Hepatic necroinflammation and fibrosis in patients with genotypes Ba and C, core-promoter and precore mutations M.-F. Yuen, 1 Y. Tanaka, 2 I. O.-L. Ng, 3 M. Mizokami, 2 J. C.-H. Yuen, 1 D. K.-H. Wong, 1 H.-J. Yuan, 1 S.-M. Sum, 1 A. O.-O. Chan 1 and C.-L. Lai 1 1 Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China; 2 Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Japan; and 3 Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China Received July 2004; accepted for publication September 2004 SUMMARY. The role of infection with hepatitis B virus (HBV) genotypes on liver histology is largely unknown. The aim of study was to investigate the relationships between HBV genotypes (B, C), core-promoter (CP) and precore mutants and liver histology in 66 patients. Liver biopsies were scored by histologic activity index (HAI). HBV genotypes were determined by enzyme-linked immunosorbent assay (ELISA). Eighteen (27.3%) and 48 patients (72.7%) had genotype B (all were subtype Ba) and C, respectively. Forty-seven (71.2%) and 27 (40.9%) had CP and precore mutations, respectively. Patients with genotype C compared with sub- type Ba had higher median scores of HAI-necroinflammation (HAI-NI) (7 vs 3), HAI-fibrosis (HAI-F) (1 vs 0) and total HAI (8.5 vs 3) (all P < 0.03). Patients with CP mutations com- pared with wild-type had higher median scores of HAI-NI (7 vs 3), HAI-F (3 vs 0) and total HAI (9 vs 3) (all P < 0.03). Forty patients (83.5%) with genotype C had CP mutations. Age and alanine aminotransferase levels were positively correlated with HAI scores while albumin levels were nega- tively correlated (P < 0.01 for all, except albumin levels and HAI-F, P ¼ 0.08). There was no association between precore mutations and HAI scores. Multivariate analysis indicated that higher alanine aminotransferase (ALT) levels were associated with higher HAI scores (P < 0.04) and CP muta- tions were associated with higher HAI-NI (P ¼ 0.034), but not with HAI-F score (P ¼ 0.3). CP mutations were associ- ated with more severe necroinflammation. The association between genotype C and poor histology was probably because of the association between genotype C and CP mutations. Keywords: core-promoter mutation, fibrosis, hepatitis B genotype, histology, necroinflammation, precore mutation. BACKGROUND The effects of hepatitis B virus (HBV) genotypes on the dis- ease profile of chronic hepatitis B (CHB) infection have been extensively studied recently. Most of the comparative studies examine the difference between patients with genotypes B and C. They are the two common genotypes found in Asia where 75% of the CHB patients in the world reside [1]. In spite of the consistent finding that patients with genotype B have an earlier hepatitis B e antigen (HBeAg) seroconversion compared with those with genotype C [2–4], whether there is a reduction in the risk of cirrhosis-related complications and hepatocellular carcinoma (HCC) remains controversial [2,4–6]. Longitudinal studies comparing patients with gen- otypes B and C may take decades to complete. Studies using histology as the primary endpoint may be a more practical alternative to determine the severity of the liver disease. It may also provide information with prognostic implications. A study by Kao et al. [5] reported no differences in the degree of necroinflammation and fibrosis between patients with genotypes B and C. Three other studies, however, have shown that patients with genotype C, compared with those with genotype B have less severe necroinflammation although there is no difference in the degree of fibrosis [7–9]. A more recent study showed that the proportion of patients with advanced fibrosis in patients with genotype B was sig- nificantly lower than that in patients with genotype C [4]. In addition, HBV genotype B has been recently subdivided into subtypes Bj (only found in Japan) and Ba (mainly found in Hong Kong and other Asian countries) [10]. There are no direct comparative studies to compare the liver histology between patients with subtype Ba and genotype C. Another important aspect to consider is whether the effect of HBV genotypes on histological findings is mediated by the two common viral mutants, namely the precore and core- promoter (CP) mutants which are associated with genotypes B and C, respectively [2,11]. It is important to examine these Abbreviations: ALT, alanine aminotransferase; CHB, chronic hepa- titis B; CP, core promoter; HAI, histological activity index; HBV, hepatitis B virus. Correspondence: Dr Man-Fung Yuen, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China. E-mail: yuenmf@netvigator.com Journal of Viral Hepatitis, 2005, 12, 513–518 doi:10.1111/j.1365-2893.2005.00629.x Ó 2005 Blackwell Publishing Ltd