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. 1994 Feb;93(2):550–555. doi: 10.1172/JCI117006

Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation.

T J Liang 1, K Hasegawa 1, S J Munoz 1, C N Shapiro 1, B Yoffe 1, B J McMahon 1, C Feng 1, H Bei 1, M J Alter 1, J L Dienstag 1
PMCID: PMC293877  PMID: 8113393

Abstract

Hepatitis B virus (HBV) variants with precore mutation(s) resulting in the absence of HBeAg production have been associated with the occurrence of fulminant hepatitis in Japan, Israel, and southern Europe, where the prevalence of this HBV strain appears common. In areas such as United States, where HBV infection is not endemic, the role of this mutant virus in fulminant hepatitis is unknown. We developed an amplification refractory mutation detection system to detect specifically the presence of the G to A mutation at nucleotide position 1898, which is the most frequently observed mutation resulting in a precore stop codon. In addition, this method provided a quantitative measurement of the relative ratio of one strain to the other. Using this system, we tested HBV strains for the presence of the stop codon mutation in sera from 40 cases of fulminant hepatitis B occurring in the United States. Serum HBV DNAs from 28 patients were analyzed successfully. A mixture of wild-type and mutant strains in various ratios were observed in 15 patients, wild type exclusively in 11, and mutant exclusively in 2. Four of these patients had undergone liver transplantation for HBV-associated cirrhosis and developed fulminant HBV-associated hepatitis after transplantation. Pre- and posttransplant serum samples from one patient were analyzed: a mixture of wild-type and mutant HBV strains was detected in both samples. Our study demonstrated that both wild-type and mutant HBV strains are associated with fulminant hepatitis, and that in some patients in the United States, factors other than precore mutations contribute to the development of fulminant hepatitis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brechot C., Bernuau J., Thiers V., Dubois F., Goudeau A., Rueff B., Tiollais P., Benhamou J. P. Multiplication of hepatitis B virus in fulminant hepatitis B. Br Med J (Clin Res Ed) 1984 Jan 28;288(6413):270–271. doi: 10.1136/bmj.288.6413.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brown J. L., Carman W. F., Thomas H. C. The clinical significance of molecular variation within the hepatitis B virus genome. Hepatology. 1992 Jan;15(1):144–148. doi: 10.1002/hep.1840150124. [DOI] [PubMed] [Google Scholar]
  3. Brunetto M. R., Giarin M. M., Oliveri F., Chiaberge E., Baldi M., Alfarano A., Serra A., Saracco G., Verme G., Will H. Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4186–4190. doi: 10.1073/pnas.88.10.4186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brunetto M. R., Oliveri F., Rocca G., Criscuolo D., Chiaberge E., Capalbo M., David E., Verme G., Bonino F. Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen. Hepatology. 1989 Aug;10(2):198–202. doi: 10.1002/hep.1840100213. [DOI] [PubMed] [Google Scholar]
  5. Brunetto M. R., Stemler M., Bonino F., Schodel F., Oliveri F., Rizzetto M., Verme G., Will H. A new hepatitis B virus strain in patients with severe anti-HBe positive chronic hepatitis B. J Hepatol. 1990 Mar;10(2):258–261. doi: 10.1016/0168-8278(90)90062-v. [DOI] [PubMed] [Google Scholar]
  6. Carman W. F., Fagan E. A., Hadziyannis S., Karayiannis P., Tassopoulos N. C., Williams R., Thomas H. C. Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis. Hepatology. 1991 Aug;14(2):219–222. [PubMed] [Google Scholar]
  7. Carman W. F., Jacyna M. R., Hadziyannis S., Karayiannis P., McGarvey M. J., Makris A., Thomas H. C. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet. 1989 Sep 9;2(8663):588–591. doi: 10.1016/s0140-6736(89)90713-7. [DOI] [PubMed] [Google Scholar]
  8. Carman W. F., Thomas H. C. Genetic variation in hepatitis B virus. Gastroenterology. 1992 Feb;102(2):711–719. doi: 10.1016/0016-5085(92)90125-i. [DOI] [PubMed] [Google Scholar]
  9. Chen H. S., Kew M. C., Hornbuckle W. E., Tennant B. C., Cote P. J., Gerin J. L., Purcell R. H., Miller R. H. The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. J Virol. 1992 Sep;66(9):5682–5684. doi: 10.1128/jvi.66.9.5682-5684.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Féray C., Gigou M., Samuel D., Reyes G., Bernuau J., Reynes M., Bismuth H., Bréchot C. Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis. Gastroenterology. 1993 Feb;104(2):549–555. doi: 10.1016/0016-5085(93)90425-c. [DOI] [PubMed] [Google Scholar]
  11. Hasegawa K., Huang J. K., Wands J. R., Obata H., Liang T. J. Association of hepatitis B viral precore mutations with fulminant hepatitis B in Japan. Virology. 1991 Nov;185(1):460–463. doi: 10.1016/0042-6822(91)90799-h. [DOI] [PubMed] [Google Scholar]
  12. Junker-Niepmann M., Bartenschlager R., Schaller H. A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J. 1990 Oct;9(10):3389–3396. doi: 10.1002/j.1460-2075.1990.tb07540.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kelen G. D., Green G. B., Purcell R. H., Chan D. W., Qaqish B. F., Sivertson K. T., Quinn T. C. Hepatitis B and hepatitis C in emergency department patients. N Engl J Med. 1992 May 21;326(21):1399–1404. doi: 10.1056/NEJM199205213262105. [DOI] [PubMed] [Google Scholar]
  14. Kosaka Y., Takase K., Kojima M., Shimizu M., Inoue K., Yoshiba M., Tanaka S., Akahane Y., Okamoto H., Tsuda F. Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. Gastroenterology. 1991 Apr;100(4):1087–1094. doi: 10.1016/0016-5085(91)90286-t. [DOI] [PubMed] [Google Scholar]
  15. Liang T. J., Baruch Y., Ben-Porath E., Enat R., Bassan L., Brown N. V., Rimon N., Blum H. E., Wands J. R. Hepatitis B virus infection in patients with idiopathic liver disease. Hepatology. 1991 Jun;13(6):1044–1051. [PubMed] [Google Scholar]
  16. Liang T. J., Hasegawa K., Rimon N., Wands J. R., Ben-Porath E. A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med. 1991 Jun 13;324(24):1705–1709. doi: 10.1056/NEJM199106133242405. [DOI] [PubMed] [Google Scholar]
  17. Liang T. J., Jeffers L., Reddy R. K., Silva M. O., Cheinquer H., Findor A., De Medina M., Yarbough P. O., Reyes G. R., Schiff E. R. Fulminant or subfulminant non-A, non-B viral hepatitis: the role of hepatitis C and E viruses. Gastroenterology. 1993 Feb;104(2):556–562. doi: 10.1016/0016-5085(93)90426-d. [DOI] [PubMed] [Google Scholar]
  18. Luo G. X., Chao M., Hsieh S. Y., Sureau C., Nishikura K., Taylor J. A specific base transition occurs on replicating hepatitis delta virus RNA. J Virol. 1990 Mar;64(3):1021–1027. doi: 10.1128/jvi.64.3.1021-1027.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Naoumov N. V., Schneider R., Grötzinger T., Jung M. C., Miska S., Pape G. R., Will H. Precore mutant hepatitis B virus infection and liver disease. Gastroenterology. 1992 Feb;102(2):538–543. doi: 10.1016/0016-5085(92)90101-4. [DOI] [PubMed] [Google Scholar]
  20. Newton C. R., Graham A., Heptinstall L. E., Powell S. J., Summers C., Kalsheker N., Smith J. C., Markham A. F. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989 Apr 11;17(7):2503–2516. doi: 10.1093/nar/17.7.2503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Okamoto H., Yotsumoto S., Akahane Y., Yamanaka T., Miyazaki Y., Sugai Y., Tsuda F., Tanaka T., Miyakawa Y., Mayumi M. Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol. 1990 Mar;64(3):1298–1303. doi: 10.1128/jvi.64.3.1298-1303.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Omata M., Ehata T., Yokosuka O., Hosoda K., Ohto M. Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med. 1991 Jun 13;324(24):1699–1704. doi: 10.1056/NEJM199106133242404. [DOI] [PubMed] [Google Scholar]
  23. Ruiz J., Sangro B., Cuende J. I., Beloqui O., Riezu-Boj J. I., Herrero J. I., Prieto J. Hepatitis B and C viral infections in patients with hepatocellular carcinoma. Hepatology. 1992 Sep;16(3):637–641. doi: 10.1002/hep.1840160305. [DOI] [PubMed] [Google Scholar]
  24. Tong S. P., Li J. S., Vitvitski L., Trépo C. Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal. Virology. 1992 Nov;191(1):237–245. doi: 10.1016/0042-6822(92)90185-r. [DOI] [PubMed] [Google Scholar]
  25. Tur-Kaspa R., Klein A., Aharonson S. Hepatitis B virus precore mutants are identical in carriers from various ethnic origins and are associated with a range of liver disease severity. Hepatology. 1992 Dec;16(6):1338–1342. doi: 10.1002/hep.1840160606. [DOI] [PubMed] [Google Scholar]
  26. Wright T. L., Hsu H., Donegan E., Feinstone S., Greenberg H., Read A., Ascher N. L., Roberts J. P., Lake J. R. Hepatitis C virus not found in fulminant non-A, non-B hepatitis. Ann Intern Med. 1991 Jul 15;115(2):111–112. doi: 10.7326/0003-4819-115-2-111. [DOI] [PubMed] [Google Scholar]

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