Nucleotide sequences from a total of 421 HEV isolates were retrieved from Genbank and analysed. Phylogenetically, HEV was classified into four major genotypes. Genotype 1 was more conserved and classified into five subtypes. The number of genotype 2 sequences was limited but can be classified into two subtypes. Genotypes 3 and 4 were extremely diverse and can be subdivided into ten and seven subtypes. Geographically, genotype 1 was isolated from tropical and several subtropical countries in Asia and Africa, and genotype 2 was from Mexico, Nigeria, and Chad; whereas genotype 3 was identified almost worldwide including Asia, Europe, Oceania, North and South America. In contrast, genotype 4 was found exclusively in Asia. It is speculated that genotype 3 originated in the western hemisphere and was imported to several Asian countries such as Japan, Korea and Taiwan, while genotype 4 has been indigenous and likely restricted to Asia. Genotypes 3 and 4 were not only identified in swine but also in wild animals such as boar and a deer. Furthermore, in most areas where genotypes 3 and 4 were characterised, sequences from both humans and animals were highly conserved, indicating they originated from the same infectious sources. Based upon nucleotide differences from five phylogenies, it is proposed that five, two, ten and seven subtypes for HEV genotypes 1, 2, 3 and 4 be designated alphabetised subtypes. Accordingly, a total of 24 subtypes (1a, 1b, 1c, 1d, 1e, 2a, 2b, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 4a, 4b, 4c, 4d, 4e, 4f and 4g) were given.

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

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

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.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(08)70255-X.pdf

Hepatitis E: an emerging infection in developed countries

Background. The source and route of autochthonous hepatitis E virus (HEV) infections are not clearly established in industrialized countries despite evidence that it is a zoonosis in pigs. We investigated the role of figatellu, a traditional pig liver sausage widely eaten in France and commonly consumed raw, as a source of HEV infection. Methods. A case-control study was conducted of 3 patients who presented autochthonous hepatitis E and 15 members of their 3 different families. Anti-HEV immunoglobulin G and immunoglobulin M antibody testing was performed with commercial assays. HEV RNA was detected in serum samples of patients and in pig liver sausages by means of real-time polymerase chain reaction and sequenced by means of in-house sequencing assays. Genetic links between HEV sequences were analyzed. Results. Acute or recent HEV infection, defined by detection of anti-HEV immunoglobulin M antibodies and/or HEV RNA, was observed in 7 of 13 individuals who ate raw figatellu and 0 of 5 individuals who did not eat raw figatellu (P = .041). Moreover, HEV RNA of genotype 3 was recovered from 7 of 12 figatelli purchased in supermarkets, and statistically significant genetic links were found between these sequences and those recovered from patients who ate raw figatellu. Conclusion. Our findings strongly support the hypothesis of HEV infection through ingestion of raw figatellu.

Pig liver sausage as a source of hepatitis E virus transmission to humans.

Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. Hepatitis E is an underdiagnosed disease, in part due to the use of serological assays with low sensitivity. However, diagnostic tools, including nucleic acid-based tests, have been improved. The epidemiology and clinical features of hepatitis E differ between developing and developed countries. HEV infection is usually an acute self-limiting disease, but in developed countries it causes chronic infection with rapidly progressive cirrhosis in organ transplant recipients, patients with hematological malignancy requiring chemotherapy, and individuals with HIV. HEV also causes extrahepatic manifestations, including a number of neurological syndromes and renal injury. Acute infection usually requires no treatment, but chronic infection should be treated by reducing immunosuppression in transplant patients and/or the use of antiviral therapy. In this comprehensive review, we summarize the current knowledge about the virus itself, as well as the epidemiology, diagnostics, natural history, and management of HEV infection in developing and developed countries.

Hepatitis E Virus Infection

To the Editor-As was reported in the Journal, by Takahashi et al. [ 1 ] as well as by the authors of a letter to the editor about Takahashi et al.'s article [2], hepatitis E virus (HEV) infection caused by genotypes III and IV seems to be cryptically endemic in Japan, with the transmission mode yet to be resolved. Zoonotic risks have been suggested for sporadic HEV infections, particularly in industrialized countries [3]. We hereby report our recent experience in Japan, which may support the zoonosis hypothesis. A 53-year-old man (patient A) was admitted to one of our hospitals for acute hepatitis on 12 March 2003. His hepatitis was a severe type, as indicated by the levels of total bilirubin (10.2 mg/dL) and prothrombin (only 17%). Despite the initial severity of the disease, he showed a rapid recovery, without developing fulminant hepatic failure. Convalescence serum obtained on 15 April was positive for both IgM and IgG classes of anti-HEV but was negative for HEV RNA. Acute-phase serum from this patient was not available. Later, to our surprise, it was revealed that, on the same day that patient A had been admitted, one of his friends (a 70year-old man; patient B) had been admitted to another hospital, for similarly severe hepatitis (total bilirubin, 17.1 mg/ dL; prothrombin, 40%). Patient B developed hepatic coma and died of fulminant hepatic failure on 13 April. Acute-phase serum obtained on 13 March was found, retrospectively, to be positive for HEV RNA. Determination of a 326-nt partial open-reading frame-1 sequence of his HEV RNA (accession no. AB114178) indicated that this isolate segregates to genotype IV During the 3 months preceding the onset of disease, neither patient A nor patient B had traveled to areas where HEV is endemic, but patient A mentioned that he and patient B had enjoyed eating uncooked boar liver together a total of 5 times from late January to early February. Among the patients' family members and friends, no one had eaten the boar liver and no one had contracted hepatitis. Chandler et al. [4] reported serological evidence suggesting boars and pigs as candidate animal reservoirs for HEV Although we could not prove that the uncooked boar liver was the source of the HEV infection (since it all had been eaten), it appears likely that this was the case.

/pdf/severe-hepatitis-e-virus-infection-after-ingestion-of-3k3pkygjbd.pdf

Severe Hepatitis E Virus Infection after Ingestion of Uncooked Liver from a Wild Boar

Hepatitis E virus (HEV) genotype 3, which usually causes asymptomatic infection in Japan, induced severe hepatitis in 8 patients. To better understand genetic features of HEV associated with increased virulence, we determined the complete or near-complete nucleotide sequences of HEV from these 8 patients and from 5 swine infected with genotype 3 strain swJ19. Phylogenetic analysis showed that the isolates from the 8 patients and the 5 swine grouped separately from the other genotype 3 isolates to create a unique cluster, designated JIO. The human JIO-related viruses encoded 18 amino acids different from those of the other HEV genotype 3 strains. One substitution common to almost all human HEV strains in the JIO cluster was located in the helicase domain (V239A) and may be associated with increased virulence. A zoonotic origin of JIO-related viruses is suspected because the isolates from the 5 swine also possessed the signature V239A substitution in helicase.

Virulent Strain of Hepatitis E Virus Genotype 3, Japan

The ancestor(s) of apparently Japan-indigenous strains of Hepatitis E virus (HEV) was probably of foreign origin, but it remains unclear when and from where it made inroads. In this study, 24 genotype 3 and 24 genotype 4 HEV strains recovered in Japan each showed a significant cluster, clearly distinct from those of foreign strains, in the phylogenetic tree constructed from an 821 nt RNA polymerase gene fragment. The evolutionary rate, approximately 0.8 x 10(-3) nucleotide substitutions per site per year, enabled tracing of the demographic history of HEV and suggested that the ancestors of Japan-indigenous HEV had made inroads around 1900, when several kinds of Yorkshire pig were imported from the UK to Japan. Interestingly, the evolutionary growth of genotype 3 in Japan has been slow since the 1920s, whereas genotype 4 has spread rapidly since the 1980s. In conclusion, these data suggest that the indigenization and spread of HEV in Japan were associated with the popularization of eating pork.

Hiroyuki Matsuda

Papers

Severe Hepatitis E Virus Infection after Ingestion of Uncooked Liver from a Wild Boar

Virulent Strain of Hepatitis E Virus Genotype 3, Japan

Molecular tracing of Japan-indigenous hepatitis E viruses