ABSTRACT BACKGROUND Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for

gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited. METHODS We followed 115,036 women from the Nurses’ Health Study (1982–2012) and 49,729

men from the Health Professionals Follow-up Study (1986–2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through

biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS During up to

pancreatic cancer (95% CI: 0.96–1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90–1.95) and 1.15 for pancreatic cancer (95% CI:

0.98–1.36). CONCLUSIONS Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas. Access through your institution Buy or subscribe This is a

preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 24 print issues and online access $259.00 per

year only $10.79 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated

during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CAUSAL EFFECTS

OF GALLSTONE DISEASE ON RISK OF GASTROINTESTINAL CANCER IN CHINESE Article 26 March 2021 ASSOCIATION BETWEEN GALLBLADDER DISEASE AND COLORECTAL NEOPLASIA: A META-ANALYSIS Article Open

access 21 February 2025 SEROPOSITIVITY FOR _HELICOBACTER PYLORI_ AND HEPATOBILIARY CANCERS IN THE PLCO STUDY Article Open access 29 June 2020 DATA AVAILABILITY Restrictions apply to the

availability of these data, which were used under license for this study. Data are available [https://sites.google.com/channing.harvard.edu/cohortdocs/] with the permission of BWH and

Harvard T.H. Chan School of Public Health. REFERENCES * Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and

mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin. 2018;68:394–424. Google Scholar  * Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer J Clin.

2019;69:7–34. Google Scholar  * Petrick JL, Braunlin M, Laversanne M, Valery PC, Bray F, McGlynn KA. International trends in liver cancer incidence, overall and by histologic subtype,

1978-2007. Int J Cancer. 2016;139:1534–45. Article  CAS  PubMed  PubMed Central  Google Scholar  * Luo G, Zhang Y, Guo P, Ji H, Xiao Y, Li K. Global patterns and trends in pancreatic cancer

incidence: age, period, and birth cohort analysis. Pancreas. 2019;48:199–208. Article  PubMed  Google Scholar  * Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM.

Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913–21. Article  CAS  PubMed  Google

Scholar  * Castro FA, Koshiol J, Hsing AW, Devesa SS. Biliary tract cancer incidence in the United States-Demographic and temporal variations by anatomic site. Int J Cancer.

2013;133:1664–71. Article  CAS  PubMed  PubMed Central  Google Scholar  * Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States.

Hepatology. 2001;33:1353–7. Article  CAS  PubMed  Google Scholar  * Stinton LM, Shaffer EA. Epidemiology of gallbladder disease: cholelithiasis and cancer. Gut liver. 2012;6:172–87. Article

  PubMed  PubMed Central  Google Scholar  * Peery AF, Crockett SD, Murphy CC, Lund JL, Dellon ES, Williams JL, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in

the United States: update 2018. Gastroenterology. 2019;156:254–272 e211. Article  PubMed  Google Scholar  * Chiba T, Marusawa H, Ushijima T. Inflammation-associated cancer development in

digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology. 2012;143:550–63. Article  CAS  PubMed  Google Scholar  * Grivennikov SI, Greten FR, Karin M.

Immunity, inflammation, and cancer. Cell. 2010;140:883–99. Article  CAS  PubMed  PubMed Central  Google Scholar  * Castro J, Amigo L, Miquel JF, Galman C, Crovari F, Raddatz A, et al.

Increased activity of hepatic microsomal triglyceride transfer protein and bile acid synthesis in gallstone disease. Hepatology. 2007;45:1261–6. Article  CAS  PubMed  Google Scholar  * Wang

HH, Liu M, Clegg DJ, Portincasa P, Wang DQ. New insights into the molecular mechanisms underlying effects of estrogen on cholesterol gallstone formation. Biochimica et biophysica Acta.

2009;1791:1037–47. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang Y, Xie LF, Lin J. Gallstones and cholecystectomy in relation to risk of liver cancer. Eur J Cancer Prev.

2019;28:61–67. Article  CAS  PubMed  Google Scholar  * Liu Y, He Y, Li T, Xie L, Wang J, Qin X, et al. Risk of primary liver cancer associated with gallstones and cholecystectomy: a

meta-analysis. PLoS ONE. 2014;9:e109733. Article  CAS  PubMed  PubMed Central  Google Scholar  * Xiong J, Wang Y, Huang H, Bian J, Wang A, Long J, et al. Systematic review and meta-analysis:

cholecystectomy and the risk of cholangiocarcinoma. Oncotarget. 2017;8:59648–57. Article  PubMed  PubMed Central  Google Scholar  * Shrikhande SV, Barreto SG, Singh S, Udwadia TE, Agarwal

AK. Cholelithiasis in gallbladder cancer: coincidence, cofactor, or cause! Eur J Surgical Oncol: J Eur Soc Surgical Oncol Br Assoc Surgical Oncol. 2010;36:514–9. Article  CAS  Google Scholar

  * Fan Y, Hu J, Feng B, Wang W, Yao G, Zhai J, et al. Increased risk of pancreatic cancer related to gallstones and cholecystectomy: a systematic review and meta-analysis. Pancreas.

2016;45:503–9. Article  PubMed  Google Scholar  * Lin G, Zeng Z, Wang X, Wu Z, Wang J, Wang C, et al. Cholecystectomy and risk of pancreatic cancer: a meta-analysis of observational studies.

Cancer causes Control. 2012;23:59–67. Article  PubMed  Google Scholar  * Tavani A, Rosato V, Di Palma F, Bosetti C, Talamini R, Dal Maso L, et al. History of cholelithiasis and cancer risk

in a network of case-control studies. Ann Oncol. 2012;23:2173–8. Article  CAS  PubMed  Google Scholar  * Lagergren J, Mattsson F, El-Serag H, Nordenstedt H. Increased risk of hepatocellular

carcinoma after cholecystectomy. Br J Cancer. 2011;105:154–6. Article  CAS  PubMed  PubMed Central  Google Scholar  * Goldacre MJ, Abisgold JD, Seagroatt V, Yeates D. Cancer after

cholecystectomy: record-linkage cohort study. Br J Cancer. 2005;92:1307–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Chow WH, Johansen C, Gridley G, Mellemkjaer L, Olsen JH,

Fraumeni JF Jr. Gallstones, cholecystectomy and risk of cancers of the liver, biliary tract and pancreas. Br J Cancer. 1999;79:640–4. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Johansen C, Chow WH, Jorgensen T, Mellemkjaer L, Engholm G, Olsen JH. Risk of colorectal cancer and other cancers in patients with gall stones. Gut. 1996;39:439–43. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Vogtmann E, Shu XO, Li HL, Chow WH, Yang G, Ji BT, et al. Cholelithiasis and the risk of liver cancer: results from cohort studies of 134,546 Chinese men

and women. J Epidemiol Community Health. 2014;68:565–70. Article  PubMed  Google Scholar  * Kao WY, Hwang CY, Su CW, Chang YT, Luo JC, Hou MC, et al. Risk of hepato-biliary cancer after

cholecystectomy: a nationwide cohort study. J Gastrointest Surg. 2013;17:345–51. Article  PubMed  Google Scholar  * Chen YK, Yeh JH, Lin CL, Peng CL, Sung FCH, wang IM, et al. Cancer risk in

patients with cholelithiasis and after cholecystectomy: a nationwide cohort study. J Gastroenterol. 2014;49:923–31. Article  PubMed  Google Scholar  * Zhao X, Wang N, Sun Y, Zhu G, Wang Y,

Wang Z, et al. Screen-detected gallstone disease and risk of liver and pancreatic cancer: The Kailuan Cohort Study. Liver Int. 2020; https://doi.org/10.1111/liv.14456. * Nogueira L, Freedman

ND, Engels EA, Warren JL, Castro F, Koshiol J. Gallstones, cholecystectomy, and risk of digestive system cancers. Am J Epidemiol. 2014;179:731–9. Article  PubMed  PubMed Central  Google

Scholar  * Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a

population-based case-control study. Clin Gastroenterol Hepatol. 2007;5:1221–8. Article  PubMed  PubMed Central  Google Scholar  * Arnold LD, Patel AV, Yan Y, Jacobs EJ, Thun MJ, Calle EE,

et al. Are racial disparities in pancreatic cancer explained by smoking and overweight/obesity? Cancer Epidemiol, Biomark Prev. 2009;18:2397–405. Article  Google Scholar  * Schernhammer ES,

Michaud DS, Leitzmann MF, Giovannucci E, Colditz GA, Fuchs CS. Gallstones, cholecystectomy, and the risk for developing pancreatic cancer. Br J Cancer. 2002;86:1081–4. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Ye W, Lagergren J, Nyren O, Ekbom A. Risk of pancreatic cancer after cholecystectomy: a cohort study in Sweden. Gut. 2001;49:678–81. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Ekbom A, Yuen J, Karlsson BM, McLaughlin JK, Adami HO. Risk of pancreatic and periampullar cancer following cholecystectomy: a population-based cohort

study. Digestive Dis Sci. 1996;41:387–91. Article  CAS  Google Scholar  * Shibata A, Mack TM, Paganini-Hill A, Ross RK, Henderson BE. A prospective study of pancreatic cancer in the elderly.

Int J Cancer. 1994;58:46–49. Article  CAS  PubMed  Google Scholar  * Leitzmann MF, Rimm EB, Willett WC, Spiegelman D, Grodstein F, Stampfer MJ, et al. Recreational physical activity and the

risk of cholecystectomy in women. N. Engl J Med. 1999;341:777–84. Article  CAS  PubMed  Google Scholar  * Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Weight cycling and risk of

gallstone disease in men. Arch Intern Med. 2006;166:2369–74. Article  PubMed  Google Scholar  * Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R, Rosner B, et al. Test of the

national death index. Am J Epidemiol. 1984;119:837–9. Article  CAS  PubMed  Google Scholar  * Petrick JL, Campbell PT, Koshiol J, Thistle JE, Andreotti G, Beane-Freeman LE, et al. Tobacco,

alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project. Br J Cancer. 2018;118:1005–12. Article  PubMed  PubMed Central  Google

Scholar  * Nordenstedt H, Mattsson F, El-Serag H, Lagergren J. Gallstones and cholecystectomy in relation to risk of intra- and extrahepatic cholangiocarcinoma. Br J Cancer.

2012;106:1011–5. Article  CAS  PubMed  PubMed Central  Google Scholar  * Hsing AW, Gao YT, Han TQ, Rashid A, Sakoda LC, Wang BS, et al. Gallstones and the risk of biliary tract cancer: a

population-based study in China. Br J Cancer. 2007;97:1577–82. Article  CAS  PubMed  PubMed Central  Google Scholar  * Andreotti G, Liu E, Gao YT, Safaeian M, Rashid A, Shen MC, et al.

Medical history and the risk of biliary tract cancers in Shanghai, China: implications for a role of inflammation. Cancer Causes Control. 2011;22:1289–96. Article  PubMed  PubMed Central 

Google Scholar  * Tavoloni N, Schaffner F. The intrahepatic biliary epithelium in the guinea pig: is hepatic artery blood flow essential in maintaining its function and structure?

Hepatology. 1985;5:666–72. Article  CAS  PubMed  Google Scholar  * Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Loof L, Danielsson A, et al. Hepatic and extrahepatic malignancies in primary

sclerosing cholangitis. J Hepatol. 2002;36:321–7. Article  PubMed  Google Scholar  * Klein AP. Genetic susceptibility to pancreatic cancer. Mol carcinogenesis. 2012;51:14–24. Article  CAS 

Google Scholar  * Raimondi S, Maisonneuve P, Lohr JM, Lowenfels AB. Early onset pancreatic cancer: evidence of a major role for smoking and genetic factors. Cancer Epidemiol, Biomark Prev.

2007;16:1894–7. Article  Google Scholar  * Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Moller E, Andersen DB, et al. Bile acids are important direct and indirect regulators of

the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. 2018;11:84–95. Article  CAS  PubMed  PubMed Central  Google Scholar  * Tomkin GH, Owens D.

Obesity diabetes and the role of bile acids in metabolism. J Transl Intern Med. 2016;4:73–80. Article  Google Scholar  * Jia W, Xie G, Jia W. Bile acid-microbiota crosstalk in

gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15:111–28. Article  CAS  PubMed  Google Scholar  * Grundy SM. Treatment of hypercholesterolemia by

interference with bile acid metabolism. Arch Intern Med. 1972;130:638–48. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We would like to thank the participants

and staff of the NHS and the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY,

LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. The authors assume full responsibility for the analyses and interpretation of these data. FUNDING

The HPFS and NHS were supported by the NCI at the NIH (grant numbers UM1 CA186107, P50 CA127003, P01 CA87969 and U01 CA167552). This work was supported by NIH grants (K07 CA188126 to XZ, and

R21 CA238651 to XZ). XZ is also supported by the American Cancer Society Research Scholar Grant (RSG NEC-130476), NIH/NCI The Method to Extend Research in Time MERIT Award (R37 CA262299),

Dana-Farber Harvard Cancer Center (DF/HCC), as well as Zhu Family Center at Harvard T.H. Chan School of Public Health. The content is solely the responsibility of the authors and does not

necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA Xiao Luo, Kana Wu, Xing Liu, Edward L. Giovannucci & Xuehong

Zhang * Department of Health Statistics, School of Public Health, China Medical University, Shenyang, Liaoning, P. R. China Xiao Luo * Channing Division of Network Medicine, Department of

Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Wanshui Yang, Amit D. Joshi, Lina Jin, Lu Long, Andrew T. Chan, Edward L. Giovannucci & Xuehong Zhang *

School of Public Health, Anhui Medical University, Hefei, Anhui, P. R. China Wanshui Yang * Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General

Hospital, Boston, MA, USA Tracey G. Simon * Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Tracey G. Simon, 

Chun-Han Lo & Andrew T. Chan * Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA Tracey G. Simon, Chun-Han Lo & Andrew T. Chan *

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA Chen Yuan & Brian M. Wolpin * Department of Epidemiology and Biostatistics, Jilin

University School of Public Health, Changchun, Jilin, P. R. China Lina Jin * Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital,

Sichuan University, Sichuan, P. R. China Lu Long * Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam,

Korea Mi Na Kim * Laboratory of Clinical Epidemiology in Hepatology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea Mi Na Kim * Department of Epidemiology,

School of Public Health, Fudan University, Shanghai, P. R. China Xing Liu * Dana-Farber Cancer Institute, Boston, MA, USA Thomas A. Abrams * Department of Epidemiology, Harvard T.H. Chan

School of Public Health, Boston, MA, USA Edward L. Giovannucci Authors * Xiao Luo View author publications You can also search for this author inPubMed Google Scholar * Wanshui Yang View

author publications You can also search for this author inPubMed Google Scholar * Amit D. Joshi View author publications You can also search for this author inPubMed Google Scholar * Kana Wu

View author publications You can also search for this author inPubMed Google Scholar * Tracey G. Simon View author publications You can also search for this author inPubMed Google Scholar *

Chen Yuan View author publications You can also search for this author inPubMed Google Scholar * Lina Jin View author publications You can also search for this author inPubMed Google

Scholar * Lu Long View author publications You can also search for this author inPubMed Google Scholar * Mi Na Kim View author publications You can also search for this author inPubMed 

Google Scholar * Chun-Han Lo View author publications You can also search for this author inPubMed Google Scholar * Xing Liu View author publications You can also search for this author

inPubMed Google Scholar * Thomas A. Abrams View author publications You can also search for this author inPubMed Google Scholar * Brian M. Wolpin View author publications You can also search

for this author inPubMed Google Scholar * Andrew T. Chan View author publications You can also search for this author inPubMed Google Scholar * Edward L. Giovannucci View author

publications You can also search for this author inPubMed Google Scholar * Xuehong Zhang View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

Drs. Luo and Zhang had full access to all the data in the study and took. responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of the data: KW,

BMW, ATC, ELG and XZ. Analysis and interpretation of the data: XL. Drafting of the manuscript: XL. Critical revision of the manuscript for important intellectual content: all authors.

Statistical analysis: XL. Obtained funding: ELG and XZ. Administrative, technical or material support: KW, BMW, ATC, ELG and XZ. Study supervision: ELG and XZ. CORRESPONDING AUTHOR

Correspondence to Xuehong Zhang. ETHICS DECLARATIONS ETHICS APPROVAL AND CONSENT TO PARTICIPATE This study was approved by the Institutional Review Boards of the Brigham and Women’s Hospital

and the Harvard T.H. Chan School of Public Health and of participating registries as required. Completion of the questionnaire was considered to imply informed consent. CONSENT TO PUBLISH

Not applicable. COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims

in published maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TABLE 1 SUPPLEMENTARY TABLE 2 SUPPLEMENTARY TABLE 3 SUPPLEMENTARY TABLE 4 SUPPLEMENTARY TABLE

5-REVISED SUPPLEMENTARY TABLE 6-REVISED SUPPLEMENTARY TABLE 7-REVISED REPRODUCIBILITY CHECKLIST RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Luo, X.,

Yang, W., Joshi, A.D. _et al._ Gallstones and risk of cancers of the liver, biliary tract and pancreas: a prospective study within two U.S. cohorts. _Br J Cancer_ 127, 1069–1075 (2022).

https://doi.org/10.1038/s41416-022-01877-5 Download citation * Received: 24 August 2020 * Revised: 12 May 2022 * Accepted: 31 May 2022 * Published: 17 June 2022 * Issue Date: 05 October 2022

* DOI: https://doi.org/10.1038/s41416-022-01877-5 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link

is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative