ISSN: 2641-2977
Archives of Hepatitis Research
Research Article       Open Access      Peer-Reviewed

Hepatitis E: New Clinical and Public Health Problem on the Western World? Review

Couto AF, Kanebley M and Focaccia R*

Metropolitan University of Santos
*Corresponding author: Roberto Focaccia, Metropolitan University of Santos, São Paulo, Avenida Higienópolis, 360, Apt. 14, São Paulo, Brazil, Code: 01238-000; Tel: 55 11 99998; 2298; E-mail:
Received: 11 January, 2017 | Accepted: 30 March, 2017 | Published: 31 March, 2017

Cite this as

Couto AF, Kanebley M, Focaccia R (2017) Hepatitis E: New Clinical and Public Health Problem on the Western World? Review. Archives of Hepatitis Research 3(1): 019-022. DOI: 10.17352/ahr.000011


Until recently, the occurrence of Hepatitis E in the western hemisphere did not amount to a clinical concern, due to its benign and usually sub-clinical evolution, as opposed to Asia and Africa, where large epidemies with high levels of lethality occur. More sensible diagnostic exams have shown a high prevalence of the infection through genotype 3 in the eastern hemisphere, with reports of hepatic infection, cirrhosis, and extremely severe systemic [1-3] and neurological extra-hepatic manifestations, especially on immunosuppressed patients [4-6]. Hepatitis E: an emerging infection in developed countries [7], suggesting the occurrence of a new and important clinical and public health problem [3,8].

Chronic viral hepatitis E is the most prevalent worldwide. According WHO, HEV causes acute hepatic lesion annually in 3.5 million people, with around 70.000 deaths per year. It presents a single-stranded RNA genome, non-feces enveloped, but present on infected patients blood and in cell cultures. High genomic diversity with at least four major recognized genotypes (HEV1-4), and a few sub-genotypes, that can occur in humans with different epidemiologic and pathogenic characteristics. The molecular mechanisms of HEV replication are not fully understood.

The genotypes HEV 1 and HEV 2 occurs with high endemicity in Asia, Northern Africa, and Mexico. Feces-oral transmission, Anthroposis (man restricted). Endemic and/or epidemic in Asia (India: 2 million cases per year).

The genotype HEV 3: Predominant in South and North America, Europe, and Southeast Asia. It infects animals (swine, poultry, rats, boar, rabbits and others) and humans. It can be transmitted through contaminated water, by meat consumption (<71 ºC), parenteral, blood, from mother to children, (perhaps sexually). Pigs have been reported to act as a reservoir for zoonotic viruses, sometimes emerging ones, and epidemiological studies have shown direct links between the consumption of uncooked pork offal and cases of hepatitis caused by the hepatitis E virus (HEV) genotype 3 in humans [9,10].

The genotype HEV 4 is predominant in Asia. Transmitted through water and contaminated food. Sporadic cases in both animals and humans.

HEV 5 only occurs in birds.

Family Hepeviridae. Gen. Orthohepevirus is a anthroposis (HEV 1, HEV 2 – restricted to humans) and anthropozoonosis (HEV 3, HEV 4 – occurs in humans and animals: swine, poultry, boar, rabbits, rats, cattle, and others). The molecular mechanisms of HEV replication are not fully understood, mostly because there are no efficient cell culture systems.

The incubation period is of 2 to 4 weeks. It can cause both acute and chronic cases. HEV infection may cause a wide range of clini­cal presentations from subclinical or asympto­matic forms to fulminant liver failure.

The diagnosis is made through serology, ELISA IgM/IgG (98% sensitivity / 75% in immunosuppressed) and molecular tests (RT-qPCR) and by validated exams, since the performance is variable. Due to false negatives, it is needed to research through Western-blot and genome ORF3 detection techniques.


To discuss, considering recent findings in the subject’s literature, the dimension of the problem and research if the Hepatitis E genotype 3, emergent and neglected in the western hemisphere, constitutes of new and important grievance to health.


Recent editions of several infectious disease books served as a basic substrate for the research. Then, the authors have investigated all relevant papers published in major 1990 databases to 2016, including:

• PUBMED - National Library of Medicine:

• Scielo:



• Google Academic:





Infection through genotype 3 is very little studied in industrialized Countries [3,7,11-13]. It can become chronic, aggravating immunosuppressed patients’ cases [14-22]. Several clinical situations of immunosuppression have been described in which the infection by HEV can produce extra-hepatic diseases and/or chronification and worsening of liver disease, such as: HIV-Aids [23-26], organ or cell receptors [1,5,15,17,27,28], hematologic patients undergoing chemotherapy and immunotherapy [1,5], stem cells receptors, patients with schistosomiasis [29] and other immunologic diseases).

In its chronic form, it can cause extra-hepatic disease: neurological [6,30-34], including cases of S. Guillain-Barrè, neurologic pain amyotrophic, encephalitis, peripheral neuropathy, vestibular neuritis), confirming that HEV in addition to hepatotropic is also neurotropic.

There have been reports of cases with involvement of other organs in the HEV infection, such as: acute pancreatitis [35,36], immune-mediated diseases [37-40], (Hashimoto’s thyroiditis, glomerulonephritis, Henoch-Schonlein purpura, myasthenia gravis), hematologic diseases [38,41], (hemolytic anemia, acute myeloid leukemia, severe, thrombocytopenia), mixed cryoglobulinemia [42], inflammatory bowel disease [43]. In pregnant women, infected during the first trimester it generates a 15% to 25% lethality, in the Eastern hemisphere [44,45]. There are also registers of premature deliveries, with a child death rate under 30%. It is little studied in the western hemisphere. However, there are no reports of cases in the Western Region.


1) Genotype 3 high seroprevalence in the western regions, the most pathogenic of all genotypes;

2) The HEV virus can be transmitted via oral-oral route, parenteral via through blood contaminated, by animal meat and inter human transmission (including mother to child). Therefore, the risk of transmission through pork meat, and other animal products, implies the need of cook the meat for long periods at high temperatures (viruses can withstand temperatures of 71 °C for 5 minutes) as boil the cow’s milk.

3) Extrahepatic neurologic manifestations are common in immunocompromised HEV infected patients, especially transplant recipients of solid organs or cells, in chemotherapy / corticoid therapy and AIDS with CD4 <250 cells / mm3. Several other extrahepatic impairments have been described in patients with HEV;

4) HEV infection may accelerate the development of liver fibrosis in immunocompromised patients and other viral hepatitis or through other etiologies, causing cirrhosis in about 3 to 5 year;

5) Reports suggest that it is a new and important clinical issue on the western hemisphere. Therefore, Hepatitis E is an emergent disease and effectively neglected in all its aspects in occidental regions.

6) The exams (serological and molecular) are not available in most eastern countries, despite having many clinical indications. More sensible exams are needed.

7) It is always necessary to suspect of HEV in patients with elevated ALT without any apparent cause in the post-transplant; blood and plasma transfusion; and in hepatitis with fulminating or chronic evolution with fast evolution to cirrhosis.

8) The need for prophylactic ribavirin usage before immunosuppressive procedures is currently under discussion.

9) Its necessary to test the HEV 239 vaccine, human trials allowed in China (87% efficiency with 3 dosages in genotypes 1 and 2) on Eastern hemisphere’s risk groups.

Stimulate the pharmaceutical industry and researchers to develop new serological and molecular exams for more sensible and specific diagnosis.

  1. Gerolami R, Moal V, Colson P (2008) Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. N Engl J Med 358: 859-860. Link:
  2. Kumar AS, Sharma KP, Singh R, Mohanty SK, Madan K, et al. (2007) Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death. J. Hepatol 46: 387-394. Link:
  3. Blasco-Perrin H, Abravanel F, Blasco-Baqu V, Peron JM (2016) Hepatitis E, the neglected one. Liver Int 36: 130-134. Link:
  4. Bazerbachi F, Haffar S, Sushil K, Garg SK (2016) Extra-hepatic manifestations associated with hepatitis E virus infection: a comprehensive: Review of the literature. Gastroenterology Report 4: 1-15. Link:
  5. Kamar N, Abravanel F, Selves J, Cyril G, Laure E, et al. (2010) Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis E virus infection after organ transplantation. Transplantation 89: 353-360. Link:
  6. Dalton HR, Kamar N, van Eijk JJ, Mclean BN, Cintas P, et al. (2016) Hepatitis E virus and neurological injury. Nat Rev Neurol 12: 77-85. Link:
  7. Dalton HR, Bendall R, Ijaz S, Banks M (2008) Hepatitis E: an emerging infection in developed countries. Lancet Infect Dis 8: 698-709. Link:
  8. Dalton HR, Webb GW, Norton BC, Woolson KL (2016) Hepatitis E Virus: Time to Change the Textbooks. Dig Dis 34: 308-316. Link:
  9. Doceul V, Bagdassarian E, Demange A, Pavio N (2016) Zoonotic Hepatitis E Virus: Classifcation, Animal Reservoirs and Transmission Routes. Viruses 8: 270. Link:
  10. Drave SA, Debing Y, Walter S, Todt D, Engelmann M, et al. (2016) Extra-hepatic replication and infection of hepatitis E virus in neuronal-derived cells. J Viral Hepat 23: 512. Link:
  11. Clemente-Casares P, Ramos-Romero C, Ramirez-Gonzalez E, Mas A (2016) Hepatitis E Virus in Industrialized Countries: The Silent Threat. Biomed Res Int 2016: 1-17. Link:
  12. Echevarria JM JE, Gonzalez JE, Lewis-Ximenez LL, Santos DRL, Munne MS, et al. (2013) Hepatitis E Virus Infection in Latin America: A Review. J Med Virol 85: 1037-1045. Link:
  13. Focaccia R, Júnior SH, Conceição OJ (1995) Hepatitis E in Brazil. Lancet 346: 1165. Link:
  14. Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, et al. (2012) Hepatitis E. Lancet 379: 2477-2488. Link:
  15. Koning L, Charlton MR, Pas SD, Heimbach JK, Osterhaus ADME, et al. (2015) Prevalence and clinical consequences of Hepatitis E in patients who underwent liver transplantation for chronic Hepatitis C in the United States. BMC Infect Dis 15: 371. Link:
  16. Kmush BL, Labrique AB, Dalton HR, Ahmed ZB, Ticehurst JR, et al. (2015) Two Generations of "Gold Standards": The Impact of a Decade in Hepatitis E Virus Testing Innovation on Population Seroprevalence. Amer J Trop Med Hyg 93: 714-717. Link:
  17. Marion O, Abravanel F, Lhomme S, Izopet J, Kamar N (2016) Hepatitis E in Transplantation. Curr Infect Dis Rep 18: 8. Link:
  18. Pérez-Gracia MT, Suay-GarcíaB, García M, Mateos-Lindemann ML (2016) Hepatitis E: latest developments in knowledge. Microbiology 11: 789-808. Link:
  19. Pérez-Gracia MT, García M, Suay B,  Mateos-Lindemann ML (2015) Current Knowledge on Hepatitis E. J Clin Transl Hepatol 3: 117-126. Link:
  20. Perrin HB, Cintas P, Abravanel F, Gérolami R, d'Alteroche J, et al. (2015) Neurologic Disorders in Immunocompetent Patients with Autochthonous Acute Hepatitis E. Emerg Infect Dis 21: 1928-1934. Link:
  21. Petrik J, Lozano M, Seed CR, Faddy HM, Keller AJ, et al. (2016) Hepatite E. Vox Sanguinis 110: 93-130. Link:
  22. Mateos-Lindemann ML, Diez-Aguilar M, González-Galdamez A, Graus-Morales J, Moreno-Zamora A, et al. (2013) Acute, chronic and fulminant hepatitis E: seven years of experience (2004-2011). Enferm Infecc Microbiol Clin 31: 595-598. Link:
  23. Jardi R, Crespo M, Homs M, Eynde E, Girones R, et al. (2012) HIV, HEV and cirrhosis: evidence of a possible link from eastern Spain. HIV Med 13: 379-383. Link:
  24. Keane F, Gompels M, Bendall R, Drayton R, Jennings L, et al. (2012) Hepatitis E virus coinfection in patients with HIV infection. HIV Med 13: 83-88. Link:
  25. Kenfak-Foguena A, Schoni-Affolter F, Bürgisser P, Witteck A, Darling KEA, et al. (2011) Hepatitis E seroprevalence and chronic infections in patients with HIV, Switzerland. Emerg Infect Dis 17: 1074-1078. Link:
  26. Mateos-Lindemann ML, Diez-Aguilar M, Galdamez AL, Galan JC, Moreno A, et al. (2014) Patients infected with HIV are at high-risk for hepatitis E virus infection in Spain. J Med Virol 86: 71-74. Link:
  27. Zylberman M, Turdó K, Odzak A, Arcondo F, AltabertN, et al. (2015) Hepatitis E virus-associated aplastic anemia. Report of a case. Medicina 75: 175-177. Link:
  28. Passos-Castilho AM, de Sena A, Domingues A, Lopes-Neto EP, Medeiros TB, et al. (2016) Hepatitis E virus seroprevalence among schistosomiasis patients in Northeastern Brazil. Braz J Infect Dis 20: 262-266. Link:
  29. Cheung MCM, Maguire J, Agarwal K, Wendon J, Agarwal K (2012) Review of Neurological Manifestation of Hepatitis E Infection. Ann Hepatol 11: 618-622. Link:
  30. Despierres LA, Kaphan E, Attarian S, Cohen-Bacrie S, Colson P, et al. (2011) Neurological disorders and hepatitis E, France, 2010. Emerg Infect Dis 17: 1510-1512. Link:
  31. Maddukuri VC, Russo MW, Ahrens WA, Emerson SU, Engle RE, et al. (2013) Chronic hepatitis E with neurological manifestations and rapid progression of liver fibrosis in a liver transplant recipient. Dig Dis Sci 58: 2413-2416. Link:
  32. Van den Berg B, Van der Eijk AA, Pas SD, Hunter JG, Madden RG, et al. (2014) Guillain-Barr_e syndrome associated with preceding hepatitis E virus infection. Neurology 82: 491-497. Link:
  33. Zhou X, Huang F, Xu L, Lin Z, de Vrij FM, et al. (2017) Hepatitis E virus infects neurons and brains J Infect Dis. Link:
  34. Martínez-Artola Y, Poncino D, García ML, Munné MS, González J, et al. (2015) Acute hepatitis E virus infection and association with a subacute thyroiditis. Ann Hepatol 14: 141-142. Link:
  35. Kamar N, Abravanel F, Lhomme S, Rostaing L, Izopet J (2015) Hepatitis E virus: chronic infection, extra-hepatic manifestations, and treatment. Clin Res Hepatol Gastroenterol 39: 20-27. Link:
  36. Kamar N, Bendall R, Legrand-Abravanel F, Xia NS, Ijaz S, et al. (2012) Hepatitis E. Lancet 379: 2477-2488. Link:
  37. Mishra P, Mahapatra M, Kumar R, Pati HP (2007) Autoimmune haemolytic anemia and erythroid hypoplasia associated with hepatitis E. Indian J Gastroenterol 26: 195-196. Link:
  38. Kamar N, Marion O, Abravanel F, Izopet J, Dalton HR (2016) Extrahepatic manifestations of hepatitis E virus. Liver Int 36: 467-472. Link:
  39. Ali G, Kumar M, Bali S, Wadhwa W (2001) Heptitis E associated immune thrombocytopenia and membranous glomerulonephritis. Indian J Nephrol 11: 70-72.
  40. Fourquet E, Mansuy JM, Bureau C, Recher C, Vinel JP, et al. (2010) Severe thrombocytopenia associated with acute autochthonous hepatitis E. J Clin Virol 48: 73-74. Link:
  41. Del Bello A, Guilbeau-Frugier C, Josse AG, Rostaing L, Izopet J, et al. (2015) Successful treatment of hepatitis E virus-associated cryoglobulinemic membranoproliferative glomerulonephritis with ribavirin. Transpl Infect Dis 17: 279-283. Link:
  42. Senosiain C, González-Tallón AA, López-Sanromán A, Mateos ML, Pérez-Gracia MT, et al. (2016) Hepatitis E seroprevalence in inflammatory bowel disease. Gastroenterol Hepatol 39: 185-190. Link:
  43. Pérez-Gracia MT, Suay-García B, Mateos-Lindemann ML (2017) Hepatitis E and pregnancy: current state. Rev Med Virol. Link:
  44. Navaneethan U, Al MM, Shata MT (2008) Hepatitis E and pregnancy: understanding the pathogenesis. Liver Int 28: 1190-1199. Link:
© 2017 Focaccia R, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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