It has been demonstrated that first-degree relatives of hepatitis B surface antigen (HBsAg) carriers with hepatocellular carcinoma (HCC) have an increased risk of HCC as compared with the same relatives of HBsAg carriers without HCC.1However, the cause for this familial clustering of HCC remains unclear.
Many possible aetiological factors have been implicated in the development of HCC, but most of these such as alcohol,
aflatoxins, gender, tobacco smoke, and certain polymorphic genes increase only a relatively modest risk of HCC.2–11Most HCC has been associated with hepatitis virus infections.11 In Taiwan, where mother-to-child vertical transmission is the predominant route of acquiring chronic hepatitis B virus (HBV) infection,12HBV is the major cause of HCC and the important source of familial effects for HCC.11The risk of developing HCC among HBsAg carriers is closely related to hepatitis activity and
Increased risk for hepatitis B-related liver
cirrhosis in relatives of patients with
hepatocellular carcinoma in northern Taiwan
Ming-Whei Yu,
aHung-Chuen Chang,
aPei-Jer Chen,
bChun-Jen Liu,
bYun-Fan Liaw,
cShi-Ming Lin,
cShou-Dong Lee,
dShee-Chan Lin,
eChih-Lin Lin
fand Chien-Jen Chen
aBackground There is a tendency for familial aggregation of hepatocellular carcinoma (HCC). The aims of this study were to assess the degree to which familial aggregation of hepatitis B surface antigen (HBsAg) carriers accounts for familiality of HCC in families of hepatitis B-related HCC patients, and whether HCC shares a familial predisposition with liver cirrhosis among HBsAg carriers.
Methods A total of 671 first-degree relatives of HBsAg-positive HCC cases were recruited using abdominal ultrasonography and tests for HBsAg and serum aminotrans-ferases. They were from 165 simplex families defined as having only one HCC case and 72 multiplex families with more than one case. In analyses of family history of HCC and cirrhosis, the data set consisted of 4471 unrelated asymptomatic HBsAg carriers recruited in a prospective study.
Results There was no significant difference in the HBsAg-positive rate among relatives between multiplex (55.7%) and simplex (48.1%) families. Sonographic evidence of liver cirrhosis was present in 14.4% of HBsAg-positive relatives from multiplex families but in only 7.8% of HBsAg-positive relatives from simplex families (multiplex versus simplex families: adjusted odds ratio [OR] = 2.29; 95% CI: 1.10–4.77). Among unrelated asymptomatic HBsAg carriers, the adjusted OR of liver cirrhosis associated with a first-degree family history of HCC was 2.80 (95% CI: 1.68–4.66). This association was stronger in HBsAg carriers 50 years. No association was seen between family history of HCC and hepatitis activity based on elevated levels of aminotransferases.
Conclusions Familial aggregation of HCC in HBsAg carriers is associated with familial cluster-ing of liver cirrhosis.
Keywords Hepatitis B, liver cirrhosis, hepatocellular carcinoma, familial aggregation
Accepted 12 June 2002
aGraduate Institute of Epidemiology, College of Public Health, National
Taiwan University, Taipei, Taiwan.
bHepatitis Research Center, National Taiwan University Hospital, Taipei,
Taiwan.
c
Liver Research Unit, Chang-Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan.
dDepartment of Medicine, Taipei Veterans General Hospital and School of
Medicine, National Yang-Ming University, Taipei, Taiwan.
eDivision of Gastroenterology, Department of Internal Medicine, MacKay
Memorial Hospital, Taipei, Taiwan.
f Division of Gastroenterology, Department of Internal Medicine, Taipei
Municipal Jen-Ai Hospital, Taipei, Taiwan.
Correspondence: Ming-Whei Yu, Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, No. 1 Jen-Ai Road, Sec.1, Rm. 1550, Taipei 100, Taiwan. E-mail: [email protected]
advanced stage of liver disease.13,14Although the HCC risk is extremely high for HBsAg carriers as compared with non-carriers,11most HBsAg carriers may have no clinical symptoms of liver disease and no or only minor histological lesions in the liver through their lifetime. Indeed, only a small fraction of HBsAg carriers develop advanced chronic liver disease, such as chronic hepatitis and liver cirrhosis, which are closely associated with the development of HCC.15–17 The cirrhosis caused by persistent HBV infection often progresses insidiously. The use-fulness of ultrasonography in the diagnosis of cirrhosis in patients with chronic hepatitis B has been established.16,18,19 Our previous prospective study found that subclinical cirrhosis diagnosed by ultrasonography is the most influential known risk factor for the development of HCC among HBsAg carriers, conferring an increased relative risk of about 12.17
This study was based on data from a cohort study of asympto-matic HBsAg carriers and a family study in which information
regarding most potentially relevant risk factors for HCC was collected from relatives of patients with HBV-related HCC. It aimed both to assess the extent to which familial aggregation of HBsAg carriers could account for familial clustering of HCC in families of hepatitis B-related HCC patients, and to investigate whether HCC shares a familial predisposition with other liver diseases, especially cirrhosis, among HBsAg carriers.
Subjects and Methods
The study population consisted of relatives of patients with HCC who participated in an ongoing family study of HCC and a cohort of unrelated asymptomatic HBsAg carriers enrolled in a prospective study on HCC, which has been in operation since 1988 (Figure 1).
Family study
Between September 1997 and May 2000 a total of 1876 (1214 of whom were HBsAg-positive) patients with HCC diagnosed on the basis of histological findings or an elevated serum α-fetoprotein level (400 ng/ml) combined with at least one positive image on angiography, sonography, and/or computed tomography were enrolled with family history interview and/or blood collection from four major hospitals in northern Taiwan. Recruitment of study families was initiated in August 1998. For the purpose of genetic linkage analysis, only families of HCC patients for whom DNA samples were available were considered. Names and telephone numbers of relatives were obtained from the HCC index case and/or family members. Relatives were eligible for inclusion if they were aged 20–75 years and residing in Taipei City or districts near Taipei. Sur-viving siblings and parents of all HBsAg-positive HCC patients and of HBsAg-negative HCC patients diagnosed with cancer before 45 years of age were asked to come to our research centre for clinical evaluation, including ultrasound scanning and tests for serum levels of aminotransferases and HBsAg. Because the average age at onset of HCC in Taiwan is about 50 years, children of the index patient were invited to participate in this study if their HBsAg status was known on the index patient’s family history questionnaire and they were tested positive for HBsAg. Since the report of physical examination including items of serological markers for hepatitis B is required for students to attend certain universities in Taiwan, many parents know whether their adult children are positive for HBsAg. Status of liver cirrhosis was determined on the basis of ultra-sonographic patterns characteristic of cirrhosis as described previously.17Ultrasonography was performed by gastroentero-logists who had no prior knowledge of the family history of HCC. Hepatitis B surface antigen was detected by enzyme immunoassay (SURASE B-96, General Biologicals Corporation, Hsinchu, Taiwan). Each relative was also asked to complete a structured questionnaire including items on sociodemographic factors, lifestyle habits, and a medical history. This study was approved by the research ethics committee at the College of Public Health, National Taiwan University and the appropriate institutional review board.
Only relatives of HBsAg-positive HCC patients were con-sidered in the present analysis. Of 1214 HBsAg-positive patients with HCC, 409 had no DNA, 20 had no or incomplete data on family history of HCC and 400 (including 146 with no surviving eligible relatives, 74 whose parents and siblings were too old, and 180 whose relatives resided in areas far away from Taipei city) had no eligible relatives. Forty-nine patients’ families could not be contacted and 98 declined to take part. The maximum possible number of eligible relatives of the 238 remaining patients’ families was 846. A total of 80% (679 relatives) of them were recruited. We excluded eight relatives diagnosed with HCC before entry into the study. A total of 671 relatives (130 parents, 474 siblings, 67 children) from 237 families (including 72 multiplex families defined as having at least one HCC case among first-degree relatives of the index cases and 165 simplex families having no HCC cases among first-degree relatives of the index cases) remained available for analysis in this study. Of the 237 patients whose relatives were included as study subjects, 64% were diagnosed with HCC before age 50, whereas the corresponding figure for the 977 patients whose
relatives were not included was 39%. Fifty-five per cent of the 237 patients had an education level of senior high school or above. However, only 38% of the 977 patients had such an education level. The average number of relatives who partici-pated in this study in each family was 2.6 (range = 1–9) for multiplex families and 2.9 (range = 1–8) for simplex families.
Cohort data
The cohort consisted of 7342 men and 667 women in which male HBsAg carriers and/or non-carriers had been included in our previous studies to examine various hypotheses for the origin of HCC.1,4–10A total of 4471 HBsAg carriers (4025 men and 446 women) were included in the present study.
A detailed description of the enrolment and follow-up of HBsAg carriers in this cohort study has been published else-where.1,4–10 Briefly, between 1988 and 1992, asymptomatic HBsAg carriers who were free of diagnosed HCC were con-secutively enrolled during routine physical examinations from the Government Employee Central Clinics and the Liver Unit of Chang-Gung Memorial Hospital. All participants gave their written informed consent. Details of their sociodemographic characteristics, lifestyle habits, as well as personal and family medical histories were collected using standardized question-naires by trained research assistants. Blood specimens were also obtained and frozen at –70°C until subsequent analysis.
Hepatitis B surface antigen carriers were periodically evalu-ated by medical examination including tests for serum alanine aminotransferase, aspartate aminotransferase, and α-fetoprotein levels. Ultrasonography was performed routinely for the detection of cirrhosis and HCC. The data collected at the initial examination were used in this study. Of the original 5508 HBsAg carriers in the cohort, 37 (0.7%) had no available data on family history of HCC and 1000 (18.2%) had no data on either ultrasonography measurement or serum aminotrans-ferases, leaving a total of 4471 HBsAg carriers in the analysis.
Statistical analysis
We used the χ2test to compare groups for categorical variables. Odds ratios (OR) comparing disease risks between relatives from multiplex and simplex families were estimated by a logit marginal model taking account of within-family dependence.20 The models were fitted by use of the GENMOD procedure of the statistical package PC-SAS version 6.12. We estimated the standard errors of the OR by use of the exchangeable working correlation matrix. When risks associated with family history of HCC among unrelated cohort HBsAg carriers were analysed, an unconditional logistic model was used instead to compute OR and their 95% CI. Multivariate models were adjusted for age (continuous variable), sex, cigarette smoking (yes or no), alcohol consumption (yes or no), and years of education (continuous variable). All P-values presented are two-sided.
Results
Parents and siblings of HCC patients from multiplex families (55.7%) had a slightly higher HBsAg-positive rate than those from the simplex families (48.1%). However, the difference by family history of HCC was not statistically significant even after adjusting for age, sex, and the relationship of the relative with the index case (mother, father, or siblings) in a logistic regression
model taking account of within-family dependence. Children were not included for this comparison because they were recruited with knowledge of HBsAg status (Table 1).
Among the 4471 cohort HBsAg carriers, 329 (7.4%) reported a first-degree relative with HCC. Only 22 of the cohort subjects with such a family history had more than one first-degree rela-tive with HCC. Table 2 shows characteristics in HBsAg carriers
by source of recruitment and family history of HCC. Among cohort subjects, HBsAg carriers with a first-degree family history of HCC were somewhat younger than those without (P = 0.029). Otherwise, cohort HBsAg carriers with and without a first-degree family history of HCC had similar distributions of gender, alcohol consumption and cigarette smoking habits, and educational levels. None of the distributions of the selected
Table 1 Hepatitis B surface antigen (HBsAg)-positive rate in parents and siblings of patients with hepatitis B virus (HBV)-related hepatocellular
carcinoma (HCC) by types of familiesa
HBsAg positivity Family type No. of family Relation to HCC index case No. of relatives tested No. (%)
Simplex 161 Parents 116 43 (37.1)b Siblings 348 180 (51.7)c All 464 223 (48.1)d Multiplex 60 Parents 14 6 (42.9) Siblings 126 72 (57.1) All 140 78 (55.7)
aMultiplex family was defined as a family containing at least one HCC case among first-degree relatives of the HCC index case. Children were not included
for this comparison because they were recruited with knowledge of HBsAg status.
bP = 0.673 for the comparison with multiplex families. cP = 0.296 for the comparison with multiplex families. dP = 0.128 for the comparison with multiplex families.
Table 2 Characteristics of hepatitis B surface antigen (HBsAg) carriers by source of recruitment and a first-degree family history of hepatocellular
carcinoma (HCC)
HCC patients’ HBsAg-positive first-degree Cohort HBsAg carriers relativesa
Without family history, % With family history, % Simplex families, % Multiplex families,b%
Characteristic (n = 4142) (n = 329) (n = 243) (n = 125) Age (years) 30 1.2c 1.5 9.9 16.8 30–39 30.5 30.7 25.5 25.6 40–49 39.2 45.3 38.3 36.0 50–59 18.0 16.4 12.7 12.8 60 11.1 6.1 13.6 8.8 Female 9.9 11.6 55.1 54.4 Years of educationd 9 20.7 25.6 37.9 37.4 10–12 21.4 18.9 33.7 36.6 12 57.9 55.5 28.4 26.0 Cigarette smoking Non-smokers 68.4 67.8 69.1 70.4 Ex-smokers 7.2 7.3 5.8 1.6 Current smokers 24.4 24.9 25.1 28.0
Frequency of alcohol consumption (days/week)
Non-drinkers 81.9 80.5 85.2 83.2
1–3 14.2 15.2 10.7 12.0
4–7 3.8 4.3 4.1 4.0
Drinkers with unknown frequency 0.1 0.0 0.0 0.8
aRelatives included parents, siblings and children.
bMultiplex family was defined as a family containing at least one HCC case among first-degree relatives of the HCC index case. cP = 0.029 for the comparison with cohort HBsAg carriers with a first-degree family history of HCC.
dData on years of education were missing for four cohort subjects without a first-degree family history of HCC, one cohort subject with a first-degree family
characteristics in Table 2 significantly differ between relatives from multiplex families and relatives from simplex families.
Among HBsAg carriers, the prevalence of elevated amino-transferase levels (defined as alanine aminoamino-transferase40 IU/l or aspartate aminotransferase35 IU/l) did not significantly differ between cohort HBsAg carriers with and without a first-degree family history of HCC, and between relatives of familial HCC patients defined as having at least one first-degree relative affected with HCC and those relatives of sporadic patients without affected first-degree relatives. However, there was an association between cirrhosis risk and family history of HCC among HBsAg carriers. The relatives (14.4%) of familial HCC patients were more likely to have ultrasonographic evidence of cirrhosis than the relatives (7.8%) of sporadic HCC patients (adjusted OR = 2.29; 95% CI: 1.10–4.77; P = 0.0263). Com-pared with cohort HBsAg carriers without a first-degree family history of HCC, the adjusted OR of having ultrasonographic evidence of cirrhosis for cohort HBsAg carriers with such a family history was 2.80 (95% CI: 1.68–4.66; P = 0.0001) (Table 3). Of the 303 HBsAg-negative parents and siblings of HCC index patients, only 30 (9.9%) had elevated aminotransferase levels and 3 (1.0%) were found to have cirrhosis by ultrasonography (data not shown).
The proportion of subjects who reported having a history of cirrhosis diagnosed by physicians was also significantly higher in cohort HBsAg carriers with a first-degree family history of HCC than in those without, although this proportion was lower in relatives of familial HCC patients than in relatives of sporadic patients. Relatives of patients with HCC may have greater diagnostic surveillance and those relatives who have had disease
may have a higher participation rate. To evaluate possible distortion of our findings by this selection bias, we repeated our analysis after excluding subjects with a history of cirrhosis. As shown in Table 3, the association between ultrasonographic evidence of cirrhosis and family history of HCC remained sig-nificant even after exclusion of subjects who reported having a history of cirrhosis diagnosed by physicians.
Table 4 shows a higher prevalence of cirrhosis diagnosed by ultrasonography among older (50 years) than among younger HBsAg carriers. However, the association between family his-tory of HCC and cirrhosis tended to be stronger in younger HBsAg carriers.
Discussion
It has long been observed that there is familial clustering of HCC and of chronic HBV infection.21Studies to elucidate hypo-thesized susceptibility to HCC thus must consider HBV. In a previous study we observed a profound familial effect for the development of HCC in the context of HBV exposure using a cohort study of 4808 HBsAg carriers and a case-control family study involving 553 HBsAg carriers with HCC and 4684 HBsAg carriers without HCC. No excess of other types of cancer was observed in the case families, but the prevalence of cirrhosis among first-degree relatives, in which information on cirrhosis was obtained from the case and control probands, was also found to be significantly greater for case subjects than for control subjects.1 That study raises the possibility that there may be genetic factors or shared environmental exposure(s) other than chronic HBV infection contributing to the familial
Table 3 Odds ratios (OR) of elevated aminotransferase levels and cirrhosis according to a first-degree family history of hepatocellular carcinoma
(HCC) among hepatitis B surface antigen (HBsAg) carriers by source of recruitmenta
HCC patients’ HBsAg-positive Cohort HBsAg carriers first-degree relativesb
Without family history With family history Simplex families Multiplex familiesc
Diagnosis (n = 4142) (n = 329) (n = 243) (n = 125)
Elevated aminotransferases
Prevalence (%) 1150 (27.8) 95 (28.9) 58 (23.9) 35 (28.0) Crude OR (95% CI) 1.0 (ref.) 1.06 (0.82–1.35) 1.0 (ref.) 1.28 (0.76–2.15) Adjusted OR (95% CI) 1.0 (ref.) 1.02 (0.79–1.31) 1.0 (ref.) 1.26 (0.74–2.15)
Cirrhosis diagnosed by ultrasonography
Prevalence (%) 105 (2.5) 19 (5.8) 19 (7.8) 18 (14.4) Crude OR (95% CI) 1.0 (ref.) 2.36 (1.43–3.89) 1.0 (ref.) 1.98 (1.01–3.88) Adjusted OR (95% CI) 1.0 (ref.) 2.80 (1.68–4.66) 1.0 (ref.) 2.29 (1.10–4.77)
History of cirrhosis
Prevalence (%) 16 (0.4) 4 (1.2) 9 (3.7) 3 (2.4)
Crude OR (95% CI) 1.0 (ref.) 3.17 (1.06–9.55) 1.0 (ref.) 0.43 (0.09–2.04) Adjusted OR (95% CI) 1.0 (ref.) 3.74 (1.22–11.52) 1.0 (ref.) 0.51 (0.11–2.41)
Cirrhosis diagnosed by ultrasonography, excluding subjects who reported having a history of cirrhosisd
Prevalence (%) 98 (2.4) 15 (4.6) 13 (5.6) 16 (13.1) Crude OR (95% CI) 1.0 (ref.) 1.99 (1.14–3.47) 1.0 (ref.) 2.55 (1.20–5.43) Adjusted OR (95% CI) 1.0 (ref.) 2.34 (1.33–4.12) 1.0 (ref.) 3.11 (1.38–7.00)
aMultivariate-adjusted OR have been adjusted for age (continuous variable), sex, cigarette smoking (yes or no), alcohol consumption (yes or no), and years
of education (continuous variable). Four cohort subjects without a first-degree family history of HCC, one cohort subject with a first-degree family history of HCC, and two relatives of familial HCC patients were not included in the multiple logistic regression analyses because of missing data on years of education.
bRelatives included parents, siblings and children.
cMultiplex family was defined as a family containing at least one HCC case among first-degree relatives of the HCC index case.
risk of HCC, perhaps the mechanism by which these factors cause familial HCC is through the process leading to cirrhosis. However, neither analysis in that study included data on HBsAg status of the relatives. Given the importance of HBsAg status for HCC risk, the role of chronic HBV infection in familial HCC merits more careful consideration.
This study, in which actual test data on the HBsAg status of the relatives were collected, maintains that HBV alone cannot explain all of the familial concordance of HCC, because the prevalence of HBsAg carrier rate in simplex and multiplex families of HCC was not significantly different. The reported increase in the risk of HCC has also been attributed to environ-mental risk factors other than HBV, particularly hepatitis C virus.2–11,22 However, most seroepidemiological surveys on the prevalence of hepatitis C virus infection using first- or second-generation immunoassay kits to test antibodies against hepatitis C virus in selected populations in northern Taiwan have reported a prevalence of 0.3–2.5%,22–24except a study conducted in a specific township with high incidence of HCC, in which the figure was as high as about 10%.25Otherwise, although intrafamilial spread of hepatitis C virus may occur, the possibility of transmission of hepatitis C virus through non-sexual household contacts seems to be low.26,27Although we failed to observe an association with family history of HCC for hepatitis activity manifested by elevated aminotransferase levels in this study, the prevalence of cirrhosis diagnosed by ultrasonography was found to be associated with familiality of HCC among HBsAg carriers. This finding is compatible with that from our previous work1and suggests that the response to persistent infection with HBV, rather than its mere presence, may play a considerable role in the familial risk of HCC.
Despite intensive recruitment, some eligible relatives in HCC index patients’ families that could be contacted refused to participate in this survey. It is conceivable that a preferential participation rate by affected compared to unaffected relatives could lead to an overestimation of the true prevalence of cirrhosis among relatives of patients with HCC. However,
the cirrhosis caused by HBV often progresses insidiously. In contrast to the prevalence of cirrhosis diagnosed by ultra-sonography, the proportion of subjects who reported having a history of cirrhosis diagnosed by physicians among HBsAg carriers is relatively low. Thus, it is reasonable to speculate that the participation rate in relatives affected by subclinical cirrhosis would be similar to that in those unaffected. On the other hand, relatives of HCC patients may receive excess ultrasonographic screening for early detection of HCC. The proportion of subjects who reported having a history of cirrhosis was also observed to be higher among cohort HBsAg carriers with a first-degree family history of HCC than among those without. However, the association between ultrasonographic evidence of cirrhosis and family history of HCC among cohort HBsAg carriers remained statistically significant even after excluding subjects who reported having a history of cirrhosis from analyses.
A limitation of our study is that a fraction of subclinical cirrhosis may not be diagnosed by ultrasonography, particularly for early liver cirrhosis.18,19Compared with liver biopsy, the specificity of ultrasonography in the diagnosis of cirrhosis was found to be very high. However, the limited sensitivity of the ultrasonographic diagnosis may have led to some under-estimation of the relationship between cirrhosis and family history of HCC.
The reasons for the familial occurrence of cirrhosis remain unknown. It may be caused by prolonged HBV replication, which was also reported to cluster in first-degree relatives of patients with HCC.28Recently, various genotypes of HBV have been identified by a novel genotyping method based on analysis of the surface gene. Genotypes B and C are the predominant strains in Taiwan. Whereas genotype C was observed to be associated with cirrhosis, genotype B may be associated with the development of early-onset HCC.29 It is possible that familial aggregation of cirrhosis in relatives of patients with HCC observed in this study may be related to the vertical transmis-sion of particularly virulent strains of HBV. Nevertheless, the exact nature of the relationship between HBV genotypes and liver disease severity remains unclear.
Table 4 Odds ratios (OR) of having cirrhosis diagnosed by ultrasonography in relation to a first-degree family history of hepatocellular carcinoma
(HCC) among hepatitis B surface antigen (HBsAg) carriers by source of recruitment and agea
HCC patients’ HBsAg-positive Cohort HBsAg carriers first-degree relativesb
Without family history With family history Simplex families Multiplex familiesc
Variable (n = 4142) (n = 329) (n = 243) (n = 125)
50 years of age
No. with cirrhosis/total no. 44/2937 12/255 11/179 12/98 Crude OR (95% CI) 1.0 (ref.) 3.25 (1.69–6.23) 1.0 (ref.) 2.13 (0.90–5.05) Adjusted OR (95% CI) 1.0 (ref.) 3.27 (1.69–6.32) 1.0 (ref.) 2.65 (0.99–7.12) 50 years of age
No. with cirrhosis/total no. 61/1205 7/74 8/64 6/27 Crude OR (95% CI) 1.0 (ref.) 1.96 (0.86–4.45) 1.0 (ref.) 1.99 (0.63–6.32) Adjusted OR (95% CI) 1.0 (ref.) 2.03 (0.89–4.64) 1.0 (ref.) 1.71 (0.49–5.97)
aMultivariate-adjusted OR have been adjusted for age (continuous variable), sex, cigarette smoking (yes or no), alcohol consumption (yes or no), and years
of education (continuous variable). Four (2 aged 50 years and 2 aged 50 years) cohort subjects without a first-degree family history of HCC, 1 cohort subject aged 50 years who had a first-degree family history of HCC, and 2 (1 aged 50 years and 1 aged 50 years) relatives of familial HCC patients were not included in the multiple logistic regression analyses because of missing data on years of education.
bRelatives included parents, siblings and children.
References
1Yu MW, Chang HC, Liaw YF et al. Familial risk of hepatocellular
carcinoma among chronic hepatitis B carriers and their relatives.
J Natl Cancer Inst 2000;92:1159–64.
2Yu MC, Tong MJ, Govindarajan S, Henderson BE. Nonviral risk
factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 1991;83:1820–26.
3Ross RK, Yuan JM, Yu MC et al. Urinary aflatoxin biomarkers and risk
of hepatocellular carcinoma. Lancet 1992;339:943–46.
4Chen CJ, Yu MW, Liaw YF et al. Chronic hepatitis B carriers with null
genotypes of glutathione S-transferase M1 and T1 polymorphisms who are exposed to aflatoxin are at increased risk of hepatocellular carcinoma. Am J Hum Genet 1996;59:128–34.
5Yu MW, Lien JP, Chiu YH, Santella RM, Liaw YF, Chen CJ. Effect of
aflatoxin metabolism and DNA adduct formation on hepatocellular carcinoma among chronic hepatitis B carriers in Taiwan. J Hepatol 1997;27:320–30.
6Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, Liaw YF,
Chen CJ. Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma.
Gastroenterology 1995;109:1266–73.
7Yu MW, Chiu YH, Chiang YC et al. Plasma carotenoids, glutathione
S-transferase M1 and T1 genetic polymorphisms, and risk of hepatocellular carcinoma: independent and interactive effects. Am J
Epidemiol 1999;149:621–29.
8Yu MW, Chiu YH, Yang SY et al. Cytochrome P450 1A1 genetic
polymorphisms and risk of hepatocellular carcinoma among chronic hepatitis B carriers. Br J Cancer 1999;80:598–603.
9Yu MW, Yang SY, Chiu YH, Chiang YC, Liaw YF, Chen CJ. A p53
genetic polymorphism as a modulator of hepatocellular carcinoma risk in relation to chronic liver disease, familial tendency, and cigar-ette smoking in hepatitis B carriers. Hepatology 1999;29:697–702.
10Yu MW, Pai CI, Yang SY et al. Role of N-acetyltransferase
poly-morphisms in hepatitis B-related hepatocellular carcinoma: impact on risk of smoking. Gut 2000;47:703–09.
11Yu MW, Chen CJ. Hepatitis B and C viruses in the development of
hepatocellular carcinoma. Crit Rev Oncol Hematol 1994;17:71–91.
12Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of
hepatitis B antigen in Taiwan. N Engl J Med 1975;292:771–74.
13Beasley RP. Hepatitis B virus: the major etiology of hepatocellular
carcinoma. Cancer 1988;61:1942–56.
14Chen PJ, Chen DS. Hepatitis B virus infection and hepatocellular
carcinoma: molecular genetics and clinical perspectives. Semin Liver
Dis 1999;19:253–62.
15Popper H, Shafritz DA, Hoofnagle JH. Relation of the hepatitis B virus
carrier state to hepatocellular carcinoma. Hepatology 1987;7:764–72.
16Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in
patients with chronic type B hepatitis: a prospective study. Hepatology 1988;8:493–96.
17Yu MW, Hsu FC, Sheen IS et al. Prospective study of hepatocellular
carcinoma and liver cirrhosis in asymptomatic chronic hepatitis B virus carriers. Am J Epidemiol 1997;145:1039–47.
In addition to the genetic variability of the virus, the course of persistent HBV infection may also depend on host genetic factors. Segregation analysis of HCC in Chinese families has demonstrated an HBV-major gene interaction.30In this study, we observed an approximately threefold increase in the cirrhosis risk for cohort HBsAg carriers with a first-degree family history of HCC compared with those HBsAg carriers without such a family history. Simulation studies have shown that a shared environmental factor, even if it is perfectly associated between relatives, is incapable of doubling disease risk in relatives of those affected compared with those unaffected, unless the factor induces a 10-fold or greater increase in risk for the disease.31,32 Moreover, our previous case-control family study found that the risk of HCC in first-degree relatives tended to be higher among patients with early-onset HCC diagnosed at less than 50 years of age.1 We also found that the association of cirrhosis with family history of HCC is stronger among HBsAg carriers 50 years in the present study. In addition, HBV carriers from multiplex families have a higher risk of cirrhosis than those from simplex families, suggesting the existence of a rare high-risk gene accounting for HBV-related cirrhosis. Mapping and
molecular characterization of the inherited susceptibility to cirrhosis could contribute substantially to the understanding of familial HCC.
In summary, we found an association of cirrhosis risk with a family history of HCC in first-degree relatives among HBsAg carriers. This finding raises an important clinical and public health issue. Should HBsAg carriers with such a family history of HCC be treated more actively to prevent progress into cirrhosis? Treatments with lamivudine or interferone have been associated with sustained suppression of HBV replication and/or substantial histological improvement in certain HBsAg car-riers.33–36However, follow-up studies are required to determine the effectiveness of such treatments in prevention of developing cirrhosis and HCC.
Acknowledgements
This study was supported by grant nos. NSC 88–2318-B-002-002 and DOH89-TD-1130 (Frontier Medical Genomic Program) from the National Science Council and the Department of Health, Executive Yuan, Taiwan.
KEY MESSAGES
• Chronic hepatitis B virus infection alone cannot explain all of the familial concordance of hepatocellular carcinoma (HCC).
• Familial aggregation of HCC in hepatitis B surface antigen (HBsAg) carriers is associated with familial clustering of liver cirrhosis.
• Prophylactic treatment to prevent liver cirrhosis should be considered for HBsAg-positive first-degree relatives of HCC patients.
18Yang PM, Huang GT, Lin JT et al. Ultrasonography in the diagnosis
of benign diffuse parenchymal liver diseases: a prospective study.
J Formosan Med Assoc 1988;87:966–77.
19Lin DY, Sheen IS, Chiu CT, Lin SM, Kuo YC, Liaw YF.
Ultrasono-graphic changes of early liver cirrhosis in chronic hepatitis B: a longi-tudinal study. J Clin Ultrasound 1993;21:303–08.
20Liang KY, Zeger SL. Regression analysis for correlated data. Annu Rev
Pub Health 1993;14:43–68.
21Tong MJ, Weiner JM, Ashcavai MW, Vyas GN. Evidence for clustering
of hepatitis B virus infection in families of patients with primary hepatocellular carcinoma. Cancer 1979;44:2338–42.
22Yu MW, You SL, Chang AS, Lu SN, Liaw YF, Chen CJ. Association
between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res 1991;51:5621–25.
23Lee SD, Chan CY, Wang YJ et al. Seroepidemiology of hepatitis C virus
infection in Taiwan. Hepatology 1991;13:830–33.
24Chang HC, Yu MW, Lu CF, Chiu YH, Chen CJ. Risk factors associated
with hepatitis C virus infection in Taiwanese government employees.
Epidemiol Infect 2001;126:291–99.
25Sun CA, Chen HC, Lu CF et al. Transmission of hepatitis C virus in
Taiwan: prevalence and risk factors based on a nationwide survey.
J Med Virol 1999;59:290–96.
26Caporaso N, Ascione A, Stroffolini T, Investigators of an Italian
Multicenter Group. Spread of hepatitis C virus infection within families. J Viral Hepat 1998;5:67–72.
27Alvarez-Muñoz MT, Vences-Aviles MA, Damacio L et al. Hepatitis C
virus RNA (HCV-RNA) in blood donors and family members seropositive for anti-HCV antibodies. Arch Med Res 2001;32:442–45.
28Tai DI, Changchien CS, Hung CS, Chen CJ. Replication of hepatitis B
virus in first-degree relatives of patients with hepatocellular carcinoma. Am J Trop Med Hyg 1999;61:716–19.
29Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate
with clinical outcomes in patients with chronic hepatitis B.
Gastroenterology 2000;118:554–59.
30Shen FM, Lee MK, Gong HM, Cai XQ, King MC. Complex segregation
analysis of primary hepatocellular carcinoma in Chinese families: interaction of inherited susceptibility and hepatitis B viral infection.
Am J Hum Genet 1991;49:88–93.
31Khoury MJ, Beaty TH, Liang KY. Can familial aggregation of disease
be explained by familial aggregation of environmental risk factors?
Am J Epidemiol 1988;127:674–83.
32Hopper JL, Carlin JB. Familial aggregation of a disease consequent
upon correlation between relatives in a risk factor measured on a continuous scale. Am J Epidemiol 1992;136:1138–47.
33Wong DKH, Cheung AM, O’Rourke K, Naylor CD, Detsky AS,
Heathcote J. Effect of alpha-interferone treatment in patients with hepatitis B e antigen-positive chronic hepatitis B: a meta-analysis.
Ann Intern Med 1993;119:312–23.
34Lok ASF, Wu PC, Lai CL et al. A controlled trial of interferon with or
without prednisone priming for chronic hepatitis B. Gastroenterology 1992;102:2091–97.
35Nevens F, Main J, Honkoop P et al. Lamivudine therapy for chronic
hepatitis B: a six-month randomized dose-ranging study. Gastroenterology 1997;113:1258–63.
36Lai CL, Chien RN, Leung NWY et al. A one-year trial of lamivudine for
