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Hepatitis B Virus Strains with Mutations in the Core Promoter in Patients with Fulminant Hepatitis

Shunichi Sato, MD; Kazuyuki Suzuki, MD; Yoshihiro Akahane, MD; Koichi Akamatsu, MD; Kenji Akiyama, MD; Kazuhiro Yunomura, MD; Fumio Tsuda, MD; Takeshi Tanaka, BS; Hiroaki Okamoto, MD; Yuzo Miyakawa, MD; and Makoto Mayumi, MD
[+] Article and Author Information

From Iwate Medical University, Iwate-Ken, Japan. Yamanashi Medical University, Yamanashi-Ken, Japan. Ehime University School of Medicine, Ehime-Ken, Japan. Asahikawa Medical College, Hokkaido, Japan. Dokkyo University School of Medicine and Jichi Medical School, Tochigi-Ken, Japan. Toshiba General Hospital and Mita Institute, Tokyo, Japan. The Japanese Red Cross Saitama Blood Center, Saitama-Ken, Japan. Requests for Reprints: Makoto Mayumi, MD, Immunology Division, Jichi Medical School, Tochigi-Ken 329-04, Japan.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;122(4):241-248. doi:10.7326/0003-4819-122-4-199502150-00001
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Objective: Fulminant hepatitis B can be induced by hepatitis B virus (HBV) strains with mutations in the precore region that cannot encode hepatitis B e antigen (HBeAg). Such mutations are rarely seen in HBV DNA clones from patients with fulminant hepatitis B in the United States and France. Thus, the other mutations in HBV strains causing fulminant hepatitis B need to be identified.

Design: Retrospective clinical, serologic, and molecular biological studies of patients with fulminant hepatitis B.

Setting: University and city hospitals in Japan.

Patients: 43 patients with fulminant hepatitis B.

Measurements: The precore region coding for a part of the HBeAg precursor and the core promoter regulating the transcription of precore messenger RNA were sequenced in HBV DNA clones.

Results: A point mutation from G to A at nucleotide 1896 in the precore region was detected in 519 (98%) of 529 HBV DNA clones from 38 patients. Two point mutations in the core promoter, from A to T at nucleotide 1762 and from G to A at nucleotide 1764, were detected in all 130 clones from the remaining 5 patients, who did not have mutations in the precore region, and in 20 (63%) of 32 clones from a patient with chronic hepatitis B who had transmitted HBV to 1 of these other 5 patients. Mutations in the core promoter were also detected in clones from 26 (68%) of the 38 patients with the precore mutation at nucleotide 1896. Neither HBeAg nor antibody to HBeAg was detected in 37 (90%) of the 41 patients tested.

Conclusions: In Japan, fulminant hepatitis B is closely associated with HBV strains that do not produce HBeAg because of mutations in the precore region, which affect translation of HBeAg, or because of mutations in the core promoter, which affect transcription of the HBeAg coding region.

Figures

Grahic Jump Location
Figure 1.
A map of the X and precore-core genes and the fragment of hepatitis B virus (HBV) DNA sequenced.

The initiation sites of two 3.5-kilobase messenger RNAs (mRNA) are indicated on the top. Boxes below represent liver-specific enhancer II, the basic core promoter, and a regulatory sequence located upstream of them. Positions of direct repeats (DR) are also shown. Sequences of HBV DNA amplified by the first or second round of polymerase chain reaction (PCR) are indicated at the bottom. nt = nucleotide.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Point mutations in the core promoter of hepatitis B virus (HBV) DNA clones from 30 patients with fulminant or acute severe hepatitis B.

The sequence of a wild-type HBV genotype B or C is indicated above. Three AT-rich regions are indicated by bars, and initiation sites for precore messenger RNA are indicated by arrows. Dashes represent nucleotides identical to those of wild-type HBV. Numbers of cases with mutations (a-k) are indicated on the right.

Grahic Jump Location

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