Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2010)

What is the significance of hepatitis E as a public health threat in the industrialized countries? Hepatitis E virus infection in Italy Hepatitis E virus (HEV) infection is likely an old disease that has been affecting humans for centuries but has only been recognized in the second half of the 20th century. The first clinical description of HEV came after an outbreak in New-Delhi in 1955 [[1]Gupta D.N. Smetana H.F. The histopathology of viral hepatitis as seen in the Delhi epidemic (1955–56).Indian J Med Res. 1957; 45: 101-113PubMed Google Scholar]. This was followed by its clinical, morphologic, serologic, and molecular characterization between 1980 and 2009 [2Khuroo M.S. Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type.Am J Med. 1980; 68: 818-824Abstract Full Text PDF PubMed Scopus (555) Google Scholar, 3Purcell R.H. Emerson S.U. Hepatitis E: an emerging awareness of an old disease.J Hepatol. 2008; 48: 494-503Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar, 4Balayan M.S. Andjaparidze A.G. Savinskaya S.S. Ketiladze E.S. Braginsky D.M. Savinov A.P. 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, 5Kane M.A. Bradley D.W. Shrestha S.M. Maynard J.E. Cook E.H. Mishra R.P. et al.Epidemic non-A, non-B hepatitis in Nepal. Recovery of a possible etiologic agent and transmission studies in marmosets.JAMA. 1984; 252: 3140-3145Crossref PubMed Scopus (228) Google Scholar, 6Yamashita T. Mori Y. Miyazaki N. Cheng R.H. Yoshimura M. Unno H. et al.Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure.Proc Natl Acad Sci USA. 2009; 106: 12986-12991Crossref PubMed Scopus (188) Google Scholar, 7Lu L. Li C. Hagedorn C.H. Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis.Rev Med Virol. 2006; 16: 5-36Crossref PubMed Scopus (651) Google Scholar]. Transmission of HEV infection and its epidemiology are similar but not identical to hepatitis A virus infection. HEV outbreaks occur through fecal-oral transmission and are mainly waterborne but may also occur through person to person contact and rarely through blood transfusion. Following the development of improved serologic and molecular diagnostic tools, the detection of autochthonous cases in non-endemic countries in the Western hemisphere and the development of several efficacious recombinant vaccines, HEV is gaining renewed global attention. Thus, Hepatitis E became the focus of two recent meetings of the Viral Hepatitis Prevention Board-VHPB in 2009 in Belgium (http://www.vhpb.org/hepatitis A and E: update on prevention and epidemiology) and the International Vaccine Institute-IVI in 2010 in Korea (http://www.ivi.int/main.asp). The true global burden of HEV disease (GBD) is not known and a number of international organizations are now collaborating and in the process of developing a model for an assessment of the GBD. A World Health Organization (WHO) estimate, based on selected seroprevalence data and case series suggests that at least one third of the world population, residing mainly in Asia, Africa, Middle East, and Central America has already been infected (WHO Viral Hepatitis Statement A62/22. http://apps.who.int/gb/ebwha/pdf). While acute hepatitis E is common in endemic countries where it is notoriously associated with a high mortality rate in pregnant women, it has recently been recognized that anti-HEV(IgG) antibodies may be detectable in 3–21% of distinct populations in the industrialized countries who had no history of clinically apparent hepatitis or travel to endemic regions. Sequencing of HEV-RNA revealed the presence of 4 major genotypes. Genotype 1and 2 infect only humans while genotypes 3 and 4 have been isolated from humans as well as from domestic pigs, wild boars, deer and other animals, mainly in industrialized countries. Genotype 3 and 4 are nowadays considered as zoonotic infections that are transmitted through a less virulent HEV as compared to the genotypes 1 and 2, prevalent in endemic regions, mainly in Asia and Africa [[8]Bihl F. Negro F. Hepatitis E virus: a zoonosis adapting to humans.J Antimicrob Chemother. 2010; 65: 817-821Crossref PubMed Scopus (33) Google Scholar]. The relatively high seroprevalence of anti-HEV(IgG) antibodies in the Western hemisphere has been linked to clinically occult infection following the consumption of uncooked meat of infected animals although person to person contact has also been reported. It is not yet known whether seroconversion to anti-HEV(IgG) persists indefinitely providing long-term immunity against a re-challenge with HEV. In the present issue of the journal, Romano and co-workers [[9]Romano L. Paladini S. Tagliacarne C. Canuti M. Bianchi S. Zanetti A.R. Hepatitis E in Italy: along-term prospective study.J Hepatol. 2011; 54: 34-40Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar] report the results of a serologic and molecular phylogenetic analysis in Italian patients with acute hepatitis E. The diagnosis of acute hepatitis E was established via serologic assays for anti-HEV (IgM) in 134/651 patients with non-A, B, C acute hepatitis of whom ∼72% had evidence for HEV viremia by HEV-RNA PCR. HEV was also identified in stool specimens of some individuals. All patients with acute HEV infection tested positive for anti-HAV (IgM) as well as anti-HEV (IgG). Interestingly, 6% of the entire 517 cohort of acute non-A, B, C, and E hepatitis tested positive for anti-HEV (IgG) but negative for anti-HEV (IgM) and undetectable HEV-RNA. These results may suggest past exposure to HEV in these non-A–E patients with acute hepatitis or rapid clearance of HEV following acute infection. This 6% seroprevalence rate may be an underestimation in view of the changing specificity of the four different commercial and one in-house anti-HAV assays used by the investigators along the study period. Not surprisingly, 81% of patients with proven HEV infection had a history of international travel to HEV endemic countries. The molecular analysis of 39 isolates obtained from such travelers revealed the presence of genotype 1. In contrast 22/134 patients (20.6%) with acute hepatitis E diagnosed between 1994 and 2009, had no history of travel to endemic countries. HEV, genotype 3, which has previously been identified in pigs, and wild boars in Italy and elsewhere was identified in five isolates from these 22 patients who did not have any known risk factor for HEV infection. Assuming that this result, obtained in 5/22 non-traveler patients is representative, it seems that genotype 3 is the dominant genotype responsible for sporadic HEV infections in Italy. This extensive survey contributes additional information to our knowledge of the epidemiology of HEV infection in industrialized countries in general and in Italy in particular. The study also confirms a number of previous observations regarding the role of HEV genotype 3 and possible exposure to contaminated food in the epidemiology of HEV in Europe. Excluding pregnant women, acute HEV infection is a self-limited disease which may cause significant morbidity but that usually has a favorable outcome. It does not lead to chronic hepatitis except in immune suppressed patients i.e. after organ transplantation [[10]Kamar N. Selves J. Mansuy J.M. Ouezzani L. Peron J.M. Guitard J. et al.Hepatitis E virus and chronic hepatitis in organ-transplant recipients.N Engl J Med. 2008; 358: 811-817Crossref PubMed Scopus (1024) Google Scholar]. It is difficult to explain why 3–20% of distinct populations in industrialized countries such as the US, various European regions including Italy, Australia, and elsewhere have evidence for past HEV infection as determined by positive anti-HEV (IgG) and undetectable HEV-RNA or anti-HAV (IgM). Genotype 3 associated acute hepatitis E seems clinically less virulent as compared to genotype 1 and 2. One hypothesis suggests that taking into account this difference in the clinical manifestations, genotype 3 HEV has been attenuated through passage in zoonotic hosts and as a result the infection in humans is sub-clinical and asymptomatic. The identification of such genotype 3 isolates and the relatively low burden of clinical disease in non-travelers are expected to have at present a limited public health impact in the industrial countries. Hepatitis E is a vaccine-preventable disease and poses a real hazard to pregnant women in Asia and Africa but significantly less so in Western countries. International travelers are at risk for HEV infection when traveling to endemic areas as also shown in the study from Italy. However, the introduction of new HEV vaccine(s) into clinical practice awaits further assessment of the GBD, prioritization of intervention and allocation of resources. Meanwhile, it is desirable to educate the public regarding the importance of avoiding the consumption of raw meat and uncooked sausages especially in industrialized countries. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.