Japanese Journal of Clinical Oncology Advance Access published online on October 22, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn108
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author (2008). Published by Oxford University Press. All rights reserved
Alcohol Drinking and Liver Cancer Risk: An Evaluation Based on a Systematic Review of Epidemiologic Evidence among the Japanese Population
1 Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga
2 Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai
3 Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Nagoya
4 Department of Epidemiology and Preventive Medicine, Gifu University School of Medicine, Gifu
5 Department of Epidemiology and International Health, Research Institute, International Medical Center of Japan, Tokyo
6 Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
For reprints and all correspondence: Keitaro Tanaka, Department of Preventive Medicine, Faculty of Medicine, Saga University 5-1-1 Nabeshima, Saga 849-8501, Japan. E-mail: tanakake{at}post.saga-med.ac.jp
Received July 6, 2008; accepted September 15, 2008
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
Background: Although alcohol consumption has been recognized as a risk factor for primary liver cancer, it will be informative to summarize relevant epidemiologic data in the Japanese who have characteristic environmental determinants (e.g. hepatitis C virus infection) and genetic traits (e.g. presence of poor acetaldehyde metabolizers).
Methods: We systematically reviewed epidemiologic studies on alcohol drinking and liver cancer among Japanese populations. Original data were obtained through searches of the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association (‘strong’, ‘moderate’, ‘weak’ or ‘no association’) in each study and the strength of evidence (‘convincing’, ‘probable’, ‘possible’ or ‘insufficient’), together with biological plausibility as previously assessed by the International Agency for Research on Cancer.
Results: Among 22 cohort studies identified, 14 (64%) reported weak to strong positive associations between alcohol and liver cancer risk, 3 (14%) reported no association and five (23%) reported weak to moderate inverse associations; such inverse associations were found mostly in follow-up studies of patients with chronic liver disease (particularly, cirrhotic patients), yet recent studies on patients with chronic hepatitis C presented fairly consistent positive associations. Of 24 case–control studies identified, 19 (79%) showed weak to strong positive associations, whereas the remainder demonstrated no association (n = 4) or a moderate inverse association (n = 1).
Conclusion: We conclude that there is ‘convincing’ evidence that alcohol drinking increases the risk of primary liver cancer among the Japanese population.
Key Words: systematic review • epidemiology • alcohol • liver cancer • Japanese
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
Alcohol has long been viewed as a hepatotoxic agent, and its heavy consumption is known to cause hepatocellular injury that can lead to enhanced fibrosis and eventually to liver cirrhosis through various mechanisms presumed (1). Alcohol drinking has also been implicated in the etiology of primary liver cancer that often develops from cirrhosis (2). In the most recent evaluation by the International Agency for Research on Cancer (IARC), the occurrence of liver cancer has been ‘causally’ related to the consumption of alcoholic beverages (3). In the second report published by the World Cancer Research Fund and the American Institute for Cancer Research, the Panel has judged that alcohol consumption is ‘probably’ a direct cause of liver cancer (4).
Primary liver cancer is one of the most common cancers in Japan (5). More than 90% of primary liver cancers in this country are hepatocellular carcinomas (HCCs) that are mostly attributable to chronic infections with hepatitis C virus (HCV) and hepatitis B virus (HBV) (6,7); HCV and HBV infections are estimated to account for 70 and 15%, respectively, of the recent occurrences of HCC in Japan (6). This tendency clearly contrasts with the situation in southeast Asia and sub-Saharan Africa where HBV represents a dominant risk factor of HCC, and with that in Western countries where HCV infection plays an increasingly important role (2,8). The role of alcohol in hepatocarcinogenesis might differ between Japan and such areas. Moreover, 
50% of the Japanese are poor metabolizers of acetaldehyde (9), the first metabolite of ethanol, which has been recognized as being possibly carcinogenic to humans (10). Such poor metabolizers have not been found in Africans or Caucasians (9), and thus the Japanese as Mongoloids might be more susceptible to alcohol than other ethnic groups.
The aim of the present study was to review and summarize epidemiologic findings on alcohol drinking and liver cancer among Japanese populations. This work was conducted as part of a project of systematic evaluation of the epidemiologic evidence regarding lifestyles and cancers in Japan (11).
|
PATIENTS AND METHOD |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
The details of the evaluation method have been described elsewhere (11). In brief, original data for this review were identified through searches of the MEDLINE (PubMed) and Ichushi (Japana Centra Revuo Medicina) databases, complemented by manual searches of references from relevant articles where necessary. All epidemiologic studies on the association between alcohol drinking and liver cancer incidence/mortality among the Japanese from 1950 (or 1983 for the Ichushi database) to June 2008, including papers in press if available, were identified using the following as keywords: alcohol, liver, hepatocellular, cohort, follow-up, case–control, Japan and Japanese. Papers written in either English or Japanese were reviewed, and only studies on Japanese populations living in Japan were included. The individual results were summarized in the tables separately as cohort or case–control studies.
The evaluation was made based on the magnitudes of association and the strength of evidence. First, the former was assessed by classifying the relative risk (RR) in each study into the following four categories, while considering statistical significance (SS) or no statistical significance (NS): (i) ‘strong’ (symbol 
or 
) when RR < 0.5 (SS) or RR > 2.0 (SS); (ii) ‘moderate’ (symbol or ) when RR < 0.5 (NS), 0.5 
RR < 0.67 (SS), 1.5 < RR 2.0 (SS) or RR > 2.0 (NS); (iii) ‘weak’ (symbol or ) when 0.5 RR < 0.67 (NS), 0.67 RR 1.5 (SS) or 1.5<RR 2.0 (NS) and (iv) ‘no association’ (symbol –) when 0.67 RR 1.5 (NS); the RR used in this paper denotes ratio measures of effect, including risk ratios, rate ratios, hazard ratios and odds ratios. When RRs for three or more exposure levels were reported, that for the highest level was employed for this classification. In the case of multiple publications of analyses of the same or overlapping data sets, only data from the largest or most updated results were included. Studies that reported RRs for indefinite exposure levels, or did not provide RRs or data necessary for the present authors to calculate relevant RRs, were excluded.
After this process, the strength of evidence was evaluated in a manner similar to that used in the WHO/FAO Expert Consultation Report (12), in which evidence was classified as ‘convincing’, ‘probable’, ‘possible’ and ‘insufficient’. We assumed that biological plausibility corresponded to the judgment of the most recent evaluation from the IARC (3). Despite the use of this quantitative assessment rule, an arbitrary assessment cannot be avoided when considerable variation exists in the magnitudes of association among the results of each study. The final judgment, therefore, was made based on a consensus of the research group members, and it was therefore not necessarily objective. When we reach a conclusion that there is ‘convincing’ or ‘probable’ evidence of an association, we conduct a meta-analysis to obtain summary estimates for the overall magnitude of association.
|
MAIN FEATURES AND COMMENTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
We identified a total of 22 cohort (13–34) (Table 1) and 24 case–control studies (35–58) (Table 2). Of those cohort studies, two presented the results by sex (19,31), seven for men only (13–16,26,29,32) and 13 for men and women combined (17,18,20–25,27,28,30,33,34). The respective numbers for the case–control studies are two (45,54), nine (36–38,42,44,48–51) and 13 (35,39–41,43,46,47,52,53,55–58). Several studies showed the results separately according to study areas (16), different age categories (31), the severity of chronic liver disease (CLD) (33) or different control groups (49,54,56).
|
|
Study populations in the cohort studies, except for one study based on male alcoholics (26), were classified broadly into two categories: mostly healthy subjects (n = 7) such as local residents (14,16,25,31,32), physicians (13) and atomic bomb survivors (19) and patients with CLD (15,17,18,20–24,27–30,33,34) (n = 14) (Table 1). Chronic infections with both HCV and HBV were taken into account in 12 studies, all of which followed patients with CLD (18,20–24,27–30,33,34). In the case–control studies, excluding one study based on military men exposed to thorotrast (38), a similar classification was possible based on the type of controls: hospital or community controls (35,37,40–46,48,49,51–56,58) (n = 18) vs. patients with CLD (39,47,50,56,57) or HBV carriers (36) (n = 6; one study (56) included hospital controls as well) (Table 2). In six case–control studies, both HCV and HBV infections were taken into account or were controlled for (46,47,50,56–58).
A summary of the magnitude of association for the cohort and case–control studies is shown in Tables 3 and 4, respectively. Among all 22 cohort studies identified, nine (13,16,21,23,24,27–30) reported strong positive associations between alcohol drinking and liver cancer, three (14,19,32) reported moderate positive associations and two reported weak positive associations (26,34) (Tables 1 and 3). Of the remaining eight studies, three (18,20,25) observed no association and five (15,17,22,31,33) demonstrated weak to moderate inverse associations; such inverse associations were detected mostly in follow-up studies of patients with CLD (particularly, cirrhotic patients) (15,17,22,33). In some cohort studies targeting mostly healthy subjects, the observed risk was higher in former than current drinkers (19,31,32). Among the seven cohort studies in which mostly healthy subjects were followed, five (13,14,16,19,32) revealed at least weak positive associations, whereas eight (21,23,24,27–30,34) out of the 14 follow-up studies of patients with CLD showed such positive associations.
|
|
Among all 24 case–control studies identified, strong positive associations were found in 14 (35,36,40,42–44,47,49–51,54–56,58), moderate positive associations in four (38,41,45,53) and a weak positive association in one (37) (Tables 2 and 4). For the remainder, no association was reported in four (39,46,48,52) and a moderate inverse association was reported in one (57). In the 18 case–control studies employing hospital or community controls, 15 (35,37,40–45,49,51,53–56,58) demonstrated at least weak positive associations, whereas four (36,47,50,56) out of six case–control studies using controls of CLD patients or HBV carriers afforded such positive associations.
Overall, about 60% of the cohort studies identified reported weak to strong positive associations between alcohol drinking and liver cancer risk, although all such studies are done on mostly healthy subjects lacking information on hepatitis virus infection. Since there is no reason to consider that individuals with chronic HCV or HBV infection tend to consume more alcohol than those without, potential confounding by such viral infection is unlikely to explain the positive associations found. Cohort studies of mostly healthy subjects demonstrated fairly consistent positive associations, yet several follow-up studies on CLD patients (particularly, cirrhotic patients) reported no association (18,20) or even inverse associations (15,17,22,33), which may be due to the following reasons.
First, among CLD patients, the severity of liver disease may confound the association with alcohol consumption. If patients with more severe liver disease tend to drink less alcohol at baseline for any reason (e.g. impaired liver function or physicians' advice), even in those with a similar diagnosis (e.g. chronic hepatitis or cirrhosis), alcohol drinking may seem to play no, or even protective, role. Second, among cirrhotic patients, competing risks (i.e. deaths from causes other than liver cancer) may be responsible. For example, if cirrhotic patients with alcoholism continue to drink heavily, they may die of hepatic failure or variceal bleeding before the development of liver cancer. Third, drinking habits at baseline among CLD patients may have changed substantially during follow-up, and the resultant misclassification may have distorted a true association. Fourth, alcohol consumption may actually play no important role in the development of liver cancer from cirrhosis. However, it appears difficult to differentiate these possibilities by observational studies.
In some cohort studies based on mostly healthy subjects, former drinkers experienced a higher risk of liver cancer than never drinkers (19,31,32); in all such studies, information on hepatitis virus infection and the presence or absence of CLD was missing. In this regard, a plausible explanation is that former drinkers may have included high-risk individuals such as hepatitis virus carriers and CLD patients who had abstained from alcohol because of illness.
In the case–control studies identified, alcohol consumption was almost consistently associated with increased liver cancer risk. This was the case regardless of the type of controls (mostly healthy subjects vs. CLD patients or hepatitis virus carriers), and only one study on patients with chronic hepatitis C reported an inverse association (57), which somewhat differs from the situation in the cohort studies. A possible change in recent drinking habits among CLD patients can be taken into account in case–control studies, but not usually in cohort studies, and this matter might partly account for the above difference, although the exact reason remains unknown.
Since about 90% of patients with HCC in Japan are known to be chronically infected with HCV or HBV (6), the postulation that heavy alcohol consumption causes alcoholic cirrhosis and thereby leads to the development of HCC does not appear to play a major role. Instead, the potential modifying effect of alcohol on HCC risk among HCV- or HBV-infected individuals is likely to be more important. In this connection, most follow-up studies of patients with chronic hepatitis C over the past decade showed fairly consistent positive associations between alcohol drinking and HCC risk (21,24,27,28,30,34), with few exceptions (33). It remains unclear to what extent alcohol consumption increases the HCC risk among the Japanese general population who are not infected with HCV or HBV because no study exists on this issue.
Potential mechanisms linking the use of alcohol with the development of liver cancer are discussed elsewhere (3). As for the role of alcohol among those with HCV infection, which is the most important risk factor of HCC in Japan, several mechanisms including increased viral replication, enhanced HCV quasispecies complexity, increased liver-cell death, suppression of immune responses, iron overload and increased oxidative stress have been suggested (59,60).
The Japanese may be more susceptible than other ethnic groups, to potential carcinogenic effects of alcohol because about half of them represent heterozygous or homozygous carriers of the inactive aldehyde dehydrogenase (ALDH) 2 allele (ALDH2*2) (9), who have an excessive accumulation of acetaldehyde after alcohol intake; acetaldehyde has been classified as being possibly carcinogenic to humans (10). Epidemiologic data on the role of the ALDH2 genotype in hepatocarcinogenesis has been conflicting (49,51,52,55,56,61). Overall, no material differences have been observed in the ALDH2 genotype distribution between liver cancer patients and control subjects, although two studies of relatively small size reported a significantly increased risk among heterozygous or homozygous carriers of ALDH2*2 (55,61). Two studies suggested a significantly elevated risk of HCC for ALDH2*2 carriers vs. non-carriers among drinkers, but not among non-drinkers (55,56).
The IARC has concluded that there is sufficient evidence for the carcinogenicity of ethanol in experimental animals (3). Taken together, this systematic review confirms a biologically plausible positive association between alcohol drinking and liver cancer risk among the Japanese, and a meta-analysis should be conducted to obtain summary estimates for the overall magnitude of association. However, the studies included in this review employed very different categories of alcohol consumption (particularly in reference categories), which has made a meaningful meta-analysis unfeasible. A meta-analysis of several large-cohort studies using common alcohol consumption categories is now underway, and we hope it will address the above issue.
|
EVALUATION OF EVIDENCE ON ALCOHOL DRINKING AND LIVER CANCER RISK AMONG JAPANESE |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
From these results and based on assumed biological plausibility as previously evaluated by the IARC (3), we conclude that there is ‘convincing’ evidence that alcohol drinking increases the risk of primary liver cancer among the Japanese population. High-risk individuals such as patients with CLD and hepatitis virus carriers are strongly recommended to abstain from alcohol use.
|
Funding |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
This work was supported by a Grant-in-Aid for the Third Term Comprehensive Control Research for Cancer from the Ministry of Health, Labor and Welfare, Japan.
|
Conflict of interest statement |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
None declared.
|
Appendix |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
Research group members: Shoichiro Tsugane [principal investigator], Manami Inoue, Shizuka Sasazuki, Motoki Iwasaki, Tetsuya Otani [until 2006], Norie Kurahashi [since 2007], Taichi Shimazu [since 2007] (National Cancer Center, Tokyo); Ichiro Tsuji [since 2004], Yoshitaka Tsubono [in 2003] (Tohoku University, Sendai); Yoshikazu Nishino (Miyagi Cancer Research Institute, Natori, Miyagi); Kenji Wakai (Nagoya University, Nagoya); Keitaro Matsuo [since 2006] (Aichi Cancer Center, Nagoya); Chisato Nagata (Gifu University, Gifu); Tetsuya Mizoue (International Medical Center of Japan, Tokyo); Keitaro Tanaka (Saga University, Saga).
|
Footnotes |
|---|
Research group members are listed in the Appendix. 
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...FundingConflict of interest statementAppendixReferences |
|---|
1 Lieber CS. Alcohol and the liver: 1994 update. Gastroenterology (1994) 106:1085–105.[Web of Science][Medline]
2 Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology (2004) 127:S35–50.[CrossRef][Web of Science][Medline]
3 International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 96. Consumption of Alcoholic Beverages and Ethyl Carbamate (Urethane). Lyon, France: IARC. (in press).
4 World Cancer Research Fund, American Institute for Cancer Research. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. (2007) Washington, DC: AICR.
5 Gann Monograph on Cancer Research No. 51. Cancer Mortality and Morbidity Statistics: Japan and the World-2004. (2004) Tokyo, Japan: Scientific Societies Press.
6 Ikai I, Arii S, Okazaki M, Okita K, Omata M, Kojiro M, et al. Report of the 17th Nationwide Follow-up Survey of Primary Liver Cancer in Japan. Hepatol Res (2007) 37:676–91.[CrossRef][Web of Science][Medline]
7 Tanaka K, Ikematsu H, Hirohata T, Kashiwagi S. Hepatitis C virus infection and risk of hepatocellular carcinoma among Japanese: possible role of type 1b (II) infection. J Natl Cancer Inst (1996) 88:742–6.
8 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet (2003) 362:1907–17.[CrossRef][Web of Science][Medline]
9 Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, Beckmann G, et al. Distribution of ADH2 and ALDH2 genotypes in different populations. Hum Genet (1992) 88:344–6.[Web of Science][Medline]
10 International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Volume 71. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. (1999) Lyon, France: IARC.
11 Inoue M, Tsuji I, Wakai K, Nagata C, Mizoue T, Tanaka K, et al. Evaluation based on systematic review of epidemiological evidence among Japanese populations: tobacco smoking and total cancer risk. Jpn J Clin Oncol (2005) 35:404–11.
12 World Health Organization. WHO Technical Reports Series 916. Diet, Nutrition and the Prevention of Chronic Diseases: Report of a Joint WHO/FAO Expert Consultation. (2003) Geneva: WHO.
13 Kono S, Ikeda M, Tokudome S, Nishizumi M, Kuratsune M. Cigarette smoking, alcohol and cancer mortality: a cohort study of male Japanese physicians. Jpn J Cancer Res (1987) 78:1323–8.[Web of Science]
14 Hirayama T. A large-scale cohort study on risk factors for primary liver cancer, with special reference to the role of cigarette smoking. Cancer Chemother Pharmacol (1989) 23(Suppl.):S114–7.[CrossRef][Web of Science][Medline]
15 Inaba Y, Kikuchi S, Namihisa T, Ichikawa S. The effect of smoking and drinking habit on the process from liver cirrhosis to liver cancer. Gan No Rinsho (1990) 36:299–304. (in Japanese).
16 Shibata A, Fukuda K, Toshima H, Tashiro H, Hirohata T. The role of cigarette smoking and drinking in the development of liver cancer: 28 years of observations on male cohort members in a farming and fishing area. Cancer Detect Prev (1990) 14:617–23.[Web of Science][Medline]
17 Kato I, Tominaga S, Ikari A. The risk and predictive factors for developing liver cancer among patients with decompensated liver cirrhosis. Jpn J Clin Oncol (1992) 22:278–85.
18 Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med (1993) 328:1797–801.
19 Goodman MT, Moriwaki H, Vaeth M, Akiba S, Hayabuchi H, Mabuchi K. Prospective cohort study of risk factors for primary liver cancer in Hiroshima and Nagasaki, Japan. Epidemiology (1995) 6:36–41.[Web of Science][Medline]
20 Chiba T, Matsuzaki Y, Abei M, Shoda J, Tanaka N, Osuga T, et al. The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. Am J Gastroenterol (1996) 91:1195–203.[Web of Science][Medline]
21 Ikeda K, Saitoh S, Suzuki Y, Kobayashi M, Tsubota A, Koida I, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol (1998) 28:930–8.[CrossRef][Web of Science][Medline]
22 Tanaka K, Sakai H, Hashizume M, Hirohata T. A long-term follow-up study on risk factors for hepatocellular carcinoma among Japanese patients with liver cirrhosis. Jpn J Cancer Res (1998) 89:1241–50.[CrossRef][Web of Science]
23 Matsushita E, Kaneko S, Kobayashi K. Evaluation of background factors related to carcinogenesis in cirrhosis. In: Proceedings of 20th Inuyama Symposium (1998) Tokyo: Chugai-igakusha. 159–64. (in Japanese).
24 Aizawa Y, Shibamoto Y, Takagi I, Zeniya M, Toda G. Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C. A long term follow-up study after histologic diagnosis. Cancer (2000) 89:53–9.[CrossRef][Web of Science][Medline]
25 Mori M, Hara M, Wada I, Hara T, Yamamoto K, Honda M, et al. Prospective study of hepatitis B and C viral infections, cigarette smoking, alcohol consumption, and other factors associated with hepatocellular carcinoma risk in Japan. Am J Epidemiol (2000) 151:131–9.
26 Noda T, Imamichi H, Tanaka H, Kawata A, Hirano K, Ando T, et al. Cause-specific mortality risk among male alcoholics residing in the Osaka metropolitan area. Psychiatry Clin Neurosci (2001) 55:465–72.[Medline]
27 Hamada H, Yatsuhashi H, Yano K, Daikoku M, Arisawa K, Inoue O, et al. Impact of aging on the development of hepatocellular carcinoma in patients with posttransfusion chronic hepatitis C. Cancer (2002) 95:331–9.[CrossRef][Web of Science][Medline]
28 Takimoto M, Ohkoshi S, Ichida T, Takeda Y, Nomoto M, Asakura H, et al. Interferon inhibits progression of liver fibrosis and reduces the risk of hepatocarcinogenesis in patients with chronic hepatitis C: a retrospective multicenter analysis of 652 patients. Dig Dis Sci (2002) 47:170–6.[CrossRef][Web of Science][Medline]
29 Uetake S, Yamauchi M, Itoh S, Kawashima O, Takeda K, Ohata M. Analysis of risk factors for hepatocellular carcinoma in patients with HBs antigen- and anti-HCV antibody-negative alcoholic cirrhosis: clinical significance of prior hepatitis B virus infection. Alcohol Clin Exp Res (2003) 27:47S–51S.[CrossRef][Web of Science][Medline]
30 Iwasaki Y, Takaguchi K, Ikeda H, Makino Y, Araki Y, Ando M, et al. Risk factors for hepatocellular carcinoma in hepatitis C patients with sustained virologic response to interferon therapy. Liver Int (2004) 24:603–10.[CrossRef][Web of Science][Medline]
31 Ogimoto I, Shibata A, Kurozawa Y, Nose T, Yoshimura T, Suzuki H, et al. Risk of death due to hepatocellular carcinoma among drinkers and ex-drinkers. Univariate analysis of JACC study data. Kurume Med J (2004) 51:59–70.[Medline]
32 Nakaya N, Tsubono Y, Kuriyama S, Hozawa A, Shimazu T, Kurashima K, et al. Alcohol consumption and the risk of cancer in Japanese men: the Miyagi cohort study. Eur J Cancer Prev (2005) 14:169–74.[CrossRef][Web of Science][Medline]
33 Ikeda K, Marusawa H, Osaki Y, Nakamura T, Kitajima N, Yamashita Y, et al. Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma: a prospective study. Ann Intern Med (2007) 146:649–56.
34 Ohki T, Tateishi R, Sato T, Masuzaki R, Imamura J, Goto T, et al. Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. Clin Gastroenterol Hepatol (2008) 6:459–64.[CrossRef][Web of Science][Medline]
35 Inaba Y, Maruchi N, Matsuda M, Yoshihara N, Yamamoto S. A case-control study on liver cancer with special emphasis on the possible aetiological role of schistosomiasis. Int J Epidemiol (1984) 13:408–12.
36 Oshima A, Tsukuma H, Hiyama T, Fujimoto I, Yamano H, Tanaka M. Follow-up study of HBs Ag-positive blood donors with special reference to effect of drinking and smoking on development of liver cancer. Int J Cancer (1984) 34:775–9.[Web of Science][Medline]
37 Hiraga M, Araki S, Murata K, Yokoyama K, Terao H. Assessment of the interaction of hepatitis B antigen and alcohol in primary hepatocellular carcinoma: a case-control study. Jpn J Public Health (1986) 33:636–9. (in Japanese).
38 Kiyosawa K, Imai H, Sodeyama T, Franca ST, Yousuf M, Furuta S, et al. Comparison of anamnestic history, alcohol intake and smoking, nutritional status, and liver dysfunction between thorotrast patients who developed primary liver cancer and those who did not. Environ Res (1989) 49:166–72.[Medline]
39 Kobayashi K, Unoura M, Tanaka N, Hattori N. A comparison between hepatocellular carcinoma-developing and non-carcinoma-developing patients with cirrhosis over a long follow-up period. Hepatogastroenterology (1990) 37:445–8.[Medline]
40 Tsukuma H, Hiyama T, Oshima A, Sobue T, Fujimoto I, Kasugai H, et al. A case-control study of hepatocellular carcinoma in Osaka, Japan. Int J Cancer (1990) 45:231–6.[Web of Science][Medline]
41 Tanaka K, Hirohata T, Takeshita S, Hirohata I, Koga S, Sugimachi K, et al. Hepatitis B virus, cigarette smoking and alcohol consumption in the development of hepatocellular carcinoma: a case-control study in Fukuoka, Japan. Int J Cancer (1992) 51:509–14.[Web of Science][Medline]
42 Haratake J, Kasai T, Takeda S. An epidemiologic comparative study of hepatocellular carcinoma caused by various etiologic factors. Gan No Rinsho (1992) 38:297–301. (in Japanese).
43 Fukuda K, Shibata A, Hirohata I, Tanikawa K, Yamaguchi G, Ishii M. A hospital-based case-control study on hepatocellular carcinoma in Fukuoka and Saga Prefectures, northern Kyushu, Japan. Jpn J Cancer Res (1993) 84:708–14.[CrossRef][Web of Science]
44 Yamaguchi G. Hepatocellular carcinoma and its risk factors–their annual changes and effects on the age at onset. Kurume Med J (1993) 40:33–40.[Medline]
45 Une H, Osajima K, Momose Y, Esaki H. A case-control study on liver cancer in the Chikuho area, Fukuoka prefecture. Minzoku Eisei (1993) 59:241–7.
46 Tanaka H, Hiyama T, Tsukuma H, Imaoka S, Morisada K, Iwanaga T. Association of HBV, HCV, drinking and smoking with the development of hepatocellular carcinoma: a case-control study using hospitalized patients. Shokaki Gan (1995) 5:117–22. (in Japanese).
47 Chiba T, Matsuzaki Y, Abei M, Shoda J, Aikawa T, Tanaka N, et al. Multivariate analysis of risk factors for hepatocellular carcinoma in patients with hepatitis C virus-related liver cirrhosis. J Gastroenterol (1996) 31:552–8.[CrossRef][Web of Science][Medline]
48 Murata M, Takayama K, Choi BC, Pak AW. A nested case-control study on alcohol drinking, tobacco smoking, and cancer. Cancer Detect Prev (1996) 20:557–65.[Web of Science][Medline]
49 Shibata A, Fukuda K, Nishiyori A, Ogimoto I, Sakata R, Tanikawa K. A case-control study on male hepatocellular carcinoma based on hospital and community controls. J Epidemiol (1998) 8:1–5.[Web of Science][Medline]
50 Mukaiya M, Nishi M, Miyake H, Hirata K. Chronic liver diseases for the risk of hepatocellular carcinoma: a case-control study in Japan. Etiologic association of alcohol consumption, cigarette smoking and the development of chronic liver diseases. Hepatogastroenterology (1998) 45:2328–32.[Medline]
51 Takeshita T, Yang X, Inoue Y, Sato S, Morimoto K. Relationship between alcohol drinking, ADH2 and ALDH2 genotypes, and risk for hepatocellular carcinoma in Japanese. Cancer Lett (2000) 149:69–76.[CrossRef][Web of Science][Medline]
52 Koide T, Ohno T, Huang XE, Iijima Y, Sugihara K, Mizokami M, et al. HBV/HCV infection, alcohol, tobacco and genetic polymorphisms for hepatocellular carcinoma in Nagoya, Japan. Asian Pac J Cancer Prev (2000) 1:237–43.[Medline]
53 Iida F, Yamagata Z, Iida R, Hosoda K, Okada S, Matsuda M, et al. Hepatocellular carcinoma in Yamanashi prefecture – a trial of case-control study (third report). Yamanashi Igaku (2002) 30:1–7. (in Japanese).
54 Matsuo M. Association between diabetes mellitus and hepatocellular carcinoma: results of a hospital- and community-based case-control study. Kurume Med J (2003) 50:91–8.[Medline]
55 Munaka M, Kohshi K, Kawamoto T, Takasawa S, Nagata N, Itoh H, et al. Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and the risk of hepatocellular carcinoma. J Cancer Res Clin Oncol (2003) 129:355–60.[CrossRef][Web of Science][Medline]
56 Sakamoto T, Hara M, Higaki Y, Ichiba M, Horita M, Mizuta T, et al. Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population. Int J Cancer (2006) 118:1501–7.[CrossRef][Web of Science][Medline]
57 Fukushima W, Tanaka T, Ohfuji S, Habu D, Tamori A, Kawada N, et al. Does alcohol increase the risk of hepatocellular carcinoma among patients with hepatitis C virus infection? Hepatol Res (2006) 34:141–9.[CrossRef][Web of Science][Medline]
58 Ohishi W, Fujiwara S, Cologne JB, Suzuki G, Akahoshi M, Nishi N, et al. Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study. Cancer Epidemiol Biomarkers Prev (2008) 17:846–54.
59 Vento S, Cainelli F. Does hepatitis C virus cause severe liver disease only in people who drink alcohol? Lancet Infect Dis (2002) 2:303–9.[CrossRef][Web of Science][Medline]
60 Koike K, Tsutsumi T, Miyoshi H, Shinzawa S, Shintani Y, Fujie H, et al. Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J Gastroenterol Hepatol (2008) 23(Suppl. 1):S87–91.[CrossRef][Web of Science][Medline]
61 Kato S, Tajiri T, Matsukura N, Matsuda N, Taniai N, Mamada H, et al. Genetic polymorphisms of aldehyde dehydrogenase 2, cytochrome p450 2E1 for liver cancer risk in HCV antibody-positive japanese patients and the variations of CYP2E1 mRNA expression levels in the liver due to its polymorphism. Scand J Gastroenterol (2003) 38:886–93.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||