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Journal of Clinical Microbiology, September 2002, p. 3209-3218, Vol. 40, No. 9
0095-1137/02/$04.00+0     DOI: 10.1128/JCM.40.9.3209-3218.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Polyphyletic Strains of Hepatitis E Virus Are Responsible for Sporadic Cases of Acute Hepatitis in Japan

Department of Internal Medicine, Kin-ikyo Chuo Hospital, Hokkaido 007-0870,¹ First Department of Internal Medicine, Iwate Medical University, Iwate-Ken 020-8505,² Department of Internal Medicine, Iwaki Kyoritsu General Hospital, Fukushima-Ken 973-8555,³ Department of Gastroenterology, National Tokyo Hospital, Tokyo 204-0023,⁴ First Department of Internal Medicine, Yamanashi Medical University, Yamanashi-Ken 409-3898,⁵ Japanese Red Cross Yamaguchi Blood Center, Yamaguchi-Ken 753-8534,⁶ Japanese Red Cross Saitama Blood Center, Saitama-Ken 338-0001,⁷ Immunology Division and Division of Molecular Virology, Jichi Medical School, Tochigi-Ken 329-0498, Japan⁸

Received 3 April 2002/ Returned for modification 23 May 2002/ Accepted 15 June 2002

Among 87 patients who were previously treated for acute hepatitis of unknown etiology between 1992 and 2001 at five hospitals in Japan, 11 (13%) patients were positive for immunoglobulin M-class antibodies to hepatitis E virus (HEV) by enzyme immunoassay and had detectable HEV RNA by reverse transcription-PCR with two independent sets of primers derived from well-conserved genomic areas in open reading frames 1 and 2. Clinical HEV infection was significantly associated with male sex (9 of 11 versus 29 of 76 patients [P < 0.01]) and older age (52 ± 11 [mean ± standard deviation] versus 41 ± 17 years [P < 0.05]), and its prevalence differed by geographic region (6 to 25%), with a higher rate in the northern part of Japan. At admission, the 11 patients with HEV-associated hepatitis had elevated alanine aminotransferase levels of 914 to 4,850 IU/liter, and all but 1 had elevated bilirubin levels of 1.5 to 24.0 mg/dl. The 11 HEV isolates were of genotype III or IV and were segregated into three groups with intergroup nucleotide differences of 9.5 to 22.0%. Phylogenetic analysis revealed that four isolates of genotype III were closely related to a Japanese isolate, while the other four isolates of the same genotype were nearest those from the United States. The remaining three isolates were close to known isolates of genotype IV in China and Taiwan but shared less than 88% identity with them. These results indicate that multiple genotypes of HEV cocirculate in Japan and contribute to the development of sporadic acute hepatitis, with the prevalence differing by age, sex, and geographic region.

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