Hepatitis E pathophysiology: Difference between revisions

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==Overview==
==Overview==
Consensus has not been reached regarding the complete [[pathogenesis]] of [[HEV]].  Evidence shows that the [[HEV|virus]] exposes its [[RNA]] within the host cell's [[cytoplasm]], where it is [[translation|translated]] into a negative [[RNA]] strand that contains [[ORF]]s 1, 2 and 3 that are involved in the [[viral replication|replication]] of the virus.  [[HEV]] is not cytopathic, and the manifestations of the disease result from the body's [[immune]] response towards the infected cells.  The [[transmission]] of the disease depends on the [[genotype]] of the virus.  It may be transmitted through [[ingestion]] of contaminated water, in [[genotype]]s 1 and 2, or [[ingestion]] of uncooked meat, [[genotype]]s 3 and 4.  Acute hepatitis E has been noted to progress to chronic disease in [[HIV]] infected patients with a low [[CD4]] count.  Solid organ transplanted patients are commonly [[asymptomatic]], or have mild symptoms of the disease.  60% of infected patients with an organ transplant, develop chronic hepatitis E, and 10% develop [[liver cirrhosis]].  [[Infection]] is usually due to [[HEV]] [[genotype]] 3, and diagnostic studies should be based on the identification of HEV [[RNA]] by [[PCR]] technique.  Histological changes of the [[liver]] of patients with chronic disease include: [[portal]] hepatitis; [[lymphocytic]] infiltrates; [[necrosis]]; and  [[fibrosis]].


==Pathogenesis==
The cellular [[receptor]] for [[HEV]] and the mode of entry of the [[HEV|virus]] into the host cell are yet to be identified.<ref name="pmid19812150">{{cite journal| author=Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S| title=Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection. | journal=J Virol | year= 2009 | volume= 83 | issue= 24 | pages= 12714-24 | pmid=19812150 | doi=10.1128/JVI.00717-09 | pmc=PMC2786843 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19812150  }} </ref> However, heparin sulfate [[proteoglycans]] are known to be required for the attachment to target cells and [[infection]].  A proposed theory for the [[viral replication|replication]] of [[HEV|virus]] is that, once within the host cell, [[HEV]] exposes its [[RNA]],  which is then [[translation|translated]] into [[proteins]] ([[ORF]]1) that will be responsible for the production of a negative-strand [[RNA]].  This newly produced strand will serve as a template for new [[RNA]]s.  The new RNAs, are translated to [[ORF]]2 and [[ORF]]3.  The [[ORF]] proteins will then transport the [[RNA]] into new [[virions]] that will use cellular [[lipids]] and [[ORF]]3 for their formation.<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref><ref name="pmid21068219">{{cite journal| author=Nagashima S, Takahashi M, Tanaka T, Yamada K, Nishizawa T et al.| title=A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells. | journal=J Gen Virol | year= 2011 | volume= 92 | issue= Pt 2 | pages= 269-78 | pmid=21068219 | doi=10.1099/vir.0.025791-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21068219  }} </ref>
Similarly to other hepatitis viruses, [[HEV]] is not cytopathic. The host's [[immune response]] towards the [[infection|infected]] cells is the cause of liver injury.<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref>


==Pathogenesis==
Although the [[pathogenesis]] behind the increased mortality of infected pregnant women is not completely understood, it is thought to be associated with [[hepatocyte]] injury from [[endotoxin]]s, and an increased [[Th2]] response.<ref name="pmid15955220">{{cite journal| author=Pal R, Aggarwal R, Naik SR, Das V, Das S, Naik S| title=Immunological alterations in pregnant women with acute hepatitis E. | journal=J Gastroenterol Hepatol | year= 2005 | volume= 20 | issue= 7 | pages= 1094-101 | pmid=15955220 | doi=10.1111/j.1440-1746.2005.03875.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15955220 }} </ref>  
The cellular [[receptor]] for [[HEV]] and the mode of entry of the [[HEV|virus]] into the host cell are yet to be identified.<ref name="pmid19812150">{{cite journal| author=Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S| title=Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection. | journal=J Virol | year= 2009 | volume= 83 | issue= 24 | pages= 12714-24 | pmid=19812150 | doi=10.1128/JVI.00717-09 | pmc=PMC2786843 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19812150  }} </ref> However, heparin sulfate [[proteoglycans]] are known to be required for the attachment to target cells and [[infection]].  A proposed theory for the [[viral replication|replication]] of [[HEV|virus]] is that, once within the host cell, [[HEV]] exposes its [[RNA]],  which is then [[translation|translated]] into [[proteins]] ([[ORF]]1) that will be responsible for the production of a negative-strand [[RNA]].  This newly produced strand will serve as a template for new [[genomic]] and subgeneric [[RNA]]s.  The new RNAs, are translated to [[ORF]]2 and [[ORF]]3.  The [[ORF]] proteins will then transport the [[RNA]] into new [[virions]] that will use cellular [[lipids]] and [[ORF]]3 for their formation.<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref><ref name="pmid21068219">{{cite journal| author=Nagashima S, Takahashi M, Tanaka T, Yamada K, Nishizawa T et al.| title=A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells. | journal=J Gen Virol | year= 2011 | volume= 92 | issue= Pt 2 | pages= 269-78 | pmid=21068219 | doi=10.1099/vir.0.025791-0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21068219 }} </ref>


===Transmission===
===Transmission===
The [[hepatitis E virus]] is transmitted mainly through the fecal-oral route, due to fecal contamination of drinking water.
Hepatitis E is mainly transmitted through the [[fecal-oral route]]. In developing countries it occurs mostly from the [[ingestion]] of contaminated water.<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref>  Although person to person [[transmission]] is uncommon, a recent case in Uganda has suggested possible [[transmission]] among persons living in the same house.<ref name="pmid21036857">{{cite journal| author=Howard CM, Handzel T, Hill VR, Grytdal SP, Blanton C, Kamili S et al.| title=Novel risk factors associated with hepatitis E virus infection in a large outbreak in northern Uganda: results from a case-control study and environmental analysis. | journal=Am J Trop Med Hyg | year= 2010 | volume= 83 | issue= 5 | pages= 1170-3 | pmid=21036857 | doi=10.4269/ajtmh.2010.10-0384 | pmc=PMC2963989 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21036857  }} </ref>


Other transmission routes have been identified, including:
Some [[genotype]]s are more associated with a specific route of [[transmission]]:<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref>
* Foodborne [[transmission]] from [[ingestion]] of products derived from [[infected]] animals
*Genotypes 1 and 2 - waterborne [[transmission]]
* [[Transfusion]] of infected [[blood]] products
*Genotypes 3 and 4 - [[ingestion]] of uncooked meat
* Vertical [[transmission]] from a pregnant woman to her [[fetus]]
* [[Ingestion]] of raw or uncooked shellfish has also been identified as the source of sporadic cases in [[endemic]] areas.


Although humans are considered the natural host for the [[hepatitis E virus]], [[antibodies]] to the [[hepatitis E virus]] or closely related [[viruses]] have been detected in primates and several other animal species, suggesting [[infection]] by the virus.
Other noted routes of [[transmission]] include:<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref><ref name="pmid23013075">{{cite journal| author=Hoofnagle JH, Nelson KE, Purcell RH| title=Hepatitis E. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 13 | pages= 1237-44 | pmid=23013075 | doi=10.1056/NEJMra1204512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23013075  }} </ref>
 
*[[Transmission]] through [[blood transfusion]]s
Hepatitis E is a waterborne disease. Contaminated water or food supplies have been implicated in major outbreaks.
*[[Transmission]] through [[organ transplant]]s
*[[Vertical transmission]] from an [[infected]] mother to the [[fetus]]


==Associated Conditions==
==Associated Conditions==
===HIV Co-Infection===
===HIV Co-Infection===
There is a low [[incidence]] of persistent infection with [[HEV]] in HIV patients.<ref name="pmid21749774">{{cite journal| author=Kenfak-Foguena A, Schöni-Affolter F, Bürgisser P, Witteck A, Darling KE, Kovari H et al.| title=Hepatitis E Virus seroprevalence and chronic infections in patients with HIV, Switzerland. | journal=Emerg Infect Dis | year= 2011 | volume= 17 | issue= 6 | pages= 1074-8 | pmid=21749774 | doi=10.3201/eid/1706.101067 | pmc=PMC3358194 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21749774  }} </ref><ref name="pmid21819531">{{cite journal| author=Keane F, Gompels M, Bendall R, Drayton R, Jennings L, Black J et al.| title=Hepatitis E virus coinfection in patients with HIV infection. | journal=HIV Med | year= 2012 | volume= 13 | issue= 1 | pages= 83-8 | pmid=21819531 | doi=10.1111/j.1468-1293.2011.00942.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21819531  }} </ref><ref name="pmid21837786">{{cite journal| author=Kaba M, Richet H, Ravaux I, Moreau J, Poizot-Martin I, Motte A et al.| title=Hepatitis E virus infection in patients infected with the human immunodeficiency virus. | journal=J Med Virol | year= 2011 | volume= 83 | issue= 10 | pages= 1704-16 | pmid=21837786 | doi=10.1002/jmv.22177 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21837786  }} </ref>  However, acute [[HEV infection]] in these patients, particularly in those with low levels of [[CD4]], is associated with progression to chronic disease.<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref>


===Organ Transplant Recipients===
===Organ Transplant Recipients===
Chronic hepatitis E is associated with [[organ transplant]]s, including [[liver transplant|liver]], [[kidney transplant|kidney]] and [[heart transplant|heart]].<ref name="pmid19866448">{{cite journal| author=Pischke S, Suneetha PV, Baechlein C, Barg-Hock H, Heim A, Kamar N et al.| title=Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients. | journal=Liver Transpl | year= 2010 | volume= 16 | issue= 1 | pages= 74-82 | pmid=19866448 | doi=10.1002/lt.21958 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19866448  }} </ref><ref name="pmid18287603">{{cite journal| author=Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J et al.| title=Hepatitis E virus and chronic hepatitis in organ-transplant recipients. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 8 | pages= 811-7 | pmid=18287603 | doi=10.1056/NEJMoa0706992 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18287603  }} </ref><ref name="pmid18287615">{{cite journal| author=Gérolami R, Moal V, Colson P| title=Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 8 | pages= 859-60 | pmid=18287615 | doi=10.1056/NEJMc0708687 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18287615  }} </ref>  Cases have been reported in which [[liver transplant]]s carrying [[HEV]], lead to rapid [[liver cirrhosis]].<ref name="pmid21798217">{{cite journal| author=Schlosser B, Stein A, Neuhaus R, Pahl S, Ramez B, Krüger DH et al.| title=Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient. | journal=J Hepatol | year= 2012 | volume= 56 | issue= 2 | pages= 500-2 | pmid=21798217 | doi=10.1016/j.jhep.2011.06.021 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21798217  }} </ref>  Patients who have received a solid [[organ transplant]], with elevated levels of [[liver enzymes]], in the absence of other causes of [[hepatitis]], should be evaluated for [[HEV]] [[RNA]].<ref name="pmid22537448">{{cite journal| author=Wedemeyer H, Pischke S, Manns MP| title=Pathogenesis and treatment of hepatitis e virus infection. | journal=Gastroenterology | year= 2012 | volume= 142 | issue= 6 | pages= 1388-1397.e1 | pmid=22537448 | doi=10.1053/j.gastro.2012.02.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22537448  }} </ref>
Chronic hepatitis E in [[organ transplant]]ed patients commonly has the following features:<ref name="pmid22549046">{{cite journal| author=Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J et al.| title=Hepatitis E. | journal=Lancet | year= 2012 | volume= 379 | issue= 9835 | pages= 2477-88 | pmid=22549046 | doi=10.1016/S0140-6736(11)61849-7 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22549046  }} </ref><ref name="pmid21354150">{{cite journal| author=Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C et al.| title=Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. | journal=Gastroenterology | year= 2011 | volume= 140 | issue= 5 | pages= 1481-9 | pmid=21354150 | doi=10.1053/j.gastro.2011.02.050 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21354150  }} </ref>
{| style="border: 2px solid #DCDCDC; font-size: 80%; width: 30%;"
|+ '''Organ Transplanted Patients'''
|-
! style="width: 75px; background: #4479BA; text-align: center;"|{{fontcolor|#FFF|Parameter}}
! style="width: 200px; background: #4479BA; text-align: center;"| {{fontcolor|#FFF|Features}}
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''Clinical Manifestations'''
| style="background: #DCDCDC; padding: 5px;"|Mild [[symptoms]] or [[asymptomatic]]<br>[[Jaundice]] is present in few patients
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''ALT Levels at Diagnosis'''
| style="background: #DCDCDC; padding: 5px;"|Mild [[ALT]] elevation (≈300 IU/L)
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''Viral Genotype'''
| style="background: #DCDCDC; padding: 5px;"|[[Genotype]] 3
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''Diagnostic Techniques'''
| style="background: #DCDCDC; padding: 5px;"|
Inaccurate [[serologic]] tests<br>Anti-HEV [[IgM]] and anti-HEV [[IgG]] may be negative<br>[[Seroconversion]] may not occur<br>[[PCR]] should make the diagnosis
|-
| style="background: #F5F5F5; padding: 5px; text-align: center;"| '''Outcomes'''
| style="background: #DCDCDC; padding: 5px;"|60% infected patients develop chronic hepatitis E<br>10% infected patients develop [[liver cirrhosis]]
|-
|}


==Gross Pathology==
Failure to clear the [[HEV|virus]] after acute infection may be explained by:<ref name="pmid18287603">{{cite journal| author=Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J et al.| title=Hepatitis E virus and chronic hepatitis in organ-transplant recipients. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 8 | pages= 811-7 | pmid=18287603 | doi=10.1056/NEJMoa0706992 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18287603  }} </ref><ref name="pmid21354150">{{cite journal| author=Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C et al.| title=Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. | journal=Gastroenterology | year= 2011 | volume= 140 | issue= 5 | pages= 1481-9 | pmid=21354150 | doi=10.1053/j.gastro.2011.02.050 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21354150  }} </ref>
*Level of [[immunosuppression]]
*Period between [[infection]] and latest episode of acute [[rejection]]
*Time since [[organ transplant]]
*Low [[leukocytes]] levels
*Low [[lymphocyte]] count
*Low levels of [[T-cell]]s


==Microscopic Pathology==
==Microscopic Pathology==
Patients who develop [[chronic liver disease]] often have changes in [[liver]] [[histology]]. These may include:<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref>
Patients who develop [[chronic liver disease]] often have changes in [[liver]] [[histology]]. These may include:<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref>
*[[Portal]] hepatitis
*[[Portal]] hepatitis
:*[[Lymphocytic]] infiltrate
*[[Lymphocytic]] infiltrates
:*[[Necrosis]]
*[[Necrosis]]
:*[[Fibrosis]]
*[[Fibrosis]]


In severe cases, these changes may evolve to [[fibrosis]] and [[cirrhosis]].<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref><ref name="pmid18287615">{{cite journal| author=Gérolami R, Moal V, Colson P| title=Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 8 | pages= 859-60 | pmid=18287615 | doi=10.1056/NEJMc0708687 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18287615  }} </ref>
In severe cases, these changes may evolve to [[fibrosis]] and [[cirrhosis]].<ref name="pmid21932388">{{cite journal| author=Aggarwal R, Jameel S| title=Hepatitis E. | journal=Hepatology | year= 2011 | volume= 54 | issue= 6 | pages= 2218-26 | pmid=21932388 | doi=10.1002/hep.24674 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21932388  }} </ref><ref name="pmid18287615">{{cite journal| author=Gérolami R, Moal V, Colson P| title=Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. | journal=N Engl J Med | year= 2008 | volume= 358 | issue= 8 | pages= 859-60 | pmid=18287615 | doi=10.1056/NEJMc0708687 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18287615  }} </ref>
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==References==
==References==
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{{reflist|2}}
{{WS}}
{{WH}}


[[Category:Hepatitis|E]]
[[Category:Hepatitis|E]]
[[Category:Viruses]]
[[Category:Viruses]]
[[Category:Gastroenterology]]
[[Category:Emergency mdicine]]
[[Category:Disease]]
[[Category:Up-To-Date]]
[[Category:Infectious disease]]
[[Category:Infectious disease]]
[[Category:Gastroenterology]]
[[Category:Hepatology]]
{{WS}}
{{WH}}

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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]

Overview

Consensus has not been reached regarding the complete pathogenesis of HEV. Evidence shows that the virus exposes its RNA within the host cell's cytoplasm, where it is translated into a negative RNA strand that contains ORFs 1, 2 and 3 that are involved in the replication of the virus. HEV is not cytopathic, and the manifestations of the disease result from the body's immune response towards the infected cells. The transmission of the disease depends on the genotype of the virus. It may be transmitted through ingestion of contaminated water, in genotypes 1 and 2, or ingestion of uncooked meat, genotypes 3 and 4. Acute hepatitis E has been noted to progress to chronic disease in HIV infected patients with a low CD4 count. Solid organ transplanted patients are commonly asymptomatic, or have mild symptoms of the disease. 60% of infected patients with an organ transplant, develop chronic hepatitis E, and 10% develop liver cirrhosis. Infection is usually due to HEV genotype 3, and diagnostic studies should be based on the identification of HEV RNA by PCR technique. Histological changes of the liver of patients with chronic disease include: portal hepatitis; lymphocytic infiltrates; necrosis; and fibrosis.

Pathogenesis

The cellular receptor for HEV and the mode of entry of the virus into the host cell are yet to be identified.[1] However, heparin sulfate proteoglycans are known to be required for the attachment to target cells and infection. A proposed theory for the replication of virus is that, once within the host cell, HEV exposes its RNA, which is then translated into proteins (ORF1) that will be responsible for the production of a negative-strand RNA. This newly produced strand will serve as a template for new RNAs. The new RNAs, are translated to ORF2 and ORF3. The ORF proteins will then transport the RNA into new virions that will use cellular lipids and ORF3 for their formation.[2][3]

Similarly to other hepatitis viruses, HEV is not cytopathic. The host's immune response towards the infected cells is the cause of liver injury.[2]

Although the pathogenesis behind the increased mortality of infected pregnant women is not completely understood, it is thought to be associated with hepatocyte injury from endotoxins, and an increased Th2 response.[4]

Transmission

Hepatitis E is mainly transmitted through the fecal-oral route. In developing countries it occurs mostly from the ingestion of contaminated water.[5] Although person to person transmission is uncommon, a recent case in Uganda has suggested possible transmission among persons living in the same house.[6]

Some genotypes are more associated with a specific route of transmission:[5]

Other noted routes of transmission include:[5][7]

Associated Conditions

HIV Co-Infection

There is a low incidence of persistent infection with HEV in HIV patients.[8][9][10] However, acute HEV infection in these patients, particularly in those with low levels of CD4, is associated with progression to chronic disease.[5]

Organ Transplant Recipients

Chronic hepatitis E is associated with organ transplants, including liver, kidney and heart.[11][12][13] Cases have been reported in which liver transplants carrying HEV, lead to rapid liver cirrhosis.[14] Patients who have received a solid organ transplant, with elevated levels of liver enzymes, in the absence of other causes of hepatitis, should be evaluated for HEV RNA.[15]

Chronic hepatitis E in organ transplanted patients commonly has the following features:[5][16]

Organ Transplanted Patients
Parameter Features
Clinical Manifestations Mild symptoms or asymptomatic
Jaundice is present in few patients
ALT Levels at Diagnosis Mild ALT elevation (≈300 IU/L)
Viral Genotype Genotype 3
Diagnostic Techniques

Inaccurate serologic tests
Anti-HEV IgM and anti-HEV IgG may be negative
Seroconversion may not occur
PCR should make the diagnosis

Outcomes 60% infected patients develop chronic hepatitis E
10% infected patients develop liver cirrhosis

Failure to clear the virus after acute infection may be explained by:[12][16]

Microscopic Pathology

Patients who develop chronic liver disease often have changes in liver histology. These may include:[2]

In severe cases, these changes may evolve to fibrosis and cirrhosis.[2][13]

References

  1. ↑ Kalia M, Chandra V, Rahman SA, Sehgal D, Jameel S (2009). "Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection". J Virol. 83 (24): 12714–24. doi:10.1128/JVI.00717-09. PMC 2786843. PMID 19812150.
  2. ↑ 2.0 2.1 2.2 2.3 Aggarwal R, Jameel S (2011). "Hepatitis E." Hepatology. 54 (6): 2218–26. doi:10.1002/hep.24674. PMID 21932388.
  3. ↑ Nagashima S, Takahashi M, Tanaka T, Yamada K, Nishizawa T; et al. (2011). "A PSAP motif in the ORF3 protein of hepatitis E virus is necessary for virion release from infected cells". J Gen Virol. 92 (Pt 2): 269–78. doi:10.1099/vir.0.025791-0. PMID 21068219.
  4. ↑ Pal R, Aggarwal R, Naik SR, Das V, Das S, Naik S (2005). "Immunological alterations in pregnant women with acute hepatitis E." J Gastroenterol Hepatol. 20 (7): 1094–101. doi:10.1111/j.1440-1746.2005.03875.x. PMID 15955220.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, Izopet J; et al. (2012). "Hepatitis E." Lancet. 379 (9835): 2477–88. doi:10.1016/S0140-6736(11)61849-7. PMID 22549046.
  6. ↑ Howard CM, Handzel T, Hill VR, Grytdal SP, Blanton C, Kamili S; et al. (2010). "Novel risk factors associated with hepatitis E virus infection in a large outbreak in northern Uganda: results from a case-control study and environmental analysis". Am J Trop Med Hyg. 83 (5): 1170–3. doi:10.4269/ajtmh.2010.10-0384. PMC 2963989. PMID 21036857.
  7. ↑ Hoofnagle JH, Nelson KE, Purcell RH (2012). "Hepatitis E." N Engl J Med. 367 (13): 1237–44. doi:10.1056/NEJMra1204512. PMID 23013075.
  8. ↑ Kenfak-Foguena A, Schöni-Affolter F, Bürgisser P, Witteck A, Darling KE, Kovari H; et al. (2011). "Hepatitis E Virus seroprevalence and chronic infections in patients with HIV, Switzerland". Emerg Infect Dis. 17 (6): 1074–8. doi:10.3201/eid/1706.101067. PMC 3358194. PMID 21749774.
  9. ↑ Keane F, Gompels M, Bendall R, Drayton R, Jennings L, Black J; et al. (2012). "Hepatitis E virus coinfection in patients with HIV infection". HIV Med. 13 (1): 83–8. doi:10.1111/j.1468-1293.2011.00942.x. PMID 21819531.
  10. ↑ Kaba M, Richet H, Ravaux I, Moreau J, Poizot-Martin I, Motte A; et al. (2011). "Hepatitis E virus infection in patients infected with the human immunodeficiency virus". J Med Virol. 83 (10): 1704–16. doi:10.1002/jmv.22177. PMID 21837786.
  11. ↑ Pischke S, Suneetha PV, Baechlein C, Barg-Hock H, Heim A, Kamar N; et al. (2010). "Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients". Liver Transpl. 16 (1): 74–82. doi:10.1002/lt.21958. PMID 19866448.
  12. ↑ 12.0 12.1 Kamar N, Selves J, Mansuy JM, Ouezzani L, Péron JM, Guitard J; et al. (2008). "Hepatitis E virus and chronic hepatitis in organ-transplant recipients". N Engl J Med. 358 (8): 811–7. doi:10.1056/NEJMoa0706992. PMID 18287603.
  13. ↑ 13.0 13.1 Gérolami R, Moal V, Colson P (2008). "Chronic hepatitis E with cirrhosis in a kidney-transplant recipient". N Engl J Med. 358 (8): 859–60. doi:10.1056/NEJMc0708687. PMID 18287615.
  14. ↑ Schlosser B, Stein A, Neuhaus R, Pahl S, Ramez B, Krüger DH; et al. (2012). "Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient". J Hepatol. 56 (2): 500–2. doi:10.1016/j.jhep.2011.06.021. PMID 21798217.
  15. ↑ Wedemeyer H, Pischke S, Manns MP (2012). "Pathogenesis and treatment of hepatitis e virus infection". Gastroenterology. 142 (6): 1388–1397.e1. doi:10.1053/j.gastro.2012.02.014. PMID 22537448.
  16. ↑ 16.0 16.1 Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C; et al. (2011). "Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants". Gastroenterology. 140 (5): 1481–9. doi:10.1053/j.gastro.2011.02.050. PMID 21354150.

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