Hepatitis E: Water, water everywhere – Now a Global Disease
Authors: Subrat Kumar Acharya, Subrat Kumar Panda
Journal: Journal of Hepatology (2010)

Hepatitis E in Italy: A long-term prospective studyJournal of HepatologyVol. 54Issue 1PreviewIn developed countries, hepatitis E is usually associated with travelling to endemic areas, but a growing number of sporadic cases are also seen in patients with no travel history. The aim of this study was to assess the impact and the molecular epidemiology of hepatitis E in Italy. Full-Text PDF Acute autochthonous hepatitis E in western patients with underlying chronic liver disease: A role for ribavirin?Journal of HepatologyVol. 54Issue 6PreviewWe read with interest the recent editorial in the Journal of Hepatology entitled "Hepatitis E: Water, water everywhere – Now a Global Disease" [1]. The authors state that in industrialized nations, acute liver failure and acute-on-chronic liver failure due to autochthonous acute hepatitis E genotype 3 (HEV3) infection have not yet been documented. This statement is inaccurate. A series of seven patients with fulminant liver failure from acute autochthonous HEV3 infection have been reported from south-west France [2]. Full-Text PDF Open Access Hepatitis E virus (HEV) is an enterically transmitted virus of 27–34 nm diameter whose genome consists of a poly-adenylated single stranded RNA of 7.2 kb length with 3′ and 5′ non-coding end and three partially overlapping open reading frames (ORFs) [[1]Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar]. While ORF1 codes for non-structural proteins necessary for its replication, ORF2 and ORF3 code for the viral capsid protein [[1]Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar]. The genome of HEV has been cloned, sequenced, its structural regions have been expressed in vitro, and both serological diagnosis and detection of HEV-RNA in sera, stool, and bile have been established by RT-PCR [1Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar, 2Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. Due to its enteric route of transmission, it is the most common cause of both acute icteric and anicteric hepatitis in areas with poor sanitation and is known as hepatitis E [[1]Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar]. Multiple epidemics of hepatitis E involving thousands of people have been reported from developing countries like India, China, Southeast and Central Asia, Northern and Western Africa [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. The source of HEV in most of these outbreaks has been traced to contaminated drinking water [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. The virus has been identified, in the faeces of volunteers who ingested faeces of patient having acute hepatitis E, using immune electron microscopy, thereby confirming its faeco-oral enteric route of transmission [3Balayan M.S. Andjaparidze A.G. Savinskaya S.S. et al.Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route.Intervirology. 1983; 20: 23-31Crossref PubMed Scopus (677) Google Scholar, 4Chauhan A. Jameel S. Dilawari J.B. Chawla Y.K. Kaur U. Ganguly N.K. Hepatitis E virus transmission to a volunteer.Lancet. 1993; 341: 149-150Abstract PubMed Scopus (185) Google Scholar]. However, transmission through contaminated food, transmission through infected blood products, and maternal-foetal transmission of HEV have been reported from hyper-endemic regions like the Indian subcontinent [[1]Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar]. Therefore, HEV remains the most frequent cause of acute hepatitis, acute liver failure, and acute-on-chronic liver failure in hyper-endemic regions and represents an important public health problem [5Acharya S.K. Sharma P.K. Singh R. Mohanty S.K. Madan K. Jha J.K. et al.Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death.J Hepatol. 2007; 46: 387-394Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 6Bhatia V. Singhal A. Panda S.K. Acharya S.K. A 20-year single center experience with acute liver failure during pregnancy: Is the prognosis really worse?.Hepatology. 2008; 48: 1577-1585Crossref PubMed Scopus (158) Google Scholar]. Reports from hyper-endemic regions like South Asia have confirmed that pregnant women and patients with chronic liver disease are at an increased risk to contract HEV and subsequently develop severe liver disease leading to liver failure and high mortality rate of around 60–70% [1Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar, 5Acharya S.K. Sharma P.K. Singh R. Mohanty S.K. Madan K. Jha J.K. et al.Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death.J Hepatol. 2007; 46: 387-394Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 6Bhatia V. Singhal A. Panda S.K. Acharya S.K. A 20-year single center experience with acute liver failure during pregnancy: Is the prognosis really worse?.Hepatology. 2008; 48: 1577-1585Crossref PubMed Scopus (158) Google Scholar]. However, acute hepatitis E in previously healthy individuals is usually self limiting and resolves within 4 to 6 weeks and case fatality rates in most epidemics have been reported to vary between 0.5% to 4% [1Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar, 2Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. Chronic sequelae among patients during epidemic and sporadic setup have not been documented [[7]Panda S.K. Acharya S.K. Hepatitis E virus infection: Where are we?.Natl Med J India. 1998; 11: 56-58PubMed Google Scholar]. In non-endemic regions (Developed Industrialized Nations), where safe water supply has been ascertained, epidemic outbreaks have never been documented and hepatitis E associated deaths have not been recorded in immune competent healthy populations. A few years back, sporadic acute hepatitis E cases from these regions were predominantly documented among exposed travellers returning from HEV hyper-endemic regions. However, in recent years, a small series of cases related to autochthonous transmission of hepatitis E are being reported from developed nations like USA, Europe, Japan, Taiwan, Australia, and Hong Kong [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. In the present issue of the journal, a long term prospective study from Italy, conducted over 15 years, evaluated the magnitude of acute hepatitis E among patients with acute non A, non C hepatitis (n = 651). This study revealed that about one fifth (n = 134, 20.6%) of tested patients had acute HEV infection, which was diagnosed by the detection of IgM anti-HEV and/or HEV-RNA in their sera [[8]Romano L. Paladini S. Tagliacarne C. Canuti M. Bianchi S. Zanetti A.R. Hepatitis E in Italy: A long-term prospective study. 2010; Google Scholar]. Among these 134 patients with acute hepatitis E, 81.3% (n = 109) developed the disease within 1 to 4 weeks after returning to Italy subsequent to travelling to the Indian subcontinent, Morocco, and other countries that are hyper-endemic for HEV. Three patients (2.3%) were considered to have acquired HEV infection through infra-familial transmission. The remaining 22 (16.4%) were diagnosed as autochthonous acute hepatitis E, because they either (1) did not travel abroad, (2) denied contact with acute hepatitis E patients or people from abroad, (3) were not drug addicts or had transfusion, (4) did not eat raw undercooked shellfish and did not have occupational risks like swine handlers/pig farmers. A proportion of viral isolates (n = 39), from patients of acute hepatitis E who travelled to hyper-endemic area, and autochthonous group (n = 5), were further analysed for genotyping of the virus using PCR products of ORF2 region which revealed that all isolates of the former group had genotype 1 HEV infection whereas all isolates of autochthonous HEV belonged to genotype 3 [[8]Romano L. Paladini S. Tagliacarne C. Canuti M. Bianchi S. Zanetti A.R. Hepatitis E in Italy: A long-term prospective study. 2010; Google Scholar]. HEV is placed in the Hepevirus genus and is the only member of this family. In 1997, Meng et al. [[9]Meng X.J. Purcell R.H. Halbur P.G. et al.A novel virus in swine is closely related to the human hepatitis E virus.Proc Natl Acad Sci USA. 1997; 94: 9860-9865Crossref PubMed Scopus (958) Google Scholar] first identified, from swine in Midwestern USA, HEV strains that shared with the Burmese and Mexican (hyper-endemic for HEV) isolates of human HEV [[10]Schlauder G.G. Dawson G.J. Erker J.C. et al.The sequence and phylogenetic analysis of novel hepatitis E virus isolated from patient with acute hepatitis reported in the United States.J Gen Virol. 1998; 79: 447-456PubMed Google Scholar], 90–92% and 79–83% identity at the amino acid level in the ORF2 and ORF3 regions, respectively. Presence of HEV RNA in faeces and anti-HEV antibodies in sera of domestic swine, cattle, donkeys, deer, mules, and other animals had been reported earlier [[11]Clayson E.T. Innis B.L. Myint K.S. Narupiti S. Vaughn D.W. Giri S. et al.Detection of hepatitis E virus infections among domestic swine in the Kathmandu Valley of Nepal.Am J Trop Med Hyg. 1995; : 53225-53232Google Scholar]. However, initial reports from the USA, on acute hepatitis E [10Schlauder G.G. Dawson G.J. Erker J.C. et al.The sequence and phylogenetic analysis of novel hepatitis E virus isolated from patient with acute hepatitis reported in the United States.J Gen Virol. 1998; 79: 447-456PubMed Google Scholar, 12Kwo P.Y. Schlauder G.G. Carpenter H.A. et al.Acute hepatitis E by a new isolate acquired in the United States.Mayo Clin Proc. 1997; 72: 1133-1136Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 13Erker J.C. Desai S.M. Schlauder G.G. Dwason G.J. Mushahwar I.K. A hepatitis E virus variant from the United States: molecular characterization and transmission in cynomolgus macaques.J Gen Virol. 1999; 80: 681-690PubMed Google Scholar] in human and HEV isolates from patients showing nucleotide and amino acid heterogeneity similar to human isolates of Burmese and Mexican strains, prompted further investigation and the search for sources of HEV reservoirs in industrialized countries. HEV has mainly been found in pigs from all parts of the world, irrespective of HEV endemicity and the frequency of acute hepatitis E in respective human populations [1Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar, 2Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. It has also been found that swine HEV naturally infects pigs, causing viremia and an antibody response that cross-reacts with human strains [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. Furthermore, zoonotic human HEV infection, particularly in industrialized and developed nations, was first suspected after the detection of closely similar HEV isolates in two autochthonous cases in regions of the USA with locally prevalent swine HEV isolates [10Schlauder G.G. Dawson G.J. Erker J.C. et al.The sequence and phylogenetic analysis of novel hepatitis E virus isolated from patient with acute hepatitis reported in the United States.J Gen Virol. 1998; 79: 447-456PubMed Google Scholar, 12Kwo P.Y. Schlauder G.G. Carpenter H.A. et al.Acute hepatitis E by a new isolate acquired in the United States.Mayo Clin Proc. 1997; 72: 1133-1136Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, 13Erker J.C. Desai S.M. Schlauder G.G. Dwason G.J. Mushahwar I.K. A hepatitis E virus variant from the United States: molecular characterization and transmission in cynomolgus macaques.J Gen Virol. 1999; 80: 681-690PubMed Google Scholar]. The zoonotic transmission of HEV was then confirmed by a Japanese case series of acute hepatitis E where patients consumed inadequately cooked deer meat a few weeks before the illness declared itself, and HEV isolated from these patients were akin to the HEV isolates detected from the frozen left over deer meat [[14]Matsuda H. Okada K. Takahashi K. Mishiro S. Severe hepatitis E virus infection after ingestion of uncooked liver from a wild boar.J Infect Dis. 2003; 188: 944Crossref PubMed Scopus (294) Google Scholar]. Various additional evidences have supported the existence of zoonotic transmission in non-endemic region [[15]Dalton H.R. Bendall R. Ijaz S. Banks M. Hepatitis E: an emerging infection in developed countries.Lancet Infect Dis. 2008; 8: 698-709Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar]. By now, multiple reports on the presence of autochthonous acute hepatitis E in non-endemic, industrialized countries like USA, France, Spain, Italy, Greece, Netherlands, UK and non-endemic developed Asian-Pacific countries like Australia, Japan and Taiwan have appeared in the English literature [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar], and isolates from these patients with acute hepatitis E have been analysed and genotyped [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. Despite the lack of consensus regarding the genotyping process, genotyping of HEV isolates is presently performed based on the ORF2 region and genotypes are defined as viruses having a nucleotide divergence of not more than 20% [[16]van der Poel H.C. van der Poel W.H. Brandstatter G. Hepatitis E: an overview.Microbes Infect. 2002; 4: 657-666Crossref PubMed Scopus (160) Google Scholar]. Based on genome sequence analysis, human and swine HEV isolates have been categorized into four distinct genotypes 1–4 (Table 1). Each genotype has several subtypes but all genotypes have common serotypes [1Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar, 2Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar, 15Dalton H.R. Bendall R. Ijaz S. Banks M. Hepatitis E: an emerging infection in developed countries.Lancet Infect Dis. 2008; 8: 698-709Abstract Full Text Full Text PDF PubMed Scopus (544) Google Scholar]. As indicated earlier, it is clear that acute autochthonous hepatitis E is being reported with increasing frequency in developed and industrialized country, thus confirming HEV as a cause of acute hepatitis all over the world. However, while genotype 1 and 2 are prevalent in hyper-endemic regions where the reservoir for HEV seems to be human (continuous subclinical infection [[17]Aggarwal R. Hepatitis E: Is it a blood-borne pathogen?.J Gastroenterol Hepatol. 2004; 19: 729-731Crossref PubMed Scopus (11) Google Scholar]), genotype 3 and 4 are prevalent in USA, Europe, and Japan where the reservoir seems to be represented by pigs, and the zoonotic transmission is considered to be the cause of infection of human beings, leading to autochthonous acute HEV. Genotype 4 has been identified in both swine and human patients with acute hepatitis E in China, Taiwan and Japan, but in the Indian subcontinent, even though swine HEV belongs to genotype 4, all human cases to date had genotype 1 infection [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. All swine isolates belong to genotype 3 and 4 and no animal isolates to date belong to genotype 1 and 2. This may indicate that genotype 1 and 2 may not be capable of crossing the species barrier whereas genotype 3 and 4 can do so. On the other hand, genotype 1 and 2 cause severe liver disease whereas genotype 3 and 4 cause milder disease [1Acharya S.K. Panda S.K. Hepatitis E Virus: epidemiology, diagnosis, pathology and prevention.Trop Gastroenterol. 2006; 27: 63-68PubMed Google Scholar, 2Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. It is further evident by the observation that the seroprevalence of anti-HEV in populations belonging to developed nations varies from 5–21% [[18]Teshale E.H. Hu D.J. Holmberg S.D. The two faces of hepatitis E virus.Clin Infect Dis. 2010; 51: 328-334Crossref PubMed Scopus (181) Google Scholar], indicating frequent exposure but epidemic outbreaks and the low frequency of autochthonous hepatitis would suggest that these viruses may be more benign than those prevalent in hyper-endemic region. Despite increasing reports on the occurrence of autochthonous acute hepatitis E in industrialized nations, acute liver failure and acute-on-chronic liver failure, due to autochthonous acute hepatitis E belonging to genotype 3 and 4, have not yet been documented.Table 1Hepatitis E virus: Genotypes, geographical prevalence, viral and disease characteristics.NK, Not Known. Open table in a new tab NK, Not Known. In the paper reported in this issue [[8]Romano L. Paladini S. Tagliacarne C. Canuti M. Bianchi S. Zanetti A.R. Hepatitis E in Italy: A long-term prospective study. 2010; Google Scholar], 96 (71.6%) patients with acute hepatitis E were viremic, as shown by the presence of HEV RNA. Even though the paper did not provide the exact frequency of viremia among autochthonous cases, many of them would presumably be viremic. It may be relevant to these populations where autoimmune hepatitis (AIH) is more prevalent and corticosteroid therapy is the mainstay of treatment. AIH in these parts of the world is frequently diagnosed by excluding known causes of viral hepatitis, and autoimmune markers may be absent in about 30–40% of such cases. Therefore, it seems that a serological test for HEV may be relevant for such patients, before embarking upon an immunosuppressive therapy. With the increasing prevalence of non-alcoholic fatty liver disease and alcoholic liver disease, HEV super-infection might be a cause of deterioration in patients who have never been investigated. HEV super-infection in such patients has already been documented to cause rapid decompensation [5Acharya S.K. Sharma P.K. Singh R. Mohanty S.K. Madan K. Jha J.K. et al.Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death.J Hepatol. 2007; 46: 387-394Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 6Bhatia V. Singhal A. Panda S.K. Acharya S.K. A 20-year single center experience with acute liver failure during pregnancy: Is the prognosis really worse?.Hepatology. 2008; 48: 1577-1585Crossref PubMed Scopus (158) Google Scholar]. However, these reports have emanated from the Indian subcontinent which is hyper-endemic for HEV where human disease is caused by HEV genotype 1 [[2]Aggarwal R. Naik S. Epidemiology of hepatitis E: current status.J Gastroenterol Hepatol. 2009; 24: 1484-1493Crossref PubMed Scopus (227) Google Scholar]. Whether HEV genotype 3 and 4 super-infection would cause such sequel is unclear and needs prospective evaluation. A prototype example is a recent report on drug induced hepatitis (DH) in the UK [[19]Dalton H.R. FFellows H.J. Stableforth W. Joseph M. Thurairajah P.H. Warshow U. et al.The role of hepatitis E virus testing in drug induced liver injury.Aliment Pharmacol Ther. 2007; 26: 1429-1435Crossref PubMed Scopus (193) Google Scholar]. In this report, in 13% of patients DH was due to acute hepatitis E, as diagnosed by a later analysis of their stored sera. Data on HEV in the developed world is inadequate because of the belief that HEV prevalence and transmission is extremely infrequent in these areas. The seroprevalence studies from these countries had used ELISA assays, to detect IgG anti-HEV antibody, manufactured by either GeneLabs (Singapore) or/and Abbott, (Germany) which uses truncated recombinant peptides of ORF2 and ORF3 regions from the Burmese and Mexican prototype sequences [[20]Ghabrah T.M. Tsarev S. Yarbough P.O. Emerson S.U. Strickland G.T. Purcell R.H. Comparison of tests for antibody to hepatitis E virus.J Med Virol. 1998; 55: 134-137Crossref PubMed Scopus (63) Google Scholar]. A recent study showed that the above mentioned ELISA assays may be less sensitive to detect IgG anti-HEV antibody in the sera [[21]Bendall R. Ellis V. Ijaz S. Ali R. Dalton H. A comparison of two commercially available anti-HEV IgG kits and a re-evaluation of anti-HEV IgG seroprevalence data in developed countries.J Med Virol. 2010; 82: 799-805Crossref PubMed Scopus (256) Google Scholar]. A recently developed, more sensitive ELISA (IgG EIA kit, Wantai, Beijing, China) with a lower limit of detection for IgG anti-HEV (0.25 WHO unit/ml) was compared with the frequently used GeneLab IgG anti-HEV kit that has a higher limit of detection for IgG anti-HEV (2.5 WHO unit/ml) [[21]Bendall R. Ellis V. Ijaz S. Ali R. Dalton H. A comparison of two commercially available anti-HEV IgG kits and a re-evaluation of anti-HEV IgG seroprevalence data in developed countries.J Med Virol. 2010; 82: 799-805Crossref PubMed Scopus (256) Google Scholar]. Both these assays were used for the analysis of stored sera of known acute hepatitis E and donor blood from the UK. The Wantai kit was positive in more sera of proven cases as compared to the GeneLab kit (98% vs 56%) and resulted in a markedly higher estimate of seroprevalence in blood donors (16.2% vs 3.6%). Therefore, the actual seroprevalence might have been underestimated in most of the industrialized countries due to the use of less sensitive assays. Furthermore, IgM anti-HEV antibody in autochthonous acute hepatitis E may not be detectable by less sensitive assays and diagnosis has been ascertained by detection of HEV-RNA in the sera or stool [[22]Moucari R. Bernuau J. Nicand E. Cazals-hatem D. Valla D. Marcellin P. et al.Acute hepatitis E with severe jaundice: report of three cases.Eur J Gastroenterol Hepatol. 2007; 19: 1012-1015Crossref PubMed Scopus (11) Google Scholar]. It may be relevant to reassess the sero-epidemiology of HEV in the developed nations, and identify the other sources of HEV transmission in view of the increasing number of reports on acute hepatitis E, as documented by the paper in this issue of the journal. In addition to zoonotic transmission, contaminated water, as a source of acute hepatitis E, has been reported from France [[23]Renou C. Moreau X. Pariente A. Cadranel J.F. Maringe E. Morin T. et al.A national survey of acute hepatitis E in France.Aliment Pharmacol Ther. 2008; 27: 1086-1093Crossref PubMed Scopus (92) Google Scholar]. During a 13 month duration, the evaluation of consecutive patients with acute hepatitis in South Hampshire, UK, revealed that acute hepatitis E was more frequent than acute hepatitis A and B and none of the patients had a history of travel abroad or had consumed any raw meat in the recent past, raising the suspicion of transmission through contaminated water or food [[24]De Silva A.N. Muddu A.K. Iredale J.P. Sheron N. Khakoo S.I. Pelosi E. Unexpectedly high incidence of indigenous acute hepatitis E within South Hampshire: time for routine testing?.J Med Virol. 2008; 80: 283-288Crossref PubMed Scopus (30) Google Scholar]. It is evident that HEV is endemic in most part of the developed and industrialized nations indicating its global prevalence. While HEV genotype 1 is hyper-endemic in Asia and Africa, where it causes outbreaks, sporadic acute hepatitis, acute liver failure, and acute-on chronic liver failure; HEV genotype 3 and 4 are prevalent in the industrialized and developed nations and increasing reports on autochothonous acute hepatitis E due to these viruses are being identified. The reservoir for genotype 1 has been identified to be human whereas the reservoir for the genotype 3 and 4 seems to be pigs, and therefore zoonotic transmission is more prevalent in these regions. However, the latter viruses have not been implicated in causing severe liver disease and more studies are needed to further clarify this observation. (Table 1). Genotype 2 like genotype 1 has been reported from Mexico and Nigeria with similar epidemiological and sporadic features. Due to the global prevalence of HEV, an effective vaccine with long lasting immunity is urgently needed to protect people throughout the world and therefore it is time that HEV associated diseases are not considered as a disease of the developing world where sanitation is inadequate. HEV, indeed, is prevalent globally and is of public health importance, which requires the attention of public health experts, academia, and the health authorities throughout the world in order to reduce the morbidity and mortality caused by it. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.