Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma

Vikrant V. Sahasrabuddhe; Munira Z. Gunja; Barry I. Graubard; Britton Trabert; Lauren M. Schwartz; Yikyung Park; Albert R. Hollenbeck; Neal D. Freedman; Katherine A. McGlynn


J Natl Cancer Inst. 2012;104(23):1808-1814. 

In This Article

Abstract and Introduction


Background Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.

Methods We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health–AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.

Results Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.

Conclusions Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.


Liver cancer, particularly hepatocellular carcinoma (HCC), is the fifth most frequently occurring cancer worldwide and the third most common cause of cancer mortality.[1] Although liver cancer is more common in developing countries, incidence and mortality rates have been rapidly rising in the United States since the 1980s.[2,3] HCC, especially with late presentation, is characterized by aggressive growth, frequent metastases, and poor survival rates, which demands intensive research on prevention of HCC to reduce the substantial disease burden.[3–5] Major risk factors for HCC include chronic infections with hepatitis B and hepatitis C viruses, excessive alcohol consumption, certain rare metabolic disorders, and consumption of food contaminated with aflatoxin. In recent years, HCC has also been associated with obesity, diabetes, and the metabolic syndrome.[6]

Almost all HCCs occur in persons with preexisting chronic liver disease (CLD).[2] Chronic hepatic inflammation, secondary to CLD, represents an early stage in the carcinogenesis process. In general, chronic inflammation is associated with persistent cell damage and consecutive regeneration, potentially leading to changes such as fibrosis and cirrhosis and eventual hepatocellular carcinoma.[7] Inflammation-mediated events, such as the production of cytokines, reactive oxygen species, and mediators of the inflammatory pathways, such as cyclooxygenase (COX), may contribute to tumor formation.[8] It is also hypothesized that the existence of an inflammatory microenvironment increases the stochastic likelihood of neoplastic progression in a nonspecific manner, synergistically with other host and environmental risk factors.[9]

Investigating the cancer chemopreventive role of modifiable anti-inflammatory agents, especially the widely used nonsteroidal anti-inflammatory drugs (NSAIDs), is an important prevention research area.[10,11] NSAIDs, including aspirin and nonaspirin NSAIDs, are widely used as analgesic drugs, and aspirin is widely used in the chemoprevention of cardiovascular and cerebrovascular disease.[12] Observational studies and clinical trials point to the substantial protective effects of aspirin on colorectal cancer and other digestive tract cancers, and modest risk reductions for breast and prostate cancers.[10,13–18]

In vitro studies and animal experiments suggest that NSAIDs have preventive and therapeutic benefit for HCC.[19–21] However, only a few human studies have investigated the association of NSAID use with liver cancer.[22,23] Results in these studies are inconsistent, likely due to a limited number of cancer endpoints. Further, whether reduction of inflammation via NSAID use decreases the risk of developing HCC or death due to CLD is not known. To examine this question, we conducted an analysis among participants in the National Institutes of Health (NIH)–AARP (formerly the American Association of Retired Persons) Diet and Health Study, a large prospective study with comprehensive data on NSAID use.