NSAID Use and Risk of Hepatocellular Carcinoma and Chronic Liver Disease

Study assesses risk factors for chronic diseases with the use of NSAIDs

By Laura Perkowski, ND

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Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst. 2012 Dec 5;104(23):1808-1814.


Prospective observational study that employed a self-administered questionnaire to assess participants’ demographic, diet, and lifestyle characteristics. Six months later, a risk factors questionnaire that included questions regarding both aspirin and non-aspirin non-steroidal anti-inflammatory drug (NSAID) use was sent to participants who did not have a self-reported history of colon, breast, or prostate cancer at baseline. Self-reported aspirin and non-aspirin NSAID use was linked with diagnoses, and risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) was assessed. CLD was tracked in those without HCC.


330,504 men and women aged 50–71 years who were part of the National Institute for Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study filled out the risk factors questionnaire and met the criteria for inclusion.

Outcome Measures

Risk reduction of developing HCC, risk reduction of death due to CLD.

Key Findings

Those who used any type of NSAID reduced their risk of developing HCC (RR=0.63; 95% CI: 0.46–0.87) and reduced their risk of death due to CLD (RR=0.49; 95% CI: 0.39–0.61) compared to those who did not use any NSAIDs.

When limited to the use of aspirin, with or without non-aspirin NSAIDs, there was a statistically significant risk reduction in HCC development (RR=0.59; 95% CI: 0.45–0.77) and mortality from CLD (RR=0.55; 95% CI: 0.45–0.67) compared to nonusers. Frequency of aspirin use (whether monthly, weekly, or daily) did not statistically affect relative risk reductions.

Aspirin-only users demonstrated the greatest risk reduction in HCC development (RR=0.51; 95% CI: 0.35–0.75) and a similar risk reduction in mortality from CLD compared to those who used any type of NSAID (RR=0.50; 95% CI: 0.38–0.65).

Those who used non-aspirin NSAIDs (regardless of aspirin use) did not have a reduced risk of developing HCC but did have a reduced risk of death from CLD compared to nonusers. This finding was only significant in those who used non-aspirin NSAIDs monthly (RR=0.60; 95% CI: 0.47–0.76), rather than weekly or daily. Use of non-aspirin only NSAIDs did not significantly reduce risk of HCC or death from CLD compared to those who used neither type of NSAID.

Practice Implications

Many published studies demonstrate a correlation between aspirin use and decreased risk of liver cancer, as well as cancer in general. A meta-analysis of 51 randomized controlled trials, 34 of which included information on cancer deaths, found that daily aspirin reduced the number of deaths due to cancer compared to control (OR=0.85; 95% CI: 0.76–0.96; P=0.008). Six of these trials showed that daily low-dose aspirin vs. control reduced risk of cancer (HR=0.88; 95% CI: 0.80–0.98; P=0.017).1 Two studies concluded that aspirin reduced cell viability and induced apoptosis in human hepatocellular carcinoma cell lines.2,3 In addition, daily aspirin decreased tumor growth in a rodent model (HepG2 xenografts).4

Why, though, does aspirin appear to be more effective at reducing the risk of HCC and death from CLD compared to non-aspirin NSAID use? Why did a 2012 study find that aspirin use decreased prostate cancer risk but prescription NSAID-use increased risk?5 Perhaps this difference can be explained by looking at the mechanism of action of these drugs.

Aspirin, and possibly other non-selective NSAIDs and selective COX-2 NSAIDs, can decrease the risk of HCC and death from CLD.

Aspirin is a dual inhibitor, meaning it non-selectively inhibits both COX-1 and COX-2. Indomethacin, naproxen, and ibuprofen are also dual inhibitors. Other NSAIDs, however, favor COX-1 over COX-2 and vice versa. COX-1 is expressed in most tissue types at relatively constant levels, while COX-2 is induced by bacteria, cytokines, and growth factors.6 COX-2 has been found to be over-expressed in chronic hepatitis, liver cirrhosis, and HCC, with greater expression occurring in low-grade compared to high-grade HCC. Koga and al explain that COX-2 may play a role in the early stages of HCC but not in advanced stages.7,8 A positive correlation between COX-2 and vascular endothelial growth factor (VEGF) has also been observed.9

The authors of this featured study stated that the questionnaire sent to subjects did not ask them to specify which non-aspirin NSAIDs they were taking. The non-aspirin NSAIDs that were assessed in this study had varying degrees of COX inhibition. The authors also pointed out the oddity that non-aspirin NSAIDs reduced the risk of death from CLD only when taken monthly, not weekly or daily. This may reflect a confounder that was not taken into consideration. The information presented suggests that aspirin, and possibly other non-selective NSAIDs and selective COX-2 NSAIDs, can decrease the risk of HCC and death from CLD.

For more research involving integrative oncology, click here.

About the Author

Laura Perkowski, ND, received her naturopathic doctorate from Bastyr University and has an undergraduate degree in physiology from Michigan State University’s Honors College. While at Bastyr, she interned at the Bastyr Integrative Oncology Research Center and studied with some of the top naturopathic oncologists in the Pacific Northwest. Previously, Perkowski served as both a writer and editor for an online natural health magazine. Perkowski provides naturopathic care to patients at Beaumont Hospital’s integrative medicine clinic in Michigan with a focus on oncology, gastrointestinal health, and autoimmune diseases.


1. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379(9826):1602-1612.

2. Hossain MA, Kim DH, Jang JY, et al. Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model. Int J Oncol. 2012. 40:1298-1304.

3. Raza H, John A, Benedict S. Acetylsalicylic acid-induced oxidative stress, cell cycle arrest, apoptosis and mitochondrial dysfunction in human hepatoma HepG2 cells. Eur J Pharmacol. 2011;668:15-24.

4. Hossain MA, Kim DH, Jang JY, et al. Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model. Int J Oncol. 2012. 40:1298-1304.

5. Veitonmaki T, Tammela TLJ, Auvinen A, Murtola TJ. Use of aspirin, but not other non-steroidal anti-inflammatory drugs is associated with decreased prostate cancer risk at the population level. Eur J Can. October 2012. Epub ahead of print.

6. Cervello M, Montalto G. Cyclooxygenases in hepatocellular carcinoma. World J Gastroenterol. 2006;12(32):5113-5121.

7. Koga H, Sakisaka S, Ohishi M, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor differentiation. Hepatology. 1999;29(3):688-696.

8. Kwon SH, Jeong SW, Jang JY, et al. Cyclooxygenase-2 and vascular endothelial growth factor in chronic hepatitis, cirrhosis and hepatocellular carcinoma. Clin Mol Hepatol. 2012;18:287-294.

9. Ibid.