The association of biomarkers of iron status with mortality in US adults

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Abstract

Background and Aims

Elevated iron biomarkers are associated with diabetes and other cardiometabolic abnormalities in the general population. It is unclear whether they are associated with an increased risk of all-cause or cause-specific mortality. The purpose of the current analysis was to evaluate the association of ferritin and transferrin saturation levels with all-cause, cardiovascular, and cancer mortality in the general US adult population.

Methods and Results

A prospective cohort study was conducted with 12,258 adults participating in the Third National Health and Nutrition Examination Survey (NHANES III), a nationally representative sample of the US population. Study participants were recruited in 1988–1994 and followed through December 31, 2006 for all-cause, cardiovascular disease, and cancer mortality. The multivariable-adjusted hazard ratios (95% confidence interval) for all-cause mortality comparing the fourth versus the second quartiles of ferritin and transferrin saturation were 1.09 (0.82–1.44; p-trend across quartiles = 0.92) and 1.08 (0.82–1.43; p-trend across quartiles = 0.62), respectively, for men, 1.43 (0.63–3.23; p-trend across quartiles = 0.31) and 1.48 (0.70–3.11; p-trend across quartiles = 0.60), respectively, for premenopausal women, and 1.03 (0.79–1.34; p-trend across quartiles = 0.95) and 1.17 (0.92–1.49; p-trend across quartiles = 0.63), respectively, for postmenopausal women. Quartile of ferritin and transferrin saturation also showed no association between biomarkers of iron status and mortality.

Conclusions

In a large nationally representative sample of US adults, within the spectrum of normal iron metabolism, ferritin and transferrin saturation were not associated with risk of mortality among people who were not taking iron supplements and did not have a baseline history of cardiovascular disease or cancer.

Introduction

Iron has a catalytic role in the generation of highly reactive oxygen species, such as hydroxyl radical, through Fenton and Haber–Weiss reactions [1]. As a result, elevated iron levels, below the levels found in genetic hemochromatosis, may have a role in a variety of disease processes. Body iron stores can be estimated using serum ferritin and previous studies have found that elevated ferritin levels, below the levels found in genetic hemochromatosis, are associated with diabetes, metabolic syndrome, hypertension, dyslipidemia, elevated fasting insulin and glucose, and abdominal adiposity [2], [3], [4]. The association of ferritin and other biomarkers of iron metabolism with mortality, however, remains controversial. Few studies are available investigating the association between iron biomarkers and mortality, and those studies are particularly limited in their ability to investigate this association in non-white populations [5], [6], [7].

The purpose of the current analysis was to evaluate the association of ferritin and transferrin saturation levels with all-cause, cardiovascular, and cancer mortality in the general US adult population. To do so, we analyzed data from the Third National Health and Nutrition Examination Survey (NHANES III) Mortality Study, a cohort study based on a nationally representative sample of US adults with ferritin and transferrin saturation measured in 1988–1994 and followed for mortality through December 31, 2006.

Section snippets

Study population

NHANES III was a stratified, multistage probability survey designed to be representative of the civilian non-institutionalized US population [8]. Overall, 18,825 adults ≥20 years of age completed the NHANES III interview and examination. We excluded 859 participants who were taking iron supplements, 227 pregnant women, 34 participants with likely hemochromatosis (serum iron >190 ug/dL for men and >175 ug/dL for women, serum ferritin >300 ng/mL for men and >200 ng/mL for women, and transferrin

Results

The median (interquartile range) of ferritin and transferrin saturation was 142 ng/mL (87–222 ng/mL) and 28% (21–35%), respectively, for men, 35 ng/mL (18–60 ng/mL) and 22% (15–31%), respectively, for premenopausal women, and 90 ng/mL (51–158 ng/mL) and 23% (18–29%), respectively, for postmenopausal women. Men, premenopausal women, and postmenopausal women with higher ferritin levels were more likely to be non-Hispanic black (except premenopausal women) and had a higher body mass index and

Discussion

In this large, population-based prospective study, higher levels of ferritin and transferrin saturation were not associated with an increased risk of mortality among NHANES III participants without a baseline history of cardiovascular disease or cancer. Among postmenopausal women, lower levels of transferrin saturation were associated with a higher risk of mortality. This finding was not observed in men or premenopausal women, and we cannot discard the possibility that this is either a chance

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