Correspondence
Body Iron Stores and the Risk of Coronary Heart Disease
N Engl J Med 1994; 331:1159-1160October 27, 1994
- Article
To the Editor:
Sempos and coworkers report data from the National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study (NHEFS) and conclude that “higher transferrin-saturation levels were not associated with an increased risk of coronary heart disease or myocardial infarction” (April 21 issue).1 Since their finding appears to conflict with ours,2 we report the results of the extended follow-up of the Kuopio Ischaemic Heart Disease Risk Factor Study.
Our first report was based on an average follow-up of three years in a study cohort of 1931 men initially free of clinical coronary heart disease. With the average follow-up extended to five years (to December 31, 1991), 83 men had acute myocardial infarctions. In a Cox model that included age, year of examination, indexes of chronic inflammatory diseases, cardiovascular diseases, pulmonary function, socioeconomic status, diabetes, family history of coronary disease, pack-years of smoking, and blood leukocyte count as fixed covariates, a serum ferritin concentration that was 200 μg or more per liter was associated with 2.0 times the risk (95 percent confidence interval, 1.2 to 3.1; P = 0.004), as compared with a lower serum ferritin level at the base-line examination. This association remained statistically significant when the following risk factors were added to the model individually and together: systolic blood pressure, height, weight, body-mass index, serum apolipoprotein B concentration, concentrations of triglycerides and the HDL2 subfraction of high-density lipoprotein cholesterol, plasma fibrinogen concentration, ischemia on exercise testing, maximal oxygen uptake, and intakes of energy and saturated fats. The analytic methods are described elsewhere.3
In 89 men in eastern Finland, the correlation between serum ferritin concentrations and intracellular erythrocyte ferritin concentrations was 0.68 (P<0.001). The erythrocyte ferritin concentration is a very specific indicator of body iron stores. The agreement between the erythrocyte and serum ferritin concentrations validates the use of serum ferritin as a measure of body iron stores. However, as Ascherio and Willett4 note in their editorial accompanying the article by Sempos et al., transferrin saturation is a poor measure of iron stores. For this reason, the title of the article by Sempos and coworkers is misleading. In our view, their data provide little evidence against the hypothesis that high body iron stores increase the risk of myocardial infarction in men who are free of coronary heart disease.
4 ReferencesJukka T. Salonen, M.D., Ph.D.
Kristiina Nyyssonen, M.Sc.
Riitta Salonen, M.D., Ph.D.
University of Kuopio, 70211 Kuopio, Finland1
Sempos CT ,Looker AC ,Gillum RF ,Makuc DM . Body iron stores and the risk of coronary heart disease. N Engl J Med 1994;330:1119-1124
Full Text | Web of Science | Medline2
Salonen JT ,Nyyssonen K ,Korpela H ,Tuomilehto J ,Seppanen R ,Salonen R . High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803-811
Web of Science | Medline3
Lakka TA ,Venalainen JM ,Rauramaa R ,Salonen R ,Tuomilehto J ,Salonen JT . Relation of leisure-time physical activity and cardiorespiratory fitness to the risk of acute myocardial infarction in men. N Engl J Med 1994;330:1549-1554
Full Text | Web of Science | Medline4
Ascherio A ,Willett WC . Are body iron stores related to the risk of coronary heart disease? N Engl J Med 1994;330:1152-1154
Full Text | Web of Science | Medline
To the Editor:
In their editorial Ascherio and Willett discuss the limitations of using the transferrin saturation and state, “Transferrin saturation is an indicator of circulating iron available to tissues, but it is poorly correlated with body iron stores, except when they are fully depleted or overloaded.” In addition, they state, “It would be of interest to know whether levels of transferrin saturation associated with iron deficiency (<15 percent) or iron overload (>60 percent) were related to the risk of coronary heart disease.”
We have reported our results using the same NHEFS data that Sempos et al. used concerning the association between the transferrin saturation and ischemic heart disease.1 Like the outcome studied by Sempos et al., our end point, ischemic heart disease (International Classification of Diseases, 9th Revision, Clinical Modification codes 410 through 414), included both hospitalization and mortality during the 15-year follow-up period. Since a number of chronic conditions may affect both body iron stores and the risk of heart disease, we excluded people with various preexisting illnesses.
For the very reasons Ascherio and Willett suggest, we used a transferrin-saturation level under 15 percent and a level over 60 percent as the cutoff points in our analyses. Using a saturation under 15 percent as the referent, we found that the relative risk of ischemic heart disease was 1.0 (95 percent confidence interval, 0.6 to 1.9) for a transferrin-saturation level of 15 to 29 percent, 1.1 (95 percent confidence interval, 0.6 to 2.1) for a saturation level of 30 to 44 percent, 0.7 (95 percent confidence interval, 0.3 to 1.7) for a saturation level of 45 to 60 percent, and 1.6 (95 percent confidence interval, 0.6 to 3.1) for a saturation level above 60 percent. People with transferrin-saturation levels above 60 percent accounted for 2 percent of the cohort. When the groups were stratified according to sex, men with saturation levels above 60 percent had a relative risk of 0.8 (95 percent confidence interval, 0.2 to 3.4), and women with levels above 60 percent had a relative risk of 2.6 (95 percent confidence interval, 0.7 to 9.2).1
Our results indicate that a possible association between the transferrin saturation and ischemic heart disease is limited to women with saturation levels above 60 percent. People with transferrin-saturation levels above 60 percent may have underlying conditions that predispose them to both a high level of transferrin saturation and coronary heart disease. In addition, it is important to point out that a transferrin-saturation level above 60 percent represents a pathologic finding reflecting various forms of iron overload that cannot be viewed as the high end of normal iron nutritional status or iron stores.
1 ReferencesWayne H. Giles, M.D.
Robert F. Anda, M.D.
David F. Williamson, Ph.D.
Ray Yip, M.D., M.P.H.
James Marks, M.D.
Centers for Disease Control and Prevention, Atlanta, GA 303331
Giles WH ,Anda RF ,Williamson DF ,Yip R ,Marks J . Iron and ischemic heart disease. Circulation 1993;87:2065-2066
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: The principal criticism of our article by Salonen et al. and Giles et al. concerns the accuracy of the transferrin-saturation level as a reflection of body iron stores over the normal range of values. We agree that ferritin is a better measure of body iron stores than the transferrin saturation.
But a problem in trying to evaluate the accuracy of the transferrin saturation as a reflection of body iron stores over the normal range is that few data on the correlation between the transferrin saturation and ferritin have been published. However, data from the second National Health and Nutrition Examination Survey, or NHANES II (1976 to 1980), can be used to address this issue.
Table 1Table 1
Mean Serum Ferritin Concentration According to the Serum Transferrin-Saturation Level in U.S. Men and Women between 45 and 74 Years of Age. shows the mean ferritin levels according to selected levels of transferrin saturation. For both men and women there appears to be a positive correlation between the two sets of measurements, even for the normal range of transferrin saturation (i.e., 20 to 44 percent). We believe these results provide documentation that the transferrin-saturation level does reflect, albeit imperfectly, body iron stores over the normal range of values.We further believe that our results do provide evidence against the hypothesis that high body iron stores increase the risk of coronary heart disease in men or women. In addition, no relation was found between ferritin and the risk of myocardial infarction in an Icelandic population2 or in U.S. physicians,3 and in a study in Finland high transferrin-saturation levels were associated with a decreased risk of death from cardiovascular disease and death from all causes.4
The risk of coronary heart disease for people with a transferrin-saturation level over 60 percent is very difficult to assess with data from the NHEFS. Giles et al. give few details about the total number of people or the number with coronary events in their analytic sample. In our analyses, however, only 4 of 21 white women and only 7 of 30 white men with transferrin-saturation levels above 60 percent had an incident coronary event. Given these small numbers and the large confidence limits reported by Giles et al., we find it difficult to comment on the risk of coronary heart disease for people with transferrin-saturation levels above 60 percent.
4 ReferencesChristopher T. Sempos, Ph.D.
Anne C. Looker, Ph.D.
Richard F. Gillum, M.D.
Diane M. Makuc, Dr.P.H.
Centers for Disease Control and Prevention, Hyattsville, MD 207821
Rose GA. Cardiovascular survey methods. 2nd ed. World Health Organization monograph series no. 56. Geneva: World Health Organization, 1982.
2
Magnusson MK ,Sigfusson N ,Sigvaldason H ,Johannesson GM ,Magnusson S ,Thorgeirsson G . Low iron-binding capacity as a risk factor for myocardial infarction. Circulation 1994;89:102-108
Web of Science | Medline3
Stampfer MJ ,Grodstein F ,Rosenberg I ,Willett W ,Hennekens C . A prospective study of plasma ferritin and risk of myocardial infarction in US physicians. Circulation 1993;87:688-688 abstract.
Web of Science4
Takkunen H ,Reunanen A ,Knekt P ,Aromaa A . Body iron stores and the risk of cancer. N Engl J Med 1989;320:1013-1014
Web of Science
- Citing Articles (22)
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Christopher T. Sempos, Anne C. Looker, Richard F. Gillum, Daniel L. Mcgee, Cuong V. Vuong, Clifford L. Johnson. (2000) Serum Ferritin and Death from all Causes and Cardiovascular Disease. Annals of Epidemiology 10:7, 441-448
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Xi Ming Yuan, Wei Li, Anders G. Olsson, Ulf T. Brunk. (1996) Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis. Atherosclerosis 124:1, 61-73
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Christopher T. Sempos, Anne C. Looker, Richard F. Gillum. (1996) Iron and Heart Disease: The Epidemiologic Data. Nutrition Reviews 54:3, 73-84
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J. T. SALONEN, H. KORPELA, K. NYYSSÖNEN, E. PORKKALA, T.-P. TUOMAINEN, J. D. BELCHER, D.R. JACOBS, R. SALONEN. (1995) Lowering of body iron stores by blood letting and oxidation resistance of serum lipoproteins: a randomized cross-over trial in male smokers. Journal of Internal Medicine 237:2, 161-168
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