Mutations in core nucleotide sequence of hepatitis B virus correlate with fulminant and severe hepatitis.

Abstract

Infection with hepatitis B virus leads to a wide spectrum of liver injury, including self-limited acute hepatitis, fulminant hepatitis, and chronic hepatitis with progression to cirrhosis or acute exacerbation to liver failure, as well as an asymptomatic chronic carrier state. Several studies have suggested that the hepatitis B core antigen could be an immunological target of cytotoxic T lymphocytes. To investigate the reason why the extreme immunological attack occurred in fulminant hepatitis and severe exacerbation patients, the entire precore and core region of hepatitis B virus DNA was sequenced in 24 subjects (5 fulminant, 10 severe fatal exacerbation, and 9 self-limited acute hepatitis patients). No significant change in the nucleotide sequence and deduced amino acid residue was noted in the nine self-limited acute hepatitis patients. In contrast, clustering changes in a small segment of 16 amino acids (codon 84-99 from the start of the core gene) in all seven adr subtype infected fulminant and severe exacerbation patients was found. A different segment with clustering substitutions (codon 48-60) was also found in seven of eight adw subtype infected fulminant and severe exacerbation patients. Of the 15 patients, 2 lacked precore stop mutation which was previously reported to be associated with fulminant hepatitis. These data suggest that these core regions with mutations may play an important role in the pathogenesis of hepatitis B viral disease, and such mutations are related to severe liver damage. (J. Clin. Invest. 1993.

Clinical relevance of hepatitis B viral mutations

“…The cytotoxic T-lymphocyte epitope in amino acid (aa) 18 to 27 was well-conserved, with mutations detected in only 2 of 15 patients. The greatest genomic variation was found in the central region of the core gene, as noted by Ehata et al 33 Patients exhibiting severe posttransplantation HBV recurrence exhibited significantly more precore/ core mutations and had a greater likelihood of being genotype D pretransplantation.…”

Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy

“…Although HBeAg positivity in immunocompromised cancer patients appears to be a risk factor for HBV reactivation (Liang et al, 1990;Yeo et al, 2000b), this has not been found to be universally the case (Lok et al, 1991;Nokamura et al, 1996), and an increased risk may be partly attributed to the presence of the precore/core promoter HBV mutant (i.e. HBeAg negative/anti-HBe positive), which had been associated with severe fulminant hepatitis (Omata et al, 1991;Ehata et al, 1993;Liang et al, 1994;Nokamura et al, 1996;Steinberg et al, 2000;Yeo et al, 2000a, b). In addition, consistent with other reports, the baseline (pretreatment) liver function including ALT, total bilirubin and albumin levels did not appear to be associated with the development of HBV reactivation.…”

Mutations of Hepatitis B Virus Correlate with Liver Disease.

“…This might be the reason why "mutation clustering regions" differed between type 1 and type 2 core sequences (Figs. 2, 3) and suggest the importance of minute alteration of the prototype sequence (11).…”