Background Recent studies have suggested an association betweenhigher body iron stores and the risk of coronary heart disease.To assess these findings, we examined the association betweentransferrin saturation and the risk of coronary heart disease,myocardial infarction, overall mortality, and mortality fromcardiovascular causes in a large population.
Methods We studied a total of 4518 men and women from the firstNational Health and Nutrition Examination Survey EpidemiologicFollow-up Study, using a multivariate Cox proportional-hazardsmodel. Base-line data were collected from 1971 to 1974, withfollow-up through 1987. Transferrin saturation (serum iron concentrationdivided by total iron-binding capacity) was used as a measureof the amount of circulating iron available to tissues.
Results The risk of coronary heart disease was not related totransferrin-saturation levels in white men or women. Estimatesof the relative risk of coronary heart disease for the fifthquintile of transferrin saturation as compared with the firstquintile were 0.72 (95 percent confidence interval, 0.51 to1.00) for men and 0.85 (95 percent confidence interval, 0.60to 1.21) for women. The results were similar for myocardialinfarction. A significant inverse association with transferrinsaturation was found for overall mortality and for mortalityfrom cardiovascular causes in white men and women. Transferrinsaturation was not associated with any of the clinical outcomesin blacks, possibly owing to the small sample.
Conclusions Higher transferrin-saturation levels were not associatedwith an increased risk of coronary heart disease or myocardialinfarction. On the contrary, the results indicate that theremay be an inverse association of iron stores with overall mortalityand with mortality from cardiovascular causes. .
A possible association between body iron status and the riskof coronary heart disease was bolstered by recent findings froma three-year Finnish study relating increased levels of bothserum ferritin and dietary iron to an increased risk of myocardialinfarction in men1. Previous support for this hypothesis wasless direct and consisted of weak correlations observed betweenhemoglobin levels or the hematocrit and the risk of coronaryheart disease2,3,4 or observations about differences in ironstatus and coronary heart disease either between countries5or in men as compared with women6. Further evaluation of thesefindings is needed because, coupled with observations suggestinga relation between iron status and the risk of cancer,7,8,9,10these findings could affect decisions about the iron-fortificationpolicies used in many countries to prevent iron deficiency.In addition, a possible association between iron status anddeath from all causes needs assessment before any changes iniron-fortification policies or dietary recommendations are contemplated.Accordingly, we used data from the first National Health andNutrition Examination Survey (NHANES I) Epidemiologic Follow-upStudy (NHEFS) to examine the putative relation between ironstatus, as measured by the serum transferrin saturation, andthe risk of coronary heart disease and overall mortality amongblacks and whites.
Methods
Study Design
The base-line data on the NHEFS cohort were collected from 1971to 1974 as part of NHANES I11,12,13,14,15. The cohort consistedof 14,407 adults who were 25 to 74 years of age at the timeof NHANES I. Follow-up was conducted from 1982 to 1984, againin 1986 (surveying those 55 years of age or older at base line),and again in 1987 (surveying the entire cohort). Subjects whowere institutionalized after the data collection at base linecontinued to be included in NHEFS. At each follow-up, the subjects(or their proxies) were interviewed again, death certificateswere obtained for subjects who had died, and hospital and nursinghome records were obtained for overnight stays that had occurredsince the most recent contact. Informed consent was obtainedfrom the study subjects, and the protocols for NHANES I andNHEFS were reviewed and approved by the appropriate institutionalreview boards.
Case Definition
Death certificates and hospital-discharge diagnoses were codedwith use of the system described in the International Classificationof Diseases, 9th Revision (ICD-9): cardiovascular diseases weredenoted by codes 390 to 448, coronary heart disease by codes410 to 414, and myocardial infarction by code 410. Incidentcases of coronary heart disease were defined on the basis ofthe death certificate (indicating the underlying or an associatedcause of death) or by the assignment of a diagnosis code from410 to 414 at hospital discharge. Underlying causes of deathwere used in the analyses of cause-specific mortality.
Study Variables
The biochemical indicators of iron status used in this study,measured at base line, included the serum transferrin saturation,the serum iron concentration, the serum total iron-binding capacity,16,17,18the hemoglobin concentration, and the hematocrit. Hemoglobin,the hematocrit, and the erythrocyte sedimentation rate19 weremeasured during the base-line examination in a mobile examinationcenter. Assays for the other indicators of iron status and otherserum covariables (albumin20 and total cholesterol21,22,23)were performed by the Centers for Disease Control and Prevention.The details of the procedures used for blood collection andspecimen storage, the assays for each indicator, and the proceduresfor ensuring quality control and obtaining informed consenthave been published elsewhere11,24. Transferrin saturation wascalculated by dividing the serum iron concentration by the totaliron-binding capacity. Serum ferritin levels were not measuredin NHANES I.
Blood pressure was measured by a physician at base line withthe subject seated25. The blood collection was categorized asoccurring before noon or after noon. The determination of diabetesstatus was based on the responses to questions about the subject'smedical history at base line. Smoking status at base line wasdetermined from a questionnaire completed by about half thesubjects; for the remaining subjects, this information was obtainedretrospectively at the first follow-up visit26,27. Dietary ironintake from food was assessed at base line and was based onthe subject's recall of foods eaten during a single 24-hourperiod. Educational level was based on the number of years ofschool completed.
Study Subjects
All black and white subjects 45 to 74 years of age for whomthere were no missing data were included in this analysis (Table 1).Excluded were 103 subjects lost to follow-up (1.6 percent)and 1097 subjects for whom any data from the base-line examinationwere missing. Also excluded from the analyses of coronary heartdisease were 78 subjects who had no follow-up interview or forwhom base-line data on a history of heart disease were missing,and 719 subjects who reported a history of heart disease atbase line (i.e., those who had ever been told by a doctor thatthey had had a heart attack or heart failure or who had usedany medicine, drugs, or pills for a weak heart during the sixmonths before base line). In addition, all deaths or incidentevents within the first five years of follow-up were excludedin order to minimize the effects of preexisting disease on theresults. There were 4518 subjects remaining in the study sample.
Table 1. Events, Persons at Risk in the Cohort, and Selected Base-Line Measurements, According to Race and Sex.
Statistical Analysis
The Cox proportional-hazards model28,29 was used to examinethe relation of iron status to the risk of an event accordingto race and sex in separate age-adjusted and multivariate models.The average follow-up period was 14.6 years. Measures of ironstatus were expressed in the models as approximate quintiles(for whites) or thirds (for blacks). The lowest group was usedas the reference category in all the analyses. Unless otherwisenoted, the multivariate models were adjusted for the followingbase-line variables: age, history of diabetes, systolic bloodpressure, smoking status, serum total cholesterol, serum albumin,and level of education. In preliminary analyses (data not shown),further adjustment for the sedimentation rate and the time ofblood collection did not affect the results30,31. Tests of thesignificance of trends across categories of transferrin saturationwere conducted in the multivariate models by treating the quintilesas ordered categories scaled to the median for each quintile32.
Failure to use weights in the sample or to account for the complexsampling design in NHANES I may produce biased results33,34.To assess the effect of weighting on the results, the Cox modelswere calculated both weighted35 and unweighted36. The weightedand unweighted models yielded consistent results. Therefore,only unweighted Cox models, which assume a simple random samplingand tend to have smaller variances, are presented here.
In parallel analyses no association was found between hemoglobinlevels, the hematocrit, or dietary iron intake and any of theincidence or mortality outcomes. Only the results for transferrinsaturation are shown here.
Results
Descriptive Data
The number of events, the population at risk, and the mean valuesfor age, transferrin saturation, and selected other variablesare shown in Table 1 according to race and sex. There were toofew cases of myocardial infarction or death from coronary heartdisease among blacks to permit examining any association withtransferrin saturation. Levels of transferrin saturation, aswell as of its component measures, were higher in men than inwomen and higher in whites than in blacks.
Coronary Heart Disease
The multivariate adjusted estimates of the relative risk ofcoronary heart disease according to quintile of transferrinsaturation are shown in Figure 1. The risk of coronary heartdisease was not related to the level of transferrin saturationin white men and women. The same was true for the risk of myocardialinfarction (Figure 2). The estimates of relative risk abovethe first quintile tended to be lower than 1, suggesting thathigher levels of transferrin saturation may be protective. Therewas, however, no apparent dose-response relation. Similar resultswere obtained when the risk of death from myocardial infarctionor coronary heart disease was evaluated (data not shown). Norwas there a relation between the risk of incident coronary heartdisease and the transferrin saturation among black men and women(Table 2). Because of the relatively small numbers of events,the estimates of relative risk for blacks had wide confidencelimits.
Figure 1. Multivariate Adjusted Risk of Coronary Heart Disease, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.
Coronary heart disease was as defined by ICD-9 codes 410 to 414. All events within the first five years of follow-up were excluded. Values are adjusted for base-line age, history of diabetes, smoking status, serum total cholesterol, serum albumin, systolic blood pressure, and level of education. Bars denote 95 percent confidence intervals. Data were obtained from NHANES I and NHEFS11,12,13,14,15. P values are for the linear test for trend.
Figure 2. Multivariate Adjusted Risk of Myocardial Infarction, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.
Myocardial infarction was as defined by ICD-9 code 410. All events within the first five years of follow-up were excluded. Values are adjusted for base-line age, history of diabetes, smoking status, serum total cholesterol, serum albumin, systolic blood pressure, and level of education. Bars denote 95 percent confidence intervals. Data were obtained from NHANES I and NHEFS11,12,13,14,15. P values are for the linear test for trend.
Table 2. Multivariate Adjusted Risk of Coronary Heart Disease and Death Either from Cardiovascular Causes or from All Causes, According to Transferrin Saturation, among Black Men and Women 45 to 74 Years of Age at Base Line.
Death from Cardiovascular Causes
For white women, there was a significant inverse linear trendindicating a decreased risk of death from cardiovascular causeswith an increasing level of transferrin saturation (Figure 3).The relative-risk estimates in the two highest quintiles werealso significantly lower than 1. No association was found betweendeath from cardiovascular causes and transferrin saturationin either white men (Figure 3) or black men and women (Table 2).
Figure 3. Multivariate Adjusted Risk of Death from Cardiovascular Disease, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.
Cardiovascular disease was as defined by ICD-9 codes 390 to 448. All events within the first five years of follow-up were excluded. Values are adjusted for base-line age, history of diabetes, smoking status, serum total cholesterol, serum albumin, systolic blood pressure, and level of education. Bars denote 95 percent confidence intervals. Data were obtained from NHANES I and NHEFS11,12,13,14,15. P values are for the linear test for trend.
Mortality from All Causes
Among white women, there was also a significant inverse trend(P = 0.013) between mortality from all causes and the levelof transferrin saturation (Figure 4). Among white men, all therelative-risk estimates were lower than 1, with no apparentdose-response relation; only the estimate for the fifth quintilewas statistically significant (P = 0.008).
Figure 4. Multivariate Adjusted Risk of Death from All Causes, According to Serum Transferrin Saturation, in White Men and Women 45 to 74 Years of Age at Base Line.
All events within the first five years of follow-up were excluded. Values are adjusted for base-line age, history of diabetes, smoking status, serum total cholesterol, serum albumin, systolic blood pressure, and level of education. Bars denote 95 percent confidence intervals. Data were obtained from NHANES I and NHEFS11,12,13,14,15. P values are for the linear test for trend.
When deaths during the first five years of follow-up were included,however, all the estimates of relative risk for white men weresignificantly lower than 1. The estimates themselves were unaffected:for the second through the fifth quintiles, they were 0.81,0.74, 0.79, and 0.70, respectively (P = 0.12). Similarly, theestimates of relative risk for the fourth and fifth quintilesamong white women were now statistically significant, whereasthe estimates were unaffected. When all deaths were included,the estimates for white women for quintiles two through fivewere 1.03, 0.82, 0.63, and 0.72, respectively (P = 0.001).
No association was found between mortality from all causes andtransferrin saturation among black men and women (Table 2).
Discussion
Our results do not support the hypothesis that body iron stores,as measured by serum transferrin saturation, are related tothe risk of coronary heart disease (including myocardial infarction).Nor do they support a direct association between the level oftransferrin saturation and the risk of dying from any causeor from cardiovascular disease. In fact, the results of thisstudy would seem to suggest an inverse association between serumtransferrin saturation and the risk of dying from any causeor from cardiovascular disease.
The assessment of whether iron status is related to the riskof disease or death is complicated by several factors: bodyiron can be divided metabolically into functional iron and storageiron; currently available biochemical indicators of iron statusreflect different aspects of these two categories of iron metabolism;and each of these indicators is also affected by non-iron-relatedfactors37,38,39. Given these circumstances, the strongest evidencefor a relation between iron and coronary heart disease wouldcome from a consistent finding of more than one indicator ofiron status. To date, this has not been the case. For example,the evidence of an association based on the serum ferritin level,which is a better indicator of iron stores than transferrinsaturation,40 has been conflicting. Salonen et al.1 reportedan increased risk of acute myocardial infarction among men witha serum ferritin level greater than 200 µg per liter,whereas preliminary results reported by Stampfer et al.41 didnot support an increase in this risk. The former study was limitedby both a small number of subjects and a short follow-up period.
Hemoglobin levels and the hematocrit are measures of the oxygen-carryingcapacity of blood and of viscosity. Evidence of a relation betweeniron status and the risk of coronary heart disease that is basedon either measure is not consistent. Many prospective studies,1,42,43,44,45,46,47,48,49,50including our own, have not found one or the other to be relatedto the risk of coronary heart disease, in contrast to a numberof other prospective,2,51,52,53,54,55 cross-sectional,56,57,58,59or case-control4 studies, especially among women.
Salonen et al.1 also reported dietary iron intake to be positivelyassociated with an increased risk of myocardial infarction.In contrast, Rimm et al.60 reported no association between dietaryiron intake and the risk of coronary heart disease. In anotheranalysis of NHEFS, Cooper and Liao61 found, as we did, no associationbetween dietary iron intake and the risk of coronary heart disease.
In evaluating the relation between iron status and the riskof coronary heart disease, it is also important to rule outnon-iron-related factors that can influence biochemical measuresof iron status. Two important factors of this type are inflammationand diurnal variation. Both influence indicators of iron statusin different ways. For example, all the iron indicators usedto relate iron status to coronary heart disease are affectedby inflammation, but serum ferritin reacts in the opposite directionfrom the others -- i.e., it increases in inflammatory states,whereas transferrin saturation, hemoglobin, and hematocrit decrease.This is due to a blocked release of iron from macrophages, sothat tissue levels increase while circulating levels decrease62,63.As a result, an association between coronary heart disease andhigher serum ferritin levels or the lack of an association betweencoronary heart disease and higher transferrin-saturation levels,hemoglobin levels, or hematocrit could be confounded by inflammation.In addition, unlike ferritin, transferrin saturation shows substantialdiurnal variation37,38,39,40. In the present study, however,adjusting for the erythrocyte sedimentation rate, a measureof inflammation, and for the time of drawing blood (before noonvs. after noon) did not affect the results.
Free-radical oxidation is hypothesized to be the basis for therelation between iron status and the risk of coronary heartdisease1. In that model, iron is considered to be a catalystfor the formation of tissue-damaging free radicals. Our resultsdo not support the hypothesis that iron status is directly relatedto the risk of coronary heart disease.
The limitations of the present study include a possible biasarising from loss to follow-up with regard to the incidenceof coronary heart disease due to missing hospital data. WhenMedicare hospitalization data were used as a gold standard,however, it was found that approximately 80 percent of hospitalstays for coronary heart disease within the three years beforethe first period of follow-up that were identified in the Medicarefiles or NHEFS were also identified by the NHEFS hospital records(unpublished data). A further source of potential bias was misclassificationresulting from the inaccuracy of the diagnoses coded on thedeath certificate or the hospital record. But these biases seemunlikely, given the consistency of the results between the mortalityand incidence of coronary heart disease and myocardial infarction,and for mortality from all causes and from cardiovascular disease.It was not possible to control for high-density lipoproteincholesterol in the multivariate models, since it was not measuredat base line.
In summary, in an analysis of a national cohort we found noevidence supporting a direct association between iron statusand coronary heart disease. On the contrary, we found a possibleinverse association between transferrin saturation and the riskof coronary heart disease and also the risk of death from anycause.
Supported by the National Center for Health Statistics; theNational Institute on Aging; the National Cancer Institute;the National Center for Chronic Disease Prevention and HealthPromotion; the National Institute of Child Health and HumanDevelopment; the National Heart, Lung, and Blood Institute;the National Institute on Alcohol Abuse and Alcoholism; theNational Institute of Mental Health; the National Instituteof Diabetes and Digestive and Kidney Diseases; the NationalInstitute of Arthritis and Musculoskeletal and Skin Diseases;the National Institute of Allergy and Infectious Diseases; andthe National Institute of Neurological and Communicative Disordersand Stroke.
We are indebted to Robert Murphy, Jurgen Rehm, Margo Denke,Clifford Johnson, Jennifer Madans, Jacob Feldman, and ManningFeinleib for their critical comments and support; to Sara Adams,Dorothy Blodgett, Shirley Gray, Sandra Payne, and Cuong Vuongfor excellent technical assistance; to the sponsoring agenciesfor assistance in developing the study; and to Westat, Inc.,for conducting the field work.
Source Information
From the National Center for Health Statistics, Centers for Disease Control and Prevention, 6525 Belcrest Rd., Rm. 1070, Hyattsville, MD 20782, where reprint requests should be addressed to Dr. Sempos.
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Body Iron Stores and the Risk of Coronary Heart Disease
Salonen J. T., Nyyssonen K., Salonen R., Giles W. H., Anda R. F., Williamson D. F., Yip R., Marks J., Sempos C. T., Looker A. C., Gillum R. F., Makuc D. M.
Extract |
Full Text
N Engl J Med 1994;
331:1159-1160, Oct 27, 1994.
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