Hepatitis D pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
Despite the limited knowledge concerning the [[pathogenesis]] of [[hepatitis delta virus]] ([[HDV]]) infection, the adaptive and innate immune systems are thought to play a pivotal role on hepatocellular injury. [[HDV]] requires the presence of [[HBV]] to be able to cause [[infection]]. Pathological changes in [[HDV]] are limited to the [[liver]], the only organ in which [[HDV]] can replicate. [[Hepatitis B virus]] ([[HBV]]) is an essential co-factor in the evolution of hepatocellular damage, and infection with both [[HBV]] and [[HDV]] leads to more severe liver injury than [[HBV infection]] alone. There is evidence supporting the possibility that the virus can be cytopathic in certain [[genotype]]s. [[HDV]] is transmitted [[percutaneously]], sexually, or through contact with infected blood or blood products. In rare occasions [[transmission]] may be perinatal. The different [[genotype]]s will influence viral assembly, and consequently [[infectivity]]. | |||
==Pathogenesis== | ==Pathogenesis== | ||
Studies demonstrate that both the adaptive and innate [[immune system]]s may play an important role in liver injury and clearance of the [[HDV|virus]], although these [[immune response]]s are poorly defined. Evidence points to an association between the quantity and quality of host [[T-cell]] responses and the level of [[infection]] control.<ref name="pmid9032359">{{cite journal| author=Nisini R, Paroli M, Accapezzato D, Bonino F, Rosina F, Santantonio T et al.| title=Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. | journal=J Virol | year= 1997 | volume= 71 | issue= 3 | pages= 2241-51 | pmid=9032359 | doi= | pmc=PMC191332 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9032359 }} </ref> [[HDV]] appears to subvert the adaptive [[immune system]] away from Th-1 biased [[CD4]] and [[CD8]] [[T-cell]] response, a necessary process for [[viral]] clearance. | |||
[[Hepatitis B virus]] ([[HBV]]) is an essential co-factor in the evolution of [[hepatocyte|hepatocellular]] damage, and infection with both [[HBV]] and [[HDV]] leads to more severe [[liver]] injury than [[HBV infection]] alone. The mechanisms determining whether a person will spontaneously clear [[HDV]], become chronically infected, or rapidly progress to [[hepatic fibrosis]] are not yet fully understood.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref> The fluctuating [[viral load]] of both [[HDV]] and [[HBV]] in different stages of infection may signify a direct association with the pathogenesis of disease progression. Studies have shown that during the acute phase of [[HDV infection]], HDV [[viremia]] is associated with an increased level of [[alanine transaminase]] ([[ALT]]) and suppressed [[HBV]]. In the later stages of the chronic phase, HDV [[RNA]] decreases, HBV reactivates, and levels of [[transaminases]] are moderately elevated. At this point, either HDV or HBV replicate and lead to [[cirrhosis]] and [[hepatocellular carcinoma]]([[HCC]]) or both viruses are cleared and there is remission. <ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref> | |||
HDV suppresses HBV replication among patients with either | [[HDV]] suppresses [[HBV]] [[replication]] among patients with either [[coinfection]] or [[superinfection]]. In fact, up to 90% of patients with HDV [[coinfection]] are HBeAg negative and have a low HBV [[viral load]]. Furthermore, once [[HDV infection]] is cleared, replication of HBV can reactivate.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref> Evidence points to the possible role of the small(p24) and large(p27) HDV proteins in suppressing HBV replication by:<ref name="pmid19625466">{{cite journal| author=Williams V, Brichler S, Radjef N, Lebon P, Goffard A, Hober D et al.| title=Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. | journal=J Gen Virol | year= 2009 | volume= 90 | issue= Pt 11 | pages= 2759-67 | pmid=19625466 | doi=10.1099/vir.0.011239-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19625466 }} </ref> | ||
* | *Repressing the activity of two enhancer regions (pIIE1 and pIIE2)in the HBV genome | ||
* | *Transactivation of the MxA gene leading to the reduction of viral HBV mRNA export from the nucleus | ||
Although [[hepatitis D]] is thought to be a largely immune-mediated disease process, there is evidence demonstrating that HDV may be cytopathic. Specifically, outbreaks of fulminant hepatitis induced by [[HDV]] [[genotype]] 3 link uncommon histological features to the potentially cytopathic nature of HDV.<ref name="pmid20051970">{{cite journal| author=Wedemeyer H, Manns MP| title=Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. | journal=Nat Rev Gastroenterol Hepatol | year= 2010 | volume= 7 | issue= 1 | pages= 31-40 | pmid=20051970 | doi=10.1038/nrgastro.2009.205 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20051970 }} </ref> More data is necessary to further the understanding of underlying mechanisms of HDV-induced disease.<ref name="pmid21511329">{{cite journal| author=Hughes SA, Wedemeyer H, Harrison PM| title=Hepatitis delta virus. | journal=Lancet | year= 2011 | volume= 378 | issue= 9785 | pages= 73-85 | pmid=21511329 | doi=10.1016/S0140-6736(10)61931-9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21511329 }} </ref> | |||
===Transmission=== | ===Transmission=== | ||
HDV is transmitted [[percutaneously]], sexually, or through contact with infected blood or blood products. [[Perinatal]] [[transmission]] is possible but uncommon. Blood is potentially infectious during all phases of active hepatitis D infection and a very small [[inoculum]] is sufficient to transmit HDV infection. Peak [[infectivity]] probably occurs just before the onset of acute disease. <ref name="GAR">World Health Organization. Global Alert Response. Hepatitis D 2001. http://www.who.int/csr/disease/hepatitis/whocdscsrncs20011/en/</ref> | |||
[[ | ===Genotype and Pathogenesis=== | ||
The [[HDV]] [[genotype]] influences the sequence of the C-terminal moiety of the large HDAg. These changes in the C-terminal moiety will influence the packaging ability of the [[virus]], which will ultimately dictate interaction with [[clathrin]] and consequently the efficiency of [[viral]] assembly and [[infectivity]].<ref name="pmid19940060">{{cite journal| author=Shih HH, Shih C, Wang HW, Su CW, Sheen IJ, Wu JC| title=Pro-205 of large hepatitis delta antigen and Pro-62 of major hepatitis B surface antigen influence the assembly of different genotypes of hepatitis D virus. | journal=J Gen Virol | year= 2010 | volume= 91 | issue= Pt 4 | pages= 1004-12 | pmid=19940060 | doi=10.1099/vir.0.017541-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19940060 }} </ref><ref name="pmid18094179">{{cite journal| author=Shih HH, Jeng KS, Syu WJ, Huang YH, Su CW, Peng WL et al.| title=Hepatitis B surface antigen levels and sequences of natural hepatitis B virus variants influence the assembly and secretion of hepatitis d virus. | journal=J Virol | year= 2008 | volume= 82 | issue= 5 | pages= 2250-64 | pmid=18094179 | doi=10.1128/JVI.02155-07 | pmc=PMC2258943 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18094179 }} </ref><ref name="pmid19793827">{{cite journal| author=Huang C, Chang SC, Yang HC, Chien CL, Chang MF| title=Clathrin-mediated post-Golgi membrane trafficking in the morphogenesis of hepatitis delta virus. | journal=J Virol | year= 2009 | volume= 83 | issue= 23 | pages= 12314-24 | pmid=19793827 | doi=10.1128/JVI.01044-09 | pmc=PMC2786706 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19793827 }} </ref> The fact that all [[genotype]]s are able to bind [[clathrin]] supports the importance of [[clathrin]] in [[HDV]] assembly.<ref name="pmid19284884">{{cite journal| author=Wang YC, Huang CR, Chao M, Lo SJ| title=The C-terminal sequence of the large hepatitis delta antigen is variable but retains the ability to bind clathrin. | journal=Virol J | year= 2009 | volume= 6 | issue= | pages= 31 | pmid=19284884 | doi=10.1186/1743-422X-6-31 | pmc=PMC2661055 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19284884 }} </ref> | |||
[[ | |||
==Gross Pathology== | |||
===Cirrhosis=== | |||
{{For|gross pathology of cirrhosis|Cirrhosis pathophysiology}} | |||
== | ===Hepatocellular Carcinoma=== | ||
{{For|gross pathology of hepatocellular carcinoma|Hepatocellular carcinoma pathophysiology}} | |||
== | ==Microscopic Pathology== | ||
===Cirrhosis=== | |||
{{For|microscopic pathology of cirrhosis|Cirrhosis pathophysiology}} | |||
=== | ===Hepatocellular Carcinoma=== | ||
{{For|microscopic pathology of hepatocellular carcinoma|Hepatocellular carcinoma pathophysiology}} | |||
{{ | |||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
{{WH}} | |||
{{WS}} | |||
[[Category:Hepatitis|D]] | [[Category:Hepatitis|D]] | ||
[[Category:Viruses]] | [[Category:Viruses]] | ||
[[Category:Emergency mdicine]] | |||
[[Category:Disease]] | |||
[[Category:Up-To-Date]] | |||
[[Category:Infectious disease]] | |||
[[Category:Hepatology]] | |||
[[Category:Gastroenterology]] | |||
Latest revision as of 22:06, 29 July 2020
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Hepatitis D |
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Hepatitis D pathophysiology On the Web |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Jolanta Marszalek, M.D. [2] João André Alves Silva, M.D. [3]
Overview
Despite the limited knowledge concerning the pathogenesis of hepatitis delta virus (HDV) infection, the adaptive and innate immune systems are thought to play a pivotal role on hepatocellular injury. HDV requires the presence of HBV to be able to cause infection. Pathological changes in HDV are limited to the liver, the only organ in which HDV can replicate. Hepatitis B virus (HBV) is an essential co-factor in the evolution of hepatocellular damage, and infection with both HBV and HDV leads to more severe liver injury than HBV infection alone. There is evidence supporting the possibility that the virus can be cytopathic in certain genotypes. HDV is transmitted percutaneously, sexually, or through contact with infected blood or blood products. In rare occasions transmission may be perinatal. The different genotypes will influence viral assembly, and consequently infectivity.
Pathogenesis
Studies demonstrate that both the adaptive and innate immune systems may play an important role in liver injury and clearance of the virus, although these immune responses are poorly defined. Evidence points to an association between the quantity and quality of host T-cell responses and the level of infection control.[1] HDV appears to subvert the adaptive immune system away from Th-1 biased CD4 and CD8 T-cell response, a necessary process for viral clearance.
Hepatitis B virus (HBV) is an essential co-factor in the evolution of hepatocellular damage, and infection with both HBV and HDV leads to more severe liver injury than HBV infection alone. The mechanisms determining whether a person will spontaneously clear HDV, become chronically infected, or rapidly progress to hepatic fibrosis are not yet fully understood.[2] The fluctuating viral load of both HDV and HBV in different stages of infection may signify a direct association with the pathogenesis of disease progression. Studies have shown that during the acute phase of HDV infection, HDV viremia is associated with an increased level of alanine transaminase (ALT) and suppressed HBV. In the later stages of the chronic phase, HDV RNA decreases, HBV reactivates, and levels of transaminases are moderately elevated. At this point, either HDV or HBV replicate and lead to cirrhosis and hepatocellular carcinoma(HCC) or both viruses are cleared and there is remission. [2]
HDV suppresses HBV replication among patients with either coinfection or superinfection. In fact, up to 90% of patients with HDV coinfection are HBeAg negative and have a low HBV viral load. Furthermore, once HDV infection is cleared, replication of HBV can reactivate.[2] Evidence points to the possible role of the small(p24) and large(p27) HDV proteins in suppressing HBV replication by:[3]
- Repressing the activity of two enhancer regions (pIIE1 and pIIE2)in the HBV genome
- Transactivation of the MxA gene leading to the reduction of viral HBV mRNA export from the nucleus
Although hepatitis D is thought to be a largely immune-mediated disease process, there is evidence demonstrating that HDV may be cytopathic. Specifically, outbreaks of fulminant hepatitis induced by HDV genotype 3 link uncommon histological features to the potentially cytopathic nature of HDV.[4] More data is necessary to further the understanding of underlying mechanisms of HDV-induced disease.[2]
Transmission
HDV is transmitted percutaneously, sexually, or through contact with infected blood or blood products. Perinatal transmission is possible but uncommon. Blood is potentially infectious during all phases of active hepatitis D infection and a very small inoculum is sufficient to transmit HDV infection. Peak infectivity probably occurs just before the onset of acute disease. [5]
Genotype and Pathogenesis
The HDV genotype influences the sequence of the C-terminal moiety of the large HDAg. These changes in the C-terminal moiety will influence the packaging ability of the virus, which will ultimately dictate interaction with clathrin and consequently the efficiency of viral assembly and infectivity.[6][7][8] The fact that all genotypes are able to bind clathrin supports the importance of clathrin in HDV assembly.[9]
Gross Pathology
Cirrhosis
Hepatocellular Carcinoma
Microscopic Pathology
Cirrhosis
Hepatocellular Carcinoma
References
- ↑ Nisini R, Paroli M, Accapezzato D, Bonino F, Rosina F, Santantonio T; et al. (1997). "Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles". J Virol. 71 (3): 2241–51. PMC 191332. PMID 9032359.
- ↑ 2.0 2.1 2.2 2.3 Hughes SA, Wedemeyer H, Harrison PM (2011). "Hepatitis delta virus". Lancet. 378 (9785): 73–85. doi:10.1016/S0140-6736(10)61931-9. PMID 21511329.
- ↑ Williams V, Brichler S, Radjef N, Lebon P, Goffard A, Hober D; et al. (2009). "Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene". J Gen Virol. 90 (Pt 11): 2759–67. doi:10.1099/vir.0.011239-0. PMID 19625466.
- ↑ Wedemeyer H, Manns MP (2010). "Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead". Nat Rev Gastroenterol Hepatol. 7 (1): 31–40. doi:10.1038/nrgastro.2009.205. PMID 20051970.
- ↑ World Health Organization. Global Alert Response. Hepatitis D 2001. http://www.who.int/csr/disease/hepatitis/whocdscsrncs20011/en/
- ↑ Shih HH, Shih C, Wang HW, Su CW, Sheen IJ, Wu JC (2010). "Pro-205 of large hepatitis delta antigen and Pro-62 of major hepatitis B surface antigen influence the assembly of different genotypes of hepatitis D virus". J Gen Virol. 91 (Pt 4): 1004–12. doi:10.1099/vir.0.017541-0. PMID 19940060.
- ↑ Shih HH, Jeng KS, Syu WJ, Huang YH, Su CW, Peng WL; et al. (2008). "Hepatitis B surface antigen levels and sequences of natural hepatitis B virus variants influence the assembly and secretion of hepatitis d virus". J Virol. 82 (5): 2250–64. doi:10.1128/JVI.02155-07. PMC 2258943. PMID 18094179.
- ↑ Huang C, Chang SC, Yang HC, Chien CL, Chang MF (2009). "Clathrin-mediated post-Golgi membrane trafficking in the morphogenesis of hepatitis delta virus". J Virol. 83 (23): 12314–24. doi:10.1128/JVI.01044-09. PMC 2786706. PMID 19793827.
- ↑ Wang YC, Huang CR, Chao M, Lo SJ (2009). "The C-terminal sequence of the large hepatitis delta antigen is variable but retains the ability to bind clathrin". Virol J. 6: 31. doi:10.1186/1743-422X-6-31. PMC 2661055. PMID 19284884.