Hepatitis D laboratory findings: Difference between revisions

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==Overview==
==Overview==
The diagnosis of hepatitis D is made by the detection of HDV RNA in circulation, with [[RT-PCR]]. The levels of [[HBsAg]] may be used during treatment to evaluate the response, and determine the duration of therapy. After recovery, markers of [[HDV infection]], such as [[IgM]] and [[IgG]] [[antibodies]] disappear within months. [[Liver biopsy]] is indicated in HDV RNA positive patients, to assess the stage of liver disease. Findings in [[liver biopsy]] are similar to those observed in [[HBV infection]]. [[Coinfection]] with [[HIV]] and [[HCV]] should be ruled out in HDV infected patients. [[Serologic]] markers such as HDV [[RNA]], HDAg, and [[IgM]] and [[IgG]] anti-HD [[antibodies]] may persist for longer periods in chronic hepatitis D.


==Laboratory Findings==
==Laboratory Findings==
[[Hepatitis D]] should be considered in any individual who is [[HBsAg]] positive or has evidence of recent [[HBV infection]]. The [[diagnosis]] of acute [[hepatitis D]] is made after evaluation of [[serologic]] tests for the [[HDV|virus]].
[[Hepatitis D]] should be considered in any individual who is [[HBsAg]] positive or that has evidence of recent [[HBV infection]]. The [[diagnosis]] of acute [[hepatitis D]] is made after evaluation of [[serologic]] tests for the [[HDV|virus]]. Persons infected with [[HDV]] develop anti-HDV antibodies. Accordingly, every individual with an [[HBsAg]] positive test result, should be studied for the presence of anti-[[HDV]] [[IgG]] antibodies.<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> Positive HDV antibodies do not necessarily represent active infection, since HDV [[RNA]] might have been cleared away (recovery), while the [[antibodies]] may remain in circulation for longer periods of time.<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><ref name="pmid16968924">{{cite journal| author=Paraná R, Kay A, Molinet F, Viana S, Silva LK, Salcedo JM et al.| title=HDV genotypes in the Western Brazilian Amazon region: A preliminary report. | journal=Am J Trop Med Hyg | year= 2006 | volume= 75 | issue= 3 | pages= 475-9 | pmid=16968924 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16968924  }} </ref> Even in cases of [[HBsAg]] [[seroconversion]], or [[liver transplant]], anti-HDV antibodies may be detected during several years.<ref name="pmid16968924">{{cite journal| author=Paraná R, Kay A, Molinet F, Viana S, Silva LK, Salcedo JM et al.| title=HDV genotypes in the Western Brazilian Amazon region: A preliminary report. | journal=Am J Trop Med Hyg | year= 2006 | volume= 75 | issue= 3 | pages= 475-9 | pmid=16968924 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16968924  }} </ref><ref name="pmid21762665">{{cite journal| author=Mederacke I, Filmann N, Yurdaydin C, Bremer B, Puls F, Zacher BJ et al.| title=Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation. | journal=J Hepatol | year= 2012 | volume= 56 | issue= 1 | pages= 115-22 | pmid=21762665 | doi=10.1016/j.jhep.2011.06.016 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21762665  }} </ref>


During therapy, the decrease in the levels of [[HBsAg]] may be used to determine the duration of treatment. It is also important to determine the levels of [[HBV]] [[DNA]], in order to assess the need for an [[HBV]] [[polymerase]] inhibitor.<ref name="pmid23242761">{{cite journal| author=Heidrich B, Manns MP, Wedemeyer H| title=Treatment options for hepatitis delta virus infection. | journal=Curr Infect Dis Rep | year= 2013 | volume= 15 | issue= 1 | pages= 31-8 | pmid=23242761 | doi=10.1007/s11908-012-0307-z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23242761  }} </ref>


The table below describes the significance of diagnostic markers in HDV infection. <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 active form of the [[HDV infection]] was initially diagnosed by the detection of anti-HDV [[IgM]] antibodies. However, today acute active [[infection]] is confirmed with [[real-time PCR]], by detecting [[serum]] [[HDV]] [[RNA]].<ref name="pmid20351206">{{cite journal| author=Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, Bock T et al.| title=Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics. | journal=J Clin Microbiol | year= 2010 | volume= 48 | issue= 6 | pages= 2022-9 | pmid=20351206 | doi=10.1128/JCM.00084-10 | pmc=PMC2884474 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20351206  }} </ref>
 
Patients presenting with [[liver disease]], following [[HDV infection]], should be tested for anti-HDV [[IgM]] antibodies, even when the [[HDV]] [[RNA]] test is negative. This is due to the fact that the [[hepatitis D virus]] shows [[genome]] variability, which might lead to [[false-negative]] results.<ref name="pmid17591028">{{cite journal| author=Manesis EK, Schina M, Le Gal F, Agelopoulou O, Papaioannou C, Kalligeros C et al.| title=Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring. | journal=Antivir Ther | year= 2007 | volume= 12 | issue= 3 | pages= 381-8 | pmid=17591028 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17591028  }} </ref><ref name="pmid15872267">{{cite journal| author=Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P et al.| title=Quantification of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different patterns of virological response to interferon therapy in chronically infected patients. | journal=J Clin Microbiol | year= 2005 | volume= 43 | issue= 5 | pages= 2363-9 | pmid=15872267 | doi=10.1128/JCM.43.5.2363-2369.2005 | pmc=PMC1153793 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15872267  }} </ref> Although the levels of [[HDV]] RNA in the serum do not correlate with the stage of the disease, or [[liver]] [[fibrosis]], the HDV [[RNA]] quantification may be used to evaluate the response to the [[antiviral]] therapy.<ref name="pmid19840253">{{cite journal| author=Zachou K, Yurdaydin C, Drebber U, Dalekos GN, Erhardt A, Cakaloglu Y et al.| title=Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis. | journal=Liver Int | year= 2010 | volume= 30 | issue= 3 | pages= 430-7 | pmid=19840253 | doi=10.1111/j.1478-3231.2009.02140.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19840253  }} </ref>
 
According to different studies, it hasn't been noted an association between [[HDV]] [[RNA]] levels, [[HBsAg]] titre, liver test results and the stage of [[liver disease]]. Therefore, [[liver biopsy]] remains an important tool to assess pathological changes in liver [[histology]].<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>
 
Each of the markers of [[HDV infection]], including [[IgM]] and [[IgG]] [[antibodies]], disappears within months after recovery. In chronic hepatitis D,  HDV [[RNA]], HDAg, and [[IgM]] and [[IgG]] anti-HD [[antibodies]] persist for longer periods.<ref>{{cite book | last = Webster | first = Robert | title = Encyclopedia of virology plus | publisher = Academic | location = San Diego | year = 1996 | isbn = 0120001039 }}</ref>
 
Below is a diagram representing the assessment of patients with hepatitis D:
 
[[File:Hep D diagnosis.png|thumb|center|700px|Hepatitis D diagnosis <SMALL> Adapted from ''Treatment Options for Hepatitis Delta Virus Infection'' - Springer Science<ref name="pmid23242761">{{cite journal| author=Heidrich B, Manns MP, Wedemeyer H| title=Treatment options for hepatitis delta virus infection. | journal=Curr Infect Dis Rep | year= 2013 | volume= 15 | issue= 1 | pages= 31-8 | pmid=23242761 | doi=10.1007/s11908-012-0307-z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23242761  }}</ref></SMALL>]]
 
==Diagnostic Markers==
The table below describes the significance of diagnostic markers in [[HDV infection]]. <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>


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[[File:Hep D diagnosis.png|thumb|center|700px|Hepatitis D diagnosis <SMALL> Adapted from ''Treatment Options for Hepatitis Delta Virus Infection'' - Springer Science<ref name="pmid23242761">{{cite journal| author=Heidrich B, Manns MP, Wedemeyer H| title=Treatment options for hepatitis delta virus infection. | journal=Curr Infect Dis Rep | year= 2013 | volume= 15 | issue= 1 | pages= 31-8 | pmid=23242761 | doi=10.1007/s11908-012-0307-z | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23242761 }}</ref></SMALL>]]
===Liver Biopsy:===
*[[Liver biopsy]] is not indicated for the routine [[diagnosis]] of acute hepatitis D, unless [[serologic]] diagnosis is inconclusive. [[Liver biopsy]] is indicated when patients are HDV RNA positive, in which case, it will help assess the severity of [[liver 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>
 
*Due to the inability of [[noninvasive]] markers of [[fibrosis]] to predict the correct stage of the disease, [[liver biopsy]] should be performed in patients with [[hepatitis D]].<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>
 
*Findings are similar to those observed in [[HBV infection]]. [[Lymphocytic]] infiltrates may be observed in [[hepatocytes]].
 
*[[Immunohistochemical staining]] may be positive for HDV antigen with suppression of [[HBsAg]] in case of [[superinfection]].
 
===Acute HBV-HDV Coinfection===
Acute [[coinfection]] of [[HDV]] with [[HBV]] is characterized by:<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref>
* Appearence of [[HBsAg]], HBeAg and HBV DNA in [[serum]] during incubation
* Appearence of anti-HBc at onset of clinical disease
* Appearence of [[IgM]] anti-HD, [[HDV]] [[RNA]], HDAg in [[serum]]
* Anti-HDV [[antibodies]] develop late in acute phase and usually decline after infection to subdetectable levels
* If HDAg is detectable early during [[infection]], it disappears as anti-HDV appears
* All markers of [[viral replication]] disappear in early [[convalescence]], and both [[IgM]] and [[IgG]] anti-HD disappear within months to years after recovery<br>
[[Image:HDV_Coinfection.png|none|thumb|600px|''[http://www.cdc.gov  Slide from the Center for Disease Control and Prevention(CDC)]''<ref name="CDC">{{Cite web | title = Center for Disease Control and Prevention (CDC) | url =  http://www.cdc.gov}}</ref>]]
 
===HBV-HDV Superinfection===
[[Superinfection]] of [[HDV]] with [[HBV]] is characterized by:<ref name=WHO>{{cite web | title = Hepatitis D | url = http://www.who.int/csr/disease/hepatitis/HepatitisD_whocdscsrncs2001_1.pdf }}</ref>
* Persistent [[HDV infection]]
* [[HDV]] [[viremia]] appears in [[serum]] during preacute phase
* High titres of [[IgM]] and [[IgG]] anti-HDV are detectable in acute phase, persisting indefinitely
* Titre of [[HBsAg]] declines when HDAg appears in [[serum]]
* Progression to chronicity is associated with persisting high levels of [[IgM]] anti-HD and [[IgG]] anti-HD
* HDAg and HDV RNA remain detectable in [[serum]] and [[liver]]
* [[Viremia]] is associated with active [[liver disease]]<br>
[[Image:HDV_Superinfection.png|none|thumb|600px|''[http://www.cdc.gov  Slide from Center for Disease Control and Prevention(CDC)]''<ref name="CDC">{{Cite web | title = Center for Disease Control and Prevention (CDC) | url =  http://www.cdc.gov}}</ref>]]
 
==Viral Dominance==
The simultaneous presence of [[HBV]], [[HDV]] and sometimes [[HCV]], influences the [[serologic]] findings in each patient. Infection by [[HDV]] and [[HBV]] (either in [[coinfection]] or [[superinfection]]) suppresses the [[replication]] of HBV genome.<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> Patients coinfected with HDV often show:<ref name="pmid18098143">{{cite journal| author=Cross TJ, Rizzi P, Horner M, Jolly A, Hussain MJ, Smith HM et al.| title=The increasing prevalence of hepatitis delta virus (HDV) infection in South London. | journal=J Med Virol | year= 2008 | volume= 80 | issue= 2 | pages= 277-82 | pmid=18098143 | doi=10.1002/jmv.21078 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18098143  }} </ref><ref name="pmid11050062">{{cite journal| author=Sagnelli E, Coppola N, Scolastico C, Filippini P, Santantonio T, Stroffolini T et al.| title=Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis. | journal=Hepatology | year= 2000 | volume= 32 | issue= 5 | pages= 1106-10 | pmid=11050062 | doi=10.1053/jhep.2000.19288 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11050062  }} </ref><ref name="pmid19566789">{{cite journal| author=Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, Wedemeyer H| title=Virological and clinical characteristics of delta hepatitis in Central Europe. | journal=J Viral Hepat | year= 2009 | volume= 16 | issue= 12 | pages= 883-94 | pmid=19566789 | doi=10.1111/j.1365-2893.2009.01144.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19566789  }} </ref>
*Negative HBeAg
*Low [[serum]] levels of [[HBV]] [[DNA]]
 
Once [[infection]] with [[HDV]] is cleared, either by host's [[immune system]] or with [[interferon]] treatment, [[replication]] of [[HBV]] will then be reactivated.<ref name="pmid16941695">{{cite journal| author=Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N et al.| title=Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. | journal=Hepatology | year= 2006 | volume= 44 | issue= 3 | pages= 728-35 | pmid=16941695 | doi=10.1002/hep.21325 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16941695  }} </ref>
 
In prolonged [[infections]], both [[virus]]es may become dominant. In which case, [[serologic]] levels of [[HBV]] [[DNA]] and [[HDV]] [[RNA]] may fluctuate.<ref name="pmid20346531">{{cite journal| author=Schaper M, Rodriguez-Frias F, Jardi R, Tabernero D, Homs M, Ruiz G et al.| title=Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. | journal=J Hepatol | year= 2010 | volume= 52 | issue= 5 | pages= 658-64 | pmid=20346531 | doi=10.1016/j.jhep.2009.10.036 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20346531  }} </ref><ref name="pmid20334947">{{cite journal| author=Wedemeyer H| title=Re-emerging interest in hepatitis delta: new insights into the dynamic interplay between HBV and HDV. | journal=J Hepatol | year= 2010 | volume= 52 | issue= 5 | pages= 627-9 | pmid=20334947 | doi=10.1016/j.jhep.2010.02.001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20334947 }} </ref>
 
In patients [[infected]] with [[HCV]], along with [[HDV]] and [[HBV]], the [[HDV]] is the dominant virus. It is able not only to suppress the [[replication]] of [[HBV]], but also to inhibit the [[replication]] of [[HCV]].<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>
 
===Coinfection with HIV===
Patients infected with the [[HDV]] should be [[screening|screened]] for concomitant infection with [[HIV]].<ref name="pmid18098143">{{cite journal| author=Cross TJ, Rizzi P, Horner M, Jolly A, Hussain MJ, Smith HM et al.| title=The increasing prevalence of hepatitis delta virus (HDV) infection in South London. | journal=J Med Virol | year= 2008 | volume= 80 | issue= 2 | pages= 277-82 | pmid=18098143 | doi=10.1002/jmv.21078 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18098143  }} </ref><ref name="pmid19566789">{{cite journal| author=Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, Wedemeyer H| title=Virological and clinical characteristics of delta hepatitis in Central Europe. | journal=J Viral Hepat | year= 2009 | volume= 16 | issue= 12 | pages= 883-94 | pmid=19566789 | doi=10.1111/j.1365-2893.2009.01144.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19566789  }} </ref>


==References==
==References==
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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

The diagnosis of hepatitis D is made by the detection of HDV RNA in circulation, with RT-PCR. The levels of HBsAg may be used during treatment to evaluate the response, and determine the duration of therapy. After recovery, markers of HDV infection, such as IgM and IgG antibodies disappear within months. Liver biopsy is indicated in HDV RNA positive patients, to assess the stage of liver disease. Findings in liver biopsy are similar to those observed in HBV infection. Coinfection with HIV and HCV should be ruled out in HDV infected patients. Serologic markers such as HDV RNA, HDAg, and IgM and IgG anti-HD antibodies may persist for longer periods in chronic hepatitis D.

Laboratory Findings

Hepatitis D should be considered in any individual who is HBsAg positive or that has evidence of recent HBV infection. The diagnosis of acute hepatitis D is made after evaluation of serologic tests for the virus. Persons infected with HDV develop anti-HDV antibodies. Accordingly, every individual with an HBsAg positive test result, should be studied for the presence of anti-HDV IgG antibodies.[1] Positive HDV antibodies do not necessarily represent active infection, since HDV RNA might have been cleared away (recovery), while the antibodies may remain in circulation for longer periods of time.[2][3] Even in cases of HBsAg seroconversion, or liver transplant, anti-HDV antibodies may be detected during several years.[3][4]

During therapy, the decrease in the levels of HBsAg may be used to determine the duration of treatment. It is also important to determine the levels of HBV DNA, in order to assess the need for an HBV polymerase inhibitor.[5]

The active form of the HDV infection was initially diagnosed by the detection of anti-HDV IgM antibodies. However, today acute active infection is confirmed with real-time PCR, by detecting serum HDV RNA.[6]

Patients presenting with liver disease, following HDV infection, should be tested for anti-HDV IgM antibodies, even when the HDV RNA test is negative. This is due to the fact that the hepatitis D virus shows genome variability, which might lead to false-negative results.[7][8] Although the levels of HDV RNA in the serum do not correlate with the stage of the disease, or liver fibrosis, the HDV RNA quantification may be used to evaluate the response to the antiviral therapy.[9]

According to different studies, it hasn't been noted an association between HDV RNA levels, HBsAg titre, liver test results and the stage of liver disease. Therefore, liver biopsy remains an important tool to assess pathological changes in liver histology.[1]

Each of the markers of HDV infection, including IgM and IgG antibodies, disappears within months after recovery. In chronic hepatitis D, HDV RNA, HDAg, and IgM and IgG anti-HD antibodies persist for longer periods.[10]

Below is a diagram representing the assessment of patients with hepatitis D:

Hepatitis D diagnosis Adapted from Treatment Options for Hepatitis Delta Virus Infection - Springer Science[5]

Diagnostic Markers

The table below describes the significance of diagnostic markers in HDV infection. [1]

Diagnostic Markers Significance
Anti-HDV IgG antibody
  • Positive in persons exposed to HDV
  • Persists, even after viral clearance
Anti-HDV IgM antibody
  • Positive in acute infection
  • Negative in past infection
  • Persists in many patients with chronic infection
HDV RNA

Qualitative

  • Marker of HDV replication
  • Positive in chronic infection
  • Negative in spontaneous or treatment-induced viral clearance

Quantitative

  • Useful in monitoring or predicting treatment response
HBsAg

Qualitative

  • Must be positive for HDV infectivity

Quantitative

  • Positively correlated with HDV RNA
  • Falling titer signals HBsAg loss, and hence HDV clearance
  • Useful in monitoring or predicting treatment response
HBeAg
  • Negative in an estimated 85% of patients
  • Associated with detectable anti-HBe
HBV DNA

Quantitative

  • Suppressed by HDV
  • Negative or low levels in most patients
  • May be increased in patients with detectable HBeAg
  • Can reactivate after spontaneous or treatment-induced clearance of HDV
ALT
  • Increased in most patients
  • Does not correlate well with degree of histological liver damage

Liver Biopsy:

Acute HBV-HDV Coinfection

Acute coinfection of HDV with HBV is characterized by:[11]

  • Appearence of HBsAg, HBeAg and HBV DNA in serum during incubation
  • Appearence of anti-HBc at onset of clinical disease
  • Appearence of IgM anti-HD, HDV RNA, HDAg in serum
  • Anti-HDV antibodies develop late in acute phase and usually decline after infection to subdetectable levels
  • If HDAg is detectable early during infection, it disappears as anti-HDV appears
  • All markers of viral replication disappear in early convalescence, and both IgM and IgG anti-HD disappear within months to years after recovery
Slide from the Center for Disease Control and Prevention(CDC)[12]

HBV-HDV Superinfection

Superinfection of HDV with HBV is characterized by:[11]

  • Persistent HDV infection
  • HDV viremia appears in serum during preacute phase
  • High titres of IgM and IgG anti-HDV are detectable in acute phase, persisting indefinitely
  • Titre of HBsAg declines when HDAg appears in serum
  • Progression to chronicity is associated with persisting high levels of IgM anti-HD and IgG anti-HD
  • HDAg and HDV RNA remain detectable in serum and liver
  • Viremia is associated with active liver disease
Slide from Center for Disease Control and Prevention(CDC)[12]

Viral Dominance

The simultaneous presence of HBV, HDV and sometimes HCV, influences the serologic findings in each patient. Infection by HDV and HBV (either in coinfection or superinfection) suppresses the replication of HBV genome.[1] Patients coinfected with HDV often show:[13][14][15]

Once infection with HDV is cleared, either by host's immune system or with interferon treatment, replication of HBV will then be reactivated.[16]

In prolonged infections, both viruses may become dominant. In which case, serologic levels of HBV DNA and HDV RNA may fluctuate.[17][18]

In patients infected with HCV, along with HDV and HBV, the HDV is the dominant virus. It is able not only to suppress the replication of HBV, but also to inhibit the replication of HCV.[1]

Coinfection with HIV

Patients infected with the HDV should be screened for concomitant infection with HIV.[13][15]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 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.
  2. ↑ 2.0 2.1 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.
  3. ↑ 3.0 3.1 Paraná R, Kay A, Molinet F, Viana S, Silva LK, Salcedo JM; et al. (2006). "HDV genotypes in the Western Brazilian Amazon region: A preliminary report". Am J Trop Med Hyg. 75 (3): 475–9. PMID 16968924.
  4. ↑ Mederacke I, Filmann N, Yurdaydin C, Bremer B, Puls F, Zacher BJ; et al. (2012). "Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation". J Hepatol. 56 (1): 115–22. doi:10.1016/j.jhep.2011.06.016. PMID 21762665.
  5. ↑ 5.0 5.1 Heidrich B, Manns MP, Wedemeyer H (2013). "Treatment options for hepatitis delta virus infection". Curr Infect Dis Rep. 15 (1): 31–8. doi:10.1007/s11908-012-0307-z. PMID 23242761.
  6. ↑ Mederacke I, Bremer B, Heidrich B, Kirschner J, Deterding K, Bock T; et al. (2010). "Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics". J Clin Microbiol. 48 (6): 2022–9. doi:10.1128/JCM.00084-10. PMC 2884474. PMID 20351206.
  7. ↑ Manesis EK, Schina M, Le Gal F, Agelopoulou O, Papaioannou C, Kalligeros C; et al. (2007). "Quantitative analysis of hepatitis D virus RNA and hepatitis B surface antigen serum levels in chronic delta hepatitis improves treatment monitoring". Antivir Ther. 12 (3): 381–8. PMID 17591028.
  8. ↑ Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P; et al. (2005). "Quantification of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different patterns of virological response to interferon therapy in chronically infected patients". J Clin Microbiol. 43 (5): 2363–9. doi:10.1128/JCM.43.5.2363-2369.2005. PMC 1153793. PMID 15872267.
  9. ↑ Zachou K, Yurdaydin C, Drebber U, Dalekos GN, Erhardt A, Cakaloglu Y; et al. (2010). "Quantitative HBsAg and HDV-RNA levels in chronic delta hepatitis". Liver Int. 30 (3): 430–7. doi:10.1111/j.1478-3231.2009.02140.x. PMID 19840253.
  10. ↑ Webster, Robert (1996). Encyclopedia of virology plus. San Diego: Academic. ISBN 0120001039.
  11. ↑ 11.0 11.1 "Hepatitis D" (PDF).
  12. ↑ 12.0 12.1 "Center for Disease Control and Prevention (CDC)".
  13. ↑ 13.0 13.1 Cross TJ, Rizzi P, Horner M, Jolly A, Hussain MJ, Smith HM; et al. (2008). "The increasing prevalence of hepatitis delta virus (HDV) infection in South London". J Med Virol. 80 (2): 277–82. doi:10.1002/jmv.21078. PMID 18098143.
  14. ↑ Sagnelli E, Coppola N, Scolastico C, Filippini P, Santantonio T, Stroffolini T; et al. (2000). "Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis". Hepatology. 32 (5): 1106–10. doi:10.1053/jhep.2000.19288. PMID 11050062.
  15. ↑ 15.0 15.1 Heidrich B, Deterding K, Tillmann HL, Raupach R, Manns MP, Wedemeyer H (2009). "Virological and clinical characteristics of delta hepatitis in Central Europe". J Viral Hepat. 16 (12): 883–94. doi:10.1111/j.1365-2893.2009.01144.x. PMID 19566789.
  16. ↑ Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N; et al. (2006). "Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up". Hepatology. 44 (3): 728–35. doi:10.1002/hep.21325. PMID 16941695.
  17. ↑ Schaper M, Rodriguez-Frias F, Jardi R, Tabernero D, Homs M, Ruiz G; et al. (2010). "Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D." J Hepatol. 52 (5): 658–64. doi:10.1016/j.jhep.2009.10.036. PMID 20346531.
  18. ↑ Wedemeyer H (2010). "Re-emerging interest in hepatitis delta: new insights into the dynamic interplay between HBV and HDV". J Hepatol. 52 (5): 627–9. doi:10.1016/j.jhep.2010.02.001. PMID 20334947.

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