Mutations in the Precore Region of Hepatitis B Virus DNA in Patients with Fulminant and Severe Hepatitis

TLDR

The hepatitis B e antigen (HBeAg) is a marker of high viral infectivity, yet fulminant hepatitis can occur in HBeAg‑negative patients, and a single point mutation in the precore region can introduce a stop codon that blocks HBeAg production. This study aimed to determine whether a precore‑mutant virus is causally linked to severe liver injury by analyzing the entire precore region in viral strains from fatal and uncomplicated hepatitis B cases, including a partner source sample. The 87‑nucleotide precore region was amplified by PCR and directly sequenced, revealing that all seven fatal cases carried a G→A mutation at nucleotide 1896 that converts tryptophan to a stop codon. The stop‑codon mutation was absent in the 10 self‑limited cases but present in all fatal cases and the partner source, indicating an association between the mutant strain and fulminant or severe hepatitis B.

Abstract

The presence of the hepatitis B e antigen (HBeAg) in serum is known to be a marker of a high degree of viral infectivity. However, fulminant hepatitis may occur in persons who are negative for HBeAg. A single point mutation has been reported to produce a stop codon in the precore region of hepatitis B virus DNA and prevent the formation of the precore protein required to make HBeAg. To determine whether a precore-mutant virus is causally related to severe liver injury, we analyzed the entire precore region in viral strains isolated from patients with fatal cases and uncomplicated cases of hepatitis B.Serum was obtained from 9 patients with fatal hepatitis B (5 with fulminant and 4 with severe exacerbations of chronic hepatitis) and 10 patients with acute, self-limited hepatitis B. Serum samples from a sex partner implicated as the source of the virus in one case of fulminant hepatitis were also studied. The 87 nucleotides in the precore region of the hepatitis B virus were amplified by the polymerase chain reaction and then directly sequenced.Of the nine patients with fatal hepatitis, seven had retrievable hepatitis B DNA: In all seven there was a point mutation from G to A at nucleotide 1896 of the precore region, converting tryptophan (TGG) to a stop codon (TAG). In contrast, this mutation was not found in the 10 patients with acute, self-limited hepatitis B. The hepatitis B DNA from the implicated source contained a sequence with the stop-codon mutation that was identical to the sequence in her partner, who had fulminant hepatitis.The presence of a mutant viral strain is associated with and may be involved in the pathogenesis of fulminant hepatitis B and severe exacerbations of chronic hepatitis B.