Dietary Flavonoid Intake and Thyroid Cancer Risk in the NIH–AARP Diet and Health Study

Discussion

In this large cohort, we found that thyroid cancer risk was inversely associated with flavan-3-ols, but positively associated with flavanones. Other classes of flavonoids and total flavonoids were not associated with thyroid cancer risk.

Epidemiologic evidence on flavonoids and thyroid cancer is limited. Several previous studies examined the intakes of flavonoid-rich foods, such as tea, wine, and citrus fruit, in relation to thyroid cancer, and reported inconsistent findings (16–18). In a case–control study conducted in San Francisco (11), the authors reported a 35% risk reduction in thyroid cancer comparing the highest versus lowest quintile of isoflavone intake [OR (95% CI): 0.65 (0.41, 1.00)]. In contrast, we did not observe an association between isoflavones and thyroid cancer risk in either men or women. There are several key differences between our study and the San Francisco study that may account for the different results. The San Francisco study had on average younger participants, with a mean age of 42, and a higher proportion of nonwhite women, including 35% Asian and 14% other race/ethnicity. Also, the dietary intake of isoflavones in the San Francisco study was much higher than that in our study: the 90th percentile in our study, 1.11 mg/d (unadjusted for total calorie), was only slightly above the 20th percentile in their study (1.05 mg/d). In the San Francisco study, a reduced risk of thyroid cancer was only observed in the highest quintile of isoflavone intake. Therefore, there may be a threshold effect, whereby isoflavones only protect against thyroid cancer at relatively high intakes. Moreover, food sources may also differ substantially between the 2 populations. Soy-based foods were top contributors of phytoestrogen in the San Francisco study, whereas soy consumption was low among the white Americans (19) and probably did not make significant contribution to isoflavone intake in our study.

Our finding suggest that the relationship between flavonoids and thyroid cancer might differ by flavonoid subgroups, which may reflect their diverse influence on carcinogenic pathways as demonstrated in in vitro and in vivo studies. Flavonoids have been shown to interfere with molecular targets, including mitogen-activated protein kinase, protein kinase C, phosphatidylinositol 3-kinase, NF-κB, and β-catenin, to produce antiproliferation, anti-inflammatory, and proapoptotic activities that may lead to reduced cancer risk (8). In contrast, flavonoids may have carcinogenic effects by affecting key enzymes in thyroid hormone biosynthesis and metabolism (20). Flavonoids may inhibit the activity of thyroid peroxidase (TPO), the enzyme that catalyzes thyroid hormone biosynthesis (10). As animal studies suggested, this may lower the level of thyroid hormone, which would enhance the secretion of thyroid stimulating hormone (TSH) and lead to the development of goiter (21, 22), a well-established risk factor for thyroid cancer (5). The anti-carcinogenesis and/or anti-thyroid effects may vary among different classes of flavonoids, because of differences in chemical structures that render distinct biochemical properties. Early studies have reported large variation among flavonoids in their efficacy in blocking cell proliferation (9) or inhibiting TPO activity (10). Therefore, the overall effect of each flavonoid class would be determined by the summation of both beneficial and adverse effects, which could potentially explain the different effects of different types of flavonoids on thyroid cancer observed in our study. Furthermore, this may also partially explain why generally no association was observed in our study for flavonoid-rich foods, such as tea, which contains more than one class of flavonoids with potentially opposite physiological effects.

Our study had several limitations. Self-reported nutrition intake via FFQs is prone to measurement error, although an early validation study in this population reported moderate-to-high agreement for flavonoids (23). Also, the FFQ did not specifically inquire about some flavonoid-rich foods such as soy, berries other than strawberries, peppers, and spices. Some participants may have included artificially flavored drinks in their report of fruit consumption, specifically orange and grapefruit juice consumption, leading to potentially false positive associations between thyroid cancer and orange and grapefruit juice consumption as well as thyroid cancer and consumption of flavanones, whose main dietary source in the study was orange and grapefruit juice. Although we controlled for potential risk factors for thyroid cancer in multivariable models, we could not exclude the possibility that the observed association was because residual confounding. For instance, dietary sources of flavonoids may contain other nutrients such as vitamin C, selenium, and iodine, which could independently influence thyroid cancer risk (5). Finally, our population of U.S. adults who were predominantly white may have had lower intakes of flavonoids compared with other populations, and thus our findings may have limited generalizability. Nonetheless, the large sample size and relatively long follow-up time allowed for an evaluation of effect modification by gender and other risk factors. Also, the prospective design decreased the likelihood of differential recall bias, an important limitation of case–control studies.

In conclusion, our findings suggest that dietary flavonoids may influence thyroid cancer risk, whereas different subgroups of flavonoids may have divergent effects. More studies are needed to elucidate the biological mechanisms underlying such associations.