Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus
Open accessAbstract
Risk factors associated with hepatocellular carcinoma (HCC) are well documented, but the synergisms between these risk factors are not well examined. We conducted a hospital-based, case-control study among 115 HCC patients and 230 non-liver cancer controls. Cases and controls were pathologically diagnosed at The University of Texas M. D. Anderson Cancer Center and were matched by 5-year age groups, sex, and year of diagnosis. Information on risk factors was collected by personal interview and medical records review. Blood samples were tested for the presence of antibodies to hepatitis C virus antigen (anti-HCV), hepatitis B surface antigen (HBsAg), and antibodies to hepatitis B core antigen (anti-HBc). Conditional logistic regression was used to determine odds ratios (ORs) by the maximum likelihood method. Multivariate ORs and 95% confidence intervals (CIs) were 15.3 (4.3-54.4), 12.6 (2.5-63.1), 4.5 (1.4-14.8), and 4.3 (1.9-9.9) for anti-HCV, HBsAg, heavy alcohol consumption (≥80 mL ethanol/d), and diabetes mellitus, respectively. Synergistic interactions on the additive model were observed between heavy alcohol consumption and chronic hepatitis virus infection (OR, 53.9; 95% CI, 7.0-415.7) and diabetes mellitus (OR, 9.9; 95% CI, 2.5-39.3). Independent of the effect of HCV, HBV, and diabetes mellitus, heavy alcohol consumption contributes to the majority of HCC cases (32%), whereas 22%, 16%, and 20% were explained by HCV, HBV, and diabetes mellitus, respectively. In conclusion, the significant synergy between heavy alcohol consumption, hepatitis virus infection, and diabetes mellitus may suggest a common pathway for hepatocarcinogenesis. Exploring the underlying mechanisms for such synergisms may indicate new HCC prevention strategies in high-risk individuals.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Exposure fractions among prevalent liver cirrhosis cases were used as a proxy for population attributable fractions, following the direct method when relative risk is high.
“We used the resulting predicted exposure fractions among prevalent cases as a proxy for PAFs for liver cirrhosis. This follows from the direct method of approximating PAFs:”
From Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis (2014) · cites this paper as [30]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Statistical methods in cancer research. Volume I - The analysis of case-control studies.
Breslow, N. E., & Day, N. E. (1980) · PubMed · Cited by 4,895 · see citing works
Rising Incidence of Hepatocellular Carcinoma in the United States
El‐Serag, H. B., & Mason, A. C. (1999) · New England Journal of Medicine · doi:10.1056/nejm199903113401001 · Cited by 2,865 · see citing works
The analysis of case-control studies
Breslow, N. E., & Day, N. E. (1980) · International Agency for Research on Cancer eBooks · Cited by 2,415 · see citing works
The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice
Moriya, K., Fujie, H., Shintani, Y., Yotsuyanagi, H., Tsutsumi, T., Ishibashi, K., Matsuura, Y., Kimura, S., Miyamura, T., & Koike, K. (1998) · Nature Medicine · doi:10.1038/2053 · Cited by 1,204 · see citing works
Oberley, L. W. (1988) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(88)90036-6 · Cited by 1,105 · see citing works
R�sen, P., Nawroth, P., King, G. L., M�ller, W., Tritschler, H., & Packer, L. (2001) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.196 · Cited by 881 · see citing works
Diabetes and serum ferritin concentration among U.S. adults.
Ford, E. S., & Cogswell, M. E. (1999) · Diabetes Care · doi:10.2337/diacare.22.12.1978 · Cited by 419 · see citing works
International trends and patterns of primary liver cancer
McGlynn, K. A., Tsao, L., Hsing, A. W., Devesa, S. S., & Fraumeni, J. F. (2001) · International Journal of Cancer · doi:10.1002/ijc.1456 · Cited by 350 · see citing works
THE ESTIMATION OF SYNERGY OR ANTAGONISM1
Rothman, K. J. (1976) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a112252 · Cited by 335 · see citing works
Liver pathology in morbidly obese patients with and without diabetes.
Silverman, J. F., O’Brien, K. F., Long, S., Leggett-Frazier, N., Khazanie, P. G., Pories, W. J., Norris, H. T., & F., J. (1990) · PubMed · Cited by 301 · see citing works
Hepatitis C Virus Infection in A Community in the Nile Delta: Risk Factors for Seropositivity
Habib, M., Mohamed, M. K., Abdel-Aziz, F., Magder, L. S., Abdel‐Hamid, M., Gamil, F. M., Madkour, S., Mikhail, N. N. H., Anwar, W. A., Strickland, G. T., et al. (2001) · Hepatology · doi:10.1053/jhep.2001.20797 · Cited by 294 · see citing works
Suppression of Apoptotic Cell Death by Hepatitis C Virus Core Protein
Ray, R. B., Meyer, K., & Ray, R. (1996) · Virology · doi:10.1006/viro.1996.0644 · Cited by 265 · see citing works
Case-Control Studies: Design, Conduct, Analysis
Shapiro, S. (1982) · JAMA · doi:10.1001/jama.1982.03330160093041 · Cited by 247 · see citing works
Alcohol-related diseases and carcinogenesis.
Lieber, C. S., Seitz, H. K., Garro, A. J., et al. (1979) · PubMed · Cited by 213 · see citing works
Sodium selenite-induced oxidative stress and apoptosis in human hepatoma HepG2 cells
Shen, H., Yang, C., & Ong, C. N. (1999) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19990531)81:5 · Cited by 194 · see citing works
Trends in alcohol consumption patterns among whites, blacks and Hispanics: 1984 and 1995.
Caetano, R., & Clark, C. L. (1998) · Journal of Studies on Alcohol · doi:10.15288/jsa.1998.59.659 · Cited by 191 · see citing works
Yu, M. C., Henderson, B. E., Tong, M. J., & Govindarajan, S. (1991) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/83.24.1820 · Cited by 190 · see citing works
Yu, M. C., Tong, M. J., Coursaget, P., Ross, R. K., Govindarajan, S., & Henderson, B. E. (1990) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/82.12.1038 · Cited by 175 · see citing works
Gullen, W. H. (1978) · JAMA · doi:10.1001/jama.1978.03280520027003 · Cited by 175 · see citing works
Mechanism of ethanol induced hepatic injury
Lieber, C. S. (1990) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(90)90032-w · Cited by 168 · see citing works
Role of Diabetes Mellitus in the Etiology of Hepatocellular Carcinoma
Λάγιου, Π. (2000) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/92.13.1096 · Cited by 162 · see citing works
Look, M. P., Rockstroh, J., Rao, G. S., et al. (1997) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1600401 · Cited by 153 · see citing works
Differential effects of BMI on diabetes risk among black and white Americans.
Resnick, H. E., Valsania, P., Halter, J. B., & Lin, X. (1998) · Diabetes Care · doi:10.2337/diacare.21.11.1828 · Cited by 147 · see citing works
Brown, J. J., Naylor, M., & Yagan, N. (1997) · Radiology · doi:10.1148/radiology.202.1.8988182 · Cited by 137 · see citing works
Etiology, pathology, and treatment of hepatocellular carcinoma in North America
Tabor, E., DIBISCEGLIE, A., & Purcell, R. H. (1991) · Medical Entomology and Zoology · Cited by 124 · see citing works
Austin, H. D., Delzell, E., Grufferman, S., Levine, R. S., Morrison, A. S., Stolley, P. D., & Cole, P. T. (1986) · PubMed · Cited by 113 · see citing works
The Role of Hepatitis C in Hepatocellular Carcinoma
Hassan, M. M., Zaghloul, A. S., El‐Serag, H. B., Soliman, O., Patt, Y. Z., Chappell, C. L., Beasley, R. P., & Hwang, L. (2001) · Journal of Clinical Gastroenterology · doi:10.1097/00004836-200108000-00006 · Cited by 103 · see citing works
Self-citationDoes oxygen free radical increased formation explain long term complications of diabetes mellitus?
Gillery, P., Monboisse, J. C., Maquart, F., & Jp, B. (1989) · Medical Hypotheses · doi:10.1016/0306-9877(89)90167-9 · Cited by 87 · see citing works
Implications of the hyperinsulinaemia-diabetes-cancer link for preventive efforts.
Moore, M. A., Park, C. B., & Tsuda, H. (1998) · PubMed · Cited by 86 · see citing works
Alcohol consumption and the risk of cirrhosis
Batey, R. G., Burns, T., Benson, R. J., & Byth, K. (1992) · The Medical Journal of Australia · doi:10.5694/j.1326-5377.1992.tb139846.x · Cited by 70 · see citing works
Release of iron from haemoglobin--a possible source of free radicals in diabetes mellitus.
Kar, M., & Chakraborti, A. S. (1999) · PubMed · Cited by 50 · see citing works
Interactions Between Alcohol and Hepatitis Viruses in the Liver
Bréchot, C., Nalpas, B., & Feitelson, M. A. (1996) · Clinics in Laboratory Medicine · doi:10.1016/s0272-2712(18)30269-5 · Cited by 47 · see citing works
Hepatitis B and C Viruses and Hepatocellular Carcinoma
Kew, M. C. (1996) · Clinics in Laboratory Medicine · doi:10.1016/s0272-2712(18)30276-2 · Cited by 44 · see citing works
Detailed microsatellite analysis of chromosome 3p region in non-papillary renal cell carcinomas
Chudek, J. T., Wilhelm, M., Bugert, P., Herbers, J., & Kovács, G. (1997) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19971009)73:2 · Cited by 32 · see citing works
Hepatitis C virus encodes a selenium-dependent glutathione peroxidase gene
Zhang, W., Cox, A. G., & Taylor, E. W. (1999) · Medizinische Klinik - Intensivmedizin und Notfallmedizin · doi:10.1007/bf03042181 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Tagger A, Donato F, Ribero ML, Chiesa R, Portera G, Gelatti U, Albertini A, et al. Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study. Int J Cancer 1999;81:695-699.
- Peguignot G, Chabert C, Eydoux H, Corcowl MA. Increased risk of liver cirrhosis with intake of alcohol. Rev Alcoholism 1974;20:191-202.
- La Vecchia C, Negri E, Decarli A, Franceschi S. Diabetes mellitus and the risk of primary liver cancer. Int J Cancer 1997;73:204-207.
Cited by
Sorted by citations
Perz, J. F., Armstrong, G. L., Farrington, L. A., Hutin, Y. J. F., & Bell, B. P. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.05.013 · Cited by 2,572 · see citing works
Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis
Mokdad, A. A., Lopez, A. D., Shahraz, S., Lozano, R., Mokdad, A. H., Stanaway, J., Murray, C. J., & Naghavi, M. (2014) · BMC Medicine · doi:10.1186/s12916-014-0145-y · Cited by 1,129 · see citing works
Metabolic syndrome and hepatocellular carcinoma: Two growing epidemics with a potential link
Siegel, A. B., & Zhu, A. X. (2009) · Cancer · doi:10.1002/cncr.24687 · Cited by 399 · see citing works
Hepatocellular carcinoma in the setting of alcohol-related liver disease
Ganne-Carrié, N., & Nahon, P. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2018.10.008 · Cited by 360 · see citing works
Molecular Mechanisms of Alcoholic Fatty Liver
Purohit, V., Gao, B., & Song, B. (2009) · Alcoholism: Clinical and Experimental Research · doi:10.1111/j.1530-0277.2008.00827.x · Cited by 312 · see citing works
Petrick, J. L., Campbell, P. T., Koshiol, J., Thistle, J. E., Andreotti, G., Beane-Freeman, L. E., Buring, J. E., Chan, A. T., Chong, D. Q., Doody, M. M., et al. (2018) · British Journal of Cancer · doi:10.1038/s41416-018-0007-z · Cited by 257 · see citing works
Chen, Y., Wang, X., Wang, J., Yan, Z., & Luo, J. (2012) · European Journal of Cancer · doi:10.1016/j.ejca.2012.02.063 · Cited by 248 · see citing works
Machida, K., Tsukamoto, H., Mkrtchyan, H., Duan, L., Dynnyk, A., Liu, H. M., Asahina, K., Govindarajan, S., Ray, R., Ou, J.-H. J., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0807390106 · Cited by 223 · see citing works
Loomba, R., Yang, H.-I., Su, J., Brenner, D., Barrett-Connor, E., Iloeje, U., & Chen, C.-J. (2013) · American Journal of Epidemiology · doi:10.1093/aje/kws252 · Cited by 221 · see citing works
Lin, C.-W., Lin, C.-C., Mo, L.-R., Chang, C.-Y., Perng, D.-S., Hsu, C.-C., Lo, G.-H., Chen, Y.-S., Yen, Y.-C., Hu, J.-T., et al. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2012.11.045 · Cited by 174 · see citing works
Alcohol-associated liver disease—Global epidemiology
Åberg, F., Jiang, Z. G., Cortez-Pinto, H., & Männistö, V. (2024) · Hepatology · doi:10.1097/hep.0000000000000899 · Cited by 163 · see citing works
Abdel-Rahman, O., Helbling, D., Schöb, O., Eltobgy, M., Mohamed, H., Schmidt, J., giryes, A., Mehrabi, A., Iype, S., John, H., et al. (2017) · Journal of Evidence-Based Medicine · doi:10.1111/jebm.12270 · Cited by 118 · see citing works
Obesity early in adulthood increases risk but does not affect outcomes of hepatocellular carcinoma
Hassan, M. M., Abdel-Wahab, R., Kaseb, A., Shalaby, A., Phan, A. T., El-Serag, H. B., Hawk, E., Morris, J., Singh Raghav, K. P., Lee, J.-S., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.03.044 · Cited by 110 · see citing works
Alcohol and hepatocellular carcinoma
Matsushita, H., & Takaki, A. (2019) · BMJ Open Gastroenterology · doi:10.1136/bmjgast-2018-000260 · Cited by 110 · see citing works
The impact of obesity and metabolic syndrome on alcoholic liver disease
Chiang, D. J., & McCullough, A. J. (2014) · Clinics in Liver Disease · doi:10.1016/j.cld.2013.09.006 · Cited by 99 · see citing works
Sakamoto, T., Hara, M., Higaki, Y., Ichiba, M., Horita, M., Mizuta, T., Eguchi, Y., Yasutake, T., Ozaki, I., Yamamoto, K., et al. (2006) · International Journal of Cancer · doi:10.1002/ijc.21505 · Cited by 88 · see citing works
Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications
Song, B.-J., Abdelmegeed, M. A., Yoo, S.-H., Kim, B.-J., Jo, S. A., Jo, I., & Moon, K.-H. (2011) · Journal of Proteomics · doi:10.1016/j.jprot.2011.05.013 · Cited by 73 · see citing works
Åberg, F., Färkkilä, M., & Männistö, V. (2020) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.14271 · Cited by 63 · see citing works
Joshi, K., Kohli, A., Manch, R., & Gish, R. (2016) · Clinics in Liver Disease · doi:10.1016/j.cld.2016.02.012 · Cited by 58 · see citing works
- Authors
- Hassan, M. M., Hwang, L.-Y., Hatten, C. J., Swaim, M., Li, D., Abbruzzese, J. L., Beasley, P., & Patt, Y. Z.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Hassan, Manal M.
- Venue
- Hepatology
- Published
- 2002-11
- Volume
- 36
- Issue
- 5
- Pages
- 1206-1213
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2158585862
- Cited by
- 762
- References
- 35
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 16 · 2023: 24 · 2022: 21 · 2021: 32 · 2020: 28 · 2019: 39 · 2018: 29 · 2017: 30 · 2016: 34 · 2015: 45 · 2014: 55 · 2013: 43 · 2012: 46
- FWCI
- 15.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Keywords
- hepatocellular carcinoma, risk factors, alcohol consumption, hepatitis C virus, hepatitis B virus, diabetes mellitus, synergistic interaction, hepatocarcinogenesis, chronic viral hepatitis, HCC prevention
- MeSH terms
- Aged, Alcohol Drinking, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Hepatitis B, Hepatitis C, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Risk Factors, Prevalence, Multivariate Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
