Sequences of 234 complete genomes and 631 hepatitis B surface antigen genes were used to assess the worldwide diversity of hepatitis B virus (HBV). Apart from the described two subgenotypes each for A and F, also B, C, and D divided into four subgenotypes each in the analysis of complete genomes supported by significant bootstrap values. The subgenotypes of B and C differed in their geographical distribution, with B1 dominating in Japan, B2 in China and Vietnam, B3 confined to Indonesia, and B4 confined to Vietnam, all strains specifying subtype ayw1. Subgenotype C1 was common in Japan, Korea, and China; C2 in China, South-East Asia, and Bangladesh, and C3 in the Oceania comprising strains specifying adrq–, and C4 specifying ayw3 is encountered in Aborigines from Australia. This pattern of defined geographical distribution was less evident for D1–D4, where the subgenotypes were widely spread in Europe, Africa, and Asia, possibly due to their divergence having occurred a longer time ago than for genotypes B and C, with D4 being the first split and still the dominating subgenotype of D in the Oceania. The genetic diversity of HBV and the geographical distribution of its subgenotypes provide a tool to reconstruct the evolutionary history of HBV and may help to complement genetic data in the understanding of the evolution and past migrations of man.

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Antituberculosis drug-induced hepatitis is one of the most prevalent drug-induced liver injuries. Isoniazid is the major drug incriminated in this hepatotoxicity. Isoniazid is mainly metabolized to hepatotoxic intermediates by N-acetyltransferase (NAT). However, the association of polymorphic NAT acetylator status and antituberculosis drug-induced hepatitis is debatable. To determine whether acetylator status is a risk factor for antituberculosis druginduced hepatitis, we genotyped NAT2 in 224 incident tuberculosis patients who received antituberculosis treatment. Antituberculosis drug-induced hepatitis was diagnosed based on a positive isoniazid rechallenge test and exclusion of viral hepatitis. Acetylator status was determined by genotyping NAT2 in patients using a polymerase chain reaction with restriction fragment length polymorphism. Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. Thirty-three patients (14.7%) were diagnosed with antituberculosis drug-induced hepatitis. Slow acetylators had a higher risk of hepatotoxicity than rapid acetylators (26.4% vs. 11.1%, P ‫؍‬ .013). Among patients with hepatotoxicity, slow acetylators had significantly higher serum aminotransferase levels than rapid acetylators. Logistic regression showed that slow-acetylator status (odds ratio [OR], 3.66; 95% CI, 1.58-8.49; P ‫؍‬ .003) and age (OR, 1.09; 95% CI, 1.04-1.14; P < .001) were the only 2 independent risk factors for antituberculosis drug-induced hepatitis. In conclusion, slow-acetylator status of NAT2 is a significant susceptibility risk factor for antituberculosis drug-induced hepatitis. Additionally, slow acetylators are prone to develop more severe hepatotoxicity than rapid acetylators. Regular monitoring of serum aminotransferase levels is mandatory in patients receiving antituberculosis treatment, especially in slow acetylators. (HEPATOLOGY 2002;35:883-889.)

A 681 nucleotide fragment of the hepatitis B virus (HBV) genome was sequenced that corresponded to the complete gene for hepatitis B surface antigen (HBsAg) in 80HBsAg-and hepatitis B e antigen (HBeAg)-positive sera of diverse geographical origins. These and 42 previously published HBV sequences within the S gene were used for the construction of a dendrogram. In this comparison, each of the 122 HBsAg genes was found to be related to one or other of the six previously identified genomic groups of HBV, A to F. The HBV strains within each genomic group showed a characteristic geographical distribution. Group A genomes were represented by 23 strains mainly originating in northern Europe and sub-Saharan Africa. The group B and C genomes, represented by 17 and 28 strains respectively, were confined to populations with origins in eastern Asia and the Far East. The group D genomes, represented by 38 strains, were found worldwide, but were the predominant strains in the Mediterranean area, the Near and Middle East, and in south Asia. Group E genomes, represented by nine strains, were indigenous to western sub-Saharan Africa as far south as Angola. There were indications that the F group, made up of six strains, represented the genomic group of HBV among populations with origins in the New World. Thus, HBV has diverged into genomic groups according to the distribution of mankind in the different continents. As well as giving information on the genetic relationship of HBV strains of different geographical origin, this study also provides information on the primary structure of HBsAg in different regions of the world. Such data might prove valuable in explaining the reported failures to obtain protection with current HBV vaccines.

We detected des-gamma-carboxy prothrombin, an abnormal prothrombin, in the serum of 69 of 76 patients (91 per cent) with biopsy-confirmed hepatocellular carcinoma (the mean level of the abnormal prothrombin was 900 ng per milliliter). In contrast, levels of the abnormal prothrombin were low in patients with chronic active hepatitis (mean, 10 ng per milliliter) or metastatic carcinoma involving the liver (mean, 42 ng per milliliter), and undetectable in normal subjects. In five patients treated with vitamin K there was no reduction in abnormal prothrombin, indicating that its presence was not due to vitamin K deficiency. Surgical resection of tumors in two patients and chemotherapy in one patient markedly reduced abnormal-prothrombin concentrations, which later increased with recurrence of disease. Serum alpha-fetoprotein levels correlated poorly with abnormal-prothrombin levels. Together, the assay for abnormal prothrombin and the alpha-fetoprotein assay identified 64 of 76 patients with hepatoma (84 per cent). Abnormal prothrombin may be useful in the laboratory diagnosis of primary hepatocellular carcinoma.