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Electronic letters published:
![[Read Comment]](/icons/misc/sectionDOWN.gif){kind=icon}
Iron and Mortality
Iron Revisited
Potential and Added Value of Secondary Data Analysis
QUESTION CONCLUSION
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Gregory J Anderson, Brisbane, Australia Head, Iron Metabolism Laboratory, The Queensland Institute of Medical Research, David M. Frazer
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Two interesting papers by Mainous and colleagues in this issue highlight the relationship between transferrin saturation, dietary iron intake and mortality. Using NHANES data, they show that higher transferrin saturation (>55%) is associated with an increased risk of all-cause mortality. These studies are consistent with other data showing a positive relationship between increased body iron and adverse health outcomes such as cancer and cardiovascular disease. While most of these studies have not used transferrin saturation as a marker of iron status, one recent study has demonstrated an increase in cancer mortality in patients with elevated transferrin saturation (Wu et al, 2004). Other support comes from a study carried out in Drosophila demonstrating an inverse relationship between the amount of iron in the diet and life span (Massie et al, 1993). The mechanism by which excess iron leads to cellular damage relate mainly to its propensity to catalyze the formation of toxic oxygen radicals via the Fenton reaction. These free radicals, and particularly the hydroxyl radical, are able to react with many cellular constituents such as lipids and proteins to disrupt metabolic processes and impair the integrity of the cells. One significant problem associated with drawing correlations between iron intake, diet and any health outcome in humans is distinguishing between effects related to iron and effects associated with other dietary constituents. For example, increased iron intake is often related to higher meat consumption. A positive relationship, therefore, would also be expected between mortality and the intake of saturated fats, which are known to increase the risk of cardiovascular disease. The studies described in these papers have their limitations. For example, the analysis is retrospective and is based on single measurements of transferrin saturation. Transferrin saturation determinations themselves require the measurement of the plasma iron concentration, which is notoriously variable. Further analysis using serum ferritin concentrations would be valuable and would provide a more complete picture of the iron status of the participants, however, this information was not available for most individuals. Overall, however, the data are consistent with the literature and suggest that diets with high iron content are potentially detrimental. Massie HR, Aiello VR, Williams TR. Inhibition of iron absorption prolongs the life span of Drosophila. Mech Ageing Dev. 1993;67:227-237. Wu T, Sempos CT, Freudenheim JL, Muti P, Smit E. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol. 2004;14:195-201. Competing interests: None declared |
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Paul R. Billings, RTP USA Physician
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Iron is an important co-factor in a variety of essential human, cell biological phenomena and biochemical processes. Its ingestion, absorption, transport, metabolism, excretion and responses to normal and variant manifestations of these events are the result of a variety of genomically encoded systems interacting with and being modified by developmental and environmental events. Transferrin is a genomically encoded human protein the saturation of which is a variable phenotype and biomarker associated with some of the systems involved with iron. The reports by Mainous and colleagues in this issue indicate that a single elevated transferring saturation of greater than 55% is associated with a comparative excess in mortality over the following 20 years when compared to those with lower percent saturation. In addition, the finding also appears associated with dietary iron intake, at least as crudely measured by a single questionnaire administered to participants once. Most of the genes involved in iron-influenced phenomenon, and the mechanisms of action that are modified by these genes, remain unknown. One locus, HFE, has been linked to the disorder hemochromatosis. Individuals with 2 variant alleles at this site have a substantially increased risk of having an elevated transferrin saturation, ferritin and liver iron content on biopsy, and for developing the multisystem manifestations and consequent secondary illnesses found in patients with hemochromatosis. The HFE gene interacts and is modified by other genomically encoded systems. How these interactions occur and the resulting phenomena that are also influenced by developmental and environmental events are largely unelucidated. Studies like these reports suggest that systems involving iron are important in the consideration of causes of human mortality and that amelioration of excess risk associated phenotypes may result from a variety of interventions. Paul R. Billings MD, PhD, FACP, FACMG is an internist, medical geneticist, and Vice President and National Director for Genetics and Genomics at Laboratory Corporation of America Holdings. Competing interests: I am an employee of Laboratory Corporation of America Holdings |
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Stephen J Zyzanski, Cleveland, OH Professor, CWRU
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This is an interesting and well-designed study that serves as an excellent example of the potential and added value that can be derived from secondary data analyses. Studies based on large cohorts, such as NHANES, bring a lot to the secondary data analysis table, e.g., statistical power, nationally representative sample, and a wide spectrum of clinical and lab data. The finding that elevated transferrin saturation is associated with increased all cause mortality has potential policy implications for both population screening for hemochromatosis and for detecting the substantial number of unrecognized cases in the general population. Elevated transferrin saturation, as a risk factor, holds promise and bears further serious investigation. Competing interests: None declared |
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NANCY.. GILBERT, CALIFORNIA, USA PHYSICIAN; V.A.
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WHILE I HAVE LONG FELT THAT SUPPLEMENTARY FE IS OVERUSED,I QUESTION YOUR CONCLUSION. I HAVE ONLY READ THE ABSTRACT. BASED ON THAT,IT WOULD SEEM THAT YOU CAN NOT CONCLUDE THAT THE DIETARY FE EXPLAINS THE INCREASED MORTALITY SINCE YOU DIDNT COMPARE TO THOSE W HIGH TRANSFERRIN SATURATION WHO HAD LOW OR NORMAL DIETARY INTAKE. LEVEL OF TRANSFERRIN FOR OTHER REASONS MAY BE PARTIALLY RESPONSIBLE. FOR EXAMPLE, AN INCREASED TRANSFERRIN LEVEL MIGHT REFLECT LIVER FUNCTION OR INFLAMMATORY STATE. PERHAPS , THIS WAS FACTORED/CONTROLLD FOR AND NOT REFLECTED IN THE ABSTRACT? Competing interests: None declared |
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