Transferrin Saturation, Dietary Iron Intake, and Risk of Cancer

Arch G. Mainous III, PhD; James M. Gill, MD, MPH; Charles J. Everett, PhD


Ann Fam Med. 2005;3(2):131-137. 

In This Article


This study shows that in a national cohort of persons with increased transferrin saturation, a higher iron intake is associated with an increased risk of cancer and cancer mortality. This finding held true after controlling for demographic differences, such as age, sex, and race, as well as for differences in health status and comorbidities. What was particularly striking was that increased transferrin saturation was associated with a higher cancer risk only when it was combined with a high iron intake. Persons with a normal iron intake did not have higher cancer rates, even when their transferrin saturation level was high. Moreover, the results indicate that transferrin saturation in the presence of high dietary iron intake carries an increased cancer risk even at levels lower than what have previously been considered to be increased transferrin saturation. These results corroborate the results of a previous study that examined the combined effect of iron intake and transferrin saturation on overall mortality.[2] In that study, high iron intake and increased serum transferrin saturation were associated with higher mortality rates; however, as with the present study, the higher risk was found only when these 2 risk factors occurred in combination.

The results of this study may also help to explain the conflicting results of previous studies regarding transferrin saturation and cancer risk. Previous studies have suggested a weak positive association between transferrin saturation levels and the risk of cancer; significant independent risk appeared only at high levels of transferrin saturation (> 60%).[5—7] By focusing on the influence of the ingestion of dietary iron on the risk of cancer among persons with increased transferrin saturation, this study elucidates the risk of cancer associated with increased transferrin saturation. It could be that these previous studies found few and inconsistent results mainly because they examined transferrin saturation without also considering iron intake. Because most people have a low iron intake, the association between iron stores and the risk of cancer is diminished when an undifferentiated population is examined without accounting for iron intake. By stratifying by iron intake, as in this study, the effect of combined iron intake and transferrin saturation indicates a relationship that is obscured when transferrin saturation is examined without accounting for iron intake.

These results have much broader implications than studies that have focused on the risk of cancer among persons with hereditary hemochromatosis, a condition that exhibits iron overload.[16—19] Some studies investigating hemochromatosis have found an increased risk of cancer. A focus on a genetic marker for hemochromatosis as a risk indicator would seem to be too restrictive, because the prevalence of the C282Y mutation of the hemochromatosis gene is estimated at 1 in 200 in countries with a predominantly northern European origin.[20] The present results suggest that more than 7% of US adults are at risk for cancer if they consume high levels of dietary iron.

Although we can only speculate here on a potential clinical profile of persons with high transferrin saturation and high dietary iron intake, some comments might still be useful. Persons in this at-risk group were more likely to be smokers and to not be obese. Smoking and obesity have both been linked to the risk of cancer development: smoking carries an increased risk, and normal weight has a lower risk than obesity.[21,22] These characteristics may have contributed to the lack of a significant unadjusted relationship between transferrin saturation and dietary iron and cancer. When both of these variables were controlled for in the analysis, however, the transferrin saturation – dietary iron variable was significant.

Limitations of the study include the use of a 24-hour dietary history to assess iron intake. Assessment of the exposure for total dietary iron was made only once and by recall rather than objective measurement. We have no information on dietary patterns after the baseline. Even so, we attempted to obtain a stable dietary measure by excluding those who indicated that their diet in the past 24 hours was not indicative of their usual diet. Other studies have shown that middle-aged people are likely to have a stable nutrient intake for many years.[23,24] A second limitation of the study is the ascertainment of the outcome variable—in this case, cancer. The measure of a cancer event was mixed between information on death certificates and family or self-report. Differences in the source of information may have decreased the reliability and validity of the combined measure. A third limitation of this study is that although it is a longitudinal cohort design, it measures associations between variables and does not assess causality. A fourth limitation of the analysis is that we were limited by the number of individuals with high transferrin saturation and high dietary iron in whom cancer developed. Thus, although we could examine the general relationship, we were unable to examine on a population level the specific types of cancer.

In summary, persons with transferrin saturation of more than 41%, a level not previously considered to be increased, and who also ingest high amounts of dietary iron have an increased risk for cancer. Having high transferrin saturation with a normal diet did not carry increased risk. The current evidence suggests that if a large proportion of the adult US population ingests high levels of dietary iron, then they have a significantly increased risk for deleterious consequences. Although severe iron deficiency causes serious adverse health effects, these data call into question the strategy of the addition of iron to food by manufacturers. Future research might focus on the benefits of dietary changes in individuals with increased transferrin saturation.

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