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ABSTRACT: In order to explore multiple risk factors of hepatocellular carcinoma (HCC), a total of 13 737 male adult residents in 12 townships were studied for an average follow-up period of 5.2 years. Sociodemographic characteristics, history of cigarette smoking and alcohol drinking, dietary habits, as well as personal and familial history of chronic liver diseases were obtained through standardized interviews based on structured questionnaires at the recruitment. Blood samples were also collected from 9688 (71%) study subjects and examined for the hepatitis B surface antigen (HBsAg). A total of 60 new HCC cases occurred giving an incidence rate of 83.3 per 100 000 person-years. Cox's proportional hazards models were used to analyse multiple risk factors of HCC. In addition the HBsAg carrier status which showed a multivariate-adjusted relative risk of 17.0, cumulative cigarette smoking, alcohol drinking quantity, vegetarian habit and low vegetable consumption were associated with the development of HCC. The multivariate-adjusted relative risk was 1.8 for those who smoked 26 or more pack-years of cigarettes compared with non-smokers, 3.1 for those who drank alcohol 50 mL or more per day compared with those who were non-drinkers or drank less than 50 mL per day, 2.5 for vegetarians compared with non-vegetarians, as well as 4.6 and 2.6, respectively, for those who had a weekly vegetable consumption frequency of less than two meals and two to five meals compared with those who had a frequency of six or more meals.
Journal of Gastroenterology and Hepatology 03/2008; 8(S1):S83 - S87. · 2.87 Impact Factor
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ABSTRACT: To investigate the temporal relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP), and precore regions of hepatitis B virus (HBV) and the risk of hepatocellular carcinoma (HCC), we conducted a nested case-control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988-1992.
The HBV DNA sequence was determined in baseline blood samples taken from 132 incident cases and 204 controls. Base exchanges during follow-up in 71 cases were compared with 81 controls with samples taken during a similar length of follow-up.
Nine single nucleotide polymorphisms in the EnhII/BCP regions (six of which were genotype C HBV related) were associated with subsequent risk of HCC. The strength of these associations decreased as the lag time between baseline measurement and diagnosis increased over 3 years. However, an increased disease risk in subjects with BCP double variants (mostly T1762/A1764) or genotype C HBV-related variants was evident 9 years or more before diagnosis. The BCP double variants (odds ratio, 1.92 (95% confidence interval, 1.14 to 3.25)) were statistically significantly associated with HCC risk even after adjusting for alanine aminotransferase levels, antibodies against HBV e antigen, HBV genotype, HBV viral load, and other sequence variants. Longitudinal analysis indicated that the increased HCC risks for at-risk sequence variants were attributable to the persistence of these variants.
HCC risk is associated with sequence variation in the EnhII/BCP regions of HBV, and persistence of at-risk sequence variants is critical for HCC development.
Gut 02/2008; 57(1):91-7. · 10.11 Impact Factor
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W-L Shih, M-W Yu,
P-J Chen,
S-H Yeh,
M-T Lo,
H-C Chang,
Y-F Liaw,
S-M Lin,
C-J Liu,
S-D Lee,
C-L Lin,
C K Hsiao,
S-Y Yang,
C-J Chen
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ABSTRACT: Chromosome 4q is one of the most common regions with a high frequency of allelic loss in hepatocellular carcinoma (HCC). To identify the HCC-susceptibility locus on chromosome 4q, we have performed linkage and family-based association analyses on Chinese families with HCC from Taiwan, where hepatitis B is hyperendemic. Using 77 microsatellite markers spanning chromosome 4q on 52 multiplex families, we found suggestive evidence of linkage to 4q22.3-28.1 with a maximum two-point heterogeneity LOD (HLOD) score of 2.55 at marker D4S3240 on chromosome 4q25. Multipoint analyses with microsatellite markers in the region 4q22.3-28.1 resulted in a maximum HLOD score of 3.12 and a maximum nonparametric linkage (NPL) Z score of 1.98 (pointwise P=0.0080; region-wide empirical P=0.021) for D4S3240. The evidence for linkage to D4S3240 was seen mostly in a subset of 28 families lacking affected parents, which showed multipoint HLOD and NPL scores of 3.25 and 2.79 (pointwise P=0.0028; region-wide empirical P=0.008), respectively. Family-based association analyses of the 77 microsatellite markers in 191 families (53 multiplex plus 138 singleton families) using the pedigree disequilibrium test provide further support for observed linkage. Additional genotyping in the 52 multiplex families informative for linkage analyses was performed for 29 single-nucleotide polymorphisms around D4S3240. A common haplotype (at markers rs7442180 and rs221330) positioned approximately 873 kb away from D4S3240 was associated with HCC, with P=0.0074.
Oncogene 06/2006; 25(22):3219-24. · 6.37 Impact Factor
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ABSTRACT: The incidence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is higher in men than in women. We examined whether endogenous sex hormone levels or hormone-related factors might affect the risk of HCC in men.
Baseline blood samples were collected from 4841 male Taiwanese HBV carriers without diagnosed HCC from 1988 through 1992. Plasma testosterone and estradiol levels and genetic polymorphisms in the hormone-related factors cytochrome P450c17 alpha (CYP17, A1 versus A2 alleles), steroid 5 alpha-reductase type II (SRD5A2, valine [V] versus leucine [L] alleles), and androgen receptor (AR, number of CAG repeats) were assayed among 119 case patients who were diagnosed with HCC during 12 years of follow-up and 238 control subjects. All statistical tests were two-sided.
The risk of HCC increased with increasing concentrations of testosterone (odds ratio [OR](highest versus lowest tertile) = 2.97; 95% confidence interval [CI] = 1.54 to 5.70; P(trend) <.001) and with increasing number of the V allele of the SRD5A2 V89L polymorphism (OR(VV versus LL genotype) = 2.47; 95% CI = 1.21 to 5.03; P(trend) =.011). Fewer AR gene CAG repeats (<23 repeats) were associated with a 1.64-fold (95% CI = 1.00 to 2.68) increased risk of HCC. Although the CYP17 genotype alone did not increase the risk of HCC, there was evidence of a gene-gene interaction, because the CYP17 A1 allele statistically significantly increased the risk of HCC in the presence of fewer AR gene CAG repeats (OR = 2.51; 95% CI = 1.06 to 5.94). We found a similar interaction between the SRD5A2 VV genotype and fewer AR gene CAG repeats (OR = 5.58; 95% CI = 1.86 to 16.71). Body mass index (BMI) modified the association of HCC with testosterone and SRD5A2 genotype; in men with low BMI, multivariate-adjusted ORs for the highest tertile of testosterone versus the lowest and the SRD5A2 VV genotype versus the LL genotype were 7.63 (95% CI = 2.13 to 27.27) and 8.64 (95% CI = 2.75 to 27.14), respectively. No clear associations were found between estradiol or testosterone-to-estradiol ratio and HCC.
Pathways involving androgen signaling may affect the risk of HBV-related HCC among men.
JNCI Journal of the National Cancer Institute 11/2001; 93(21):1644-51. · 13.76 Impact Factor
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ABSTRACT: This study evaluated the roles of multiple factors in hepatitis C virus (HCV) infection, with emphasis on the modification of various individual characteristics on the risk associated with percutaneous exposure to blood. Serum samples taken from 4869 men in Taiwan within a cohort study were tested for HCV antibody. The overall positive rate of anti-HCV was 1.6%. In a logistic regression, factors positively associated with anti-HCV positivity were previous blood transfusion (odds ratio [OR] = 7.28: 95% confidence interval [CI] = 4.26-12.45), a history of surgery (OR = 2.06: 95% CI = 1 23-3.46), and lower educational levels (OR = 1.94; 95% CI = 1.14-3.32). The anti-HCV positive rate was significantly lower in hepatitis B surface antigen (HBsAg) carriers than in non-carriers (OR = 0.60; 95% CI = 0.37-0.95). Ageing, lower educational levels, O blood group, and Taiwanese ethnicity enhanced the likelihood of HCV infection through blood transfusion/surgery, whereasHBsAg status, cigarette smoking, and habitual alcohol drinking reduced it.
Epidemiology and Infection 05/2001; 126(2):291-9. · 2.84 Impact Factor
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M W Yu,
S W Cheng,
M W Lin,
S Y Yang,
Y F Liaw,
H C Chang,
T J Hsiao,
S M Lin,
S D Lee,
P J Chen,
C J Liu,
C J Chen
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ABSTRACT: Worldwide, hepatocellular carcinoma (HCC) is more prevalent in men than in women, suggesting that sex hormones and/or X-chromosome-linked genes may be involved in hepatocarcinogenesis. We investigated the association of a trinucleotide (CAG) repeat in the androgen receptor (AR) gene (located on the X chromosome) termed "AR-CAG repeats," levels of plasma testosterone, and the risk of HCC in Taiwanese men. Chronic hepatitis B virus (HBV) infection, which is associated with risk of HCC, is hyperendemic in Taiwan.
We compared the number of AR-CAG repeats in 285 HBV carriers with HCC and in 349 HBV carriers without HCC. We also conducted a nested case--control study on participants in a cohort study. Blood was collected prospectively from 110 case patients and 239 control subjects and was used to determine the number of AR-CAG repeats and plasma testosterone level. All statistical tests were two-sided.
The overall odds ratio (OR) for HCC was 1.72 (95% confidence interval [CI] = 1.03--2.89) for HBV carriers with 20 or fewer AR-CAG repeats compared with those with more than 24 repeats. This association was observed only in patients with late-onset HCC (OR = 2.37; 95% CI = 1.28--4.38). In the nested case-control study, HBV carriers in the highest tertile of testosterone levels had a statistically significantly increased risk of HCC (OR = 2.06; 95% CI = 1.14--3.70) compared with those in the lowest tertile. Elevated testosterone was more strongly associated with early-onset (OR = 4.67; 95% CI = 1.41--15.38) than late-onset disease. HBV carriers with 20 or fewer AR-CAG repeats and higher testosterone levels had a fourfold increase in HCC risk compared with those with more than 24 repeats and testosterone levels in the lowest tertile.
Higher levels of androgen signaling, reflected by higher testosterone levels and 20 or fewer AR-CAG repeats, may be associated with an increased risk of HBV-related HCC in men.
JNCI Journal of the National Cancer Institute 01/2001; 92(24):2023-8. · 13.76 Impact Factor
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ABSTRACT: Persistent infection with hepatitis B virus (HBV) causes chronic phasic necroinflammation and regenerative proliferation in the liver. The sustained hepatocellular proliferation may render chronic HBV carriers more susceptible to the effects of environmental carcinogens. Aromatic amines are potential hepatocarcinogens in humans. N-acetyltransferase (NAT) is involved in the metabolic activation and detoxification of these compounds.
To investigate if genetic polymorphisms in N-acetylation are related to hepatocellular carcinoma (HCC) among chronic HBV carriers.
Genotyping of NAT1 and NAT2 was performed using polymerase chain reaction-restriction fragment length polymorphism on peripheral leucocyte DNA from 151 incident cases of HCC and 211 controls. All subjects were male, and were chronic HBV surface antigen carriers.
A significant association between NAT2 genetic polymorphism and HCC was observed among chronic HBV carriers who were smokers but not among those who were non-smokers. For smoking HBV carriers, the odds ratios of developing HCC for those heterozygous and homozygous for the NAT2*4 functional allele compared with those without any copies of the functional allele (reference group) were 2.67 (95% confidence interval 1.15-6.22) and 2.58 (95% confidence interval 1.04-6.43), respectively. The interaction between cigarette smoking and the presence of the NAT2*4 allele just failed to reach statistical significance (p=0.06). No association between NAT1 genotype and HCC was evident overall or within the smoking stratified subgroups.
Our results suggest that NAT2 activity may be particularly critical in smoking related hepatocarcinogenesis among chronic HBV carriers. Our data also indirectly support a role for tobacco smoke derived aromatic amines in the aetiology of HCC.
Gut 12/2000; 47(5):703-9. · 10.11 Impact Factor
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ABSTRACT: Familial predisposition as a risk factor for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers has not been thoroughly explored.
The HCC risk associated with having parents and/or siblings with HCC was evaluated by use of a cohort study of 4808 male HBV carriers. A case-control family study was also conducted on data from first-degree relatives of 553 HBV carriers who had newly diagnosed HCC (case subjects) and 4684 HBV carriers without HCC (control subjects).
In the cohort study, HBV carriers with a family history of HCC had a multivariate-adjusted rate ratio for HCC of 2.41 (95% confidence interval [CI] = 1.47-3.95) compared with HBV carriers without a family history of HCC. For carriers with two or more affected relatives, the ratio increased to 5.55 (95% CI = 2.02-15.26). Cumulative HCC risk by age 70 years was 235.6 per 1000 (95% CI = 95. 3-375.9 per 1000) for HBV carriers with family history compared with 88.9 per 1000 (95% CI = 67.9-109.9 per 1000) for those without. In the case-control family study, first-degree relatives of case subjects were more likely to have HCC (age-sex-adjusted odds ratio [OR] = 2.57; 95% CI = 2.03-3.25) than first-degree relatives of control subjects. The excess risk of HCC among relatives was particularly evident in siblings (sisters-age-adjusted OR = 4.55 [95% CI = 2.22-9.31]; brothers-age-adjusted OR = 3.73 [95% CI = 2. 64-5.27]), but it was also observed in parents. The cumulative risk of HCC to age 80 years was 83.0 per 1000 among relatives of case subjects and 42.0 per 1000 among relatives of control subjects. Among relatives of case subjects, the cumulative risk of HCC was greater if the case subjects were diagnosed before age 50 years (two-sided P =.047). Liver cirrhosis was 2.29 (95% CI = 1.68-3.11) times more frequent in relatives of case subjects than in relatives of control subjects.
First-degree relatives of patients with HBV-related HCC appear to be at increased risk of HCC and should be considered in the formulation of HCC-screening programs.
JNCI Journal of the National Cancer Institute 08/2000; 92(14):1159-64. · 13.76 Impact Factor
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ABSTRACT: There is a wide variation of hepatitis B virus (HBV) infection in the Asia-Pacific region. The prevalence of chronic HBV infection is lowest (<1%) in North America, Australia and New Zealand, 2-4% in Japan, 5-18% in China and highest (15-20%) in Taiwan as well as several other countries in South East Asia. Perinatal transmission is common in HBV-hyperendemic areas. Geographical clusters of horizontal HBV infection have been reported in both high- and low-risk countries. Common sources of infection, including iatrogenic and sexual transmission, have been implicated. Migrant studies indicate the importance of childhood environments in the determination of HBV infection. Rural urban and ethnic differences in the prevalence of HBV infection have also been reported. There has been a decrease in the prevalence of HBV infection after mass HBV vaccination programmes in some Asia-Pacific countries, which may be due to the intervention of possible transmission routes through the use of disposable syringes and needles, screening of HBV infection markers in blood banks, and prevention of high-risk tattooing, acupuncture, ear-piercing and sexual contact. A striking decrease in the incidence of HBV infection and hepatocellular carcinoma has been observed among children in Taiwan and other areas where mass vaccination programmes have been implemented.
Journal of Gastroenterology and Hepatology 06/2000; 15 Suppl:E3-6. · 2.87 Impact Factor
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ABSTRACT: Both experimental and epidemiologic studies have linked a low dietary intake of selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcinoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7,342 men in Taiwan who were recruited by personal interview and blood draw during 1988-1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p = 0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and alpha-tocopherol in relation to HCC risk.
American Journal of Epidemiology 09/1999; 150(4):367-74. · 5.22 Impact Factor
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ABSTRACT: Cigarette smoking has been associated with increased risk of hepatocellular carcinoma (HCC) in some epidemiological studies. Cytochrome P450 1A1 (CYP1A1) is involved in the biotransformation of tobacco-derived polycyclic aromatic hydrocarbons (PAHs) into carcinogenic metabolites. The aim of this study was to determine whether CYP1A1 polymorphisms were related to HCC risk among chronic hepatitis B virus (HBV) carriers. Genotypic variants of CYP1A1 were determined using polymerase chain reaction in 81 incident cases of HCC and 409 controls nested in a cohort study of 4841 male chronic HBV carriers. No overall association between CYP1A1 genotypes and HCC was observed. The presence of the Mspl (odds ratio (OR) 3.15, P = 0.0196) or Ile-Val (OR 1.99, P = 0.0855) variant allele of CYP1A1 increased HCC risk among smokers, but posed no increased risk among non-smokers. The smoking-related HCC risk was most pronounced among those who had a susceptible allele of the CYP1A1 and a deficient genotype of glutathione S-transferase M1, which detoxifies PAH electrophilic metabolites produced by CYP1A1. In the absence of the Ile-Val variant allele, the Mspl polymorphism was still associated with smoking-related HCC. This study suggests that tobacco-derived PAHs play a role in HCC risk among chronic HBV carriers, and CYP1A1 polymorphism is an important modulator of the hepatocarcinogenic effect of PAHs. The Mspl and Ile-Val polymorphisms of CYP1A1 may have different mechanisms for increasing susceptibility to smoking-related HCC.
British Journal of Cancer 06/1999; 80(3-4):598-603. · 5.04 Impact Factor
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ABSTRACT: This study was conducted to assess the role of carotenoid and glutathione S-transferase (GST) M1 and T1 genetic polymorphisms in the development of hepatocellular carcinoma (HCC). A total of 84 incident cases of HCC and 375 matched controls selected from a cohort of 7,342 men (4,841 chronic hepatitis B carriers and 2,501 noncarriers) who were recruited between 1988 and 1992 in Taiwan were studied. Neither GST M1/T1 polymorphisms nor plasma levels of various carotenoids were independently associated with HCC, but they modulated smoking- and/or drinking-related HCC risk. Cumulative exposure to tobacco smoke significantly increased HCC risk in a dose-dependent manner among subjects with low plasma beta-carotene levels (p for trend = 0.047) but not among those with high levels. A statistically significant effect of habitual alcohol drinking on HCC risk was observed only for those with low plasma levels of beta-carotene, alpha-carotene, or lycopene and for GST M1 null subjects. There was evidence suggesting an interaction between the GST M1/T1 genotype and certain carotenoids in HCC associated with smoking and drinking. The strongest effect of smoking and drinking was noted among GST M1 null subjects with low plasma levels of beta-carotene (smoking: adjusted odds ratio (OR) = 3.54, 95% confidence interval (CI) 1.06-11.83; drinking: OR = 8.28, 95% CI 2.40-28.61).
American Journal of Epidemiology 05/1999; 149(7):621-9. · 5.22 Impact Factor
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ABSTRACT: This study evaluated whether the codon 72 p53 polymorphism was related to hepatocellular carcinoma (HCC). Genotypes of p53 were determined in 80 incident cases of HCC and 328 controls nested in a cohort study of 4,841 male chronic hepatitis B carriers. No overall increase in HCC risk with the Pro variant allele of the p53 polymorphism was apparent. However, there were synergistic effects on HCC development for the Pro allele with chronic liver disease and family history of HCC in first-degree relatives. Compared with subjects without the Pro allele and chronic liver disease, the increase in HCC risk associated with chronic liver disease among those without the Pro allele was only threefold. Subjects with both chronic liver disease and the Pro allele were at an increased risk of 7.60 (95% CI = 2.28-25.31). When subjects without family history of HCC and the Pro allele were considered as the reference group, there was no apparent increased risk of HCC for those without the Pro allele who had family history of HCC. Among those with both factors, there was a significantly increased risk of 3.29 (95% CI = 1.10-9.85). Both cigarette smoking and glutathione S-transferase M1 genotype modified the risk of HCC associated with the p53 polymorphism. Significantly increased risk associated with the p53 genotype was observed only among smokers who were glutathione S-transferase-null (Pro/Pro vs. Arg/Arg: odds ratio = 6.46; 95% CI = 1.55-26.94). The p53 polymorphism also interacted with the cytochrome P450 1A1 and carotenoid levels in smoking-related hepatocarcinogenesis.
Hepatology 04/1999; 29(3):697-702. · 11.66 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) is one of the major cancers in the world. There is a striking variation in HCC incidence rates between various countries, with a highest-to-lowest ratio of 112.5 for males and 54.7 for females. The high-risk populations are clustered in sub-Saharan Africa and eastern Asia. The male-to-female ratio for HCC ranges from < 1 to 6.4 and mostly from 2 to 4. There exist significant variations in the incidence of HCC among different ethnic groups living in the same area and among migrants of the same ethnic groups living in different areas. The age curves of HCC are significantly different in various countries, suggesting variability in exposure to risk factors. Chronic carriers of hepatitis B and C viruses (HBV and HCV, respectively) have an increased risk of HCC. The relative and attributable HCC risk of HBV and HCV carrier status varies in different countries. There exists a synergistic interaction on HCC between the two viruses. Aflatoxin exposure, cigarette smoking, heavy alcohol consumption, low vegetable intake, inorganic arsenic ingestion, radioactive thorium dioxide exposure, iron overload and the use of oral contraceptives and anabolic steroids have been documented as HCC risk factors. Recent molecular epidemiological studies have shown that low serum retinol levels as well as elevated serum levels of testosterone, neu oncoprotein and aflatoxin B1-albumin adduct are associated with an increased HCC risk. There is a synergistic interaction on HCC between chronic HBV infection and aflatoxin exposure. Familial aggregation of HCC exists and a major susceptibility gene of HCC has been hypothesized. Patients of some genetic diseases are at an increased risk of HCC. The genetic polymorphisms of cytochrome P450 2E1 and 2D6 and arylamine N-acetyltransferase 2 are associated with the development of HCC. A dose-response relationship between aflatoxin exposure and HCC has been observed among chronic HBV carriers who have null genotypes of glutathione S-transferase M1 or T1, but not among those who have non-null genotypes. Human hepatocarcinogenesis is a multistage process with the involvement of a multifactorial aetiology. Gene-environment interactions are involved in the development of HCC in humans.
Journal of Gastroenterology and Hepatology 10/1997; 12(9-10):S294-308. · 2.87 Impact Factor
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ABSTRACT: Aflatoxins (AFs) are established hepatic carcinogens in several animal species. This study was performed to establish whether aflatoxin exposure may affect the risk of developing hepatocellular carcinoma in chronic hepatitis B virus carriers.
Urinary AF metabolites were measured for 43 HCC cases and 86 matched controls nested in a cohort of 7342 men in Taiwan. Thirty hepatocellular carcinoma cases and 63 controls were also tested for AFB1-albumin adducts.
There was a dose-response relationship between urinary AFM1 levels and risk of hepatocellular carcinoma in chronic hepatitis B virus carriers. Comparing the highest with the lowest tertile of urinary AFM1 levels, the multivariate-adjusted odds ratio (OR) was 6.0 (95% confidence interval (CI) = 1.2-29.0). The hepatocellular carcinoma risk associated with AFB1 exposure was more striking among the hepatitis B virus carriers with detectable AFB1-N7-guanine adducts in urine. Compared with chronic hepatitis B virus carriers who were negative for AFB1-albumin adducts and urinary AFB1-N7-guanine, no elevated risk was observed for those who were positive for either marker. But an extremely high risk of hepatocellular carcinoma among those having both markers was found (OR = 10.0, 95% CI = 1.6-60.9). The proportion of AFB1 converted to AFM1 decreased with the progress of liver disease, whereas the formation of AFP1 increased. The difference in patterns of AFB1 metabolite formation was an independent risk factor for hepatocellular carcinoma after adjustment for total AFB1 excretion. There was a synergistic interaction between glutathione S-transferase M1 genotype and AFB1 exposure in hepatocellular carcinoma risk.
AFB1 intake and expression of enzymes involved in AFB1 activation/detoxification may play an important role in hepatitis B virus-related hepatocarcinogenesis.
Journal of Hepatology 09/1997; 27(2):320-30. · 9.26 Impact Factor
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ABSTRACT: The authors conducted a study to assess the importance of underlying liver cirrhosis in the development of hepatocellular carcinoma (HCC) and the multifactorial etiology of liver cirrhosis in chronic carriers of hepatitis B virus (HBV). Between November 1980 and May 1990, all male hepatitis B surface antigen (HBsAg) carriers who routinely attended a clinic for asymptomatic HBV carriers at the Liver Unit of Chang-Gung Memorial Hospital, Taiwan, were enrolled in the study (n = 1,506). The authors used this cohort to investigate prospectively for liver cirrhosis and HCC at 6-month intervals by means of ultrasonography and clinical assessment. There were 16 incident cases of HCC and 89 cases of liver cirrhosis (78 of whom were detected during follow-up) identified after an average follow-up of 7.1 years. Subclinical liver cirrhosis diagnosed by ultrasonography was significantly associated with the risk for HCC (multivariate-adjusted relative risk (RR) = 11.8, 95% confidence interval (CI) 3.9-35.8). By multivariate analysis, the significant risk factors found for liver cirrhosis in HBsAg carriers were age, hepatitis B e antigen (HBeAg) carrier status, chronic hepatitis manifested by sustained elevated serum aminotransferase levels for > or = 6 months, cigarette smoking, non-A blood types, and low educational levels. Habitual alcohol drinking was not independently related to liver cirrhosis. However, the risk of liver cirrhosis associated with smoking was more striking among drinkers than nondrinkers (> or = 20 cigarettes/day vs. nonsmokers: drinkers, RR = 9.3, 95% CI 1.1-78.8; nondrinkers, RR = 1.85, 95% CI 0.98-3.51), which suggests a possible modification effect of alcohol drinking on the liver cirrhosis risk of cigarette smoking. The authors observed synergistic effects on liver cirrhosis development for cigarette smoking with HBeAg carrier status and chronic hepatitis.
American Journal of Epidemiology 07/1997; 145(11):1039-47. · 5.22 Impact Factor
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ABSTRACT: Epidemiological evidence indicates that aflatoxin B1 (AFB1) intake is associated with an increased risk of hepatocellular carcinoma (HCC). The hepatocarcinogenesis is initiated by covalent binding of AFB1 to cellular DNA. To determine whether nutritional factors and hormonal status may influence the binding of AFB1 to hepatic DNA, a cross-sectional study was performed on a total of 42 male asymptomatic hepatitis B surface antigen (HBsAg) carriers and 43 male non-carriers in a cohort study on the multistage development of HCC in Taiwan. The major AFB1-DNA adduct in vivo, AFB1-N7-guanine, was measured by high-performance liquid chromatography in urine. Urinary AFB1-N7-guanine was detectable in 40% of the subjects. HBsAg carriers had a higher detection rate of urinary AFB1-DNA adducts than non-carriers and the difference was statistically significant after multivariate adjustment. After taking into account the total AFB1 urinary metabolite level, chronic HBsAg carrier status, and other potential confounders, plasma levels of cholesterol, alpha-tocopherol, and alpha- and beta-carotene were positively associated with the detection rate of the AFB1-DNA adducts in a dose-dependent manner, whereas plasma lycopene level was inversely related to the presence of the adducts in urine. The association of urinary AFB1-DNA adducts with the plasma levels of cholesterol, alpha-tocopherol, lycopene, and alpha- and beta-carotene was observed at both low and high exposure levels of AFB1. There was a synergistic interaction of plasma alpha-tocopherol with alpha- and beta-carotene on the adduct levels. No association with the adducts was found for plasma levels of retinol and testosterone. This study demonstrated different associations of antioxidant vitamins with AFB1-DNA adduct formation. The data consistent with our previous finding in cultured woodchuck hepatocytes that alpha-tocopherol and beta-carotene enhanced AFB1-DNA adduct formation suggest that prospective investigation of the relationship between plasma micronutrients and risk of AFB1-related HCC is warranted.
Carcinogenesis 07/1997; 18(6):1189-94. · 5.70 Impact Factor
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ABSTRACT: Covalent binding of aflatoxin B1 (AFB1) with hepatic DNA may be a critical step in hepatocarcinogenesis. The extent of the AFB1 binding to DNA may depend on various endogenous factors and concurrent exposure to other environmental agents. This study was performed to determine whether any individual characteristics correlated with the formation of AFB1-DNA adducts. The major AFB1-DNA adduct, AFB1-N7-guanine, was measured using a high performance liquid chromatographic assay in urine samples from 43 asymptomatic hepatitis B virus surface antigen carriers and 43 noncarriers randomly selected from a cohort study in Taiwan. The total aflatoxin metabolite level was associated with the detection rate of urinary AFB1-N7-guanine adducts in a dose-dependent manner. The AFB1-DNA adduct excreted in the urine was detectable in 60% of individuals who smoked cigarettes but abstained from alcohol, 64% of individuals who had a habit of drinking alcohol but not smoking cigarettes, and only 29% of those who neither smoked nor drank alcohol. The association between urinary AFB1-DNA adduct level and habits of smoking cigarettes and drinking alcohol remained statistically significant when adjustment was made for potential confounders. There was a significant increase with age for the detection rate of urinary AFB1-N7-guanine adducts. Age and habits of cigarette smoking and alcohol drinking were also found to be associated with a higher percentage of AFB1-N7-guanine in total AFB1 metabolite excretion, indicating an increased activation of AFB1. No significant association with the AFB1-DNA adduct level was observed for hepatitis B virus surface antigen carrier status, educational level, and ethnicity. These data suggest a potential role of age, cigarette smoking, and alcohol drinking in AFB1-induced hepatocarcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 09/1996; 5(8):613-9. · 4.12 Impact Factor
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ABSTRACT: This study was carried out to elucidate the effect of glutathione S-transferase (GST) Ml and Tl polymorphisms on the aflatoxin-related hepatocarcinogenesis among chronic carriers of hepatitis B surface antigen (HBsAg). A total of 32 newly diagnosed hepatocellular carcinoma (HCC) cases and 73 age-matched controls selected from a cohort of 4,841 chronic HBsAg carriers who had been followed for 5 years were studied. The level of aflatoxin B1 (AFB1)-albumin adducts in their serum samples collected at the recruitment was examined by competitive enzyme-linked immunosorbance assay, and genotypes of GST M1 and T1 were determined by PCR. There was a dose-response relationship between serum level of AFB1-albumin adducts and risk of HCC. The biological gradients between serum AFB1-albumin adducts level and HCC risk were observed among chronic HBsAg carriers who had null genotypes of GST M1 and/or T1 but not among those who had non-null genotypes. The multivariate-adjusted odds ratios of developing HCC for those who had low and high serum levels of AFB1-albumin adducts compared with those who had a undetectable adduct level as the referent (odds ratio = 1.0) were 4.1 and 12.4, respectively, for HBsAg carriers with null GST M1 genotype (P < .01, on the basis of the significance test for trend); 0.7 and 1.4 for those with non-null GST Ml genotype (P = .98); 1.8 and 10.2 for those with null GST T1 genotype (P < .05); and 1.3 and 0.8 for those with non-null GST T1 genotype (P = .93). The interaction between serum AFB1-albumin adduct level and polymorphisms of GST M1 and T1 was at marginal statistical significance levels (.05 < P < .10).
The American Journal of Human Genetics 07/1996; 59(1):128-34. · 10.60 Impact Factor
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ABSTRACT: In order to assess associations between the genetic polymorphism of L-myc and glutathione S-transferase M1 (GST M1) and the risk of hepatocellular carcinoma (HCC), a total of 46 surgically treated HCC patients who were seropositive in hepatitis B surface antigen (HBsAg) and 88 HBs-Ag positive controls were recruited for this study. L-myc and GST M1 genetic polymorphism was examined using a polymerase chain reaction-based restriction fragment length polymorphism assay on DNA extracted from liver and peripheral blood samples. There was no significant difference in GST M1 genotypes between HCC patients and matched controls. A gene dosage trend of association with HCC risk was observed for L-myc genotype. The dose-response relationship remained statistically significant in the multiple logistic regression analysis.
Cancer Letters 07/1996; 103(2):171-6. · 4.24 Impact Factor
