Hepatitis B pathophysiology: Difference between revisions

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{{Taxobox | color = violet
__NOTOC__
| name = Hepatitis B virus
| image = Hepatitis B virus 01.jpg
| image_width = 200px
| image_caption = Micrograph showing hepatitis B virions
| virus_group = VII
| familia = ''[[Hepadnaviridae]]''
| genus = ''Orthohepadnavirus''
| species = ''Hepatitis B virus''
}}
{{Hepatitis B}}
{{Hepatitis B}}
{{CMG}}; '''Associate Editor In Chief:''' {{CZ}}
{{CMG}}; {{AE}} {{JS}}, {{SaraM}}


==Pathophysiology==
==Overview==
Hepatitis B is a serious disease caused by a virus that attacks the liver. The virus, which is called hepatitis B virus (HBV), can cause lifelong infection, cirrhosis (scarring) of the liver, liver cancer, liver failure, and death.  
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>


HBV is a 42-nm DNA virus classified in the Hepadnaviridae family. The liver is the primary site of HBV replication. After a susceptible person is exposed, the virus enters the liver via the bloodstream; no evidence exists indicating that the virus replicates at mucosal surfaces. HBV infection can produce either asymptomatic or symptomatic infection. The average incubation period is 90 days (range: 60--150 days) from exposure to onset of jaundice and 60 days (range: 40--90 days) from exposure to onset of abnormal serum alanine aminotransferase (ALT) levels.  
==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]].<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>


===Structure===
===Life Cycle===
* 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>


Virions consist of an outer [[lipid]] envelope and an icosahedral [[nucleocapsid]] core composed of [[protein]]. The nucleocapsid encloses the viral DNA and a DNA polymerase that has [[reverse transcriptase]] activity. The outer envelope contains embedded proteins which are involved in viral binding of, and release into, susceptible cells. Virion shape is generally spherical with a diameter of 40 - 48 nanometers (nm), but [[pleomorphic]] forms exist, including filamentous and spherical bodies lacking a core. These "subviral" particles are not infectious.
* 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>


The DNA [[genome]] is not segmented but rather partially double-stranded, containing a long and short segment which overlap approximately 240 [[nucleotide]]s to form an open circle. The longer strand is 3020-3320 nucleotides long, and the shorter is 1700-2800 nucleotides long.<ref>[http://phene.cpmc.columbia.edu/ICTVdB/00.030.htm Hepadnaviridae characteristics] - ICTVdB</ref> The virus can be divided into four major [[serotype]]s (adr, adw, ayr, ayw) based on antigenic [[epitope]]s present on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome. Different genotypes have distinct geographic distributions. For example, genotypes B and C are prevalent in China and neighboring countries.
*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>


===Replication===
* 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>


Hepatitis B is one of a few known [[retrovirus|non-retroviral]] viruses which employ [[reverse transcription]] as a part of its replication process. ([[HIV]], a completely unrelated virus, also uses reverse transcription, but it is a retrovirus.) HBV invades [[hepatocyte]]s by binding to surface receptors and becoming internalized. The viral core particles then migrate to the nucleus and the partially double-stranded, relaxed circular genomes (RC-DNA) are repaired to form a covalently closed circular DNA (cccDNA), which is the template for transcription of viral genomic and sub-genomic RNAs by cellular [[RNA polymerase II]]. Of these, the pregenomic RNA (pgRNA) is selectively packaged into progeny capsids and is then reverse-transcribed into new RC-DNA. The core can either bud into the [[endoplasmic reticulum]] to be enveloped and exported from the cell or recycled back into the nucleus for conversion to cccDNA.
* 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 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 Antigens and Antibodies===
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center
|+
! style="background: #4479BA; width: 120px;" | {{fontcolor|#FFF|Nomenclature}}
! style="background: #4479BA; width: 300px;" | {{fontcolor|#FFF|Full Name}}
! 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: #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.
|-
| 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;" |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: #F5F5F5;" |''Hepatitis B Core Antigen''
| style="padding: 5px 5px; background: #F5F5F5;" |The antigenic specificity.
|-
| style="padding: 5px 5px; background: #DCDCDC;" | '''HBeAg'''
| 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.
|-
| 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;" |Specific antibodies that are produced in response to their respective antigenic determinants.
|-
|}


===Transmission===
===Transmission===
[[Image:HBV prevalence 2005.png|thumb|left|350px|Prevalence of Hepatitis B virus as of 2005.]]
* [[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>
Transmission results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include (but are not limited to) [[unprotected sex|unprotected sexual contact]], [[blood transfusion]]s, [[needle sharing|re-use of contaminated needles]] and syringes, and [[vertical transmission]] from mother to child during childbirth.  Without intervention, a mother who is positive for the hepatitis B surface antigen confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for the hepatitis B e <!-- sic! see Replication, above --> antigen. HBV can also be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV.<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>
* 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>
:* [[unprotected sex|Unprotected sexual contact]]
:* [[Blood transfusions]]
:* [[needle sharing|Re-use of contaminated needles and syringes]]
:* [[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]]


The primary method of transmission reflects the prevalence of chronic HBV infection in a given area. In low prevalence areas such as the continental [[United States]] and Western [[Europe]], where less than 2% of the population is chronically infected, injection drug abuse and unprotected sex are the primary methods, although other factors may be important.<ref>{{cite journal | title=Patient-to-patient transmission of hepatitis B virus associated with oral surgery | author=Redd JT, Baumbach J, Kohn W, ''et al.'' | journal=J Infect Dis | year=2007 | volume=195 | issue=9 | pages=1311&ndash;4 | url=http://www.journals.uchicago.edu/JID/journal/issues/v195n9/36695/36695.web.pdf }}</ref> In moderate prevalence areas, which include Eastern Europe, Russia, and Japan, where 2-7% of the population is chronically infected, the disease is predominantly spread among children. In high prevalence areas such as China and South East Asia, transmission during childbirth is most common, although in other areas of high endemicity such as Africa, transmission during childhood is also a significant factor.<ref name="pmid12616449">{{cite journal |author=Alter MJ |title=Epidemiology and prevention of hepatitis B |journal=Semin. Liver Dis. |volume=23 |issue=1 |pages=39-46 |year=2003 |pmid=12616449 |doi=10.1055/s-2003-37583}}</ref> The prevalence of chronic HBV infection in areas of high endemicity is at least 8%.
==Coinfections==
===Hepatitis D===
* 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>


Roughly 16-40% of unimmunized sexual partners of individuals with hepatitis B will be infected through sexual contact. The risk of transmission is closely related to the rate of viral replication in the infected individual at the time of exposure.
:*[[Coinfection]] - usually resolves on its own
:*[[Superinfection]] - causes frequently chronic [[HDV]] infection and chronic active hepatitis


===Immunopathogenesis===
* 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>
* 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.<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>


During HBV infection, the host [[immune response]] causes both hepatocellular damage and viral clearance. While the innate immune response does not play a significant role in these processes, the adaptive immune response, particularly virus-specific [[cytotoxic T lymphocytes]] (CTLs), contributes to nearly all of the liver injury associated with HBV infection. By killing infected cells and by producing antiviral [[cytokine]]s capable of purging HBV from viable hepatocytes, CTLs 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> Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology and [[platelets]] may facilitate the accumulation of CTLs into the liver.<ref name=Iannacone_2005>{{cite journal |author=Iannacone M, Sitia G, Isogawa M, Marchese P, Castro M, Lowenstein P, Chisari F, Ruggeri Z, Guidotti L |title=Platelets mediate cytotoxic T lymphocyte-induced liver damage |journal=Nature Medicine |volume=11 |issue=11 |pages=1167-1169 |year=2005 |url=http://www.nature.com/nm/journal/v11/n11/abs/nm1317.html |pmid=16258538}}</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>


==Histopathology==
==References ==   
Click on the arrow to view the pathologic findings in viral hepatitis:{{#ev:youtube|_hXvbpSxFZw}}
{{Reflist|2}}
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== References ==   
{{Reflist|2}}  


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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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