| author=Zhang YY, Hu KQ| title=Rethinking the pathogenesis of hepatitis B virus (HBV) infection. | journal=J Med Virol | year= 2015 | volume= 87 | issue= 12 | pages= 1989-99 | pmid=25989114 | doi=10.1002/jmv.24270 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25989114  }} </ref><ref name="pmid27570126">{{cite journal| author=Chang KM, Liu M| title=Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics. | journal=Curr Opin Pharmacol | year= 2016 | volume= 30 | issue=  | pages= 93-105 | pmid=27570126 | doi=10.1016/j.coph.2016.07.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27570126  }} </ref>


==Pathogenesis==
==Pathogenesis==
===Immunopathogenesis===
===Immunopathogenesis===
* During [[HBV infection]], the host [[immune response]] causes both hepatocellular damage and [[viral]] clearance.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
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]].<ref name=WHO-Guideline-Hepatitis-B> 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</ref><ref name="pmid25989114">{{cite journal| author=Zhang YY, Hu KQ| title=Rethinking the pathogenesis of hepatitis B virus (HBV) infection. | journal=J Med Virol | year= 2015 | volume= 87 | issue= 12 | pages= 1989-99 | pmid=25989114 | doi=10.1002/jmv.24270 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25989114  }} </ref><ref name="pmid27570126">{{cite journal| author=Chang KM, Liu M| title=Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics. | journal=Curr Opin Pharmacol | year= 2016 | volume= 30 | issue=  | pages= 93-105 | pmid=27570126 | doi=10.1016/j.coph.2016.07.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27570126  }} </ref>
 
* 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]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
 
* By killing [[infected]] cells and by producing antiviral [[cytokine]]s capable of purging HBV from viable [[hepatocytes]], [[cytotoxic T lymphocytes]] also eliminate the virus.<ref name=Iannacone_2006>{{cite journal | author=Iannacone M. ''et al'' | title=Pathogenetic and antiviral immune responses against hepatitis B virus | journal=[http://www.futuremedicine.com/doi/abs/10.2217/17460794.1.2.189 Future Virology] | year=2006 | pages=189-196 | volume=1 | issue=2</ref>


===Life Cycle===
===Life Cycle===
{| style="float: right;"
* The [[HBV]] [[virion]] binds to a receptor at the surface of the [[hepatocyte]].<ref name=WHO-Guideline-Hepatitis-B> 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</ref><ref name="pmid25989114">{{cite journal| author=Zhang YY, Hu KQ| title=Rethinking the pathogenesis of hepatitis B virus (HBV) infection. | journal=J Med Virol | year= 2015 | volume= 87 | issue= 12 | pages= 1989-99 | pmid=25989114 | doi=10.1002/jmv.24270 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25989114  }} </ref>
| [[File:Hepatitis B life cycle.png|300px|thumb|none|Systematic Diagram of the Life Cycle of HBV <SMALL>Courtesy: ''[http://www.who.int/en/ World Health Organization]''<ref>{{Cite web | title = http://www.who.int/en/ | url = http://www.who.int/en/}}</ref></SMALL>]]
|-
|}
* The [[HBV]] [[virion]] binds to a receptor at the surface of the [[hepatocyte]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>


* Several cellular receptors have been identified, including the [[transferrin]] receptor, the asialoglycoprotein receptor [[molecule]], and the 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.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref><ref>{{cite book | last = Nathanson | first = Neal | title = Viral pathogenesis | publisher = Lippincott-Raven | location = Philadelphia | year = 1997 | isbn = 0781702976 }}</ref><ref name="pmid8057429">{{cite journal| author=Guidotti LG, Martinez V, Loh YT, Rogler CE, Chisari FV| title=Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice. | journal=J Virol | year= 1994 | volume= 68 | issue= 9 | pages= 5469-75 | pmid=8057429 | doi= | pmc=PMC236947 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8057429  }} </ref>
* 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.<ref name=WHO-Guideline-Hepatitis-B> 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</ref><ref name=Nathanson>{{cite book | last = Nathanson | first = Neal | title = Viral pathogenesis | publisher = Lippincott-Raven | location = Philadelphia | year = 1997 | isbn = 0781702976 }}</ref><ref name=Plotkin>{{cite book | last = Plotkin | first = Stanley | title = Vaccines | publisher = W.B. Saunders Co | location = Philadelphia | year = 1999 | isbn = 0721674437 }}</ref><ref name="pmid8057429">{{cite journal| author=Guidotti LG, Martinez V, Loh YT, Rogler CE, Chisari FV| title=Hepatitis B virus nucleocapsid particles do not cross the hepatocyte nuclear membrane in transgenic mice. | journal=J Virol | year= 1994 | volume= 68 | issue= 9 | pages= 5469-75 | pmid=8057429 | doi= | pmc=PMC236947 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8057429  }} </ref>


*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.<ref>{{cite book | last = Nathanson | first = Neal | title = Viral pathogenesis | publisher = Lippincott-Raven | location = Philadelphia | year = 1997 | isbn = 0781702976 }}</ref><ref>{{cite book | last = Plotkin | first = Stanley | title = Vaccines | publisher = W.B. Saunders Co | location = Philadelphia | year = 1999 | isbn = 0721674437 }}</ref>
*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.<ref name=Nathanson>{{cite book | last = Nathanson | first = Neal | title = Viral pathogenesis | publisher = Lippincott-Raven | location = Philadelphia | year = 1997 | isbn = 0781702976 }}</ref><ref>{{cite book | last = Plotkin | first = Stanley | title = Vaccines | publisher = W.B. Saunders Co | location = Philadelphia | year = 1999 | isbn = 0721674437 }}</ref>


* 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).<ref>{{cite book | last = Nathanson | first = Neal | title = Viral pathogenesis | publisher = Lippincott-Raven | location = Philadelphia | year = 1997 | isbn = 0781702976 }}</ref><ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Elsevier/Churchill Livingstone | location = New York | year = 2005 | isbn = 0443066434 }}</ref>
* These transcripts are [[polyadenylation|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).<ref name=Nathanson>{{cite book | last = Nathanson | first = Neal | title = Viral pathogenesis | publisher = Lippincott-Raven | location = Philadelphia | year = 1997 | isbn = 0781702976 }}</ref><ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Elsevier/Churchill Livingstone | location = New York | year = 2005 | isbn = 0443066434 }}</ref>


* 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 [[viral envelope protein|envelope proteins]] insert themselves as [[integral membrane protein|integral membrane proteins]] into the [[lipid membrane]] of the [[endoplasmic reticulum]] (ER). The 3.5 kb species, which spans the entire genome and is 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.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
* 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 [[endoplasmic reticulum|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.<ref name=WHO-Guideline-Hepatitis-B> 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</ref>


===HBV and Antibody Nomenclature===
===HBV Antigens and Antibodies===
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
|+
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Nomenclature}}
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Nomenclature}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Full Name}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Full Name}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Description}}
! style="background: #4479BA; width: 550px;" | {{fontcolor|#FFF|Description<ref name=WHO-Guideline-Hepatitis-B> 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</ref>}}
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''HBV'''
| style="padding: 5px 5px; background: #DCDCDC;" |'''HBV'''
| style="padding: 5px 5px; background: #F5F5F5;" |''Hepatitis B Virus (complete infectious virion)''
| style="padding: 5px 5px; background: #F5F5F5;" |''Hepatitis B Virus (complete infectious virion)''
| style="padding: 5px 5px; background: #F5F5F5;" |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.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |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.
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''HBsAg'''
| style="padding: 5px 5px; background: #DCDCDC;" |'''HBsAg'''
| style="padding: 5px 5px; background: #F5F5F5;" |''Hepatitis B Surface Antigen (envelope antigen)''
| style="padding: 5px 5px; background: #F5F5F5;" |''Hepatitis B Surface Antigen (envelope antigen)''
| style="padding: 5px 5px; background: #F5F5F5;" |The complex of antigenic determinants found on the surface of HBV and of 22 nm particles and tubular forms.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |The complex of antigenic determinants found on the surface of HBV and of 22 nm particles and tubular forms.
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" |'''HBcAg'''
| style="padding: 5px 5px; background: #DCDCDC;" |'''HBcAg'''
| style="padding: 5px 5px; background: #F5F5F5;" |''Hepatitis B Core Antigen''
| style="padding: 5px 5px; background: #F5F5F5;" |''Hepatitis B Core Antigen''
| style="padding: 5px 5px; background: #F5F5F5;" |The antigenic specificity.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |The antigenic specificity.
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBeAg'''
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBeAg'''
| style="padding: 5px 5px; background: #F5F5F5;" |Hepatitis B e Antigen
| style="padding: 5px 5px; background: #F5F5F5;" |Hepatitis B e Antigen
| style="padding: 5px 5px; background: #F5F5F5;" |The antigenic determinant that is closely associated with the nucleocapsid of HBV. It also circulates as a soluble protein in serum.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |The antigenic determinant that is closely associated with the nucleocapsid of HBV. It also circulates as a soluble protein in serum.
|-
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''Anti-HBs'''<br>'''Anti-HBc'''<br>'''Anti-HBe'''
| style="padding: 5px 5px; background: #DCDCDC;" | '''Anti-HBs'''<br>'''Anti-HBc'''<br>'''Anti-HBe'''
| style="padding: 5px 5px; background: #F5F5F5;" |Antibody to HBsAg<br>Antibody to HBcAg<br>Antibody to HBeAg
| style="padding: 5px 5px; background: #F5F5F5;" |Antibody to HBsAg<br>Antibody to HBcAg<br>Antibody to HBeAg
| style="padding: 5px 5px; background: #F5F5F5;" |Specific antibodies that are produced in response to their respective antigenic determinants.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
| style="padding: 5px 5px; background: #F5F5F5;" |Specific antibodies that are produced in response to their respective antigenic determinants.
|-
|-
|}
|}


===Transmission===
===Transmission===
* [[Transmission]] results from exposure to [[infectious]] blood or [[body fluids]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
* [[Transmission]] results from exposure to [[infectious]] blood or [[body fluids]].<ref name=WHO-Guideline-Hepatitis-B> 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</ref>
 
* Possible modes of [[transmission]] include:<ref name=WHO-Guideline-Hepatitis-B> 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</ref><ref name="pmid791124">{{cite journal| author=Petersen NJ, Barrett DH, Bond WW, Berquist KR, Favero MS, Bender TR et al.| title=Hepatitis B surface antigen in saliva, impetiginous lesions, and the environment in two remote Alaskan villages. | journal=Appl Environ Microbiol | year= 1976 | volume= 32 | issue= 4 | pages= 572-4 | pmid=791124 | doi= | pmc=170308 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=791124 }} </ref>
* Possible forms of [[transmission]] include:<ref> name="pmid791124">{{cite journal |author=Petersen NJ, Barrett DH, Bond WW, Berquist KR, Favero MS, Bender TR, Maynard JE |title=Hepatitis B surface antigen in saliva, impetiginous lesions, and the environment in two remote Alaskan villages |journal=Appl. Environ. Microbiol. |volume=32 |issue=4 |pages=572-574 |year=1976 |pmid=791124}}</ref>
:* [[unprotected sex|Unprotected sexual contact]]
:* [[unprotected sex|Unprotected sexual contact]]
:* [[Blood transfusion]]s
:* [[Blood transfusions]]
:* [[needle sharing|Re-use of contaminated needles]] and syringes
:* [[needle sharing|Re-use of contaminated needles and syringes]]
:* [[Vertical transmission]] from mother to child during childbirth (20% risk of [[transmission]]/ risk is as high as 90% if the mother is also positive for the hepatitis B e antigen)
:* [[Vertical transmission]] from mother to child during childbirth (20% risk of [[transmission]]; the risk can be as high as 90% if the mother is also positive for the hepatitis B e antigen)
:* [[Transmission]] between family members within households, possibly by contact of nonintact [[skin]] or [[mucous membrane]] with [[secretions]] or saliva containing [[HBV]].
:* [[Transmission]] between family members within households, possibly by contact of nonintact [[skin]] or [[mucous membrane]] with [[secretions]] or saliva containing [[HBV]]
 
==Associated Conditions==
===Polyarthritis Nodosa===
 
===Hepatocellular Carcinoma===
* [[Hepatitis B]] is often associated with [[hepatocellular carcinoma]].
 
* More than 85% of examined hepatocellular tumours 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.<ref>{{cite book | last = Fields | first = Bernard | title = Fields virology | publisher = Wolters Kluwer Health/Lippincott Williams & Wilkins | location = Philadelphia | year = 2007 | isbn = 0781760607 }}</ref><ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Elsevier/Churchill Livingstone | location = New York | year = 2005 | isbn = 0443066434 }}</ref><ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
 
* 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]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>


==Coinfections==
==Coinfections==
===Hepatitis D===
===Hepatitis D===
Hepatitis Delta virus (HDV) is a defective virus that is only infectious in the presence of active HBV infection. HDV infection occurs as either coinfection with HBV or superinfection of an HBV carrier. Coinfection usually resolves. Superinfection, however, causes frequently chronic HDV infection and chronic active hepatitis. Both types of infections may cause fulminant hepatitis. Routes of transmission are similar to those of HBV. Preventing acute and chronic HBV infection of susceptible persons by vaccination will also prevent HDV infection.
* Hepatitis Delta virus ([[HDV]]) is a defective [[virus]] that is only [[infectious]] in the presence of active [[HBV infection]].<ref name="pmid25989114">{{cite journal| author=Zhang YY, Hu KQ| title=Rethinking the pathogenesis of hepatitis B virus (HBV) infection. | journal=J Med Virol | year= 2015 | volume= 87 | issue= 12 | pages= 1989-99 | pmid=25989114 | doi=10.1002/jmv.24270 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25989114  }} </ref><ref name="pmid27570126">{{cite journal| author=Chang KM, Liu M| title=Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics. | journal=Curr Opin Pharmacol | year= 2016 | volume= 30 | issue=  | pages= 93-105 | pmid=27570126 | doi=10.1016/j.coph.2016.07.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27570126  }} </ref>
* [[HDV]] infection occurs as either [[coinfection]] with HBV or [[superinfection]] of an HBV carrier:<ref name="pmid25989114">{{cite journal| author=Zhang YY, Hu KQ| title=Rethinking the pathogenesis of hepatitis B virus (HBV) infection. | journal=J Med Virol | year= 2015 | volume= 87 | issue= 12 | pages= 1989-99 | pmid=25989114 | doi=10.1002/jmv.24270 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25989114  }} </ref><ref name="pmid27570126">{{cite journal| author=Chang KM, Liu M| title=Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics. | journal=Curr Opin Pharmacol | year= 2016 | volume= 30 | issue=  | pages= 93-105 | pmid=27570126 | doi=10.1016/j.coph.2016.07.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27570126  }} </ref><ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Elsevier/Churchill Livingstone | location = New York | year = 2005 | isbn = 0443066434 }}</ref>


===HIV===
:*[[Coinfection]] - usually resolves on its own
:*[[Superinfection]] - causes frequently chronic [[HDV]] infection and chronic active hepatitis


==Pathology==
* Both types of [[infections]] may cause [[fulminant hepatitis]].<ref name="pmid25989114">{{cite journal| author=Zhang YY, Hu KQ| title=Rethinking the pathogenesis of hepatitis B virus (HBV) infection. | journal=J Med Virol | year= 2015 | volume= 87 | issue= 12 | pages= 1989-99 | pmid=25989114 | doi=10.1002/jmv.24270 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25989114  }} </ref><ref name="pmid27570126">{{cite journal| author=Chang KM, Liu M| title=Chronic hepatitis B: immune pathogenesis and emerging immunotherapeutics. | journal=Curr Opin Pharmacol | year= 2016 | volume= 30 | issue=  | pages= 93-105 | pmid=27570126 | doi=10.1016/j.coph.2016.07.013 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27570126  }} </ref>
[[Immune complexes]], such as surface antigen-antibody, are important in the [[pathogenesis]] of other disease syndromes characterized by severe damage of [[blood vessels]]:
* Routes of [[transmission]] are similar to those of [[HBV]].
*'''Acute necrotizing vasculitis (polyarteritis nodosa)'''<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
* Preventing acute and chronic [[HBV]] infection of susceptible persons by [[vaccination]] will also prevent HDV infection.<ref name=WHO-Guideline-Hepatitis-B> 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</ref><ref name=Mandell>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>


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]].<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
===HIV===
*About 10% of people living with [[HIV]] in the United States are coinfected with [[HBV]].<ref name=AIDS> 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</ref>
*HIV-positive patients who are [[coinfection|coinfected]] with HBV are at increased risk for serious, life-threatening health complications. HIV/HBV coinfection can also complicate the management of [[HIV]] infection.<ref name=AIDS> 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</ref>
*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]].<ref name=WHO-Guideline-Hepatitis-B> 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</ref>
*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.<ref name=WHO-Guideline-Hepatitis-B> 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</ref>


*'''Membranous glomerulonephritis''':
==References == 
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.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
{{Reflist|2}}


*'''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.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>


Why only a small proportion of patients with circulating complexes develop [[vasculitis]] or [[polyarteritis]] is still not clear.<ref name=WHO>{{cite web | title = Hepatitis B | url = http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf }}</ref>
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==References==
{{reflist|2}}
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[[Category:Hepatitis|B]]
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Latest revision as of 22:05, 29 July 2020

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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. doi:10.1002/jmv.24270. PMID 25989114.
  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. doi:10.1016/j.coph.2016.07.013. PMID 27570126.
  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 236947. 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 170308. 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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