Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M
First Department of Medicine, Chiba University School of Medicine, Japan.
N Engl J Med. 1991 Jun 13;324(24):1699-704. doi: 10.1056/NEJM199106133242404.
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.
血清中乙肝e抗原（HBeAg）的存在是病毒高度传染性的一个标志物。然而，HBeAg阴性的患者也可能发生暴发性肝炎。据报道，单个点突变可在乙肝病毒DNA的前核心区产生一个终止密码子，阻止生成HBeAg所需的前核心蛋白的形成。为了确定前核心区突变病毒是否与严重肝损伤存在因果关系，我们分析了从乙肝致死病例和非复杂性病例中分离出的病毒株的整个前核心区。
从9例乙肝致死患者（5例暴发性肝炎和4例慢性肝炎严重加重患者）和10例急性自限性乙肝患者中获取血清。还研究了1例暴发性肝炎中被认为是病毒来源的性伴侣的血清样本。通过聚合酶链反应扩增乙肝病毒前核心区的87个核苷酸，然后直接测序。
在9例乙肝致死患者中，7例可检测到乙肝DNA：在所有这7例中，前核心区核苷酸1896处有一个从G到A的点突变，将色氨酸（TGG）转变为终止密码子（TAG）。相比之下，在10例急性自限性乙肝患者中未发现这种突变。来自相关病毒源的乙肝DNA含有与她患有暴发性肝炎的伴侣的序列相同的终止密码子突变序列。
突变病毒株的存在与暴发性乙肝及慢性乙肝严重加重的发病机制相关，且可能参与其中。
