Hepatitis D pathophysiology: Difference between revisions

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{{Hepatitis D}}
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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.


===Life Cycle===
[[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>
To replicate efficiently, a [[virus]] requires the cooperation of the host cell at all stages of the replicative cycle:
#Attachment
#Penetration
#Uncoating
#Provision of appropriate metabolic conditions for the synthesis of viral macromolecules
#Final assembly of viral subunits
#Release of new virions
[[HDV]] also requires the presence of a helper [[hepadnavirus]] to provide the [[protein]] components for its own envelope. How HDV enters hepatocytes is still not known, but it may involve the interaction between HBsAg-L and a cellular receptor. The incoming [[HDV]] [[RNA]] is then transported into the [[nucleus]], probably by the small form of delta antigen, ''HDAg-S''. Binding of HDAg to RNA also protects the HDV RNAs from degradation.
 
 
 
 
 
 
<!--
The receptor that HDV recognizes on human hepatocytes has not been identified; however it is thought to be the same as the HBV receptor because both viruses have the same outer coat.<ref>{{cite journal|last=Barrera|first=A|coauthors=Guerra, B, Notvall, L, Lanford, RE|title=Mapping of the Hepatitis B Virus Pre-S1 Domain Involved in Receptor Recognition|journal=Journal of virology|date=2005 Aug|volume=79|issue=15|pages=9786–98|pmid=16014940|doi=10.1128/JVI.79.15.9786-9798.2005|pmc=1181564}}</ref> HDV recognizes its receptor via the N-terminal domain of the large hepatitis B surface antigen, HBsAg.<ref>{{cite journal|last=Engelke|first=M|coauthors=Mills, K, Seitz, S, Simon, P, Gripon, P, Schnölzer, M, Urban, S|title=Characterization of a hepatitis B and hepatitis delta virus receptor binding site|journal=Hepatology (Baltimore, Md.)|date=2006 Apr|volume=43|issue=4|pages=750–60|pmid=16557545|doi=10.1002/hep.21112}}</ref> Mapping by mutagenesis of this domain has shown that aminoacid residues 9-15 make up the receptor binding site.<ref>{{cite journal|last=Schulze|first=A|coauthors=Schieck, A, Ni, Y, Mier, W, Urban, S|title=Fine Mapping of Pre-S Sequence Requirements for Hepatitis B Virus Large Envelope Protein-Mediated Receptor Interaction|journal=Journal of virology|date=2010 Feb|volume=84|issue=4|pages=1989–2000|pmid=20007265|doi=10.1128/JVI.01902-09|pmc=2812397}}</ref> After entering the hepatocyte, the virus is uncoated and the nucleocapsid translocated to the nucleus due to a signal in HDAg<ref>{{cite journal|last=Xia|first=YP|coauthors=Yeh, CT, Ou, JH, Lai, MM|title=Characterization of nuclear targeting signal of hepatitis delta antigen: nuclear transport as a protein complex|journal=Journal of virology|date=1992 Feb|volume=66|issue=2|pages=914–21|pmid=1731113|pmc=240792}}</ref> Since the nucleocapsid does not contain an RNA polymerase to replicate the virus’ genome, the virus makes use of the cellular [[RNA polymerases]] Initially just RNA pol II,<ref>{{cite journal|author=Lehmann E, Brueckner F, Cramer P|title=Molecular basis of RNA-dependent RNA polymerase II activity|journal=Nature|volume=450|issue=7168|pages=445–9|year=2007|month=November|pmid=18004386|doi=10.1038/nature06290}}</ref><ref>{{cite journal|author=Filipovska J, Konarska MM|title=Specific HDV RNA-templated transcription by pol II in vitro|journal=RNA|volume=6|issue=1|pages=41–54|year=2000|month=January|pmid=10668797|pmc=1369892|url=http://www.rnajournal.org/cgi/pmidlookup?view=long&pmid=10668797|doi=10.1017/S1355838200991167}}</ref> now RNA polymerases I and III have also been shown to be involved in HDV replication<ref>{{cite journal|last=Greco-Stewart|first=VS|coauthors=Schissel, E, Pelchat, M|title=The hepatitis delta virus RNA genome interacts with the human RNA polymerases I and III|journal=Virology|date=2009-03-30|volume=386|issue=1|pages=12–5|pmid=19246067|doi=10.1016/j.virol.2009.02.007}}</ref>  
Normally RNA polymerase II utilizes DNA as a template and produces mRNA. Consequently, if HDV indeed utilizes RNA polymerase II during replication, it would be the only known pathogen capable of using a DNA-dependent polymerase as an RNA-dependent polymerase.


The RNA polymerases treat the RNA genome as double stranded DNA due to the folded rod-like structure it is in. Three forms of RNA are made; circular genomic RNA, circular complementary antigenomic RNA, and a linear polyadenylated antigenomic RNA, which is the mRNA containing the open reading frame for the HDAg. Synthesis of antigenomic RNA occurs in the nucleous, mediated by RNA Pol I, whereas synthesis of genomic RNA takes place in the nucleoplasm, mediated by RNA Pol II.<ref>{{cite journal|last=Li|first=YJ|coauthors=Macnaughton, T, Gao, L, Lai, MM|title=RNA-Templated Replication of Hepatitis Delta Virus: Genomic and Antigenomic RNAs Associate with Different Nuclear Bodies|journal=Journal of virology|date=2006 Jul|volume=80|issue=13|pages=6478–86|pmid=16775335|doi=10.1128/JVI.02650-05|pmc=1488965}}</ref> HDV RNA is synthesized first as linear RNA that contains many copies of the genome. The genomic and antigenomic RNA contain a sequence of 85 nucleotides that acts as a [[ribozyme]], which self-cleaves the linear RNA into monomers. This monomers are then ligated to form circular RNA <ref>{{cite journal|last=Branch|first=AD|coauthors=Benenfeld, BJ, Baroudy, BM, Wells, FV, Gerin, JL, Robertson, HD|title=An ultraviolet-sensitive RNA structural element in a viroid-like domain of the hepatitis delta virus|journal=Science|date=1989-02-03|volume=243|issue=4891|pages=649–52|pmid=2492676|doi=10.1126/science.2492676}}</ref><ref>{{cite journal|last=Wu|first=HN|coauthors=Lin, YJ, Lin, FP, Makino, S, Chang, MF, Lai, MM|title=Human hepatitis delta virus RNA subfragments contain an autocleavage activity|journal=Proceedings of the National Academy of Sciences of the United States of America|date=1989 Mar|volume=86|issue=6|pages=1831–5|pmid=2648383|pmc=286798|doi=10.1073/pnas.86.6.1831}}</ref>  
[[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


There are eight reported genotypes of HDV with unexplained variations in their geographical distribution and pathogenicity.
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===
The routes of transmission of hepatitis D are similar to those for [[hepatitis B]]. Infection is largely restricted to persons at high risk of [[hepatitis B]] infection, particularly injecting drug users and persons receiving clotting factor concentrates.
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>


[[Transmission]] is similar to that of [[HBV]]:
===Genotype and Pathogenesis===
* Bloodborne and sexual
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>
* Percutaneous ([[IV drug use]], [[Haemophilia|haemophiliacs]])
* Permucosal (sexual)
* Perinatal (rare)
[[HDV]] is transmitted [[percutaneously]] or sexually through contact with [[infected]] [[blood]] or blood products.


[[Blood]] is potentially [[infectious]] during all phases of active hepatitis D infection. Peak [[infectivity]] probably occurs just before the onset of acute disease.
==Gross Pathology==
===Cirrhosis===
{{For|gross pathology of cirrhosis|Cirrhosis pathophysiology}}


==Associated Conditions==
===Hepatocellular Carcinoma===
{{For|gross pathology of hepatocellular carcinoma|Hepatocellular carcinoma pathophysiology}}


==Macroscopic Pathology==
==Microscopic Pathology==
===Cirrhosis===
{{For|microscopic pathology of cirrhosis|Cirrhosis pathophysiology}}


===Microscopic Pathology===
===Hepatocellular Carcinoma===
 
{{For|microscopic pathology of hepatocellular carcinoma|Hepatocellular carcinoma pathophysiology}}
{{#ev:youtube|_hXvbpSxFZw}}


==References==
==References==
{{reflist|2}}
{{reflist|2}}
{{WH}}
{{WS}}
[[Category:Hepatitis|D]]
[[Category:Hepatitis|D]]
[[Category:Viruses]]
[[Category:Viruses]]
 
[[Category:Emergency mdicine]]
{{WH}}
[[Category:Disease]]
{{WS}}
[[Category:Up-To-Date]]
[[Category:Infectious disease]]
[[Category:Hepatology]]
[[Category:Gastroenterology]]

Latest revision as of 22:06, 29 July 2020

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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

For gross pathology of cirrhosis, see Cirrhosis pathophysiology.

Hepatocellular Carcinoma

For gross pathology of hepatocellular carcinoma, see Hepatocellular carcinoma pathophysiology.

Microscopic Pathology

Cirrhosis

For microscopic pathology of cirrhosis, see Cirrhosis pathophysiology.

Hepatocellular Carcinoma

For microscopic pathology of hepatocellular carcinoma, see Hepatocellular carcinoma pathophysiology.

References

  1. ↑ 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. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ World Health Organization. Global Alert Response. Hepatitis D 2001. http://www.who.int/csr/disease/hepatitis/whocdscsrncs20011/en/
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.

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