Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies
Abstract
OBJECTIVE: We performed a meta-analysis of observational studies to quantify the magnitude of the association between non-alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers. DESIGN: We systematically searched PubMed, Scopus and Web of Science databases from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy-proven NAFLD were available for the analysis. Meta-analysis was performed using random-effects modelling. RESULTS: We included 10 cohort studies with 182 202 middle-aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow-up of 5.8 years. NAFLD was significantly associated with a nearly 1.5-fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2-fold to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias. CONCLUSION: This large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development.
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MASLD is associated with higher risk of HCC and certain extrahepatic cancers, mostly thyroid and gastrointestinal.
“but it is associated with higher risk of HCC and certain extrahepatic cancers, mostly thyroid and gastrointestinal. 30”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [30]
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Cites
Quantifying heterogeneity in a meta‐analysis
Higgins, J. P. T., & Thompson, S. G. (2002) · Statistics in Medicine · doi:10.1002/sim.1186 · Cited by 36,763 · see citing works
Stroup, D. F. (2000) · JAMA · doi:10.1001/jama.283.15.2008 · Cited by 20,623 · see citing works
Operating characteristics of a rank correlation test for publication bias
Begg, C. B., & Mazumdar, M. (1994) · Biometrics · doi:10.2307/2533446 · Cited by 16,955 · see citing works
Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008) · Nature · doi:10.1038/nature07205 · Cited by 11,399 · see citing works
Self-citationCumpston, M., Li, T., Page, M. J., Chandler, J., Welch, V. A., Higgins, J. P., & Thomas, J. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.ed000142 · Cited by 7,218 · see citing works
Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
Younossi, Z., Anstee, Q. M., Marietti, M., Hardy, T., Henry, L., Eslam, M., George, J., & Bugianesi, E. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.109 · Cited by 5,249 · see citing works
Byrne, C. D., & Targher, G. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2014.12.012 · Cited by 3,082 · see citing works
Self-citationAngulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.043 · Cited by 2,987 · see citing works
Ekstedt, M., Hagström, H., Nasr, P., Fredrikson, M., Stål, P., Kechagias, S., & Hultcrantz, R. (2015) · Hepatology · doi:10.1002/hep.27368 · Cited by 2,287 · see citing works
Estes, C., Anstee, Q. M., Arias, M., Bantel, H., Bellentani, S., Caballería, J., Colombo, M., Craxı̀, A., Crespo, J., Day, C. P., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.05.036 · Cited by 1,986 · see citing works
Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Younossi, Z., Tacke, F., Arrese, M., Chander Sharma, B., Mostafa, I., Bugianesi, E., Wai‐Sun Wong, V., Yilmaz, Y., George, J., Fan, J., et al. (2019) · Hepatology · doi:10.1002/hep.30251 · Cited by 1,858 · see citing works
Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis
Targher, G., Byrne, C. D., Lonardo, A., Zoppini, G., & Barbui, C. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.05.013 · Cited by 1,429 · see citing works
Self-citationFrom NASH to HCC: current concepts and future challenges
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O., & Heikenwalder, M. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0145-7 · Cited by 1,392 · see citing works
The intestinal microbiota fuelling metabolic inflammation
Tilg, H., Zmora, N., Adolph, T. E., & Elinav, E. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0198-4 · Cited by 1,089 · see citing works
Self-citationTaylor, R. S., Taylor, R. J., Bayliss, S., Hagström, H., Nasr, P., Schattenberg, J. M., Ishigami, M., Toyoda, H., Wai-Sun Wong, V., Peleg, N., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2020.01.043 · Cited by 1,069 · see citing works
Vilar-Gomez, E., Calzadilla-Bertot, L., Wai-Sun Wong, V., Castellanos, M., Aller-de la Fuente, R., Metwally, M., Eslam, M., Gonzalez-Fabian, L., Alvarez-Quiñones Sanz, M., Conde-Martin, A. F., et al. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.04.034 · Cited by 806 · see citing works
Candido, J., & Hagemann, T. (2012) · Journal of Clinical Immunology · doi:10.1007/s10875-012-9847-0 · Cited by 745 · see citing works
Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort
Simon, T. G., Roelstraete, B., Khalili, H., Hagström, H., & Ludvigsson, J. F. (2021) · Gut · doi:10.1136/gutjnl-2020-322786 · Cited by 673 · see citing works
Complications, morbidity and mortality of nonalcoholic fatty liver disease
Mantovani, A., Scorletti, E., Mosca, A., Alisi, A., Byrne, C. D., & Targher, G. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154170 · Cited by 558 · see citing works
Self-citationMantovani, A., Petracca, G., Beatrice, G., Tilg, H., Byrne, C. D., & Targher, G. (2021) · Gut · doi:10.1136/gutjnl-2020-322572 · Cited by 481 · see citing works
Self-citationGut microbiome, liver immunology, and liver diseases
Wang, R., Tang, R., Li, B., Ma, X., Schnabl, B., & Tilg, H. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00592-6 · Cited by 466 · see citing works
Self-citationMantovani, A., Petracca, G., Beatrice, G., Csermely, A., Lonardo, A., Schattenberg, J. M., Tilg, H., Byrne, C. D., & Targher, G. (2022) · Gut · doi:10.1136/gutjnl-2020-323082 · Cited by 402 · see citing works
Self-citationAssociation between non-alcoholic fatty liver disease and cancer incidence rate
Kim, G., Lee, H. C., Choe, J., Kim, M.-J., Lee, M. J., Chang, H.-S., Bae, I. Y., Kim, H., An, J., Shim, J. H., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.09.012 · Cited by 330 · see citing works
Allen, A. M., Hicks, S. B., Mara, K. C., Larson, J. J., & Therneau, T. M. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.08.018 · Cited by 313 · see citing works
High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis
Wong, V. W., Wong, G. L., Tsang, S. W., Fan, T., Chu, C. W., Woo, J., Chan, A. W. H., Choi, P. C. L., Chim, A. M.-L., Lau, J. Y. W., et al. (2011) · Gut · doi:10.1136/gut.2011.237974 · Cited by 254 · see citing works
How big a problem is non-alcoholic fatty liver disease?
Anstee, Q. M., McPherson, S., & Day, C. (2011) · BMJ · doi:10.1136/bmj.d3897 · Cited by 200 · see citing works
Nonalcoholic fatty liver disease: an independent risk factor for colorectal neoplasia
Stadlmayr, A., Aigner, E. S., Steger, B., Scharinger, L., Lederer, D., Mayr, A., Straßer, M., Brunner, E., Heuberger, A., Hohla, F., et al. (2011) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2011.02377.x · Cited by 127 · see citing works
Tests for diagnosing and monitoring non-alcoholic fatty liver disease in adults
Byrne, C. D., Patel, J., Scorletti, E., & Targher, G. (2018) · BMJ · doi:10.1136/bmj.k2734 · Cited by 110 · see citing works
Self-citationMantovani, A., Dauriz, M., Byrne, C. D., Lonardo, A., Zoppini, G., Bonora, E., & Targher, G. (2018) · Metabolism · doi:10.1016/j.metabol.2018.06.004 · Cited by 110 · see citing works
Self-citationLee, Y. I., Lim, Y., & Park, H. S. (2011) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2011.06816.x · Cited by 94 · see citing works
Associations Between Nonalcoholic Fatty Liver Disease and Cancers in a Large Cohort in China
Wang, Z., Zhao, X., Chen, S., Wang, Y., Cao, L., Liao, W., Sun, Y., Wang, X., Yuan, Z., Wu, S., et al. (2020) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2020.05.009 · Cited by 90 · see citing works
Huang, K.-H., Leu, H., Wang, Y., et al. (2013) · Colorectal Disease · doi:10.1111/codi.12172 · Cited by 86 · see citing works
Liu, S., Ma, X., Zhao, J., Du, S.-X., Zhang, J., Dong, M., & Xin, Y. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-01288-6 · Cited by 82 · see citing works
Lee, J., Park, Y., Yun, J., Ahn, Y., Lee, K., Kim, D. B., Lee, J. M., Han, K., & Ko, S. (2020) · PLoS ONE · doi:10.1371/journal.pone.0226351 · Cited by 56 · see citing works
Arase, Y., Kobayashi, M., Suzuki, F., Suzuki, Y., Kawamura, Y., Akuta, N., Imai, N., Kobayashi, M., Sezaki, H., Matsumoto, N., et al. (2011) · Hepatology Research · doi:10.1111/j.1872-034x.2011.00915.x · Cited by 53 · see citing works
Hamaguchi, M., Hashimoto, Y., Obora, A., et al. (2019) · BMJ Open Gastroenterology · doi:10.1136/bmjgast-2019-000295 · Cited by 45 · see citing works
Choi, Y. J., Lee, D. H., Han, K.-D., Yoon, H., Shin, C. M., Park, Y. S., & Kim, N. (2018) · PLoS ONE · doi:10.1371/journal.pone.0201308 · Cited by 44 · see citing works
Kodama, K., Tokushige, K., Hashimoto, E., Taniai, M., & Shiratori, K. (2013) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2012.01900.x · Cited by 40 · see citing works
Chang, C., Tseng, Y., Huang, H., Shih, Y., Hsieh, T., & Lin, H. (2017) · Internal and Emergency Medicine · doi:10.1007/s11739-017-1774-x · Cited by 37 · see citing works
Relationship between Non-Alcoholic Fatty Liver Disease and Breast Cancer.
Nseir, W., Zuhair, A.-R., Tsipis, A., et al. (2017) · PubMed · Cited by 37 · see citing works
Yang, Y. J., Bang, C. S., Shin, S. P., & Baik, G. H. (2017) · PLoS ONE · doi:10.1371/journal.pone.0182014 · Cited by 36 · see citing works
Association Between Fatty Liver Index and Risk of Breast Cancer: A Nationwide Population-Based Study
Park, J. H., Choi, I. S., Han, K., Park, H., Kim, K. H., & Kim, J.-S. (2020) · Clinical Breast Cancer · doi:10.1016/j.clbc.2020.02.004 · Cited by 36 · see citing works
Ding, W., Fan, J., & Qin, J. (2015) · PubMed · Cited by 34 · see citing works
Nonalcoholic fatty liver disease is a negative risk factor for prostate cancer recurrence
Choi, W., Lee, J., Yoon, J., et al. (2014) · Endocrine Related Cancer · doi:10.1530/erc-14-0036 · Cited by 26 · see citing works
Yamamoto, K., Ikeya, T., Okuyama, S., Fukuda, K., & Kobayashi, D. (2020) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15350 · Cited by 25 · see citing works
Nonalcoholic Cirrhosis Increased Risk of Digestive Tract Malignancies
Sun, L.-M., Lin, M., Lin, C., et al. (2015) · Medicine · doi:10.1097/md.0000000000002080 · Cited by 19 · see citing works
Kim, N. H., Jung, Y. S., Park, J. H., Park, D. I., & Sohn, C. I. (2020) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2019.360 · Cited by 16 · see citing works
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Younossi, Z. M., Kalligeros, M., & Henry, L. (2025) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2024.0431 · Cited by 960 · see citing works
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Miao, L., Targher, G., Byrne, C. D., Cao, Y.-Y., & Zheng, M.-H. (2024) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2024.02.007 · Cited by 781 · see citing works
Self-citationMantovani, A., Csermely, A., Petracca, G., Beatrice, G., Corey, K. E., Simon, T. G., Byrne, C. D., & Targher, G. (2021) · The Lancet Gastroenterology & Hepatology · doi:10.1016/s2468-1253(21)00308-3 · Cited by 674 · see citing works
Self-citationKarlsen, T. H., Sheron, N., Zelber-Sagi, S., Carrieri, P., Dusheiko, G., Bugianesi, E., Pryke, R., Hutchinson, S. J., Sangro, B., Martin, N. K., et al. (2022) · The Lancet · doi:10.1016/s0140-6736(21)01701-3 · Cited by 652 · see citing works
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- Authors
- Mantovani, A., Petracca, G., Beatrice, G., Csermely, A., Tilg, H., Byrne, C. D., & Targher, G.
- Affiliations
- University of Verona (IT)
- Innsbruck Medical University (AT)
- Southampton General Hospital (GB)
- Corresponding author
- Targher, Giovanni
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2021-03-08
- Volume
- 71
- Issue
- 4
- Pages
- 778-788
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W3133993131
- Cited by
- 363
- References
- 47
- Citations by year
- 2026: 52 · 2025: 75 · 2024: 99 · 2023: 75 · 2022: 47 · 2021: 15
- FWCI
- 9.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Funders
- National Institute for Health and Care Research
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Risks and Factors
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- non-alcoholic fatty liver disease, extrahepatic cancer, cancer risk, gastrointestinal cancer, breast cancer, gynecologic cancer, lung cancer, urinary tract cancer, pancreatic cancer, colorectal cancer, esophageal cancer
- MeSH terms
- Humans, Middle Aged, Neoplasms, Risk Factors, Cohort Studies, Observational Studies as Topic, Non-alcoholic Fatty Liver Disease
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