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Regular Aspirin Use Is Associated with a Reduced Risk of Hepatocellular Carcinoma (HCC) in Chronic Liver Disease: a Systematic Review and Meta-analysis

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Abstract

Purpose

Aspirin reduces the incidence of various gastrointestinal (GI) malignancies. This meta-analysis assessed the efficacy and safety of regular aspirin use on the incidence of hepatocellular carcinoma (HCC) in patients with chronic liver disease.

Methods

Electronic reference databases were searched for studies in patients with chronic liver disease exposed to aspirin. The primary outcome was the incidence of HCC in regular aspirin users compared to non-users. The secondary outcome was the incidence of major GI bleeding events in both groups. The propensity score (PS) and non-PS-adjusted pooled hazard ratio (HR) were calculated using random-effects models.

Results

Six observational studies with 71,211 subjects were included. The median duration of follow-up ranged from 2.7 to 7.9 years. Four studies included patients with viral hepatitis; five studies used aspirin 100 mg/day. All six studies reported the non-PS-matched HR, and there was a 54% reduction in the incidence of HCC among regular aspirin users [HR (95% CI): 0.46(0.31–0.67), p < 0.001]. Four studies reported on the PS-matched HR; this showed a 46% reduced incidence of HCC in those using aspirin [HR (95% CI): 0.54(0.38–0.79), p < 0.001]. Subgroup analysis on studies restricted to viral hepatitis (n = 4) showed a 28% reduction in HCC incidence in aspirin users [HR (95% CI): 0.72(0.64–0.80), p < 0.001]. Four studies reported the incidence of major GI bleeds, there was no significant difference between the two groups [HR (95% CI: 1.00(0.69–1.45), p = 0.90]. All outcome analysis, except the subgroup analysis, had significant inter-study heterogeneity.

Conclusion

Regular aspirin use in chronic liver disease is associated with reduced incidence of HCC without increasing the risk of major GI bleeding.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76. https://doi.org/10.1053/j.gastro.2007.04.061.

    Article  CAS  PubMed  Google Scholar 

  2. Singal AG, Lampertico P, Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol. 2020;72:250–61. https://doi.org/10.1016/j.jhep.2019.08.025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Petrick JL, McGlynn KA. The changing epidemiology of primary liver cancer. Curr Epidemiol Rep. 2019;6:104–11. https://doi.org/10.1007/s40471-019-00188-3.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Flossmann E, Rothwell PM, British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007;369:1603–13. https://doi.org/10.1016/S0140-6736(07)60747-8

  5. Bosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C. Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019. Ann Oncol. 2020;31:558–68. https://doi.org/10.1016/j.annonc.2020.02.012.

    Article  CAS  PubMed  Google Scholar 

  6. Yoshida S, Ikenaga N, Liu SB, Peng Z-W, Chung J, Sverdlov DY, et al. Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology. 2014;147:1378–92. https://doi.org/10.1053/j.gastro.2014.08.038.

    Article  CAS  PubMed  Google Scholar 

  7. Malehmir M, Pfister D, Gallage S, Szydlowska M, Inverso D, Kotsiliti E, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med. 2019;25:641–55. https://doi.org/10.1038/s41591-019-0379-5.

    Article  CAS  PubMed  Google Scholar 

  8. Lee T-Y, Hsu Y-C, Tseng H-C, Lin J-T, Wu M-S, Wu C-Y. Association of daily aspirin therapy with hepatocellular carcinoma risk in patients with chronic hepatitis C virus infection. Clin Gastroenterol Hepatol. 2020;18:2784-2792.e7. https://doi.org/10.1016/j.cgh.2020.04.036.

    Article  CAS  PubMed  Google Scholar 

  9. Lee T-Y, Hsu Y-C, Tseng H-C, Yu S-H, Lin J-T, Wu M-S, et al. Association of daily aspirin therapy with risk of hepatocellular carcinoma in patients with chronic hepatitis B. JAMA Intern Med. 2019;179:633–40. https://doi.org/10.1001/jamainternmed.2018.8342.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lee M, Chung GE, Lee J-H, Oh S, Nam JY, Chang Y, et al. Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment. Hepatology. 2017;66:1556–69. https://doi.org/10.1002/hep.29318.

    Article  CAS  PubMed  Google Scholar 

  11. Simon TG, Duberg A-S, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382:1018–28. https://doi.org/10.1056/NEJMoa1912035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shin S, Lee SH, Lee M, Kim JH, Lee W, Lee HW, et al. Aspirin and the risk of hepatocellular carcinoma development in patients with alcoholic cirrhosis. Medicine (Baltimore). 2020;99:e19008. https://doi.org/10.1097/MD.0000000000019008.

    Article  PubMed  Google Scholar 

  13. Booth A, Clarke M, Dooley G, Ghersi D, Moher D, Petticrew M, et al. The nuts and bolts of PROSPERO: an international prospective register of systematic reviews. Syst Rev. 2012;1:2. https://doi.org/10.1186/2046-4053-1-2.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Brooke BS, Schwartz TA, Pawlik TM. MOOSE reporting guidelines for meta-analyses of observational studies. JAMA Surg. 2021;156:787–8. https://doi.org/10.1001/jamasurg.2021.0522.

    Article  PubMed  Google Scholar 

  15. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2000.

  16. R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2013. http://www.R-project.org/.

  17. Du Z-Q, Zhao J-Z, Dong J, Bi J-B, Ren Y-F, Zhang J, et al. Effect of low-dose aspirin administration on long-term survival of cirrhotic patients after splenectomy: A retrospective single-center study. World J Gastroenterol. 2019;25:3798–807. https://doi.org/10.3748/wjg.v25.i28.3798.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pang Q, Jin H, Qu K, Man Z, Wang Y, Yang S, et al. The effects of nonsteroidal anti-inflammatory drugs in the incident and recurrent risk of hepatocellular carcinoma: a meta-analysis. Onco Targets Ther. 2017;10:4645–56. https://doi.org/10.2147/OTT.S143154.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Qiao Y, Yang T, Gan Y, Li W, Wang C, Gong Y, et al. Associations between aspirin use and the risk of cancers: a meta-analysis of observational studies. BMC Cancer. 2018;18:288. https://doi.org/10.1186/s12885-018-4156-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang S, Yu Y, Ryan PM, Dang M, Clark C, Kontogiannis V, et al. Association of aspirin therapy with risk of hepatocellular carcinoma: A systematic review and dose-response analysis of cohort studies with 2.5 million participants. Pharmacol Res. 2020;151:104585. https://doi.org/10.1016/j.phrs.2019.104585

  21. Simon TG, Ma Y, Ludvigsson JF, Chong DQ, Giovannucci EL, Fuchs CS, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol. 2018;4:1683–90. https://doi.org/10.1001/jamaoncol.2018.4154.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hwang IC, Chang J, Kim K, Park SM. Aspirin use and risk of hepatocellular carcinoma in a national cohort study of korean adults. Sci Rep. 2018;8:4968. https://doi.org/10.1038/s41598-018-23343-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Petrick JL, Sahasrabuddhe VV, Chan AT, Alavanja MC, Beane-Freeman LE, Buring JE, et al. NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project. Cancer Prev Res (Phila Pa). 2015;8:1156–62. https://doi.org/10.1158/1940-6207.CAPR-15-0126.

    Article  CAS  Google Scholar 

  24. Tsoi KK, Ho JM, Chan FC, Sung JJ. Long-term use of low-dose aspirin for cancer prevention: A 10-year population cohort study in Hong Kong. Int J Cancer. 2019;145:267–73. https://doi.org/10.1002/ijc.32083.

    Article  CAS  PubMed  Google Scholar 

  25. Tanwar S, Rhodes F, Srivastava A, Trembling PM, Rosenberg WM. Inflammation and fibrosis in chronic liver diseases including non-alcoholic fatty liver disease and hepatitis C. World J Gastroenterol. 2020;26:109–33. https://doi.org/10.3748/wjg.v26.i2.109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ogunwobi OO, Liu C. Hepatocyte growth factor upregulation promotes carcinogenesis and epithelial-mesenchymal transition in hepatocellular carcinoma via Akt and COX-2 pathways. Clin Exp Metastasis. 2011;28:721–31. https://doi.org/10.1007/s10585-011-9404-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology. 1999;29:688–96. https://doi.org/10.1002/hep.510290355.

    Article  CAS  PubMed  Google Scholar 

  28. He J, Gerstenlauer M, Chan LK, Leithäuser F, Yeh MM, Wirth T, et al. Block of NF-kB signaling accelerates MYC-driven hepatocellular carcinogenesis and modifies the tumor phenotype towards combined hepatocellular cholangiocarcinoma. Cancer Lett. 2019;458:113–22. https://doi.org/10.1016/j.canlet.2019.05.023.

    Article  CAS  PubMed  Google Scholar 

  29. Arsura M, Cavin LG. Nuclear factor-kappaB and liver carcinogenesis. Cancer Lett. 2005;229:157–69. https://doi.org/10.1016/j.canlet.2005.07.008.

    Article  CAS  PubMed  Google Scholar 

  30. Wang SS, Chen YH, Chen N, Wang LJ, Chen DX, Weng HL, et al. Hydrogen sulfide promotes autophagy of hepatocellular carcinoma cells through the PI3K/Akt/mTOR signaling pathway. Cell Death Dis. 2017;8:e2688. https://doi.org/10.1038/cddis.2017.18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bhat M, Sonenberg N, Gores GJ. The mTOR pathway in hepatic malignancies. Hepatology. 2013;58:810–8. https://doi.org/10.1002/hep.26323.

    Article  CAS  PubMed  Google Scholar 

  32. Huang Z, Fang W, Liu W, Wang L, Liu B, Liu S, et al. Aspirin induces Beclin-1-dependent autophagy of human hepatocellular carcinoma cell. Eur J Pharmacol. 2018;823:58–64. https://doi.org/10.1016/j.ejphar.2018.01.031.

    Article  CAS  PubMed  Google Scholar 

  33. Mandrekar P, Szabo G. Signalling pathways in alcohol-induced liver inflammation. J Hepatol. 2009;50:1258–66. https://doi.org/10.1016/j.jhep.2009.03.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Witters P, Freson K, Verslype C, Peerlinck K, Hoylaerts M, Nevens F, et al. Review article: blood platelet number and function in chronic liver disease and cirrhosis. Aliment Pharmacol Ther. 2008;27:1017–29. https://doi.org/10.1111/j.1365-2036.2008.03674.x.

    Article  CAS  PubMed  Google Scholar 

  35. Muciño-Bermejo J, Carrillo-Esper R, Uribe M, Méndez-Sánchez N. Coagulation abnormalities in the cirrhotic patient. Ann Hepatol. 2013;12:713–24. https://doi.org/10.1016/S1665-2681(19)31312-2.

    Article  PubMed  Google Scholar 

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Author information

Author notes

  1. Jin Lin Tan and Sandeep Sidhu-Brar are co-first authors.

Authors and Affiliations

  1. Division of Medicine, Lyell McEwin Hospital, Haydown Road, Elizabeth Vale, SA, 5112, Australia

    Jin Lin Tan & Sandeep Sidhu-Brar

  2. Flinders Centre for Epidemiology and Biostatistics, Flinders University, Sturt Rd, Bedford Park, SA, 5042, Australia

    Richard Woodman

  3. Department of Gastroenterology/Hepatology, Lyell McEwin Hospital, Haydown Road, Elizabeth Vale, SA, 5112, Australia

    Mohamed Asif Chinnaratha

  4. Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia

    Mohamed Asif Chinnaratha

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Contributions

All authors contributed to the study conception and design. Systematic review and data collection were performed by Jin Lin Tan and Sandeep Sidhu-Brar with supervision by Mohamed Asif Chinnaratha. The first draft of the manuscript was written by Jin Lin Tan, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jin Lin Tan.

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Tan, J.L., Sidhu-Brar, S., Woodman, R. et al. Regular Aspirin Use Is Associated with a Reduced Risk of Hepatocellular Carcinoma (HCC) in Chronic Liver Disease: a Systematic Review and Meta-analysis. J Gastrointest Canc 54, 325–331 (2023). https://doi.org/10.1007/s12029-022-00842-y

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