Study: NSAID use and risk of hepatocellular carcinoma and chronic liver disease

reference

Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al. Use of nonsteroidal anti-inflammatory drugs, chronic liver disease and hepatocellular carcinoma.J Natl Cancer Inst. December 5, 2012;104(23):1808-1814.

design

Prospective observational study using a self-administered questionnaire to assess participants' demographic characteristics, diet and lifestyle. Six months later, a risk factor questionnaire that included questions about both aspirin and non-aspirin-containing nonsteroidal anti-inflammatory drugs (NSAIDs) was mailed to participants who did not self-report a history of colon, breast, or prostate cancer at baseline. Self-reported use of aspirin and non-aspirin NSAIDs was associated with diagnoses and assessed risk of hepatocellular carcinoma (HCC) and death from chronic liver disease (CLD). CLD has been observed in patients without HCC.

Participant

330,504 men and women aged 50 to 71 years participating in the National Institute for Health-American Association of Retired Persons (NIH-AARP) Nutrition and Health Study completed the risk factor questionnaire and met inclusion criteria.

Target parameters

Reducing the risk of developing HCC and reducing the risk of dying from 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 dying of CLD (RR = 0.49; 95% CI: 0.39-0.61) compared to those who did not use NSAIDs.

When limiting the use of aspirin, with or without non-aspirin NSAIDs, there was a statistically significant reduction in the risk of 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 non-users. The frequency of aspirin use (whether monthly, weekly, or daily) had no statistical impact on relative risk reduction.

Aspirin-only users showed 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 taking any type of NSAID (RR = 0.50; 95%). CI: 0.38–0.65).

Those who took non-aspirin NSAIDs (regardless of taking aspirin) did not have a lower risk of developing HCC, but did have a lower risk of dying from CLD compared to non-users. This finding was significant only in those who took non-aspirin NSAIDs monthly (RR = 0.60; 95% CI: 0.47-0.76) rather than weekly or daily. Use of non-aspirin NSAIDs did not significantly reduce the risk of HCC or death from CLD compared to those who did not use either type of NSAID.

Effects on practice

Many published studies show a link between aspirin consumption and a reduced risk of liver cancer and 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 cancer-related deaths compared to control (OR = 0.85; 95% CI: 0.76-0.96; P = 0.008). ). Six of these studies showed that daily use of low-dose aspirin reduced the risk of cancer compared to the control group (HR = 0.88; 95% CI: 0.80-0.98; P = 0.017).¹Two studies concluded that aspirin reduced cell viability and induced apoptosis in human hepatocellular carcinoma cell lines.^2.3Furthermore, daily aspirin intake reduced tumor growth in a rodent model (HepG2 xenografts).⁴

However, why does aspirin appear to be more effective at reducing the risk of HCC and death from CLD than non-aspirin NSAID use? Why did a 2012 study find that taking aspirin reduced the risk of prostate cancer, but taking prescription NSAIDs increased the risk?⁵Perhaps 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 may reduce the risk of HCC and death from CLD.

Aspirin is a dual inhibitor, meaning it does not selectively inhibit both COX-1 and COX-2. Indomethacin, naproxen and ibuprofen are also dual inhibitors. However, other NSAIDs favor COX-1 over COX-2 and vice versa. COX-1 is expressed at relatively constant levels in most tissue types, while COX-2 is induced by bacteria, cytokines and growth factors.⁶COX-2 has been found to be overexpressed in chronic hepatitis, liver cirrhosis and HCC, with expression being more pronounced in low-grade HCC than in high-grade HCC. Koga and others explain that COX-2 may play a role in the early stages of HCC but not in advanced stages.^7.8A positive correlation between COX-2 and vascular endothelial growth factor (VEGF) was also observed.⁹

The authors of this presented study stated that the questionnaire sent to subjects did not ask them to report which non-aspirin NSAIDs they were taking. The non-aspirin NSAIDs examined in this study had varying degrees of COX inhibition. The authors also pointed out the curiosity that non-aspirin NSAIDs reduced the risk of dying from CLD only when taken monthly and not weekly or daily. This may be due to a confounding factor that was not taken into account. The information presented suggests that aspirin and possibly other non-selective NSAIDs and selective COX-2 NSAIDs may reduce the risk of HCC and death from CLD.

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