In the current study, serum ferritin was not associated with all-cause, cancer, or cardiovascular mortality. As serum ferritin was positively associated with several markers of oxidative stress or inflammation in our previous study [10
], we had hypothesized the positive associations between serum ferritin and mortality. However, the results did not support this hypothesis. On the other hand, consistent with the inverse associations between %TS and markers of oxidative stress or inflammation [10
], %TS was inversely associated with all-cause and cardiovascular mortality in both men and postmenopausal women. Men also showed the inverse association between %TS and cancer mortality.
It is worthwhile to compare our results to those of Menke et al. [7
] in more detail because both studies used the dataset from NHANES III. The lack of an association with serum ferritin was also observed by Menke et al., while the inverse association between %TS and mortality found in our study differed from the lack of association that they found. In spite of using the same dataset, the results differed primarily due to different inclusion criteria of study subjects. We analyzed only the subjects aged 50 years or older while Menke et al. analyzed the subjects aged 20 years or older. The possible harmful effect of iron that has been suspected to be caused by oxidative stress and the accumulation of oxidant-damage, which can cause chronic diseases such as cancer and cardiovascular disease or death, may require a long time. Therefore, we hypothesized that it would be more appropriate to study older persons to explore the associations between markers of iron and mortality because cancer or cardiovascular mortality are lower in young people [21
]. In fact, the Menke et al. study [7
] separately reported the results of postmenopausal women and found results similar to ours, but they interpreted the findings as being due to chance or remaining confounders. Unlike our hypothesis, however, mortality was found not to be positively associated with any marker of iron, even among subjects aged 50 years or older, but only %TS was inversely associated with mortality. In fact, the previous study reporting an inverse association between %TS and all-cause mortality using the NHANES I also had subjects aged 45 years or older [6
]. At present, it is unclear why %TS inversely predicted mortality. One speculation is that moderately increased %TS may act as an antioxidant reaction through binding free iron because the generation of free radicals is caused only by catalytically active free iron.
However, one study using the data from NHANES I reported that subjects with a %TS ≥55% had an increased risk of all-cause mortality [5
]. These conflicting results may be related to levels of %TS. %TS has been criticized as a poor measure of iron stores because it reflects iron stores only when it is fully depleted (%TS <16%) or fully overloaded (%TS >60%) [23
]. From this viewpoint, only a very high %TS level can represent an iron overload and possibly increased free iron. In the current study, the cutoff points for %TS of the highest quintile in men and postmenopausal women were %TS ≥35.2% and %TS ≥30.2%, respectively. When we repeated the analyses to compare subjects with %TS ≥55% vs. < 55%, an increased risk of all-cause mortality was observed among men with an adjusted hazard ratio of 1.49 (95% CI, 1.07 to 2.08). However, risk of cancer and among subjects with %TS ≥55% (data not shown). As there were only small numbers of subjects with %TS ≥55% in this study (51 subjects in men, and 19 subjects in postmenopausal women), the association between very high %TS and mortality needs to be evaluated in future studies with a sufficient number of study subjects with %TS ≥55%.
Even though serum ferritin is used as the most reliable marker of stored iron [25
], epidemiological findings on serum ferritin in relation to the risk of cancer or cardiovascular disease are inconsistent. Some studies have reported that elevated serum ferritin was associated with a high risk of cancer or cardiovascular disease [26
] while other studies reported that there is no association between serum ferritin and cancer or cardiovascular disease [29
]. Indeed, serum ferritin seems to be complicatedly connected with catalytically active free iron. Like transferrin, ferritin can act as an anti-oxidant by sequestering unbound or free iron [31
]. However, there are studies showing that free iron may be more easily released and presumably more available for participation in redox reactions as ferritin iron content increases [31
Our study has several limitations. First of all, even though we used serum ferritin and %TS as markers of body iron stores, iron-induced oxidative stress requires catalytically active free iron. Therefore, neither of these markers may be appropriate to reflect the levels of catalytically active free iron. As it would be practically very difficult to measure catalytically active free iron in human serum, the failure to find possible positive associations of serum ferritin or %TS should not be regarded as evidence of the lack of harmfulness of iron. Another limitation was that serum ferritin and transferrin saturation may be affected by within-individual variability even though NHANES III was conducted with a well-designed protocol and quality control to minimize flaws such as within-individual variability.
In conclusion, we found that ferritin was not associated with the risk of all-cause, cancer, or cardiovascular mortality in men or postmenopausal women aged 50 years or older while %TS was inversely associated with all-cause, cancer, and cardiovascular mortality. These results appear to show that a moderately high %TS may be protective against oxidative stress. These findings may be helpful in understanding the association between body iron and chronic disease which is related to oxidative stress.