Review
Hepatitis E: an emerging infection in developed countries

https://doi.org/10.1016/S1473-3099(08)70255-XGet rights and content

Summary

Hepatitis E is endemic in many developing countries where it causes substantial morbidity. In industrialised countries, it is considered rare, and largely confined to travellers returning from endemic areas. However, there is now a growing body of evidence that challenges this notion. Autochthonous hepatitis E in developed countries is far more common than previously recognised, and might be more common than hepatitis A. Hepatitis E has a predilection for older men in whom it causes substantial morbidity and mortality. The disease has a poor prognosis in the context of pre-existing chronic liver disease, and is frequently misdiagnosed as drug-induced liver injury. The source and route of infection remain uncertain, but it might be a porcine zoonosis. Patients with unexplained hepatitis should be tested for hepatitis E, whatever their age or travel history.

Introduction

Hepatitis E is an important public-health concern as a major cause of enterically transmitted hepatitis worldwide, and is responsible for over 50% of cases of acute viral hepatitis in endemic countries.1, 2 The virus is transmitted primarily by the faecal–oral route and is associated with both sporadic infections and epidemics in areas with poor sanitation and weak public-health infrastructures. In developed countries, hepatitis E infections were traditionally thought to occur infrequently and only in individuals who had become infected while travelling in an area where the virus is endemic.3 However, cases of sporadic hepatitis E in people with no history of recent travel have been reported in developed regions such as North America, Europe, Japan, New Zealand, and Australia.4, 5, 6, 7, 8, 9, 10, 11, 12 The reporting of such infections together with the availability of more comprehensive molecular and serological data has led to the re-evaluation of hepatitis E virus (HEV) epidemiology, and the acceptance that autochthonous (locally acquired) hepatitis E is a clinical problem in developed countries.

Section snippets

The HEV virus

HEV is a single-stranded, positive-sense RNA virus and the sole member of the genus Hepevirus. Two major species of the virus are recognised: mammalian HEV, a virus that causes acute hepatitis in human beings and has a reservoir in pigs and possibly a range of other mammals; and avian HEV, causing big liver and spleen disease in chickens.13 This Review focuses on mammalian HEV, since avian HEV differs genetically from mammalian HEV, has never been recovered from mammals, and has not been

HEV in developing countries

HEV was not recognised as a distinct aetiological agent until the 1980s; until then, epidemics of hepatitis in the developing world had been linked to hepatitis A virus (HAV) infections.25, 26 The subsequent development of serological assays showed HEV to be endemic throughout tropical and subtropical countries, with periodic epidemics reported from the Indian subcontinent,27, 28, 29, 30 southeast Asia,31, 32 Africa,33, 34, 35 and Mexico.36 Although foodborne epidemics have been reported in

Clinical and laboratory features

The clinical features of autochthonous hepatitis E infection range from asymptomatic infection to mild hepatitis to subacute liver failure.4, 5, 6, 7, 8, 9, 10, 11, 12, 52 In a UK hospital-based study of patients with unexplained hepatitis, 40 patients with autochthonous hepatitis E were identified, of whom 75% were icteric, with affected individuals presenting a range of other non-specific symptoms (table 1).52

The incubation period of autochthonous hepatitis E infection ranges from 2 to 9

Conclusions

Hepatitis E in developed regions is far more common than previously recognised and could have a zoonotic source. The disease has a predilection for older men in whom it carries a substantial morbidity and mortality, particularly in patients with chronic liver disease. Hepatitis E should be included in the differential diagnosis in patients with unexplained hepatitis, whatever their age or travel history. The incidence of autochthonous hepatitis E in developed countries is unknown, as is the

Search strategy and selection criteria

Data for this Review were identified by searches of Medline, Current Contents, and references from relevant articles; several articles were identified through searches of the extensive files of the authors. Search terms used were “hepatitis E”, “HEV in animals”, “HEV transmission”, “HEV genotypes”, and “HEV serology”. No language or date restrictions were set in these searches.

References (158)

  • JM Peron et al.

    Hepatitis E is an autochthonous disease in industrialized countries. Analysis of 23 patients in south-west France over a 13-month period and comparison with hepatitis A

    Gastroenterol Clin Biol

    (2006)
  • A Chauhan et al.

    Hepatitis E virus transmission to a volunteer

    Lancet

    (1993)
  • HR Dalton et al.

    Locally acquired hepatitis E in chronic liver disease

    Lancet

    (2007)
  • VA Arankalle et al.

    Aetiological association of a virus-like particle with enterically transmitted non-A, non-B hepatitis

    Lancet

    (1988)
  • KS Myint et al.

    Hepatitis E antibody kinetics in Nepalese patients

    Trans R Soc Trop Med Hyg

    (2006)
  • HY Chen et al.

    Comparison of a new immunochromatographic test to enzyme-linked immunosorbent assay for rapid detection of immunoglobulin M antibodies to hepatitis E virus in human sera

    Clin Diagn Lab Immunol

    (2005)
  • RH Purcell et al.

    Pre-clinical immunogenicity and efficacy trial of a recombinant hepatitis E vaccine

    Vaccine

    (2003)
  • SW Li et al.

    A bacterially expressed particulate hepatitis E vaccine: antigenicity, immunogenicity and protectivity on primates

    Vaccine

    (2005)
  • M Ferguson et al.

    Report of a collaborative study to assess the suitability of a reference reagent for antibodies to hepatitis E virus

    Biologicals

    (2002)
  • N Jothikumar et al.

    A broadly reactive one-step real-time RT-PCR assay for rapid and sensitive detection of hepatitis E virus

    J Virol Methods

    (2006)
  • X Ding et al.

    Present state of hepatitis E virus epidemiology in Tokyo, Japan

    Hepatol Res

    (2003)
  • R Aggarwal et al.

    Epidemiology of hepatitis E: past, present and future

    Trop Gastroenterol

    (1997)
  • PO Yarbough

    Hepatitis E virus. Advances in HEV biology and HEV vaccine approaches

    Intervirology

    (1999)
  • E Schwartz et al.

    Hepatitis E virus infection in travelers

    Clin Infect Dis

    (1999)
  • BA Chapman et al.

    Community acquired viral hepatitis in New Zealand: a case of sporadic hepatitis E virus infection

    Aust N Z J Med

    (1993)
  • HR Dalton et al.

    Hepatitis E in New Zealand

    J Gastroenterol Hepatol

    (2007)
  • TC Heath et al.

    Locally acquired hepatitis E in the Northern Territory of Australia

    Med J Aust

    (1995)
  • S Ijaz et al.

    Non-travel-associated hepatitis E in England and Wales: demographic, clinical, and molecular epidemiological characteristics

    J Infect Dis

    (2005)
  • JM Mansuy et al.

    Hepatitis E in the south west of France in individuals who have never visited an endemic area

    J Med Virol

    (2004)
  • S Sainokami et al.

    Epidemiological and clinical study of sporadic acute hepatitis E caused by indigenous strains of hepatitis E virus in Japan compared with acute hepatitis A

    J Gastroenterol

    (2004)
  • TH Tsang et al.

    Acute hepatitis E infection acquired in California

    Clin Infect Dis

    (2000)
  • MA Widdowson et al.

    Cluster of cases of acute hepatitis associated with hepatitis E virus infection acquired in the Netherlands

    Clin Infect Dis

    (2003)
  • Y Buisson et al.

    Identification of a novel hepatitis E virus in Nigeria

    J Gen Virol

    (2000)
  • H Cuyck-Gandre et al.

    Characterization of hepatitis E virus (HEV) from Algeria and Chad by partial genome sequence

    J Med Virol

    (1997)
  • M Banks et al.

    Evidence for the presence of hepatitis E virus in pigs in the United Kingdom

    Vet Rec

    (2004)
  • RE Engle et al.

    Hepatitis E virus (HEV) capsid antigens derived from viruses of human and swine origin are equally efficient for detecting anti-HEV by enzyme immunoassay

    J Clin Microbiol

    (2002)
  • O Garkavenko et al.

    Detection and characterisation of swine hepatitis E virus in New Zealand

    J Med Virol

    (2001)
  • ID Wibawa et al.

    Prevalence of antibodies to hepatitis E virus among apparently healthy humans and pigs in Bali, Indonesia: identification of a pig infected with a genotype 4 hepatitis E virus

    J Med Virol

    (2004)
  • L Lu et al.

    Phylogenetic analysis of global hepatitis E virus sequences: genetic diversity, subtypes and zoonosis

    Rev Med Virol

    (2006)
  • YC Wang et al.

    Prevalence, isolation, and partial sequence analysis of hepatitis E virus from domestic animals in China

    J Med Virol

    (2002)
  • PG Halbur et al.

    Comparative pathogenesis of infection of pigs with hepatitis E viruses recovered from a pig and a human

    J Clin Microbiol

    (2001)
  • MS Balayan et al.

    Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route

    Intervirology

    (1983)
  • ET Clayson et al.

    Association of hepatitis E virus with an outbreak of hepatitis at a military training camp in Nepal

    J Med Virol

    (1998)
  • JB Dilawari et al.

    Hepatitis E virus: epidemiological, clinical and serological studies of north Indian epidemic

    Indian J Gastroenterol

    (1994)
  • SR Naik et al.

    A large waterborne viral hepatitis E epidemic in Kanpur, India

    Bull World Health Organ

    (1992)
  • MA Rab et al.

    Water-borne hepatitis E virus epidemic in Islamabad, Pakistan: a common source outbreak traced to the malfunction of a modern water treatment plant

    Am J Trop Med Hyg

    (1997)
  • AL Corwin et al.

    A waterborne outbreak of hepatitis E virus transmission in southwestern Vietnam

    Am J Trop Med Hyg

    (1996)
  • K Bile et al.

    Contrasting roles of rivers and wells as sources of drinking water on attack and fatality rates in a hepatitis E epidemic in Somalia

    Am J Trop Med Hyg

    (1994)
  • M Isaacson et al.

    An outbreak of hepatitis E in Northern Namibia, 1983

    Am J Trop Med Hyg

    (2000)
  • O Velazquez et al.

    Epidemic transmission of enterically transmitted non-A, non-B hepatitis in Mexico, 1986–1987

    JAMA

    (1990)
  • Cited by (578)

    View all citing articles on Scopus
    View full text