Hepatitis E Virus


The hepatitis E virus (HEV) infection is a worldwide disease. HEV is usually responsible of an acute self‐limiting infection, but pregnant women and patients with preexisting liver disease can suffer from severe forms. HEV infections can lead to chronic hepatitis and cirrhosis in immunocompromised patients. Extrahepatic manifestations can also occur. In developing countries, HEV is transmitted via contaminated water. In developed countries, transmission is zoonotic due to consumption of uncooked or undercooked infected meat and direct contact with infected animals. Transfusion‐transmitted HEV infections were also described. HEV infections are diagnosed by detecting anti‐HEV antibodies in the serum. In immunocompromised patients, detecting HEV RNA in the blood or faeces is needed. A 3‐month course of ribavirin is effective for treating chronic infection: a sustained virologic response occurs in 78% of patients. Vaccine has been recently licensed for use in China and provides protection against hepatitis E for up to 4.5 years.

Key Concepts

  • The hepatitis E virus infection is a worldwide disease.
  • Animal reservoir is responsible for autochthonous HEV infection in developed countries.
  • Chronic infections are possible in immunocompromised patients.
  • Treatment of choice for chronic HEV infections is a 3‐month course of ribavirin.
  • Vaccine afforded a sustained protection.

Keywords: hepatitis E virus; zoonosis; chronic hepatitis; diagnosis; treatment; prevention

Figure 1. Hepatitis E virus genome. The 5′ end of the RNA genome is capped with 7‐methylguanosine (7 mG), and the 3′ end is polyadenylated (poly A). ORF1 encodes the nonstructural proteins, including a methyl transferase (MT), cysteine protease (P), helicase (Hel) and RNA polymerase (RdRp), as well as three regions of unknown function (Y, PPR and X).
Figure 2. HEV lifecycle. HEV particles become bound to the proteoglycan heparan sulphate at the cell surface (1), interact with their unknown specific receptor (2) and are internalised in a clathrin‐dependent process (3). The virus uncoats (4). RNA is released and is translated into nonstructural proteins in the host cell cytoplasm (5). Virus polymerase replicates the positive‐sense (+) genomic RNA to form a negative‐sense (−) transcript (6). This RNA(−) serves as a template for the synthesis of full‐length positive‐sense transcripts (7) or a 2.2‐kb subgenomic RNA (8). The RNA(+) is translated into ORF2 (triangle) and ORF3 (circles) proteins (9). The ORF2 protein passes through the endoplasmic reticulum and packages the virus genomic RNA to assemble new virions (10). The ORF3 is also associated with the endomembrane and is probably implicated in virus egress (11). Mature virions are associated with ORF3 protein and lipids (12).
Figure 3. Worldwide distribution of the four major genotypes of HEV.
Figure 4. Course of an acute hepatitis E virus infection.
Figure 5. Diagnostic algorithm for acute hepatitis E.


Abravanel F, Mansuy JM, Huynh A, et al. (2012) Low risk of hepatitis E virus reactivation after haematopoietic stem cell transplantation. Journal of Clinical Virology 54 (2): 152–155.

Abravanel F, Chapuy‐Regaud S, Lhomme S, et al. (2013a) Performance of anti‐HEV assays for diagnosing acute hepatitis E in immunocompromised patients. Journal of Clinical Virology 58 (4): 624–628.

Abravanel F, Chapuy‐Regaud S, Lhomme S, et al. (2013b) Performance of two commercial assays for detecting hepatitis E virus RNA in acute or chronic infections. Journal of Clinical Microbiology 51 (6): 1913–1916.

Abravanel F, Lhomme S, Chapuy‐Regaud S, et al. (2014) Hepatitis E virus reinfections in solid‐organ‐transplant recipients can evolve to chronic infections. Journal of Infectious Diseases 209 (12): 1900–1906.

Aggarwal R (2011) Clinical presentation of hepatitis E. Virus Research 161 (1): 15–22.

Aggarwal R (2012) Diagnosis of hepatitis E. Nature Reviews Gastroenterology & Hepatology 10 (1): 24–33.

Aggarwal R (2013) Hepatitis E: clinical presentation in disease‐endemic areas and diagnosis. Seminars in Liver Disease 33 (1): 30–40.

Balayan MS, Andjaparidze AG, Savinskaya SS, et al. (1983) Evidence for a virus in non‐A, non‐B hepatitis transmitted via the fecal‐oral route. Intervirology 20 (1): 23–31.

Barnaud E, Rogee S, Garry P, Rose N and Pavio N (2012) Thermal inactivation of infectious hepatitis E virus in experimentally contaminated food. Applied and Environmental Microbiology 78 (15): 5153–5159.

Bendall R, Ellis V, Ijaz S, Ali R and Dalton H (2010) A comparison of two commercially available anti‐HEV IgG kits and a re‐evaluation of anti‐HEV IgG seroprevalence data in developed countries. Journal of Medical Virology 82 (5): 799–805.

Bhatia V, Singhal A, Panda SK and Acharya SK (2008) A 20‐year single‐center experience with acute liver failure during pregnancy: is the prognosis really worse? Hepatology 48 (5): 1577–1585.

Colson P, Borentain P, Queyriaux B, et al. (2010) Pig liver sausage as a source of hepatitis E virus transmission to humans. Journal of Infectious Diseases 202 (6): 825–834.

le Coutre P, Meisel H, Hofmann J, et al. (2009) Reactivation of hepatitis E infection in a patient with acute lymphoblastic leukaemia after allogeneic stem cell transplantation. Gut 58 (5): 699–702.

Crossan C, Scobie L, Godwin J, et al. (2013) Hepatitis E virus and porcine‐derived heparin. Emerging Infectious Diseases 19 (4): 686–688.

van Cuyck H, Fan J, Robertson DL and Roques P (2005) Evidence of recombination between divergent hepatitis E viruses. Journal of Virology 79 (14): 9306–9314.

Dalton HR, Fellows HJ, Stableforth W, et al. (2007) The role of hepatitis E virus testing in drug‐induced liver injury. Alimentary Pharmacology & Therapeutics 26 (10): 1429–1435.

Dalton HR, Bendall RP, Rashid M, et al. (2011) Host risk factors and autochthonous hepatitis E infection. European Journal of Gastroenterology & Hepatology 23 (12): 1200–1205.

Davern TJ, Chalasani N, Fontana RJ, et al. (2011) Acute hepatitis E infection accounts for some cases of suspected drug‐induced liver injury. Gastroenterology 141 (5): 1665‐72.e1–1665‐72.e9.

Graff J, Torian U, Nguyen H and Emerson SU (2006) A bicistronic subgenomic mRNA encodes both the ORF2 and ORF3 proteins of hepatitis E virus. Journal of Virology 80 (12): 5919–5926.

Holla RP, Ahmad I, Ahmad Z and Jameel S (2013) Molecular virology of hepatitis E virus. Seminars in Liver Disease 33 (1): 3–14.

Kamar N, Izopet J, Cintas P, et al. (2010) Hepatitis E virus‐induced neurological symptoms in a kidney‐transplant patient with chronic hepatitis. American Journal of Transplantation 10 (5): 1321–1324.

Kamar N, Garrouste C, Haagsma EB, et al. (2011a) Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology 140 (5): 1481–1489.

Kamar N, Bendall RP, Peron JM, et al. (2011b) Hepatitis E virus and neurologic disorders. Emerging Infectious Diseases 17 (2): 173–179.

Kamar N, Rostaing L, Legrand‐Abravanel F and Izopet J (2013) How should hepatitis e virus infection be defined in organ‐transplant recipients? American Journal of Transplantation 13 (7): 1935–1936.

Kamar N, Dalton HR, Abravanel F and Izopet J (2014a) Hepatitis E virus infection. Clinical Microbiology Reviews 27 (1): 116–138.

Kamar N, Izopet J, Tripon S, et al. (2014b) Ribavirin for chronic hepatitis E virus infection in transplant recipients. New England Journal of Medicine 370 (12): 1111–1120.

Khuroo MS, Kamili S and Jameel S (1995) Vertical transmission of hepatitis E virus. Lancet 345 (8956): 1025–1026.

Khuroo MS, Kamili S and Khuroo MS (2009) Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV‐infected mothers. Journal of Viral Hepatitis 16 (7): 519–523.

Legrand‐Abravanel F, Thevenet I, Mansuy JM, et al. (2009) Good performance of immunoglobulin M assays in diagnosing genotype 3 hepatitis E virus infections. Clinical and Vaccine Immunology 16 (5): 772–774.

Legrand‐Abravanel F, Kamar N, Sandres‐Saune K, et al. (2010) Characteristics of autochthonous hepatitis E virus infection in solid‐organ transplant recipients in France. Journal of Infectious Diseases 202 (6): 835–844.

Legrand‐Abravanel F, Kamar N, Sandres‐Saune K, et al. (2011) Hepatitis E virus infection without reactivation in solid‐organ transplant recipients, France. Emerging Infectious Disease 17 (1): 30–37.

Lhomme S, Abravanel F, Dubois M, et al. (2012) HEV quasispecies and the outcome of acute hepatitis E in solid‐organ transplant patients. Journal of Virology 86 (18): 10006–10014.

Lhomme S, Abravanel F, Dubois M, et al. (2014) Characterization of the polyproline region of the hepatitis E virus in immunocompromised patients. Journal of Virology 88 (20): 12017–12025.

Lu L, Li C and Hagedorn CH (2006) Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis. Reviews in Medical Virology 16 (1): 5–36.

Mansuy JM, Huynh A, Abravanel F, et al. (2009) Molecular evidence of patient‐to‐patient transmission of hepatitis E virus in a hematology ward. Clinical Infectious Diseases 48 (3): 373–374.

Mansuy JM, Bendall R, Legrand‐Abravanel F, et al. (2011) Hepatitis E virus antibodies in blood donors, France. Emerging Infectious Disease 17 (12): 2309–2312.

Meng XJ (2013) Zoonotic and foodborne transmission of hepatitis E virus. Seminars in Liver Disease 33 (1): 41–49.

Nagashima S, Jirintai S, Takahashi M, et al. (2014) Hepatitis E virus egress depends on the exosomal pathway, with secretory exosomes derived from multivesicular bodies. Journal of General Virology 95 (Pt 10): 2166–2175.

Navaneethan U, Al Mohajer M and Shata MT (2008) Hepatitis E and pregnancy: understanding the pathogenesis. Liver International 28 (9): 1190–1199.

Nguyen HT, Torian U, Faulk K, et al. (2012) A naturally occurring human/hepatitis E recombinant virus predominates in serum but not in faeces of a chronic hepatitis E patient and has a growth advantage in cell culture. Journal of General Virology 93 (Pt 3): 526–530.

Pischke S, Stiefel P, Franz B, et al. (2012) Chronic hepatitis e in heart transplant recipients. American Journal of Transplantation 12 (11): 3128–3133.

Reyes GR, Purdy MA, Kim JP, et al. (1990) Isolation of a cDNA from the virus responsible for enterically transmitted non‐A, non‐B hepatitis. Science 247 (4948): 1335–1339.

Robson SC, Adams S, Brink N, Woodruff B and Bradley D (1992) Hospital outbreak of hepatitis E. Lancet 339 (8806): 1424–1425.

Shukla P, Nguyen HT, Torian U, et al. (2011) Cross‐species infections of cultured cells by hepatitis E virus and discovery of an infectious virus‐host recombinant. Proceedings of the National Academy of Sciences of the United States of America 108 (6): 2438–2443.

Smith DB, Simmonds P, Jameel S, et al. (2014) Consensus proposals for classification of the family Hepeviridae. Journal Of General Virology 95 (Pt 10): 2223–2232.

Takahashi M, Tanaka T, Takahashi H, et al. (2010) Hepatitis E Virus (HEV) strains in serum samples can replicate efficiently in cultured cells despite the coexistence of HEV antibodies: characterization of HEV virions in blood circulation. Journal of Clinical Microbiology 48 (4): 1112–1125.

Tam AW, Smith MM, Guerra ME, et al. (1991) Hepatitis E virus (HEV): molecular cloning and sequencing of the full‐length viral genome. Virology 185 (1): 120–131.

Versluis J, Pas SD, Agteresch HJ, et al. (2013) Hepatitis E virus: an underestimated opportunistic pathogen in recipients of allogeneic hematopoietic stem cell transplantation. Blood 122 (6): 1079–1086.

Zhang J, Shih JW, Wu T, Li SW and Xia NS (2013) Development of the hepatitis E vaccine: from bench to field. Seminars in Liver Disease 33 (1): 79–88.

Zhang J, Zhang XF, Huang SJ, et al. (2015) Long‐term efficacy of a hepatitis E vaccine. New England Journal of Medicine 372 (10): 914–922.

Further Reading

Aggarwal R (2013) Hepatitis E: clinical presentation in disease‐endemic areas and diagnosis. Seminars in Liver Disease 33 (1): 30–40.

van den Berg B, van der Eijk AA, Pas SD, et al. (2014) Guillain‐Barre syndrome associated with preceding hepatitis E virus infection. Neurology 82 (6): 491–497.

Colson P, Romanet P, Moal V, et al. (2012) Autochthonous infections with hepatitis E virus genotype 4, France. Emerging Infectious Disease 18 (8): 1361–1364.

van Eijk JJ, Madden RG, van der Eijk AA, et al. (2014) Neuralgic amyotrophy and hepatitis E virus infection. Neurology 82 (6): 498–503.

Gerolami R, Moal V and Colson P (2008) Chronic hepatitis E with cirrhosis in a kidney‐transplant recipient. New England Journal of Medicine 358 (8): 859–860.

Hakze‐van der Honing RW, van Coillie E, Antonis AF and van der Poel WH (2011) First isolation of hepatitis E virus genotype 4 in Europe through swine surveillance in the Netherlands and Belgium. PLoS One 6 (8): e22673.

Kamar N, Mansuy JM, Cointault O, et al. (2008) Hepatitis E virus‐related cirrhosis in kidney‐ and kidney‐pancreas‐transplant recipients. American Journal of Transplantation 8 (8): 1744–1748.

Krawczynski K, Meng XJ and Rybczynska J (2011) Pathogenetic elements of hepatitis E and animal models of HEV infection. Virus Research 161 (1): 78–83.

Okamoto H (2011) Hepatitis E virus cell culture models. Virus Research 161 (1): 65–77.

Purdy (2014) http://ictvonline.org/taxonomyHistory.asp?taxnode_id=20132053&taxa_name=Hepatitis%20E%20virus

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lhomme, Sebastien, Abravanel, Florence, Chapuy‐Regaud, Sabine, Dubois, Martine, Mansuy, Jean‐Michel, Peron, Jean‐Marie, Alric, Laurent, Rostaing, Lionel, Kamar, Nassim, and Izopet, Jacques(Sep 2015) Hepatitis E Virus. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001030.pub3]