Reply:
Authors: Chih-Lin Lin, Chun-Jen Liu, Jia-Horng Kao
Journal: Hepatology (2007)

We thank Dr. Liaw for his comments on our article discussing the role of hepatitis B viral factors in hepatitis B e antigen (HBeAg)-negative carriers with persistently normal serum alanine aminotransferase levels (PNALT) in Taiwan.1 In HBeAg-negative carriers, the threshold hepatitis B virus (HBV) DNA level associated with elevated serum alanine aminotransferase (ALT) level has not been clarified, and earlier studies, most from Western countries, revealed a lower frequency of serum HBV DNA > 105 copies/mL in this special clinical setting (Dr. Liaw's figure 1). However, in line with our findings, a recent study from Japan showed that 65.3% and 29.5% of 95 HBeAg-negative carriers with PNALT had serum HBV DNA level > 104 and 105 copies/mL, respectively.2 These discrepant results could be explained by host factors such as different genetic backgrounds and immune responses or viral factors including different HBV genotypes and frequencies of precore/core promoter mutations. Due to the unique distribution of HBV genotypes in Asian and Western countries, genotype-dependent virologic characteristics may account for varied clinical phenotypes, including viral load.3 For example, HBV genotypes B and C are prevalent in Asia, and genotype C is associated with a higher serum HBV DNA level and higher frequency of core promoter mutation as compared with genotype B. Similarly, genotypes A and D are dominant in Western countries and genotype D has a lower frequency of core promoter mutation than does genotype A.4 In addition, in vitro data showed that expression of HBV DNA is higher for genotypes B and C than genotypes A and D,5 and core promoter mutation may enhance HBV replication.6 Taking these lines of evidence together, in countries where HBV genotype B and C as well as core promoter mutant infection are endemic, such as Taiwan and Japan, a significant proportion of HBeAg-negative carriers with PNALT could still have a serum HBV DNA level > 104 copies/mL, and viremia levels in HBeAg-negative carriers may vary in different geographic areas. We agree that HBeAg-negative carriers with PNALT by conventional criteria are too loose to be defined as inactive hepatitis B surface antigen (HBsAg) carriers. The main theme of our study was thus to compare hepatitis B viral factors between chronic hepatitis B patients with low-normal and high-normal serum ALT, and we did find that those with high-normal serum ALT had higher frequencies of these viral characteristics associated with adverse outcomes. In addition, a higher serum HBV DNA level may be associated with future increase in serum ALT. In our subgroup analysis (data not shown in the published article), 100 patients had regular follow-up longer than 1 year after enrollment. Mean duration of the follow-up was 30 ± 16 months (range, 12 to 77 months). Of 86 patients having detectable serum HBV DNA at study entry, 8 (8%) with abnormal serum ALT level of 1–2 × upper limit of normal (ULN) at last follow-up had significantly higher baseline serum HBV DNA levels (7.4 ± 2.4 log10 copies/mL) than 76 with PNALT (5.8 ± 1.1 log10 copies/mL). If we further defined hepatitis flare by persistent elevation of serum ALT level > 2 × ULN for 3 months, there were 3 patients (3%) with hepatitis flare during the follow-up. All 3 patients had genotype B infection and baseline serum HBV DNA level > 105 copies/mL. Because we only focused on the relationship between serum HBV DNA level and serum ALT profile in patients with so-called PNALT, these 11 patients with ALT level > 1 × ULN at last follow-up were excluded for analysis. Therefore, when these patients were taken into account, the cumulative probability of hepatitis flare was 11% during long-term follow-up in these carriers, which was comparable to Dr. Liaw's previous observation. As per Dr. Liaw's suggestion, we reanalyzed hepatitis B viral factors in 183 HBeAg-negative carriers with serum HBV DNA level < 104 copies or 2000 IU/mL (Table 1). The mean age of these patients with high-normal serum ALT was significantly higher than those patients with low-normal serum ALT (40 versus 35 years, P < 0.001). Patients with high-normal serum ALT again had a significantly higher mean HBV DNA level than patients with low-normal serum ALT (3.4 versus 3.1 log10 copies/mL, P = 0.005). In addition, patients with high-normal serum ALT showed a significantly higher prevalence of basal core promoter A1762T/G1764A mutant than did patients with low-normal serum ALT (15 of 90, 28.8% versus 9 of 93, 12.8%; P = 0.031). Our findings indicated that even low viremic HBeAg-negative patients with PNALT are not a homogenous group, and those with high-normal serum ALT still harbor viral characteristics associated with adverse outcomes.7-10 In summary, our current results suggest that more stringent viral and biochemical criteria such as serum HBV DNA level < 2000 IU/mL and ALT level < 0.5 × ULN should be adopted to define inactive HBsAg carriers in our clinical practice. Chih-Lin Lin*, Chun-Jen Liu §, Jia-Horng Kao § ¶, * Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan, Graduate Institute of Clinical Medicine, Taipei, Taiwan, Hepatitis Research Center, Taipei, Taiwan, § Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan, ¶ Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan.