The results of this study confirm that HBV genotype C is associated with an increased risk of HCC, and is independent of the presence of liver cirrhosis. Patient age, sex, HBeAg positivity, and ALT levels had no independent impact on the cumulative probability of HCC development after five years of follow up.
The overall incidence of HCC in this study was 1052 cases per 100 000 person years. The high incidence of HCC in this study may be related to the 11% of patients who had clinical liver cirrhosis with a very high incidence of HCC (7998 cases per 100 000 person years). If only non-cirrhotic patients are considered, and incidence of HCC was 743 cases per 100 000 person years. This is comparable with the reported incidence in Taiwan (822 per 100 000 person years) but still higher than that reported in Toronto, Canada (470 per 100 000 person years).3,4
One reason may be related to the long history of chronic hepatitis B among Asian patients who usually acquire the infection at early infancy. Different viral genotypes between Asian and Canadian patients may be another contributing factor for the observed difference. As in all other studies, the possibility of occult HCC, particularly among patients who had cirrhotic liver, could not be excluded.
In this prospective study, clinical liver cirrhosis was the most important independent risk factor for HCC development. As liver cirrhosis is defined by clinical criteria, all patients in this category have established liver cirrhosis while patients with early liver cirrhosis may be classified as non-cirrhotic. This explains the relatively high cumulative incidence of HCC among cirrhotic patients in this study compared with previous series among compensated cirrhotic patients.10
The use of clinical criteria to classify liver cirrhosis enables an undisputable diagnosis of liver cirrhosis while the diagnosis of early liver cirrhosis on histology may be affected by biopsy size and interobserver variations.28
As liver biopsy may not be a routine procedure for all chronic hepatitis B patients, particularly among those who have normal liver enzymes as in our centre, a clinical diagnosis is more feasible in clinical practice.
Patients who have developed liver cirrhosis are usually older, and male patients generally have more advanced liver disease than female patients.9,29
The same association also holds true in the case of HCC, as shown in the univariate analysis. When liver cirrhosis was included in the multivariate analysis equation, the impact of these two demographic factors on HCC development became insignificant. Therefore, in surveillance programmes for HCC, the importance of patient age and sex should not be overemphasised as long as the status of clinical liver cirrhosis is taken into consideration.
HBV genotype C was found to be an independent risk factor for HCC development, which concurs with results of case control studies reported previously.15,16
This association was not as obvious on univariate analysis, probably due to the younger age and marginal female predominance among patients infected with HBV genotype C. Although BCP mutations are strongly associated with HBV genotype C,21,23
no association between BCP mutations and HCC development was found in this study on multivariate analysis. More patients infected with HBV genotype C had persistently positive HBeAg and fluctuating HBeAg whereas more patients infected with genotype B had persistently negative HBeAg on follow up. This may reflect a relatively higher level of viraemia among patients infected with HBV genotype C.30,31
One of two patients who developed HCC from a non-cirrhotic liver in this study had elevated HBV DNA levels despite persistently negative HBeAg on follow up. Viral genotype and high viraemia may be an independent direct cause of hepatocarcinogenesis in addition to liver cirrhosis, which is the result of continuous necroinflammation.32
The direct carcinogenic mechanism may act through increasing cis
activation of the proto-oncogene, suppression of tumour suppressor gene, or transactivation by HBV X protein.33,34
In contrast with the Taiwan report, a single HBeAg result at baseline could not predict the risk of HCC development in this study.11
One probable reason is that a significant proportion of HBeAg positive patients underwent HBeAg seroconversion while some HBeAg negative patients had HBeAg reversion during follow up. In fact, none of the 51 patients who underwent sustained HBeAg seroconversion developed HCC in the present cohort. This concurs with previous reports that sustained HBeAg seroconversion is associated with a favourable prognosis.2,35
In contrast, fluctuating HBeAg status may associate with more aggressive disease progression although it was not confirmed in this study (4/25 (11%) with HCC versus 42/401 (16%) without HCC; p
In this study, the impact of baseline HBV DNA level on HCC development was not evaluated. As HBV DNA is closely related to HBeAg status and tends to change with time, particularly on HBeAg seroconversion, serial monitoring of HBV DNA is necessary.30,31
In summary, HBV genotype C is an independent risk factor for the development of HCC in addition to liver cirrhosis. Viral genotype should therefore be determined on risk stratification in future HCC surveillance programmes. The exact reason for the higher risk of hepatocarcinogenesis associated with HBV genotype C warrants further investigation but direct viral effects in addition to necroinflammation and liver cirrhosis are possible.