Hepatitis B virus (HBV) infection is the main cause of Controversial data were recently published concerning the fulminant hepatitis (FH) in several geographic areas, includassociation of hepatitis B virus (HBV) variants with fulminant ing the Mediterranean basin. 1 Traditionally the fulminant hepatitis (FH). In this study, we first analyzed the complete course of an HBV infection has been ascribed to an enhanced nucleotide sequences of HBV genomes isolated from serum host immune response against viral antigens. 2 There is some samples from a surgeon and his mother, who was accidentally evidence, however, indicating that viral factors may also be infected by the son; both died of FH. The infecting viruses involved in the pathogenesis of this disease. 3,4 A number of were genetically almost identical in both patients; all the papers have recently reported a significant association of FH clones examined carried a double nucleotide mutation in the with infection by HBV variants unable to produce HBe prostart codon of the pre-S2 region that prevented the synthesis tein (HBeAg) because of a translational stop codon in the of the corresponding protein. Analyses of different serum samprecore region of the viral genome 5-9 or because of point ples from the son revealed only wild-type precore sequences mutations at the level of the core promoter located in the X in a high viremic serum, whereas hepatitis B e antigen region (nucleotides 1,742-1,849). 10 Nevertheless, the possi-(HBeAg)-defective strains were prevalent when the viremia ble role of HBeAg-defective variants in the development of had decreased. Subsequently, we extended the analysis to the FH is controversial, since an association between these viral viral genomes isolated from 18 additional patients with acute mutants and the acute liver failure was not found in all HBV infection and different clinical behaviors: 3 of 5 patients the studies, 11-14 evaluation of HBV genomic heterogeneity in with FH and without previous liver disease had pre-S2 start cases of FH was generally limited to examination of part of codon mutations preventing pre-S2 protein synthesis, the viral genome, 5-14 and HBV molecular analysis was perwhereas none of the 13 control cases had similar genomic formed on serum samples collected when the viremia had rearrangements. Analysis of the precore region showed that already decreased to levels detectable only by the polymerase viral populations normally producing HBeAg were the only chain reaction (PCR) amplification technique. 5-14 or the prevalent viral strains in all of these cases. In summary,
In this study, we have had the opportunity to analyze the our results support the hypothesis that the pre-S2 protein is entire nucleotide sequence of HBV genomes isolated from not essential for HBV infectivity. They also show that infection two members of a family who both died from FH type B. In by pre-S2-defective virus is frequently associated with FH, addition, serum samples collected during both high and low indicating that this variant might play a pathogenetic role viremic phases of the disease from one of these patients were in cases of acute liver failure. Finally, they suggest that the also available for examination. Finally, we extended the evalemergence of HBeAg-defective viruses might be a late event uation of HBV genomic heterogeneity to additional cases of in the course of FH, occurring when HBeAg-producing viruses fulminant or self-limited acute type B hepatitis. have been mostly cleared. (HEPATOLOGY 1997;26:495-499.) PATIENTS AND METHODS Patients. We have retrospectively examined serum samples col-Abbreviations: HBV, hepatitis B virus; FH, fulminant hepatitis; HBeAg, hepatitis B lected from two members of a family who both died of FH type B. e antigen; PCR, polymerase chain reaction; HCV, hepatitis C virus; HDV, hepatitis Neither patient had any history of previous liver disease, and for delta virus; HGV, hepatitis G virus; HBsAg, hepatitis B surface antigen; IgM anti-HBc, both of them other toxic or infectious causes of liver damage were immunoglobulin M to hepatitis B core antigen; ALT, alanine aminotransferase; MAbs, excluded, including hepatitis C (HCV), Delta (HDV) and G (HGV) monoclonal antibodies; P/N, positive/negative.
virus infections, evaluated by testing serum samples both for specific