View source for Hepatitis E

{{Short description|Human disease caused by Orthohepevirus A}}
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{{Infobox medical condition (new)
| name            = Hepatitis E
| synonyms        =
| image           = Hepatitis E virus.jpg
| caption         = [[Hepatitis E virus]]
| pronounce       =
| field           = [[Infectious disease (medical specialty)|Infectious disease]], [[Hepatology]]
| symptoms        = Nausea, [[jaundice]]<ref name="nidd">{{cite web |title=Hepatitis E {{!}} NIDDK |url=https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-e |website=National Institute of Diabetes and Digestive and Kidney Diseases |access-date=24 June 2018}}</ref>
| complications   = [[Liver failure]]<ref name=nidd/>
| onset           =
| duration        =
| types           =
| causes          = Hepatitis E virus (HEV)<ref name=nidd/>
| risks           =
| diagnosis       = Blood test<ref name=nidd/>
| differential    = [[Hepatitis A]]<ref>{{cite web |title=Hepatitis A Differential Diagnoses |url=https://emedicine.medscape.com/article/177484-differential |website=emedicine.medscape.com |access-date=27 July 2019}}</ref>
| prevention      =
| treatment       = Rest, [[ribavirin]] (if chronic)<ref name=nidd/>
| medication      =
| prognosis       =
| frequency       = 28 million worldwide (2013)<ref name=GBD2013/>
| deaths          =
}}
'''Hepatitis E''' is inflammation of the liver caused by [[infection]] with the [[hepatitis E virus]] (HEV);<ref>{{cite journal|title=Hepatitis E: Background, Etiopathophysiology, Epidemiology |url=https://emedicine.medscape.com/article/178140-overview |publisher=Medscape |website=medscape.com|date=2019}}</ref><ref name="emer">{{cite journal |last1=Kamar |first1=Nassim |last2=Dalton |first2=Harry R. |last3=Abravanel |first3=Florence |last4=Izopet |first4=Jacques |title=Hepatitis E Virus Infection |journal=Clinical Microbiology Reviews |date=2014 |volume=27 |issue=1 |pages=116–138 |doi=10.1128/CMR.00057-13 |pmid=24396139 |pmc=3910910 |issn=0893-8512}}</ref> it is a type of [[viral hepatitis]].<ref>{{Cite web |title=Hepatitis (Viral) NIDDK |url=https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis |access-date=2020-06-19 |website=The National Institute of Diabetes and Digestive and Kidney Diseases}}</ref> Hepatitis E has mainly a [[Fecal–oral route|fecal-oral transmission route]] that is similar to [[hepatitis A]], although the viruses are unrelated.<ref>{{cite web |title=What is hepatitis? |url=https://www.who.int/features/qa/76/en/ |publisher=WHO |website=www.who.int|access-date=17 April 2019}}</ref><ref name="hepe">{{cite web |title=Hepatitis E |url=https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-e |website=www.who.int |publisher=WHO|access-date= 17 April 2019|language=en}}</ref><ref>{{cite book |last1=Weston |first1=Debbie |last2=Burgess |first2=Alison |last3=Roberts |first3=Sue |title=Infection Prevention and Control at a Glance |date=2016 |publisher=John Wiley & Sons |isbn=978-1-118-97355-4 |page=12 |url=https://books.google.com/books?id=IyYPDQAAQBAJ&pg=PA12|language=en}}</ref> HEV is a [[Sense (molecular biology)|positive-sense]], single-stranded, nonenveloped, RNA icosahedral [[virus]] and one of five known human [[hepatitis]] viruses: A, [[hepatitis B|B]], [[hepatitis C|C]], [[hepatitis D|D]], and E.

Like hepatitis A, hepatitis E usually follows an acute and [[Self-limiting (biology)|self-limiting course of illness]] (the condition is temporary and the individual recovers) with low death rates in resource-rich areas; however, it can be more severe in pregnant women and people with a [[Immunocompromised|weakened immune system]], with substantially higher death rates. In [[Pregnancy|pregnant women]], especially in the third trimester, the disease is more often severe and is associated with a clinical syndrome called [[fulminant liver failure]], with death rates around 20%.<ref name=hepe/><ref name=pregn/><ref name=cdchev/> Whereas pregnant women may have a rapid and severe course, [[organ transplant]] recipients who receive medications to weaken the immune system and prevent organ rejection can develop a slower and more persistent form called chronic hepatitis E,<ref name="Zhou X, de Man RA, de Knegt RJ, Metselaar HJ, Peppelenbosch MP, Pan Q. 2013 295–304">{{cite journal |author=Zhou X, de Man RA, de Knegt RJ, Metselaar HJ, Peppelenbosch MP, Pan Q.|title=Epidemiology and management of chronic hepatitis E infection in solid organ transplantation: a comprehensive literature review |journal=Rev. Med. Virol. |volume=23 |issue=5 |pages=295–304 |year=2013|pmid=23813631 |doi=10.1002/rmv.1751|last2=De Man |last3=De Knegt |last4=Metselaar |last5=Peppelenbosch |last6=Pan |s2cid=41424447 }}</ref> which is so diagnosed after 3 months of continuous viremia.<ref>{{cite journal |last1=Kamar |first1=Nassim |last2=Izopet |first2=Jacques |last3=Dalton |first3=Harry R. |title=Chronic hepatitis e virus infection and treatment |journal=Journal of Clinical and Experimental Hepatology |volume=3 |issue=2 |pages=134–140 |doi=10.1016/j.jceh.2013.05.003 |pmid=25755487 |pmc=3940092 |issn=0973-6883|year=2013 }}</ref> HEV can be clustered genetically into 8 genotypes, and genotypes 3 and 4 tend to be the ones that cause chronic hepatitis in the immunosuppressed.<ref>{{cite journal |last1=Kamar |first1=N. |last2=Abravanel |first2=F. |last3=Selves |first3=J. |last4=Garrouste |first4=C. |last5=Esposito |first5=L. |last6=Lavayssière |first6=L. |last7=Cointault |first7=O. |last8=Ribes |first8=D. |last9=Cardeau |first9=I. |last10=Nogier |first10=M. B. |last11=Mansuy |first11=J. M. |last12=Muscari |first12=F. |last13=Peron |first13=J. M. |last14=Izopet |first14=J. |last15=Rostaing |first15=L. |date=2010 |title=Influence of Immunosuppressive Therapy on the Natural History of Genotype 3 Hepatitis-E Virus Infection After Organ Transplantation |journal=Transplantation |volume=89 |issue=3 |pages=353–360 | pmid=20145528 | doi=10.1097/tp.0b013e3181c4096c|s2cid=19917145 |doi-access=free }}</ref><ref>{{cite journal |last1=Dalton |first1=Harry R. |last2=Kamar |first2=Nassim |last3=Baylis |first3=Sally A. |last4=Moradpour |first4=Darius |last5=Wedemeyer |first5=Heiner |last6=Negro |first6=Francesco |title=EASL Clinical Practice Guidelines on hepatitis E virus infection |journal=Journal of Hepatology |date=June 2018 |volume=68 |issue=6 |pages=1256–1271 |doi=10.1016/j.jhep.2018.03.005 |pmid=29609832 |url=https://www.journal-of-hepatology.eu/article/S0168-8278(18)30155-7/fulltext |doi-access=free |url-access=subscription }}</ref><ref name="gen8">{{cite journal |last1=Sridhar |first1=Siddharth |last2=Teng |first2=Jade L. L. |last3=Chiu |first3=Tsz-Ho |last4=Lau |first4=Susanna K. P. |last5=Woo |first5=Patrick C. Y. |title=Hepatitis E Virus Genotypes and Evolution: Emergence of Camel Hepatitis E Variants |journal=International Journal of Molecular Sciences |date=20 April 2017 |volume=18 |issue=4 |pages=869 |doi=10.3390/ijms18040869 |pmid=28425927 |pmc=5412450 |issn=1422-0067|doi-access=free }}</ref>

In 2017, hepatitis E was estimated to affect more than 19 million people.<ref name="GBD2013">{{cite journal |title=Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 |journal=Lancet |date=10 November 2018 |volume=392 |issue=10159 |pages=1789–1858 |doi=10.1016/S0140-6736(18)32279-7 |pmid=30496104 |pmc=6227754 |issn=0140-6736 |last1=James |first1=Spencer L. |last2=Abate |first2=Degu |last3=Abate |first3=Kalkidan Hassen |last4=Abay |first4=Solomon M. |last5=Abbafati |first5=Cristiana |last6=Abbasi |first6=Nooshin |last7=Abbastabar |first7=Hedayat |last8=Abd-Allah |first8=Foad |last9=Abdela |first9=Jemal |last10=Abdelalim |first10=Ahmed |last11=Abdollahpour |first11=Ibrahim |last12=Abdulkader |first12=Rizwan Suliankatchi |last13=Abebe |first13=Zegeye |last14=Abera |first14=Semaw F. |last15=Abil |first15=Olifan Zewdie |last16=Abraha |first16=Haftom Niguse |last17=Abu-Raddad |first17=Laith Jamal |last18=Abu-Rmeileh |first18=Niveen M E. |last19=Accrombessi |first19=Manfred Mario Kokou |last20=Acharya |first20=Dilaram |last21=Acharya |first21=Pawan |last22=Ackerman |first22=Ilana N. |last23=Adamu |first23=Abdu A. |last24=Adebayo |first24=Oladimeji M. |last25=Adekanmbi |first25=Victor |last26=Adetokunboh |first26=Olatunji O. |last27=Adib |first27=Mina G. |last28=Adsuar |first28=Jose C. |last29=Afanvi |first29=Kossivi Agbelenko |last30=Afarideh |first30=Mohsen |display-authors=1 }}</ref> Those most commonly at risk of HEV are men aged 15 to 35 years of age.<ref name="izo">{{cite journal |last1=Izopet |first1=Jacques |last2=Abravanel |first2=Florence |last3=Dalton |first3=Harry R. |last4=Kamar |first4=Nassim |date=1 January 2014 |title=Hepatitis E Virus Infection |journal=Clinical Microbiology Reviews |language=en |volume=27 |issue=1 |pages=116–138 |doi=10.1128/CMR.00057-13 |issn=0893-8512 |pmc=3910910 |pmid=24396139}}</ref> A [[Prophylaxis#Prophylaxis|preventive vaccine]] (HEV 239) is approved for use in [[China]].<ref>{{Cite journal| last1 = Li| first1 = Shao-Wei| last2 = Zhao| first2 = Qinjian| last3 = Wu| first3 = Ting| last4 = Chen| first4 = Shu| last5 = Zhang| first5 = Jun| last6 = Xia| first6 = Ning-Shao| date = 2015-02-25| title = The development of a recombinant hepatitis E vaccine HEV 239| journal = Human Vaccines & Immunotherapeutics| volume = 11| issue = 4| pages = 908–914| doi = 10.1080/21645515.2015.1008870| issn = 2164-5515| pmc = 4514148| pmid = 25714510}}</ref>

The virus was discovered in 1983 by researchers investigating an outbreak of unexplained hepatitis among Soviet soldiers [[Soviet–Afghan War|serving in Afghanistan]].<ref name="izo" /> The earliest well-documented epidemic of hepatitis E occurred in 1955 in [[New Delhi]] and affected tens of thousands of people (hepatitis E virus was identified as the etiological agent at fault retrospectively through testing of stored samples).<ref>{{cite journal |last1=Kumar |first1=Subrat |last2=Subhadra |first2=Subhra |last3=Singh |first3=Bhupinder |last4=Panda |first4=B.K. |date=April 2013 |title=Hepatitis E virus: the current scenario |url=https://www.ijidonline.com/article/S1201-9712(12)01319-7/fulltext |journal=International Journal of Infectious Diseases |language=en |volume=17 |issue=4 |pages=e228–e233 |doi=10.1016/j.ijid.2012.11.026 |issn=1201-9712 |pmid=23313154 |doi-access=free}}</ref>
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==Signs and symptoms==

===Acute infection===
The average [[incubation period]] of hepatitis E is 40 days, ranging from 2 to 8 weeks. After a short [[Prodrome|prodromal phase]] symptoms may include [[jaundice]], fatigue, and [[nausea]], though most HEV infections are asymptomatic. The symptomatic phase coincides with elevated hepatic [[aminotransferase]] levels.<ref>{{cite book |last1=Sanford |first1=Christopher A. |last2=Jong |first2=Elaine C. |last3=Pottinger |first3=Paul S. |title=The Travel and Tropical Medicine Manual E-Book |date=2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-41742-6 |page=324 |url=https://books.google.com/books?id=jyTRDAAAQBAJ&pg=PA324|language=en}}</ref><ref name=tran>{{cite web|title=Hepatitis E Fact sheet|url=https://www.who.int/mediacentre/factsheets/fs280/en/|publisher=WHO|access-date= 17 April 2019|language=en}}</ref><ref name=Hoofnagle2012>{{Cite journal | last1 = Hoofnagle | first1 = J. H. | last2 = Nelson | first2 = K. E. | last3 = Purcell | first3 = R. H. | doi = 10.1056/NEJMra1204512 | title = Hepatitis E | journal = New England Journal of Medicine | volume = 367 | issue = 13 | pages = 1237–1244 | year = 2012 | pmid =  23013075| s2cid = 32198953 }}</ref><ref>{{cite web |title=Facts about hepatitis E |url=https://ecdc.europa.eu/en/hepatitis-e/facts |website=ecdc.europa.eu|date=30 March 2017 |publisher=European Centre for Disease Prevention and Control |access-date=17 April 2019 |language=en}}</ref> Viral RNA becomes detectable in [[Human feces|stool]] and blood serum during the incubation period. Serum IgM and IgG [[antibodies]] against HEV appear just before the onset of clinical symptoms. Recovery leads to virus clearance from the blood, while the virus may persist in stool for much longer. Recovery is also marked by disappearance of IgM antibodies and increase of levels of IgG antibodies.<ref name=hepe/><ref name=Hoofnagle2012/>

===Chronic infection===
While usually lasting weeks and then resolving, in people with [[immunocompromised|weakened immune systems]]—particularly in people who have had solid organ transplant—hepatitis E may cause a chronic [[infection]].<ref name=Bonnet2012>{{Cite journal | last1 = Bonnet | first1 = D. | last2 = Kamar | first2 = N. | last3 = Izopet | first3 = J. | last4 = Alric | first4 = L. | title = L'hépatite virale E : Une maladie émergente | doi = 10.1016/j.revmed.2012.01.017 | journal = La Revue de Médecine Interne | volume = 33 | issue = 6 | pages = 328–334 | year = 2012 | pmid = 22405325 }}</ref> Occasionally this may result in a life-threatening illness such as fulminant liver failure or liver [[cirrhosis]].<ref>{{Cite journal| last1 = Behrendt| first1 = Patrick| last2 = Steinmann| first2 = Eike| last3 = Manns| first3 = Michael P.| last4 = Wedemeyer| first4 = Heiner| date = 2014-12-01| title = The impact of hepatitis E in the liver transplant setting| journal = Journal of Hepatology| volume = 61| issue = 6| pages = 1418–1429| doi = 10.1016/j.jhep.2014.08.047| pmid = 25195557| doi-access = free| hdl = 10033/346563| hdl-access = free}}</ref><ref>{{cite journal |last1=Kamar |first1=Nassim |last2=Pischke |first2=Sven |title=Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment |journal=Cold Spring Harbor Perspectives in Medicine |volume=9 |issue=7 |pages=a031872 |date=7 May 2018 |doi=10.1101/cshperspect.a031872 |pmid=29735575 |pmc=6601456 |issn=2157-1422}}</ref>

===Other organs===
Infection with hepatitis E virus can also lead to problems in other organs. For some of these reported conditions such as musculoskeletal or immune-mediated manifestations the relationship is not entirely clear, but for several neurological and blood conditions the relationship appears more consistent:<ref>{{cite journal|last1=Bazerbachi|first1=F|last2=Haffar|first2=S|last3=Garg|first3=SK|last4=Lake|first4=JR|title=Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive review of the literature.|journal=Gastroenterology Report|date=February 2016|volume=4|issue=1|pages=1–15 <!-- do not change to art number -->|pmc=4760069|doi=10.1093/gastro/gov042|pmid=26358655}}</ref><ref name=juarez>{{cite journal |last1=Rivero-Juárez |first1=Antonio |last2=Aguilera |first2=Antonio |last3=Avellón |first3=Ana |last4=García-Deltoro |first4=Miguel |last5=García |first5=Federico |last6=Gortazar |first6=Christian |last7=Granados |first7=Rafael |last8=Macías |first8=Juan |last9=Merchante |first9=Nicolás |last10=Oteo |first10=José Antonio |last11=Pérez-Gracia |first11=María Teresa |last12=Pineda |first12=Juan Antonio |last13=Rivero |first13=Antonio |last14=Rodriguez-Lazaro |first14=David |last15=Téllez |first15=Francisco |last16=Morano-Amado |first16=Luis E. |title=Executive summary: Consensus document of the diagnosis, management and prevention of infection with the hepatitis E virus: Study Group for Viral Hepatitis (GEHEP) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) |journal=Enfermedades Infecciosas y Microbiologia Clinica |volume=38 |issue=1 |pages=28–32 |date=30 July 2018 |doi=10.1016/j.eimc.2018.06.014 |pmid=30072282 |issn=1578-1852|doi-access=free |hdl=10498/23059 |hdl-access=free }}</ref><ref>{{cite journal |last1=Kamar |first1=Nassim |last2=Bendall |first2=Richard P. |last3=Peron |first3=Jean Marie |last4=Cintas |first4=Pascal |last5=Prudhomme |first5=Laurent |last6=Mansuy |first6=Jean Michel |last7=Rostaing |first7=Lionel |last8=Keane |first8=Frances |last9=Ijaz |first9=Samreen |last10=Izopet |first10=Jacques |last11=Dalton |first11=Harry R. |title=Hepatitis E virus and neurologic disorders |journal=Emerging Infectious Diseases |date=2011 |volume=17 |issue=2 |pages=173–179 |doi=10.3201/eid1702.100856 |pmid=21291585 |pmc=3298379 |issn=1080-6059}}</ref><ref>{{cite journal |last1=Dalton |first1=Harry R. |last2=Kamar |first2=Nassim |last3=van Eijk |first3=Jeroen J. J. |last4=Mclean |first4=Brendan N. |last5=Cintas |first5=Pascal |last6=Bendall |first6=Richard P. |last7=Jacobs |first7=Bart C. |title=Hepatitis E virus and neurological injury |journal=Nature Reviews Neurology |date=29 December 2015 |volume=12 |issue=2 |pages=77–85 |doi=10.1038/nrneurol.2015.234 |pmid=26711839 |s2cid=25495184 |issn=1759-4766}}</ref>
* [[Acute pancreatitis]] (HEV genotype 1<ref name=emer/>)
* Neurological complications (though the mechanism of neurological damage is unknown at this point.<ref name=izo/>) include: [[Guillain-Barré syndrome]] (acute limb weakness due to nerve involvement), [[Parsonage–Turner syndrome|neuralgic amyotrophy]] (arm and shoulder weakness, also known as Parsonage-Turner syndrome), acute [[transverse myelitis]] and acute [[meningoencephalitis]].
* [[Glomerulonephritis]] with [[nephrotic syndrome]] and/or cryoglobulinemia
* Mixed [[cryoglobulinemia]], where antibodies in the bloodstream react inappropriately at low temperatures
* Severe [[thrombocytopenia]] (low platelet count in the blood) which confers an increased risk of dangerous bleeding

=== Infection in pregnancy ===
Pregnant women show a more severe course of infection than other populations. Liver failure with mortality rates of 20% to 25% has been reported from outbreaks of genotype 1 and 2 HEV in developing countries. Besides signs of an acute infections, adverse effects on the mother and fetus may include [[preterm delivery]], abortion, [[stillbirth]], and neonatal death.<ref name="pregn">{{Cite journal|last1=Patra|first1=Sharda|last2=Kumar|first2=Ashish|last3=Trivedi|first3=Shubha Sagar|last4=Puri|first4=Manju|last5=Sarin|first5=Shiv Kumar|date=2007-07-03|title=Maternal and Fetal Outcomes in Pregnant Women with Acute Hepatitis E Virus Infection|journal=Annals of Internal Medicine|language=en|volume=147|issue=1|pages=28–33|doi=10.7326/0003-4819-147-1-200707030-00005|pmid=17606958|s2cid=44504380|issn=0003-4819|url=https://www.semanticscholar.org/paper/dedb6d08e9678a676c029307197bd44c18cd5567}}</ref><ref>{{Cite journal|title=Wiley Online Library|doi=10.1016/j.ijgo.2003.11.018 |pmid=15145258| volume=85|issue=3|year=2004|journal=International Journal of Gynecology & Obstetrics|pages=240–244|author=Kumar A., Beniwal M., Kar P., Sharma J.B., Murthy N.S.|s2cid=72665101 }}</ref><ref>{{cite journal |last1=Khuroo |first1=Mohammad S. |last2=Khuroo |first2=Mehnaaz S. |last3=Khuroo |first3=Naira S. |title=Transmission of Hepatitis E Virus in Developing Countries |journal=Viruses |date=20 September 2016 |volume=8 |issue=9 |pages=253 |doi=10.3390/v8090253 |pmid=27657112 |pmc=5035967 |issn=1999-4915|doi-access=free }}</ref>

The pathological and biological mechanisms behind the adverse outcomes of [[pregnancy]] infections remain largely unclear. Increased [[viral replication]] and influence of hormonal changes on the immune system are currently thought to contribute to worsening the course of infection.<ref name=perez/> Furthermore, studies showing evidence for viral replication in the placenta or reporting the full [[viral life cycle]] in placental-derived cells in vitro suggest that the human [[placenta]] may be a site of viral replication outside the liver.<ref>{{Cite journal|last1=Bose|first1=Purabi Deka|last2=Das|first2=Bhudev Chandra|last3=Hazam|first3=Rajib Kishore|last4=Kumar|first4=Ashok|last5=Medhi|first5=Subhash|last6=Kar|first6=Premashis|date=2014|title=Evidence of extrahepatic replication of hepatitis E virus in human placenta|journal=Journal of General Virology|volume=95|issue=6|pages=1266–1271|doi=10.1099/vir.0.063602-0|pmid=24622580|doi-access=free}}</ref> The primary reason for HEV severity in pregnancy remains enigmatic.<ref name=izo/>

==Virology==
{{main|Orthohepevirus A}}
===Classification===
HEV is classified into the family ''Hepeviridae'', which is divided in two genera, ''Orthohepevirus'' (all mammalian and avian HEV isolates) and ''Piscihepevirus'' (cutthroat trout HEV).<ref name="perez">{{cite journal |last1=Pérez-Gracia |first1=María Teresa |last2=Suay-García |first2=Beatriz |last3=Mateos-Lindemann |first3=María Luisa |title=Hepatitis E and pregnancy: current state |journal=Reviews in Medical Virology |volume=27 |issue=3 |pages=e1929 |date=20 March 2017 |doi=10.1002/rmv.1929 |pmid=28318080 |s2cid=44761962 |issn=1099-1654}}</ref> Only one [[serotype]] of the human virus is known,  and classification is based on the [[nucleotide]] sequences of the genome.<ref>{{cite book |last1=Feldman |first1=Mark |last2=Friedman |first2=Lawrence S. |last3=Brandt |first3=Lawrence J. |title=Sleisenger and Fordtran's Gastrointestinal and Liver Disease E-Book: Pathophysiology, Diagnosis, Management, Expert Consult Premium Edition - Enhanced Online Features |date=2010 |publisher=Elsevier Health Sciences |isbn=978-1-4377-2767-8 |page=1337 |url=https://books.google.com/books?id=zEZOqB6r9hwC&dq=only+1+serotype+HEV&pg=PA1337 |access-date=27 June 2020 |language=en}}</ref> [[Genotype]] 1 can be further subclassified into five subtypes,<ref name="wang">{{cite book |last1=Wang |first1=Youchun |title=Hepatitis E Virus |date=2016 |publisher=Springer |isbn=978-94-024-0942-0 |page=75 |url=https://books.google.com/books?id=B3hCDQAAQBAJ&pg=PA75|language=en}}</ref> genotype 2 into two subtypes,<ref>{{cite book |last1=Wang |first1=Youchun |title=Hepatitis E Virus |date=2016 |publisher=Springer |isbn=978-94-024-0942-0 |page=10 |url=https://books.google.com/books?id=B3hCDQAAQBAJ&pg=PA10|language=en}}</ref> and genotypes 3 and 4 have been divided into 10<ref name="boyer">{{cite book |last1=Boyer |first1=Thomas D. |last2=Manns |first2=Michael Peter |last3=Sanyal |first3=Arun J. |last4=Zakim |first4=David |title=Zakim and Boyer's Hepatology: A Textbook of Liver Disease |date=2012 |publisher=Elsevier Health Sciences |isbn=978-1-4377-0881-3 |page=609 |url=https://books.google.com/books?id=zjYof6MJZkkC&pg=PA609|language=en}}</ref> and seven subtypes.<ref name=boyer/> Additionally there are  genotypes 5, 6, 7 and 8.<ref name= gen8/> Rat HEV was first isolated from Norway rats in Germany,<ref>{{cite journal |last1=Johne |first1=Reimar |last2=Heckel |first2=Gerald |last3=Plenge-Bönig |first3=Anita |last4=Kindler |first4=Eveline |last5=Maresch |first5=Christina |last6=Reetz |first6=Jochen |last7=Schielke |first7=Anika |last8=Ulrich |first8=Rainer G. |title=Novel hepatitis E virus genotype in Norway rats, Germany |journal=Emerging Infectious Diseases |date=2010 |volume=16 |issue=9 |pages=1452–1455 |doi=10.3201/eid1609.100444 |pmid=20735931 |pmc=3294985 |issn=1080-6059}}</ref> and a 2018 CDC article indicated the  detection of rat HEV RNA in a transplant recipient.<ref>{{cite journal |last1=Sridhar |first1=Siddharth |last2=Yip |first2=Cyril C.Y. |last3=Wu |first3=Shusheng |last4=Cai |first4=Jianpiao |last5=Zhang |first5=Anna Jin-Xia |last6=Leung |first6=Kit-Hang |last7=Chung |first7=Tom W.H. |last8=Chan |first8=Jasper F.W. |last9=Chan |first9=Wan-Mui |last10=Teng |first10=Jade L.L. |last11=Au-Yeung |first11=Rex K.H. |last12=Cheng |first12=Vincent C.C. |last13=Chen |first13=Honglin |last14=Lau |first14=Susanna K.P. |last15=Woo |first15=Patrick C.Y. |last16=Xia |first16=Ning-Shao |last17=Lo |first17=Chung-Mau |last18=Yuen |first18=Kwok-Yung |title=Rat Hepatitis E Virus as Cause of Persistent Hepatitis after Liver Transplant |journal=Emerging Infectious Diseases |date=December 2018 |volume=24 |issue=12 |pages=2241–2250 |doi=10.3201/eid2412.180937 |pmid=30457530 |pmc=6256372 |language=en-us}}</ref>

====Distribution====
* '''Genotype 1 '''has been isolated from tropical and several subtropical countries in [[Asia]] and [[Africa]].<ref name="gen">{{Cite journal| last = Song| first = Yoon-Jae| date = 2010-11-01| title = Studies of hepatitis E virus genotypes| journal = The Indian Journal of Medical Research| volume = 132| issue = 5| pages = 487–488| issn = 0971-5916| pmc = 3028963| pmid = 21149996}}</ref>
* '''Genotype 2 '''has been isolated from [[Mexico]], [[Nigeria]], and [[Chad]].<ref>{{Cite journal| last1 = Pelosi| first1 = E| last2 = Clarke| first2 = I| date = 2008-11-07| title = Hepatitis E: a complex and global disease| journal = Emerging Health Threats Journal| volume = 1| pages = e8| doi = 10.3134/ehtj.08.008| doi-broken-date = 2024-11-02| issn = 1752-8550| pmc = 3167588| pmid = 22460217}}</ref>
* '''Genotype 3''' has been isolated almost worldwide including Asia, [[Europe]], [[Oceania]], and [[North America|North]] and [[South America]].<ref>{{cite report|last1=Hepatitis E Vaccine Working Group |title=Recommendations of HEV Working Group on the use of hepatitis E vaccine |url=https://www.who.int/immunization/sage/meetings/2014/october/3_Hep_E_vacc_WG_SAGE_Recs_final_1Oct2014.pdf |website=www.who.int|publisher=WHO |date=1 October 2014}}</ref>
* '''Genotype 4''' appears to be limited to Asia and indigenous cases from Europe.<ref name=gen/><ref>{{cite book |last1=Guerrant |first1=Richard L. |last2=Walker |first2=David H. |last3=Weller |first3=Peter F. |title=Tropical Infectious Diseases: Principles, Pathogens and Practice (Expert Consult – Online and Print) |date=2011 |publisher=Elsevier Health Sciences |isbn=978-1-4377-3777-6 |page=424 |url=https://books.google.com/books?id=A7GVvFh4WZwC&pg=PA424|language=en}}</ref>

Genotypes 1 and 2 are restricted to humans and often associated with large outbreaks and epidemics in developing countries with poor sanitation conditions.<ref name=gen/> Genotypes 3 and 4 infect humans, pigs, and other animal species and have been responsible for sporadic cases of hepatitis E in both developing and industrialized countries.<ref>{{Cite journal|last=Meng|first=X. J.|author-link=Xiang-Jin Meng|date=2010-01-27|title=Hepatitis E virus: Animal Reservoirs and Zoonotic Risk|journal=Veterinary Microbiology|volume=140|issue=3–4|pages=256–65|doi=10.1016/j.vetmic.2009.03.017|issn=0378-1135|pmc=2814965|pmid=19361937}}</ref><ref>{{cite journal |last1=Woolson |first1=K. L. |last2=Forbes |first2=A. |last3=Vine |first3=L. |last4=Beynon |first4=L. |last5=McElhinney |first5=L. |last6=Panayi |first6=V. |last7=Hunter |first7=J. G. |last8=Madden |first8=R. G. |last9=Glasgow |first9=T. |last10=Kotecha |first10=A. |last11=Dalton |first11=H. C. |last12=Mihailescu |first12=L. |last13=Warshow |first13=U. |last14=Hussaini |first14=H. S. |last15=Palmer |first15=J. |last16=Mclean |first16=B. N. |last17=Haywood |first17=B. |last18=Bendall |first18=R. P. |last19=Dalton |first19=H. R. |title=Extra-hepatic manifestations of autochthonous hepatitis E infection |journal=Alimentary Pharmacology & Therapeutics |date=2014 |volume=40 |issue=11–12 |pages=1282–1291 |doi=10.1111/apt.12986 |pmid=25303615 |s2cid=207050371 |language=en |issn=1365-2036|doi-access=free }}</ref>

===Transmission===
[[image:Hepatitis E Virus in Pork Liver Sausage.jpg|thumb|390px|Hepatitis E virus in pork liver sausage (the arrows in panel A point to the virion, those in B, C & D point to bound gold nanoparticles used in virus detection)<ref name="pmid23347828">{{cite journal |vauthors=Berto A, Grierson S, Hakze-van der Honing R, Martelli F, Johne R, Reetz J, Ulrich RG, Pavio N, Van der Poel WH, Banks M |title=Hepatitis E virus in pork liver sausage, France |journal=Emerging Infectious Diseases |volume=19 |issue=2 |pages=264–6 |date=February 2013 |pmid=23347828 |pmc=3563277 |doi=10.3201/eid1902.121255 |url=}}</ref>]]
Hepatitis E (genotype 1 and, to a lesser extent genotype 2) is endemic and can cause outbreaks in Southeast Asia, northern and central Africa, India, and Central America.<ref name=emer/><ref>{{Cite book| url = https://books.google.com/books?id=BBPOBQAAQBAJ| title = Molecular Detection of Human Viral Pathogens| last = Liu| first = Dongyou| date = 2010-11-23| publisher = CRC Press|page=102| isbn = 978-1-4398-1237-2| language = en}}</ref> It is spread mainly by the [[fecal–oral route]] due to contamination of water supplies or food; direct person-to-person transmission is uncommon.<ref name=emer/><ref name=tran/> In contrast to genotypes 1 and 2, genotypes 3 and 4 cause sporadic cases thought to be contracted zoonotically, from direct contact with animals or indirectly from contaminated water or undercooked meat.<ref name=emer/><ref>{{cite journal |last1=Dai |first1=Xing |last2=Dong |first2=Chen |last3=Zhou |first3=Zhenxian |last4=Liang |first4=Jiuhong |last5=Dong |first5=Min |last6=Yang |first6=Yan |last7=Fu |first7=Jianguang |last8=Tian |first8=Hua |last9=Wang |first9=Song |last10=Fan |first10=Jie |last11=Meng |first11=Jihong |last12=Purdy |first12=Michael A. |title=Hepatitis E Virus Genotype 4, Nanjing, China, 2001–2011 |journal=Emerging Infectious Diseases |date=2013 |volume=19 |issue=9 |pages=1528–1530 |doi=10.3201/eid1909.130013 |pmid=23965731 |pmc=3810912 |issn=1080-6040}}</ref>

Outbreaks of epidemic hepatitis E most commonly occur after heavy rainfalls, especially [[monsoons]] because of their disruption of water supplies; heavy flooding can causes sewage to contaminate water supplies.<ref>{{cite book |last1=Kanki |first1=Phyllis |last2=Grimes |first2=D. Jay |title=Infectious Diseases: Selected Entries from the Encyclopedia of Sustainability Science and Technology |date=2012 |publisher=Springer Science & Business Media |isbn=978-1-4614-5719-0 |page=391 |url=https://books.google.com/books?id=qOEQpa-ZfHEC&pg=PA391|language=en}}</ref><ref>{{Cite book| url = https://books.google.com/books?id=bjcycxFpqEwC| title = Public Health and Infectious Diseases| last1 = Griffiths| first1 = Jeffrey| last2 = Maguire| first2 = James H.| last3 = Heggenhougen| first3 = Kristian| last4 = Quah| first4 = Stella R.| date = 2010-03-09| publisher = Elsevier| isbn = 978-0-12-381507-1| language = en}}</ref>{{rp|78}} The World Health Organization recommendation for chlorine on HEV inactivation, a free chlorine residual of {{Convert|0.5|mg/L|oz/gal|abbr=on}} for 30 min (pH, <8.0)<ref>{{cite journal |last1=Guerin |first1=Philippe Jean |last2=Nicand |first2=Elisabeth |last3=Ciglenecki |first3=Iza |last4=Grais |first4=Rebecca Freeman |last5=Moren |first5=Alain |last6=Diaz |first6=Francisco |last7=Tatay |first7=Mercedes |last8=Nizou |first8=Jacques-Yves |last9=Pinoges |first9=Loretxu |last10=Hamid |first10=Nuha |last11=Boccia |first11=Delia |last12=Klovstad |first12=Hilde |last13=Guthmann |first13=Jean-Paul |title=A Large Outbreak of Hepatitis E among a Displaced Population in Darfur, Sudan, 2004: The Role of Water Treatment Methods |journal=Clinical Infectious Diseases |date=15 June 2006 |volume=42 |issue=12 |pages=1685–1691 |doi=10.1086/504321 |pmid=16705572 |language=en |issn=1058-4838|doi-access=free }}</ref> Major outbreaks have occurred in [[New Delhi]], India (30,000 cases in 1955–1956),<ref name="wil">{{Cite book| url = https://books.google.com/books?id=udw_K4RGUCAC| title = Wastewater Microbiology| last = Bitton| first = Gabriel| date = 2005-05-27| publisher = John Wiley & Sons|page=132| isbn = 978-0-471-71791-1| language = en}}</ref> [[Burma]] (20,000 cases in 1976–1977),<ref>{{Cite book| url = https://books.google.com/books?id=UPjo6_FQI-EC&pg=PA189| title = Microbial Zoonoses and Sapronoses| last1 = Hubálek| first1 = Zdenek| last2 = Rudolf| first2 = Ivo| date = 2010-11-25| publisher = Springer Science & Business Media|page=189| isbn = 978-90-481-9657-9| language = en}}</ref> [[Kashmir|Kashmir, India]] (52,000 cases in 1978),<ref>{{Cite journal| last = Khuroo| first = Mohammad Sultan| date = 2011-10-01| title = Discovery of hepatitis E: The epidemic non-A, non-B hepatitis 30 years down the memory lane| journal = Virus Research| series = Hepatitis E Viruses| volume = 161| issue = 1| pages = 3–14| doi = 10.1016/j.virusres.2011.02.007| pmid = 21320558}}</ref> [[Kanpur, India]] (79,000 cases in 1991),<ref name=wil/> and China (100,000 cases between 1986 and 1988).<ref>{{Cite journal| last1 = Cowie| first1 = Benjamin C.| last2 = Adamopoulos| first2 = Jim| last3 = Carter| first3 = Karen| last4 = Kelly| first4 = Heath| date = 2005-03-01| title = Hepatitis E Infections, Victoria, Australia| journal = Emerging Infectious Diseases| volume = 11| issue = 3| pages = 482–484| doi = 10.3201/eid1103.040706| issn = 1080-6040| pmc = 3298235| pmid = 15757573}}</ref> According to Rein et al., HEV genotypes 1 and 2 caused some  20.1 million hepatitis E infections, along with 3.4 million cases of symptomatic disease, and 70,000 deaths in 2005; however the aforementioned paper  did not estimate the burden of genotypes 3 and 4.<ref>{{cite journal |last1=Rein |first1=David B. |last2=Stevens |first2=Gretchen A. |last3=Theaker |first3=Jordan |last4=Wittenborn |first4=John S. |last5=Wiersma |first5=Steven T. |title=The global burden of hepatitis E virus genotypes 1 and 2 in 2005 |journal=Hepatology |date=2012 |volume=55 |issue=4 |pages=988–997 |doi=10.1002/hep.25505 |pmid=22121109 |s2cid=25571762 |language=en |issn=1527-3350}}</ref>

According to the Department for Environment, Food and Rural Affairs, evidence indicated the increase in hepatitis E in the U.K. was due to food-borne [[zoonoses]], citing a study that found in the U.K. that 10% of pork sausages contained the hepatitis E virus. Some research suggests that food must reach a temperature of {{Convert|70|°C}} for 20 minutes to eliminate the risk of infection. The [[Animal Health and Veterinary Laboratories Agency]] discovered hepatitis E in almost half of all pigs in Scotland.<ref name=obserrver20130921>{{cite news | url=https://www.theguardian.com/lifeandstyle/2013/sep/21/chefs-pork-pink | title=Chefs fight for the right to serve their pork pink | work=The Observer newspaper | date=21 September 2013 | author=Doward, Jamie}}</ref><ref name=iri/>

Hepatitis E infection appeared to be more common in people on hemodialysis, although the specific risk factors for transmission are not clear.<ref>{{Cite journal| last1 = Haffar| first1 = Samir| last2 = Bazerbachi| first2 = Fateh| date = 2017-09-04| title = Systematic review with meta-analysis: the association between hepatitis E seroprevalence and haemodialysis| journal = Aliment Pharmacol Ther| volume = 46| issue = 9| pages = 790–799|  doi = 10.1111/apt.14285| pmid = 28869287| s2cid = 24480333| doi-access = free}}</ref>

===Animal reservoir===
Hepatitis E due to genotypes other than 1 and 2 is thought to be a [[zoonosis]], in that animals are thought to be the primary reservoir; deer and swine have frequently been implicated.<ref>{{Cite journal| last1 = Pavio| first1 = Nicole| last2 = Meng| first2 = Xiang-Jin| last3 = Renou| first3 = Christophe| date = 2010-01-01| title = Zoonotic hepatitis E: animal reservoirs and emerging risks| journal = Veterinary Research| volume = 41| issue = 6| doi = 10.1051/vetres/2010018| issn = 0928-4249| pmc = 2865210| pmid = 20359452| pages=46}}</ref> Domestic animals have been reported as a reservoir for the hepatitis E virus, with some surveys showing infection rates exceeding 95% among domestic pigs.<ref>{{cite journal |author=Satou K, Nishiura H |title=Transmission Dynamics of Hepatitis E Among Swine: Potential Impact upon Human Infection |journal=BMC Vet. Res. |volume=3|pages=9 |year=2007 |pmid=17493260 |doi=10.1186/1746-6148-3-9 |pmc=1885244|last2=Nishiura |doi-access=free }}</ref>
Replicative virus has been found in the [[small intestine]], [[lymph node]]s, [[Colon (anatomy)|colon]], and [[liver]] of experimentally infected [[pig]]s. Transmission after consumption of [[wild boar]] meat and uncooked deer meat has been reported as well.<ref>{{cite journal |vauthors=Li TC, Chijiwa K, Sera N |title=Hepatitis E Virus Transmission from Wild Boar Meat |journal=Emerging Infect. Dis. |volume=11 |issue=12 |pages=1958–60 |year=2005 |pmid=16485490 |doi=10.3201/eid1112.051041 |pmc=3367655 }}</ref>  The rate of transmission to humans by this route and the public health importance of this are, however, still unclear.<ref>{{cite journal|author=Kuniholm MH & Nelson KE|title=Of Organ Meats and Hepatitis E Virus: One Part of a Larger Puzzle Is Solved|journal=J Infect Dis|year=2008|volume=198|issue=12|pages=1727–1728|doi=10.1086/593212|pmid=18983247|doi-access=free}}</ref> Other animal reservoirs are possible but unknown at this time<ref name=izo/>

A number of other small mammals have been identified as potential reservoirs: the lesser bandicoot rat (''[[Bandicota bengalensis]]''), the black rat (''[[Rattus rattus]] brunneusculus'') and the Asian house shrew (''[[Suncus murinus]]''). A new virus designated rat hepatitis E virus has been isolated.<ref>{{cite journal |author=Johne R, Plenge-Bönig A, Hess M, Ulrich RG, Reetz J, Schielke A |title=Detection of a novel hepatitis E-like virus in faeces of wild rats using a nested broad-spectrum RT-PCR |journal=J. Gen. Virol. |volume=91 |issue=Pt 3 |pages=750–758 |date=2010 |pmid=19889929 |doi=10.1099/vir.0.016584-0 |last2=Plenge-Bönig |last3=Hess |last4=Ulrich |last5=Reetz |last6=Schielke |doi-access=free }}</ref>

===Genomics===
{{Main|Hepatitis E Virus}}
HEV has three [[Open reading frame|open reading frames (ORFs)]] encoding two polyproteins (O1 and O2 protein). ORF2 encodes three [[capsid]] proteins whereas O1 encodes seven fragments involved in viral replication, among others.<ref>{{cite book |last1=Balakrishnan |first1=V. |last2=Rajesh |first2=G. |title=Practical Gastroenterology |date=2016 |publisher=JP Medical Ltd |isbn=978-93-5250-190-8 |page=195 |url=https://books.google.com/books?id=5keJDAAAQBAJ&pg=PA195|access-date=22 July 2019 |language=en}}</ref><ref>{{cite journal |last1=Cocquerel |first1=Laurence |last2=Dubuisson |first2=Jean |last3=Meuleman |first3=Philip |last4=d'Autume |first4=Valentin de Masson |last5=Farhat |first5=Rayan |last6=Aliouat-Denis |first6=Cécile-Marie |last7=Duvet |first7=Sandrine |last8=Saas |first8=Laure |last9=Wychowski |first9=Czeslaw |last10=Saliou |first10=Jean-Michel |last11=Sayed |first11=Ibrahim M. |last12=Montpellier |first12=Claire |last13=Ankavay |first13=Maliki |title=New insights into the ORF2 capsid protein, a key player of the hepatitis E virus lifecycle |journal=Scientific Reports |date=18 April 2019 |volume=9 |issue=1 |pages=6243 |doi=10.1038/s41598-019-42737-2 |pmid=31000788 |pmc=6472401 |language=en |issn=2045-2322|bibcode=2019NatSR...9.6243A }}</ref><ref>{{cite journal |last1=Ahmad |first1=Imran |last2=Holla |first2=R. Prasida |last3=Jameel |first3=Shahid |title=Molecular Virology of Hepatitis E Virus |journal=Virus Research |date=October 2011 |volume=161 |issue=1 |pages=47–58 |doi=10.1016/j.virusres.2011.02.011 |pmid=21345356 |pmc=3130092 |issn=0168-1702}}</ref>

The smallest ORF of the HEV genome, ORF3 is translated from a subgenomic RNA into O3, a protein of 113–115 amino acids. ORF3 is proposed to play critical roles in immune evasion by HEV. Previous studies showed that ORF3 is bound to viral particles found in patient sera and produced in cell culture. Although in cultured cells ORF3 has not appeared essential for HEV RNA replication, viral assembly, or infection, it is required for particle release.<ref>{{cite journal |last1=Ding |first1=Qiang |last2=Heller |first2=Brigitte |last3=Capuccino |first3=Juan M. V. |last4=Song |first4=Bokai |last5=Nimgaonkar |first5=Ila |last6=Hrebikova |first6=Gabriela |last7=Contreras |first7=Jorge E. |last8=Ploss |first8=Alexander |title=Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles |journal=Proceedings of the National Academy of Sciences of the United States of America |date=2017 |volume=114 |issue=5 |pages=1147–1152 |doi=10.1073/pnas.1614955114 |pmid=28096411 |pmc=5293053 |bibcode=2017PNAS..114.1147D |issn=1091-6490|doi-access=free }}</ref>

[[image:Geldanamycin.svg|thumb|100px|Geldanamycin]]

=== Virus lifecycle ===
The lifecycle of hepatitis E virus is unknown; the capsid protein obtains viral entry by binding to a cellular receptor. ORF2 (c-terminal) moderates viral entry by binding to [[HSPA8|HSC70]].<ref name="cao">{{Cite journal| last1 = Cao| first1 = Dianjun| last2 = Meng| first2 = Xiang-Jin| date = 2012-08-22| title = Molecular biology and replication of hepatitis E virus| url= | journal = Emerging Microbes & Infections| language = en| volume = 1| issue = 8| pages = e17| doi = 10.1038/emi.2012.7| pmc = 3630916| pmid = 26038426}}</ref><ref name="pmid19622744">{{cite journal|last=Tao|first=TS|author2=Liu, Z |author3=Ye, Q |author4=Mata, DA |author5=Li, K |author6=Yin, C |author7=Zhang, J |author8= Tao, YJ |title=Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Aug 4, 2009|volume=106|issue=31|pages=12992–7|pmid=19622744|bibcode=2009PNAS..10612992G|doi=10.1073/pnas.0904848106|pmc=2722310|doi-access=free}}</ref>

[[Geldanamycin]] blocks the transport of HEV239 capsid protein, but not the binding/entry of the truncated capsid protein, which indicates that [[Hsp90]] plays an important part in HEV transport.<ref name="cao" />

==Diagnosis==
In terms of the diagnosis of hepatitis E, only a laboratory blood test that confirms the presence of HEV RNA or IgM antibodies to HEV can be trusted.<ref name=cdchev/><ref>{{cite journal |last1=Aggarwal |first1=Rakesh |title=Diagnosis of hepatitis E |journal=Nature Reviews Gastroenterology & Hepatology |date=2 October 2012 |volume=10 |issue=1 |pages=24–33 |doi=10.1038/nrgastro.2012.187 |pmid=23026902 |s2cid=11958858 |language=En |issn=1759-5045}}subscription needed</ref> In the United States no serologic tests for diagnosis of HEV infection have ever been authorized by the [[Food and Drug Administration]].<ref name="cdchev">{{cite web |title=Hepatitis E Questions and Answers for Health Professionals  |url=https://www.cdc.gov/hepatitis/hev/hevfaq.htm |website=www.cdc.gov |publisher=CDC|language=en-us |date=13 June 2018}}</ref> The [[World Health Organization]] has developed an international standard strain for detection and quantification of HEV RNA.<ref>{{cite journal |last1=Baylis |first1=Sally A. |last2=Blümel |first2=Johannes |last3=Mizusawa |first3=Saeko |last4=Matsubayashi |first4=Keiji |last5=Sakata |first5=Hidekatsu |last6=Okada |first6=Yoshiaki |last7=Nübling |first7=C. Micha |last8=Hanschmann |first8=Kay-Martin O. |title=World Health Organization International Standard to Harmonize Assays for Detection of Hepatitis E Virus RNA |journal=Emerging Infectious Diseases |date=May 2013 |volume=19 |issue=5 |pages=729–735 |doi=10.3201/eid1905.121845 |pmid=23647659 |pmc=3647515 |issn=1080-6040}}</ref> In acute infection the viremic window for detection of HEV RNA closes 3 weeks after symptoms begin.<ref>{{cite journal |last1=Webb |first1=Glynn W. |last2=Dalton |first2=Harry R. |title=Hepatitis E: an underestimated emerging threat |journal=Therapeutic Advances in Infectious Disease |date=3 April 2019 |volume=6|pages=204993611983716 |doi=10.1177/2049936119837162 |pmid=30984394 |pmc=6448100 |issn=2049-9361}}</ref>

===Virological markers===
Assuming that vaccination has not occurred, tests may show:<ref name=emer/>
* if the person's ''immune system is normal'', then
** if '''IgM anti-HEV''' is negative, then there is no evidence of recent HEV infection
** if '''IgM anti-HEV''' is positive, then the person is likely to have a recent or current HEV infection
* if the person's ''immune system is [[immunocompromised|weakened by disease or medical treatment]]'', as in the case of a person who has received a solid organ transplant, then
** if '''IgM anti-HEV''' is negative, then if additional blood testing reveals
*** '''positive HEV RNA''' then the person has HEV infection
*** '''negative HEV RNA''' then there is no evidence of current or recent infection
** if '''IgM anti-HEV''' is positive, then the person is likely to have a recent or current HEV infection, and HEV RNA may be useful to track resolution

==Prevention==

===Sanitation===
[[Sanitation]] is the most important measure in prevention of hepatitis E; this consists of proper treatment and disposal of human waste, higher standards for public water supplies, improved personal hygiene procedures, and sanitary food preparation. Thus, prevention strategies of this disease are similar to those of many other diseases that plague developing nations.<ref name=tran/> Cooking meat at {{Convert|71|°C|1}} for five minutes kills the hepatitis E virus, different temperatures means different time to inactivate the virus.<ref name="iri">{{cite web |title=Hepatitis E Virus and Food |publisher=Food Safety Authority of Ireland |url=https://www.fsai.ie/faq/hepatitis_e.html |website=www.fsai.ie |date=11 July 2017 |access-date=27 July 2019 |archive-date=28 May 2019 |archive-url=https://web.archive.org/web/20190528205824/https://www.fsai.ie/faq/hepatitis_e.html |url-status=dead }}</ref>

===Blood products===
The amount of virus present in blood products required to cause transfusion-transmitted infection (TTI) appears variable. Transfusion transmission of hepatitis E virus can be screened via minipool HEV NAT (Nucleic acid testing) screening.<ref>{{cite book |last1=Hillyer |first1=Christopher D. |last2=Shaz |first2=Beth H. |last3=Zimring |first3=James C. |last4=Abshire |first4=Thomas C. |title=Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects |date=2009 |publisher=Elsevier |isbn=978-0-08-092230-0 |page=364 |url=https://books.google.com/books?id=cGBaz0hp_fcC&pg=PA364|language=en}}</ref><ref>{{cite journal |last1=Dreier |first1=Jens |last2=Knabbe |first2=Cornelius |last3=Vollmer |first3=Tanja |title=Transfusion-Transmitted Hepatitis E: NAT Screening of Blood Donations and Infectious Dose |journal=Frontiers in Medicine |date=1 February 2018 |volume=5 |pages=5 |doi=10.3389/fmed.2018.00005 |pmid=29450199 |pmc=5799287 |issn=2296-858X|doi-access=free }}</ref> NAT is a technique used to screen blood molecularly, when blood donations are received; it screens for TTI.<ref>{{cite journal |last1=Hans |first1=Rekha |last2=Marwaha |first2=Neelam |title=Nucleic acid testing-benefits and constraints |journal=Asian Journal of Transfusion Science |date=2014 |volume=8 |issue=1 |pages=2–3 |doi=10.4103/0973-6247.126679 |pmid=24678164 |pmc=3943139 |issn=0973-6247 |doi-access=free }}</ref>

===Vaccines===
A vaccine based on [[Protein production|recombinant]] viral proteins was developed in the 1990s and tested in a high-risk population (in [[Nepal]]) in 2001.<ref>{{cite journal |vauthors=Shrestha MP, Scott RM, Joshi DM |title=Safety and efficacy of a recombinant hepatitis E vaccine |journal=New England Journal of Medicine |volume=356 |issue=9 |pages=895–903 |year=2007|pmid=17329696 |doi=10.1056/NEJMoa061847|doi-access=free }}</ref> The vaccine appeared to be effective and safe, but development was stopped for lack of profitability, since hepatitis E is rare in developed countries.<ref name="10.1038/491021a"/> No hepatitis E vaccine is licensed for use in the United States.<ref name="cdchev"/>

The exception is China; after more than a year of scrutiny and inspection by China's State Food and Drug Administration (SFDA), a hepatitis E vaccine developed by Chinese scientists was available at the end of 2012. The vaccine—called [[HEV 239 vaccine|HEV 239]] by its developer [[Xiamen Innovax Biotech]]—was approved for prevention of hepatitis E in 2012 by the Chinese Ministry of Science and Technology, following a controlled trial on 100,000+ people from [[Jiangsu|Jiangsu Province]] where none of those vaccinated became infected during a 12-month period, compared to 15 in the group given placebo.<ref>{{Cite journal| last1 = Labrique| first1 = Alain B.| last2 = Sikder| first2 = Shegufta S.| last3 = Krain| first3 = Lisa J.| last4 = West| first4 = Keith P.| last5 = Christian| first5 = Parul| last6 = Rashid| first6 = Mahbubur| last7 = Nelson| first7 = Kenrad E.| date = 2012-09-01| title = Hepatitis E, a Vaccine-Preventable Cause of Maternal Deaths| journal = Emerging Infectious Diseases| volume = 18| issue = 9| pages = 1401–1404| doi = 10.3201/eid1809.120241| issn = 1080-6040| pmc = 3437697| pmid = 22931753}}</ref> The first vaccine batches came out of Innovax's factory in late October 2012, to be sold to Chinese distributors.<ref name="10.1038/491021a">{{Cite journal | last1 = Park | first1 = S. B. | title = Hepatitis E vaccine debuts | doi = 10.1038/491021a | journal = Nature | volume = 491 | issue = 7422 | pages = 21–22| date = November 2012 | pmid = 23128204 | bibcode = 2012Natur.491...21P | doi-access = free }}</ref>

Due to lack of evidence, the [[World Health Organization]] has not made a recommendation regarding routine use of the HEV 239 vaccine as of 2015.<ref name=WHO2015/> Its 2015 position was that national authorities may decide to use the vaccine based on their local epidemiology.<ref name=WHO2015>{{cite journal|title=Hepatitis E vaccine: WHO position paper, May 2015.|journal=Relevé Épidémiologique Hebdomadaire|date=1 May 2015|volume=90|issue=18|pages=185–200|pmid=25935931|url=https://www.who.int/wer/2015/wer9018.pdf?ua=1}}</ref>

==Treatment==
There is no drug that has established safety and effectiveness for hepatitis E, and there have been no large randomized clinical trials of antiviral drugs.<ref name=hepe/> Reviews of existing small studies suggest that [[ribavirin]] can be considered effective in immunocompromised people who have developed chronic infection.<ref>{{cite journal |last1=Dalton |first1=Harry R. |last2=Kamar |first2=Nassim |title=Treatment of hepatitis E virus |journal=Current Opinion in Infectious Diseases |volume=29 |issue=6 |pages=639–644 |doi=10.1097/QCO.0000000000000316 |pmid=27607911 |issn=1473-6527|year=2016 |s2cid=25304902 }}</ref><ref>{{Cite journal|last1=Peters van Ton|first1=A. M.|last2=Gevers|first2=T. J. G.|last3=Drenth|first3=J. P. H.|date=Dec 2015|title=Antiviral therapy in chronic hepatitis E: a systematic review|journal=Journal of Viral Hepatitis|volume=22|issue=12|pages=965–973|doi=10.1111/jvh.12403|issn=1365-2893|pmid=25760481|s2cid=10199788}}</ref>

Chronic HEV infection is associated with immunosuppressive therapies, and when that happens in individuals with solid-[[organ transplantation]], reducing [[immunosuppression|immunosuppressive]] medications can result in clearance of HEV in one third of patients.<ref name=emer/>

==Epidemiology==
The hepatitis E virus causes around 20 million infections a year. These result in around three million acute illnesses and resulted in 44,000 deaths during 2015.<ref name= hepe/> Pregnant women are particularly at risk of complications due to HEV infection, who can develop an acute form of the disease that is fatal in 30% of cases or more. HEV is a major cause of illness and of death in the developing world and disproportionate cause of deaths among pregnant women. Hepatitis E is [[endemic]] in Central Asia, while Central America and the Middle East have reported outbreaks.<ref>{{cite web |last1=Teshale|first1=Eyasu H.|title=Hepatitis E – Infectious Diseases Related to Travel Chapter 3 – 2018 Yellow Book |url=https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-to-travel/hepatitis-e|publisher=CDC |website=www.cdc.gov |date=31 May 2017}}</ref><ref>{{Cite journal| last1 = Navaneethan| first1 = Udayakumar| last2 = Mohajer| first2 = Mayar Al| last3 = Shata| first3 = Mohamed T| date = 2008| title = Hepatitis E and Pregnancy- Understanding the pathogenesis| journal = Liver International | volume = 28| issue = 9| pages = 1190–1199| doi = 10.1111/j.1478-3231.2008.01840.x| issn = 1478-3223| pmc = 2575020| pmid = 18662274}}</ref> Increasingly, hepatitis E is being seen in developed nations, with reports in 2015 of 848 cases of hepatitis E virus infection in England and Wales.<ref>{{cite web |last1=Public Health England |first1=infection report |title=Common animal associated infections quarterly report (England and Wales) – fourth quarter 2015 |url=https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/500321/hpr0616_zoos.pdf |website=gov.uk |access-date=27 July 2019}}</ref>

===Recent outbreaks===

In October 2007, an epidemic of hepatitis E occurred in [[Kitgum]] District of northern Uganda. This outbreak progressed to become one of the largest known hepatitis E outbreaks in the world. By June 2009, it had resulted in illness in 10,196 persons and 160 deaths.<ref name="tes">{{cite journal |vauthors=Teshale EH, Howard CM, Grytdal SP |title=Hepatitis E epidemic, Uganda |journal=Emerging Infect. Dis. |volume=16 |issue=1 |pages=126–129 |date=2010 |pmid=20031058 |pmc=2874362 |doi=10.3201/eid1601.090764}}</ref> The aforementioned outbreak occurred despite no previous epidemics having been documented in the country, women were the most affected by HEV.<ref name=tes/>
[[image:LocationNamibia.svg|thumb|200px|Namibia, Africa]]
In July 2012, an outbreak was reported in South Sudanese refugee camps in [[Maban County]] near the [[Sudan]] border. [[South Sudan]]'s Ministry of Health reported over 400 cases and 16 fatalities as of 13 September 2012.<ref>{{Cite report| url = https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6229a2.htm| title = Investigation of Hepatitis E Outbreak Among Refugees — Upper Nile, South Sudan, 2012–2013| website = www.cdc.gov|publisher=CDC Morbidity and Mortality Weekly Report| date = 26 July 2013 |volume= 62|issue=29|pages=581–586}}</ref> Progressing further, as of 2 February 2013, 88 died due to the outbreak. The medical charity [[Medecins Sans Frontieres]] said it treated almost 4000 people.<ref>{{cite news |author=Hereward Holland |title=Hepatitis outbreak kills 88 in South Sudan—aid agency |date=2 February 2013 |url=http://uk.reuters.com/article/uk-southsudan-hepatitis-idUKBRE91108420130202|archive-url=https://web.archive.org/web/20160305034459/http://uk.reuters.com/article/uk-southsudan-hepatitis-idUKBRE91108420130202|url-status=dead|archive-date=March 5, 2016|work=Reuters}}</ref> In April 2014, an outbreak in the [[Morang District|Biratnagar Municipality]] of [[Nepal]] resulted in infection of over 6000 locals and at least 9 dead.<ref name=Republica2014>{{cite web |last1=Sharma|first1=Christopher|title=Nepal, hepatitis E epidemic: 9 dead and over 6 thousand infected |url=http://www.asianews.it/news-en/Nepal,-hepatitis-E-epidemic:-9-dead-and-over-6-thousand-infected-31029.html |website=www.asianews.it |date=5 September 2014}}</ref>

During an outbreak in [[Namibia]], the number of affected people rose from 490 in January 2018, to 5014 (with 42 deaths) by April 2019, to 6151 cases (with 56 deaths) by August 2019; the WHO estimated that the case fatality rate was 0.9%.<ref>{{cite news|title=Hepatitis E cases in Namibia rise to 490|publisher=Xinhua News|language=en|url=http://www.xinhuanet.com/english/2018-01/25/c_136924873.htm|archive-url=https://web.archive.org/web/20180129140651/http://www.xinhuanet.com/english/2018-01/25/c_136924873.htm|url-status=dead|archive-date=January 29, 2018|work=www.xinhuanet.com|date=28 January 2018}}</ref><ref>{{cite web |title=Weekly bulletins on outbreaks and other emergencies |url=https://apps.who.int/iris/bitstream/handle/10665/312048/OEW16-1521042019.pdf |website=World Health Organization |publisher=WHO.int |access-date=20 May 2019}}</ref><ref>{{cite web |title=Outbreaks and Emergencies Bulletin, Week 33: 12 – 18 August 2019 |url=https://www.afro.who.int/node/11624 |website=WHO {{!}} Regional Office for Africa |access-date=20 August 2019 |language=en}}</ref>

In [[Hong Kong]] in May 2020,  there were at least 10 cases of hepatitis E that were transmitted by rats, and possibly hundreds of cases that had a transmission mechanism that is not fully understood.<ref>{{cite web |author=Jessie Yeung |title=Rats are infecting humans with hepatitis, and nobody knows how |url=https://www.cnn.com/2020/05/08/health/hong-kong-rat-hepatitis-intl-hnk-scn/index.html |website=CNN |date=8 May 2020 |access-date=11 May 2020}}</ref>

2024 outbreak in [[Finland]]. A record number of hepatitis E cases have been diagnosed in Finland so far this year, according to figures released on Tuesday by public health authority THL. Data from the authority's Infectious Diseases Register showed that a total of 92 lab-confirmed infections have been recorded since the beginning of January until 12 March, with 42 people requiring hospital treatment. The outbreak has been suspected to be caused by a batch of mettwurst that has been recalled.<ref>{{cite web |title=THL: Finland faces hepatitis E epidemic with record number of cases |url=https://yle.fi/a/74-20078824 |website= YLE |date=12 March 2024 |access-date=13 March 2024}}</ref>

== Evolution ==
The strains of HEV that exist today may have arisen from a shared ancestor virus 536 to 1344 years ago.<ref name="yury">{{cite journal |last1=Khudyakov |first1=Yury E. |last2=Purdy |first2=Michael A. |title=Evolutionary History and Population Dynamics of Hepatitis E Virus |journal=PLOS ONE |date= 2010 |volume=5 |issue=12 |pages=e14376 |doi=10.1371/journal.pone.0014376 |pmid=21203540 |pmc=3006657 |language=en |issn=1932-6203|bibcode=2010PLoSO...514376P |doi-access=free }}</ref>
Another analysis has dated the origin of Hepatitis E to ~6000 years ago, with a suggestion that this was associated with domestication of pigs.<ref name=Baha2019>{{Cite journal|last1=Baha|first1=Sarra|last2=Behloul|first2=Nouredine|last3=Liu|first3=Zhenzhen|last4=Wei|first4=Wenjuan|last5=Shi|first5=Ruihua|last6=Meng|first6=Jihong|date=2019-10-29|title=Comprehensive analysis of genetic and evolutionary features of the hepatitis E virus|journal=BMC Genomics|volume=20|issue=1|pages=790|doi=10.1186/s12864-019-6100-8|issn=1471-2164|pmid=31664890|pmc=6820953 |doi-access=free }}</ref> At some point, two [[clades]] may have diverged — an anthropotropic form and an enzootic form — which subsequently evolved into genotypes 1 and 2 and genotypes 3 and 4, respectively.<ref name=Mirazo2016>{{cite journal | author = Mirazo S, Mir D, Bello G, Ramos N, Musto H, Arbiza J | year = 2016 | title = New insights into the hepatitis E virus genotype 3 phylodynamics and evolutionary history | journal = Infect Genet Evol | volume = 43 | pages = 267–273 | doi = 10.1016/j.meegid.2016.06.003 | pmid = 27264728 | bibcode = 2016InfGE..43..267M }}</ref>

Whereas genotype 2 remains less commonly detected than other genotypes, genetic evolutionary analyses suggest that genotypes 1, 3, and 4 have spread substantially during the past 100 years.<ref name=izo/>

==References==
''This article incorporates public domain text from the CDC as cited''
{{Reflist}}

{{Academic peer reviewed|Q=Q73053451|doi-access=free}}

==Further reading==
* {{Cite journal|title = Chronic hepatitis E infection: risks and controls|journal = Intervirology|date = 2013-01-01|issn = 1423-0100|pmid = 23689166|pages = 213–216|volume = 56|issue = 4|doi = 10.1159/000349888|first = Mohammad Khalid|last = Parvez|url=https://zenodo.org/record/895805|doi-access = free}}
* {{cite web |first1=Rakesh |last1=Aggarwa |first2=Sanjay |last2=Gandhi |title=A systematic review on prevalence of hepatitis E disease and seroprevalence of hepatitis E virus antibody |date=2010 |publisher=World Health Organization |url=http://whqlibdoc.who.int/hq/2010/WHO_IVB_10.14_eng.pdf |id=WHO/IVB/10.14 |access-date=2012-02-12 |archive-date=2013-02-19 |archive-url=https://web.archive.org/web/20130219160025/http://whqlibdoc.who.int/hq/2010/WHO_IVB_10.14_eng.pdf |url-status=dead }}

== External links ==
{{Medical resources
| ICD10           = {{ICD10|B|17|2|b|15}}
| ICD9            = {{ICD9|070.4}}
| DiseasesDB      = 5794
| MedlinePlus     =
| eMedicineSubj   = med
| eMedicineTopic  = 995
| MeshID          = D016751
| SNOMED CT       = 7111000119109
}}
{{Scholia|topic}}
{{Commons category|Hepatitis E}}

{{Viral systemic diseases}}
{{Pathology of pregnancy, childbirth and the puerperium}}
{{Consumer Food Safety}}
{{Vaccines}}
{{Authority control}}

[[Category:Hepatitis|+E]]
[[Category:Rodent-carried diseases]]
[[Category:Animal viral diseases]]
[[Category:Zoonoses]]
[[Category:Vaccine-preventable diseases]]
[[Category:Viral hepatitis|E]]