Our study is the first effort to evaluate the relationship between serum salicylate levels and risk of recurrent adenoma. In this regard we had several notable findings. First, we are able to confirm that salicylic acid levels are detectable in human serum, in individuals with little or no reported regular intake of ASA-containing compounds. This is consistent with growing literature on dietary and endogenous sources of SA (9
). Benzoic acid is a natural constituent of plants and found in large amounts in fruits such as berries. (17
) Patterson et al have reported the conversion of benzoic acid to SA in humans (12
). One of the main metabolites of benzoic acid, hippuric acid, which is metabolized to salicylate, may be also formed endogenously in man (18
). Several factors likely contribute to serum SA levels, such as differences in dietary intakes of fruits, vegetables, benzoic acid, and red meats, variation in endogenous cellular production through metabolism of hippuric acid, or from de novo synthesis by colonic bacteria. There is evidence that the SA content of certain food dishes, such as vindaloo curry is comparable to low dose (75 mg) aspirin (11
). Other factors such as genetic factors, polymorphisms affecting enzyme activities, and the interaction of genetic, dietary and environmental factors are currently being investigated. Recent evidence suggests that chronic consumption of low dose aspirin (75 mg) reduces long-term colorectal cancer incidence and mortality (23
), Whether comparable chemoprotection can be achieved from SA derived from non-ASA sources is an important question. We found no association between serum SA and risk of adenomas or advanced adenomas on colonoscopy performed 3 years later (or in a few instances in the interval between), and no modification by SA level of the effect of calcium in reducing risk of all recurrent adenomas or advanced adenomas among non-users of ASA. The findings of a possible threshold effect when quartiles of serum SA were used in the model should be interpreted with caution, particularly since we did not see similar trend for advanced adenoma. We chose not to specifically test for the threshold effect, because post hoc nature of the test would invalidate it.
There is ample literature on ASA intake and reduction in risk of adenomas and colorectal cancer from observational studies (5
) and ASA supplementation as a chemopreventive agent for adenomas and advanced adenomas from randomized clinical trials (2
). However, in the absence of ASA use, our results suggest that serum SA levels, derived from dietary and endogenous sources may be insufficient to confer protection from risk of subsequent adenomas, or to demonstrate an interaction with calcium supplementation.
Our study has several limitations. There is a possibility of type II error, as the the risk estimates do suggest a threshold effect. Serum SA levels were not available in all 930 subjects, and the 691 subjects included in this analysis, although they did not differ in baseline or outcomes variables of interest, they may differ in other characteristics that could affect adenoma risk. We had no information regarding aspirin use specifically in the day before the blood draw, and it is possible some subjects thought to be off aspirin had actually taken the drug. We measured serum SA onetime only, although the literature supports that the measurements are reproducible (12
). We measured SA in serum only, whereas the literature reports measurement of urinary salicylate levels. Urine salicylate levels may be a more useful measure of the body’s SA exposure than serum SA because they reflect use over a longer time period. We did not have information on the timing of the blood draws in relation to the participants’ last meals, which may influence serum SA levels. Strengths of our study include large sample size, randomization of calcium supplementation and separate analysis of advanced adenomas.
Our data suggest a lack of an association of risk of adenoma occurrence with serum SA among non-users of ASA. Further research would be desirable to confirm this, ideally with prospective, long-term designs and careful correlation of serum levels with proximate measurement of ASA intake.