Hepatitis B Vaccination and Hepatocellular Carcinoma Rates in Boys and Girls FREE

Hepatocellular carcinoma (HCC) occurs mainly in adults 40 to 60 years of age.¹ However, in areas hyperendemic for hepatitis B virus (HBV) infection, HCC may develop in children.² We have found a nearly 100% hepatitis B surface antigen seropositivity rate in Taiwanese children with HCC, indicating an intimate relationship between HBV and childhood HCC.² In 1984, a hepatitis B vaccination program was launched and has effectively reduced the prevalence of HBV infection, chronic HBV infection rate,³ and incidence of HCC in children in Taiwan.⁴

A male predominance of HCC has long been observed.^5- 6 The mechanism is unknown, but a tumorigenic effect of androgens has been suggested.⁷ We found a male-female ratio of 3-4:1 in children with HCC,⁸ which is similar to that in adults. Since the influence of hormones in children is much less than that in adults, investigating HCC in children may facilitate understanding of the mechanism of HCC. We therefore studied children with HCC by sex before and after the implementation of the HBV vaccination program.

A vaccination program was implemented in Taiwan in July 1984.⁹ Hepatitis B immunoglobulin was given to neonates of highly infectious mothers carrying hepatitis B e antigen. All infants received 3 or 4 doses of HBV vaccine.

According to our previous observation, HCC in children was diagnosed mainly in those older than 6 years,² while hepatoblastoma was diagnosed in younger children.¹⁰ In this study, we included children 6 to 14 years of age with liver cancer to preclude the inclusion of hepatoblastoma.

Two independent childhood hepatoma registry systems were used in this study to ensure accuracy. Data from the following 2 systems, including the name, identification number, birth date, sex, address, etc, were checked and merged, and any repetition was deleted. The case information was confirmed by the reporting hospitals. The capture-recapture method was used to estimate the total number of cases of childhood HCC (Epi Info, version 6.04; Centers for Disease Control and Prevention and the World Health Organization). The number of cases identified by systems 1 and 2 was estimated to be 86% (95% confidence interval [CI], 80%-92%) of the actual total number of children with HCC.

Cases of hepatoma diagnosed between July 1981 and June 1996 were analyzed from the data bank of the National Cancer Registry System at the National Department of Health. This registry was established in 1979. Cases are reported by the department of medical records in each of the 167 hospitals with more than 50 beds in Taiwan.

To ensure the accuracy of the data from the National Cancer Registry, we formed a multicenter Childhood Hepatoma Study Group to register children with hepatoma during the same study period. Pediatric gastroenterologists or oncologists from 17 major hospitals, including all 12 tertiary referral centers in Taiwan, participated.

The study population was stratified both by age at diagnosis and the year of birth. Children with HCC who were older than 6 years on July 1, 1984, when the HBV vaccination program was launched, were born before July 1978. Children born before 1978 and after 1984 were the respective cohorts without and with the effect of HBV vaccination. Children born between 1978 and 1984 were born during the transition to full implementation of the HBV vaccination program. They might have received HBV vaccination beyond infancy.

Age-specific and birth-year–specific incidences of HCC were calculated for boys and girls. Relative incidences of HCC among children divided into groups by age, birth cohort, and sex were analyzed using Poisson regression.¹¹ The modification of age effect on HCC incidence by sex was statistically tested by cross production of age and sex variables (the interaction term) and expressed in separate models when the age trends were significantly different between female and male.

A consistent predominance of HCC in boys was found throughout the observation period. The incidence of childhood HCC declined gradually in boys during 1981-1996, while the incidence in girls remained stable (Table 1). Although the trend of the predominance in boys remained, the boy/girl ratio of the incidence of HCC declined gradually with time from 4.5 for years of diagnosis 1981-1984 to 1.9 for years of diagnosis 1990-1996.

The relative risk (RR) of HCC in boys born between 1978 and 1984 declined significantly in comparison with those born before 1978 (RR, 0.83; P = .02); the trend of decrease in the RR of HCC was even more evident in those born after 1984 when compared with those born before 1978 (RR, 0.72; P = .002) (Table 2). However, the trend of decline in girls was not significant for the birth cohort born between 1978 and 1983 vs those born before 1978 (RR, 1.02; P = .90) or for those born after 1984 vs those born before 1978 (RR, 0.77; P = .20).

The age trend of HCC risk was significantly modified by sex. The risk of HCC in boys remained constant from age 6 to 14 years, while the risk of HCC in girls, though lower than in boys, increased significantly with age. In separate models, there was no significant age trend for boys (RR, 0.97; 95% CI, 0.92-1.03; P = .33), while the incidence of HCC in girls increased significantly by 1.15 times for each year increment of age (RR, 1.15; 95% CI, 1.04-1.28; P = .007). The age effect in boys and girls was the same before and after vaccination (Figure 1).

In the present study, we observed a predominance of HCC in boys both before and after the HBV vaccination program. This predominance cannot be explained by the effect of sex hormones, as in adults. Tumor suppression gene regulation, the metabolism of carcinogens, or genetic alterations have been proposed to differ between men and women and need further study.⁵

This predominance decreased after the vaccination program because the incidence of HCC decreased significantly in boys but not in girls. Why the vaccination program seems to have had more of an effect on boys remains unclear. The low incidence of HCC in girls may render the statistical comparison of the incidences difficult. It is possible that HCC in girls is less intimately related to HBV infection than in boys, but seems unlikely given our previous observations² and evidence of HBV infection in girls with HCC born after implementation of the program (unpublished data by authors). The possibility that intrauterine infection with HBV, which would not be affected by vaccination, occurs more frequently in female infants also is unlikely, as there was no female predominance in infants who were seropositive for the hepatitis B surface antigen at birth.¹² Additionally, there was no difference in the vaccination coverage rate between male and female infants in Taiwan. (National Taiwan University Hospital's coverage rate is 100% for all mature neonates. The number of delivery of neonates is approximately 3000 per year. The national coverage rate for neonates was between 84% and 94% for 1986 to 1994 [M. H. Chang, unpublished data]). It also seems unlikely that case finding for such a serious disease would differ between boys and girls or change over time.

Seroepidemiologic studies in Taipei conducted in both 1984 and 1994 in children showed no or a slight predominance in boys in the incidence of HBV infection.^3,13 In contrast, the remarkable predominance of HCC in boys suggests that factor(s) in addition to chronic HBV infection may contribute to hepatocarcinogenesis in males, particularly the early occurrence in prepubertal males.