Should Iron be in your multivitamin?
A review article, and opinion, by Donald P. Goldberg, R.Ph
For most people, iron should be included as part of the daily multivitamin supplement program. There are exceptions, and those will be explained below. As is the case with so many things, iron has two sides, and we have to decide whether its advantages outweigh its disadvantages.
When evaluating the question of iron supplementation, we have to remember that iron deficiency is one of the most common nutritional shortfalls in the United States today.1 We have to remember, as well, that we can be deficient in iron, and may be unaware of it.
The initial stage of iron deficiency usually has no symptoms. It occurs when the body’s iron stores are depleted or exhausted, a condition reflected by a drop in the blood’s iron levels and an increase in transferrin—a protein that transports iron through the blood stream. As the iron supply to the b one marrow dwindles, so does the marrow’s ability to produce healthy red blood cells, which require iron. If the iron balance worsens, full-blown iron-deficiency anemia—characterized by low hemoglobin levels—can gradually develop. Since iron is an essential component of hemoglobin, a shortage of iron can impair the transport of oxygen from the lungs to the body’s cells; as a result, work performance will be impaired.
It can take months or even years for symptoms of iron deficiency—such as weakness, shortness of breath, paleness, poor appetite, and increased susceptibility to infection—to become evident. These usually disappear when iron stores are rebuilt.1
On the other hand, many people with “iron-overload”, or hemochromatosis, often have no symptomsIron: Why Is It Essential?
All cells in the body contain iron. It plays a vital role in many biochemical reactions. Perhaps its most important role is related to its incorporation in hemoglobin, the oxygen-carrying protein that gives blood its red color, and in the myoglobin in muscle. Myoglobin, like hemoglobin, is a transporter of oxygen—it supplies oxygen to the muscle cells for use in the chemical reaction that results in muscle contraction. Low iron intake over a long period of time can gradually lead to a depletion of iron stored in the body. This is of special concern when there is loss of blood, as in menstruation. “Iron is therefore the main determinant of how much oxygen reaches and is used by all body tissues, including the brain, muscles, heart, and liver.”15
“Iron is also necessary for collagen synthesis. Iron is found in the brain as a cofactor in neurotransmitter synthesis for serotonin, dopamine, and noradrenalin, which are known to regulate behavior.”14 “Iron strengthens the immune system and increases resistance to colds, infections, and disease.”15Why is Iron Supplementation Necessary?
As the iron supply to the bone marrow dwindles, so does the marrow’s ability to produce healthy red blood cells, which require iron. If the iron deficiency continues, full-blown iron-deficiency anemia, characterized by low hemoglobin levels, can develop.
“It can take months or even years for symptoms of iron deficiency—such as weakness, shortness of breath, paleness, poor appetite, and increased susceptibility to infection—to become evident. These usually disappear when iron stores are rebuilt.”1
According to Murray, “Although the human body contains only about 0.004 percent iron, it is one of the most significant elements in nutrition and consequently very necessary to life. Iron deficiency is said to be the second most common nutritional problem in the United States, following obesity.”13
“Without an adequate iron supply, people are at risk for developing a variety of symptoms, such as reduced work capacity; more rapid build-up of lactic acid in exercising muscle; irritability and apathy; lower resistance to infections; spoon-shaped, thin nails; and pale nail beds. It is difficult to get sufficient iron from the diet because all food sources are not all equal in value. For example, spinach is rich in iron, but the mineral is bound by chelates and takes it out of the body before it can be properly absorbed. Other chelates include tannins in tea; phytates in whole grains, brans and soybeans; polyphenols in coffee; and phosvitin in egg yolk 13.”
“Unusual food cravings are associated with an iron deficiency. Cravings for ice, starch, clay, and other nonfood items have been attributed to a deficiency. Children who are deficient have a tendency to hperactivity, decreased attention span, and lower IQ’s. This conditions can be helped if iron amounts are restored.”14
“Iron is the most important mineral for the prevention of anemia during menstruation. Iron may also be beneficial in the treatment of leukemia and colitis. Plummer-Vinson syndrome is cured with iron. This disease can lead to esophageal and stomach cancer. Candida and herpes simplex are helped with sufficient levels of iron if deficient already. Iron-requiring proteins generate oxygen radicals that kill bacteria like the ones in mother’s first milk. Muscle weakness and exercise endurance are improved with iron. Both cardiac and muscular performance are included.”14Why is Iron Supplementation discouraged by some?
It has become popular to warn about the dangers of iron. There is the author who “was forced to give up her career after being stricken with an unidentified disabling illness. After 12 years of going from doctor to doctor, she was finally diagnosed with iron overload and elevated levels of aluminum, lead and copper… Following her treatment and recovery, she began researching the scientific literature on the subject of iron overload, a potentially lethal, but underdiagnosed and undertreated medical condition. Her book…”4
Then, you have a occasional study that implicates iron with problems, such as heart disease. Probably the most often quoted study of this type is one published in 1992, usually referred to as the Finnish study.5
The fact that this study could not be duplicated in two subsequent studies seems to have little effect on those who persist in looking to blame iron for various health ills.6,7
Dr. Steve Austin,9 for example, is quick to point out that “this is not so with all such reports. For example, in the November 18, 1997 issue of Circulation, a prospective study found ferritin to be the ‘strongest risk predictor of overall progression of atherosclerosis.”8 And Dr. Austin follows up with another article highlighting a study in Greece that claims to show a relationship between dietary iron intake in men and increased risk of heart disease.10
A study of Finnish men published, 1992 made headlines when it offered evidence that even "normal" levels of iron stored to the body may increase the risk of a heart attack. Is iron one more risk factor men should worry about? Not at this point For one thing, a high level of iron may be a marker for some other factor that's the real culprit Also, the men in the study already had relatively high iron levels compared to Americans, as well as a high incidence of heart attacks--among the highest in the world. Another point: only a small amount of dietary iron is absorbed by the body, and that amount is affected by many factors including other foods you consume and your body's needs Thus, an iron-rich diet doesn't necessarily lead to iron overload,
At this point, there is not nearly enough evidence supporting the link between iron and heart disease Until a stronger case is made, healthy men should continue to eat foods that supply their daily requirement of iron.1
The problem with studies like this is that they deal in possibilities, not facts. In other words, it is sometimes difficult to determine whether we are looking a the cause, or the effect. For example, a patient with high iron levels may have high levels because he is a long-time heavy meat eater. Is the fact that he is at high risk of heart disease a function of the high level of stored iron, or is the iron merely a coincidental result of the heavy meat diet, with other factors related to animal fat intake the real culprit?
Another problem with iron is that iron storage diseases such as hemochromatosis are more common than previously thought.
Iron and Lipid Peroxidation
All of the functions that iron performs in the body are based on its ability to donate and accept electrons, i.e. participate in oxidation-reduction reactions. It is this characteristic that makes iron a highly reactive and potentially toxic nutrient. This can be said for many of the powerful antioxidants found throughout biological systems.
It is now commonly accepted that the oxidation of low-density lipoprotein (LDL) results in the modified LDL being taken up more readily by macrophages, which results in the development of the fatty streak, the initial lesion of atherosclerosis. Iron, as well as copper, has been shown to promote the modification of LDL in vitro and is suspected of participating in these reactions in the body. Is this really a problem?
Although many studies provide convincing evidence that iron does participate in free radical reactions and the modification of LDL under experimental conditions, it remains unknown what conditions must exist in the body for iron to participate in these reactions. Normally, the body takes great care in keeping iron in a nonreactive state. For example, the potential for free iron to exist in serum is low, because the iron transport protein, transferrin, is only approximately 30% saturated with iron under normal conditions. This allows for a large capacity to deal with changes in iron concentration within the serum pool (Beard, 1993). Only as transferrin saturation approaches 100% does iron become available to participate in free radical generation under normal conditions. However, free iron has been observed in the plasma of hemochromatosis patients whose transferrin saturation was much less than 100% (Aruoma et al., 1988). This may be indicative of an inability of transferrin to bind iron sufficiently in hemochromatosis patients. After delivery of iron to the cell, the transferrin-iron complex enters the cell through receptor-mediated endocytosis. Once in the cell, iron is utilized by iron-dependent systems, and any surplus iron is stored tightly chelated in a nonreactive state in ferritin and hemosiderin (McCord, 1991). Ferritin, because of its iron-binding properties, is a strong cytoprotective antioxidant (Balla et al., 1992; Gutteridge and Quinlan, 1993). Moreover, pools of dormant ferritin mRNAs exist in the cytoplasm which can be rapidly translated to yield a large number of ferritin subunits in response to increases in cellular iron (Munro, 1993). This prevents the accumulation of iron within the cytoplasm and the peroxidation of cell lipids, DNA, and various proteins. If the storage capacity of ferritin is exhausted, excess iron is then stored in the form of hemosiderin, which is a more insoluble iron deposit that is not readily available to the organism (Welch, 1992). Therefore, the association of iron with transferrin, ferritin, and hemosiderin prevents iron's participation in undesirable reactions thought to be involved in the development of atherosclerotic lesions.11
Nevertheless, extreme levels of iron in the body can result in myocardial tissue damage as evidenced by the clinical manifestation of heart disease in hemochromatosis and other iron-storage disease patients. Furthermore, the ability of iron chelators to reduce injury to heart tissue immediately after a cardiac arrest demonstrates that iron does contribute to heart damage age after a heart attack has occurred (Babbs, 1985; Bernier et al., 1986; Williams et al., 1991). However, it must be recognized that these are extreme conditions that do not implicate normal iron status as a risk factor for atherogenesis in healthy individuals.11
Free radicals are generated in the body as part of normal cellular processes. For instance, the body utilizes free radicals as a way to kill invading bacteria. “Fortunately, free radical scavenger systems, such as superoxide dismutase and glutathione peroxidase, exist to prevent or terminate the undesirable accumulation of free radicals generated in these situations. Consequently, nutritional status of nutrients known to have antioxidant functions or integral roles in free radical scavenger systems (i.e. copper, zinc, selenium, carotenoids, and vitamins A, E, and C), is important to consider. It may be a deficiency of these nutrients that creates an opportunistic environment that promotes atherosclerotic sclerotic lesions and not just the presence of transitional metals such as iron (Ames et al., 1993; Manson, 1993…”11The Finnish Study
We have already alluded to the often quoted Finnish Study (Salonen, et.al, 1992. They found that eastern Finnish men with serum ferritin levels greater than 200 μg/L had a 2.2-fold risk-factor-adjusted risk of acute myocardial infarction (AMI) compared with men with lower serum ferritin levels. This was a prospective 3-year followup study of 1931 eastern Finnish men aged 42, 48, 54, and 60 years who had no previous history of heart disease upon entry into the study.
Although these results indicate that serum ferritin in the uppernormal range was a risk factor for AMI in the population studied, it has been questioned whether the data can be readily extrapolated to other groups (Beard, 1993). The nutritional patterns of a similar group of eastern Finnish men were reported by Ihanainen et al. (1989), who collected nutritional data on 1157 eastern Finnish men aged 54 years. Results of this analysis showed the consumption of vegetables in this population to be low (110 g/day), whereas coffee (586 g/day) and fat intake (40% of energy intake) were high. Intake of saturated fat was four times greater than that of polyunsaturated fat, and dairy product consumption consisted of 70% butter. Meat intake comprised mainly sausage (39%), beef (37%), and pork (21%), and the mean daily intake of cholesterol was 480 mg. The average intake of nutrients known to protect against lipid peroxidation, such as vitamin E, copper, and selenium, was below recommended dietary allowances. The authors of this study indicated their findings were consistent with other studies that have evaluated the diet of the Finnish population (Uusitalo, 1987; Seppanen, 1981).
The enormous range in serum ferritin levels (10-2270 μg/L) in these subjects is a strong indicator that the recessive hemochromatosis gene was present in this cohort and possibly driving the observed association between stored iron and AMI (Beard, 1993). Other explanations for such high serum ferritin levels include the presence of undetected conditions known to elevate ferritin levels, such as liver disease and cancer (Finch et al., 1986). It is these population attributes and the fact that eastern Finnish men have the highest recorded incidence and mortality from CHD (Keys, 1980) that makes extrapolation to other populations difficult. Moreover, although ferritin was found to be a significant risk factor for AMI with a relative risk of 1.03 in this population, several other factors were also found to be statistically significant and have greater relative risks for AMI than serum ferritin. For instance, serum copper, serum apolipoprotein B, and diabetes had approximately 600, 400, and 250 percent greater relative hazards of AMI than ferritin, respectively. The weaker association of ferritin to AMI compared with these other factors may be due to ferritin's ability to sequester iron in a nonreactive form (Balla et al., 1992; Gutteridge and Quinlan, 1993).11Does Iron Accumulate With Age?
Much of the concern about iron in supplements arises from the belief that in men, especially sedentary men, there is little means by which stored iron can be lost, and therefore it continues to build up over the years, eventually reaching “overload” levels. This may not be the case:
The hypothesis that iron stores are related to the risk of cardiovascular disease (CVD) arose in part from the observation that the incidence of CVD increases with age in men and in postmenopausal women (Kannel et al., 1976; Gordon et al., 1978). Other studies reported that iron stores also accumulated with age in men and in postmenopausal women (Cook et al., 1976). Thus, Sullivan hypothesized that the two observations were related (Sullivan, 1981). However, NHANES II and NHANES III pilot study data appear to indicate that iron may not accumulate with age. Figure 1 represents data of mean serum ferritin values of non-hispanic white (NHW) males and females at various ages from NHANES II and NHANES III pilot data of all persons measured. As can be observed from the graph, ferritin values do not increase appreciably with age in men, but values do increase in women as they pass through menopause. Interestingly, Solonen et al. (1992) reported that serum ferritin concentrations decreased after 48 years of age in the eastern Finnish men they studied.
The recent proposal of a setpoint theory, whereby iron stores regulate iron absorption to maintain an individual's preset iron stores, challenges the idea that iron stores accumulate with age. Garry et al. (1992) proposed the setpoint theory after assessing iron stores in 27 postmenopausal healthy women who donated 5 units of blood over 1 year compared with 59 controls. Iron stores in the control group did not change over 2 years, despite large differences in baseline iron stores and similar dietary iron intakes. The authors speculated that a setpoint exists for individual iron stores which is under genetic control. If this is so, it would be difficult to increase iron stores through diet or supplementation when iron stores are at or near an individual's predetermined setpoint. Gavin et al. (1994) further investigated the setpoint theory in 21 individuals selected from the same study population as that used by Garry et al. (1992). Iron absorption changed according to changes in baseline iron stores, and 70% of the variation in iron absorption was explained by the changes in iron stores from baseline, indicating an adaptation to the level of depletion of iron stores below the setpoint. If iron stores are regulated as described by the setpoint theory, iron stores would not be expected to increase with age.Is Low Iron Protective Against Heart Disease?
If high iron levels are related to increased risk of heart disease, as some claim, it would be logical to assume that low levels would infer a protective effect. But this does not seem to be the case.
Within the iron/heart disease paradigm, it would be predicted that other indicators of iron deficiency, such as a low transferrin saturation (serum iron divided by total iron binding capacity x 100), would indicate protection against heart disease, because a low transferrin saturation would possess potent antioxidant activity. As indicated by Beard (1993), determination of transferrin saturation could provide a better understanding of the association of iron and heart disease. Magnusson et al. (1994) studied 2036 men and women between the ages of 25 and 74 years who were participating in a large epidemiological study. It was found that increased total iron binding capacity (TIBC) was protective against MI, whereas serum ferritin had no significant association. It was also observed that transferrin saturation had less predictive power for MI than did TIBC. Another study was recently completed on 46,932 subjects whose serum iron and TIBC were measured and who were followed for a 14-year period (Baer et al., 1994). During the followup period, 969 men and 871 women had an AMI-related hospital stay. Results did not show iron deficiency, as indicated by low transferrin saturation, to be protective against heart disease. Liao et al. (1994) examined data from the 4237 respondents of NHANES I aged 40-74 years (1827 men and 2410 women). Hemoglobin, serum iron, and the total iron-binding capacity of transferrin (TIBC) were determined. During the 13-year followup, 489 persons had an AMI, and 1151 developed CHD. Hemoglobin, hematocrit, and TIBC were not associated with the incidence of MI or CHD. Transferrin saturations in both men and women who developed CHD were lower than in those who did not, and each 10% increase in transferrin saturation was associated with a 9% decrease in risk of CHD among men and a 12% decrease among women. The authors caution that these results are only suggestive, because the influence of diurnal variation and other factors such as inflammation and malignancy were not monitored or controlled. Sempos et al. (1994) also assessed the association between the risk of MI and serum transferrin saturation in 4518 men and women who were part of NHANES I. The risk of CHD was not related to transferrin saturation levels, and results indicated there may even be an inverse relationship. 11Other Research On Iron and Cardiovascular Disease
As briefly mentioned earlier in this report, there is a considerable body of research that does not support the proposed connection between iron and heart disease. The following summary was presented in the article by Proulx and Weaver.11
Since the publication of the Finnish study by Salonen et al. (1992), many other studies that have investigated the association of iron and heart disease have been completed. Researchers from the Karolinska Institute in Stockholm, Sweden, conducted a case-control study to investigate the effect of iron on the risk of AMI at a young age (Regnstrom et al., 1994). Ninety-four men who experienced an MI before the age of 45 years were compared with 100 age-matched population controls. There was no association between the measure of iron status and severity of coronary atherosclerosis, suggesting that iron stores were not a risk factor for premature coronary atherosclerosis. In another investigation, 252 patients between the ages of 29 and 84 who were admitted for cardiac catheterization to Duke University Medical Center also had their blood analyzed for serum ferritin, total iron, TIBC, and transferrin along with lipoprotein profiles (Lin et al., 1994). When coronary artery disease (CAD) risk factors (age, sex, body mass index, lipid-lowering drugs, smoking, and special diet) were controlled for, no relationship between indicators of iron status and extent of CAD was found. A prospective study of plasma ferritin and risk of MI in 238 men with MI and 238 controls matched for age and smoking found that, after adjustment for other coronary risk factors, men with serum ferritin levels greater than 200 μg/L had a relative risk of 1.1 (Stampfer et al., 1993). This suggests little or no increased risk associated with normal ferritin levels. Aronow (1993) evaluated the association between serum ferritin levels and CAD in 171 men and 406 women. The mean age of men (n = 74) and women (n = 172) with CAD was 82 years; that of men and women without CAD was 81 years. The mean serum ferritin concentration was not significantly different between men and women with and without CAD, indicating ferritin was not a risk factor for CAD in these elderly men and women. Miller and Hutchins (1993) selected 130 adult patients from 48,000 autopsy records performed from 1889 to 1993 at Johns Hopkins University. These patients were carefully matched for age, sex, and time of death. Sixty-five of these had iron overload and 65 did not. The researchers concluded that people with iron overload did not appear to have significant amounts of CAD. Only 3 of the 65 patients with iron overload had one coronary artery with 90% or more blockage.
Salonen et al. (1992) also reported that the intake of dietary iron was strongly associated with the risk of AMI in eastern Finnish men. However, Rimm et al. (1993) measured dietary iron intake through a food frequency questionnaire during a 4-year followup of 45,720 men aged 40-75 years with no previous history of heart disease. Eight-hundred eighty cases of coronary disease were documented, and, after adjusting for other risk factors, men with the highest intake of iron had an insignificant relative risk of heart disease compared with men with the lowest intake of iron. The relative risk of CHD for each milligram increase in dietary iron was 1.0, indicating no increased risk. Ascherio and Willet (1994) studied iron intake and its association with coronary disease in 44,933 men aged 40-75 years and found that higher intakes of heme iron were associated with greater risks for MI but not dietary iron in general.Is Lower Heart Disease Among Premenopausal Women Due To Lower Iron Levels?
Based on the iron/heart disease theory, premenopausal women are thought to have increased protection against heart disease due to iron loss as a result of menstruation. If iron loss via menstrual blood flow was responsible, those women who take oral contraceptives, which decreases menstrual blood flow, would not exhibit this protective effect. In fact, significant differences in iron stores have been found between users and nonusers of oral contraceptives (Frassinelli-Gunderson et al., 1985). But this does not seem to be related to iron levels in the body.
Moreover, earlier studies found that current and discontinued use of oral contraceptives was associated with an increased risk of heart disease (Slone et al., 1981). Dr. Sullivan hypothesized that the increased risk for CHD among oral contraceptive users was due to the accumulation of iron (Sullivan, 1981). A recent study on the effects of low-dose oral contraception on menstrual blood loss and iron status found that menstrual blood loss was reduced by approximately 44% in women taking low-dose oral contraceptives (Larsson, 1992). However, serum ferritin concentrations in these subjects remained unchanged over the 6-month period of the study. Stampfer et al. (1988) studied 119,000 women who were 30 to 55 years of age and found that the use of oral contraceptive agents in the past did not raise a woman's risk of heart disease. Because oral contraceptives decrease menstrual blood loss and increase iron stores, it would be expected that longer usage of oral contraceptives would be associated with an increased risk. However, Stampfer et al. (1988) noted that women who had previously used oral contraceptives for more than 10 years had no increased risk. On the other hand, current users of oral contraceptives did have an increased risk of CHD of 2.5, but this excess risk was observed predominately in smokers. Porter et al. (1985) studied more than 65,000 women, 15 to 44 years of age, who were healthy nonsmokers and found that no MIs occurred in users of oral contraceptives. The 11 deaths due to CVD in the 6-year period occurred in the women who were not using oral contraceptives (Porter et al., 1987). The increased incidence of MI in older users of oral contraceptives appears to be due to higher doses of estrogen in the formulations taken by these women. Stampfer et al. (1991) observed less benefit among women taking more than 1.25 mg of estrogen daily. In another study, an increased incidence of heart disease was found only among older users who had other known risk factors for heart disease (Mann et al., 1976). Mant et al. (1987) analyzed results from a large cohort study in Britain and found the risk ratio for MI in current users of oral contraceptives was not increased, and no MIs were found in women who used formulations with less than 50 μg of estrogen. Therefore, the increased risk of heart disease that has been observed in women who use oral contraceptives, past and present, appears to be strongly associated with the dose of estrogen and smoking habits rather than iron stores.11Does Menopause Support the Iron-Heart Disease Paradigm?
If increased levels of stored iron was responsible for increase heart disease, it would be expected that postmenopausal women would have a remarkable increase in coronary heart disease, due to posmenopausal amenorrhea. Indeed, there is an increase of CHD, but iron may not be the real culprit. Instead, what may be in operation in this case is the protective effect of estrogen.
However, this theory ignores the observed role of estrogen in the decreased incidence of heart disease among women (Colditz et al., 1987; Stampfer et al., 1991; Wolf et al., 1991). Several investigations have found that women who have had a hysterectomy (cessation of menses) without removal of the ovaries (retained estrogen) have an increased coronary risk (Gordon, 1978; Palmer, 1992). Nevertheless, estrogen-replacement therapy has been shown to have favorable effects upon lipoprotein profiles in postmenopausal women with as much as a 40% reduction in CVD being reported (Green and Bain, 1993). Stampfer et al. (1991) have reviewed the issue of estrogen-replacement therapy and heart disease and found that, of 15 prospective studies, 14 found no increased risk of heart disease among estrogen users. Colditz et al. (1987) also investigated the association of estrogen and heart disease in a prospective cohort of 121,700 U.S. female nurses. In this study, 14,000 women experienced natural menopause, and another 8061 reported hysterectomy alone. After controlling for age and cigarette smoking, women who experienced natural menopause and who had not received hormone-replacement therapy had no appreciable increased risk of CHD when compared with premenopausal women. However, women who had undergone bilateral oophorectomy (loss of estrogen) and who had never taken estrogen after menopause had an increased risk. This risk appeared to be eliminated in women who used estrogen in the postmenopausal period. Mathews et al. (1989) found that natural menopause had negative effects on lipid metabolism, indicated by decreases in high-density lipoprotein (HDL) and increases in low-density lipoprotein (LDL) cholesterol, but women who had received hormone replacement therapy (estrogen) did not experience any changes in HDL or LDL cholesterol. Estrogen has been found to exhibit antioxidant activity by protecting against the cytotoxicity of oxidized LDL by inhibiting LDL oxidation outside the cell and by enhancing cellular resistance against oxidized LDL in the cell (Negre-Salvayre et al., 1993). Estrogen-replacement therapy, either past or present, was strongly associated with lower LDL-cholesterol, glucose, insulin, fibrinogen, obesity, and age and higher HDL-cholesterol (Manolio et al., 1993). Physiological levels of estrogen cause vasodilation of endothelium in the forearm of postmenopausal women, which may be partly responsible for the observed long-term effects of estrogen replacement therapy on cardiovascular incidents in postmenopausal women (Gilligan et al., 1994). Estrogen's apparent ability to improve blood cholesterol profiles as well as act as an antioxidant and vasodilator make it effective in lowering risk of heart disease in premenopausal women and women using postmenopausal hormone replacement.Summary
There is no question that in certain circumstances the accumulation of excess iron is possible. In its most severe form, hemochromatosis, large amount of iron can be deposited in the liver, spleen and other tissues, causing pronounced impairment in function and tissue damage. This condition was thought to be rare, and usually associated with a genetic disorder that results in abnormal absorption or iron.
On the other hand, adequate levels of iron is essential to optimal health. Iron is difficult to absorb from vegetables, fruits, beans, whole grains and supplements. Even in the absence of overt anemia, iron deficiency can produce such symptoms as fatigue, behavioral problems (decreased alertness and attention span), muscle weakness and increased susceptibility to infections.17
Even if iron-overload is more common than once was thought, the evidence does not support a blanket recommendation that iron be completely eliminated from the diet, or from supplementation, for certain population groups. The average American diet is too poor, and iron deficiency is too prevalent, to make such a generalization.
While there may be a preponderance of anti-iron commentary in certain areas, it is important to maintain a proper perspective, especially when looking at epidemiological studies. For example, it is known that Candida infections of the skin and mucous membranes are more common in patients who are iron deficient.17 This is true for herpes simplex infections as well. Certainly, the majority of those who are outspoken critics of iron supplements are at the same time aware of what could almost be called a “candida epidemic.” Can we not then conclude that this epidemic of candida albicans is related to low iron levels?
The same could be said, perhaps, of what we are calling “chronic fatigue syndrome.” Muscle weakness and decreased exercise tolerance are frequently associated with iron-deficiency anemia. But these symptoms can occur even when there is iron deficiency but not anemia and can be resolved when the iron deficiency is corrected.17
And, as pointed out by Dr. Murray, when commenting on the oft-quoted Finnish Study, “Another way of expressing the results of the study would be to simply state that Finnish men eating more meat have an increased risk for heart attacks, elevated LDL-cholesterol levels, and elevated iron stores. Therefore, the study simply provided additional evidence that high meat intake increases the risk of heart attack. This is nothing new; it is just a different way in which high meat intake can lead to premature death.”18
The following conclusion by Proulx, et.al. sums it up quite nicely: “Although the iron and heart disease hypothesis offers an intriguing explanation for many of the factors associated with heart disease, subsequent research has not been supportive of the paradigm. Confounding variables inherent in the study of eastern Finnish men (i.e., the presence of serum ferritin levels of 2200 μg/L, the known high level of CAD, high concentration of LDL, and the potentially atherogenic diet in this population) make definitive conclusions and extrapolations to other population groups difficult. However, other factors analyzed in this investigation that were found to have more substantial relative risks for AMI than ferritin may be worthy of further investigation. Manttari et al. (1993) found that there was a linear trend in CHD risk with increasing ceruloplasmin, the copper transport protein, in dyslipidemic men. In the Finnish study, serum copper had the highest relative risk of all factors analyzed. Numerous studies investigating the relationship between iron and heart disease largely have been unable to support the findings of the Finnish study and the iron/heart disease paradigm. On the other hand, research supporting estrogen as the main factor explaining the difference in rates of heart disease between men and premenopausal women is convincing. Nevertheless, when the negative consequences of iron deficiency are considered along with the prevalence of iron-overload disease, prudent but timely action on this issue is imperative. Universal screening for iron storage diseases as recommended by Herbert (1992) seems to be an efficacious and reasonable approach to the public health problem of iron overload, because measurements of iron status are relatively inexpensive and effective treatment is available. Those found to have levels of iron that would put them at risk for toxicity should be advised to reduce their iron levels and avoid iron supplements. Otherwise, until sound scientific evidence indicates differently, the rest of the general public should be encouraged to consume as near the RDA for iron for their age and gender as possible.”11The rational approach
Holford, in his book The Optimum Nutrition Bible, discusses the Finnish Study, and the correlation between blood ferritin levels and cardiovascular risk. He reports Sullivan’s theory that “this might explain why menstruating women, who lose iron each month, have a lesser risk of cardiovascular disease than men until after the menopause.” But he concludes that “This theory is yet to be proven, but suggests that meat-eating men should not go overboarfd on iron supplements. In practice, this means limiting the dose to 10 mg a day.2
As Dr. Robert Atkins says, “If both low and high levels of iron can be bad, then which is worse? Well, by the time you’ve reached your seventies the answer is high iron is better, according to a 1997 U.S. government survey of nearly four thousand seniors. Men and women with the highest serum level had 38 percent and 28 percent lower all-cause death rates, respectively.3
“The toxicity of iron is low, and harmful effects of daily intakes of up to 75 milligrams per day are unlikely in healthy individuals. The body has a highly effective mechanism that prevents an overload of iron from entering it and causing toxicity. The amount of iron the body absorbs is carefully regulated by the intestines, according to the body's needs. The greater the need, the higher the rate of absorption. Growing children, pregnant women, and anemic individuals have higher rates of absorption. When a deficiency occurs, the rate of absorption increases to two to three times higher than normal. (Unfortunately, this response does not appear to be sufficient to prevent anemia in iron-deficient subjects who are only mildly anemic and whose iron intake is marginal.)
There have been conflicting scientific reports concerning iron and the risk of coronary heart disease. Some studies have shown that high iron levels in the blood appear to increase the risk of heart disease, while other studies have failed to confirm these findings. Some studies have demonstrated that high levels of serum ferritin (a complex in which iron is stored in the tissues) or of total iron binding capacity (TIBC) appear to increase the risk of heart disease, while other studies have failed to confirm these findings, as well. What does all this mean?
We know that antioxidants are our natural defense against free radical oxidative stress, and that iron is a very powerful pro-oxidant-an initiator of oxidative stress. The discrepancies in the study findings may be the result of the balance of antioxidants and iron. Even though iron is essential to the functioning of our bodies, too much iron combined with poor antioxidant defense, due to poor intake of antioxidants would put anyone at high risk for increased oxidative stress, which is believed to be a culprit in heart disease. Since we can easily measure iron, TIBC, and ferritin levels in our blood, these levels should routinely be screened during physical exams. If high levels are present, a reduction of iron intake should be discussed with your physician.
In some cases, a dangerous condition known as hemochromatosis can cause the excessive absorption of iron. This results in a build-up of excess iron in the tissues of many organs, possibly leading to damage to the liver, heart, pancreas, and other organs. 1n genetic hemochromatosis, there is inappropriately high absorption of dietary iron from birth. Acquired hemochromatosis may occur as a result of transfusions, medical conditions, or excessive long-term iron intake, This condition, too, can easily be detected through blood tests. If the tests confirm the condition, steps should be taken to avoid iron in food and supplements, and to avoid foods cooked in cast iron cookware or stored in metal cans. 12
In response to the claim that iron promotes oxidation, contributing to heart disease in men and rheumatoid arthritis, Dr. Saul Hendler offers the following observation: “That iron can generate free radicals is well known. Unbound iron in the ferrous (or ‘plus two’) state is a potent generator of hydroxy radicals, which can be very destructive to cells. However, unbound iron occurs only under certain conditions. Patients with hemochromatosis, a genetic disorder of excessive iron accumulation, can have a significant quantity of unbound iron in their cells, and this may give rise to extensive damage to liver, heart, pancrease and skin. These genetic disorders, however, are rare. And there is no convincing evidence at present that iron is active in either rheumatoid arthritis or atherosclerotic disease. Most iron we come in contact with is tightly bound to protein and does not generate dangerous free radicals….Prolonged administration or iron supplements very rarely causes iron overload…Iron supplements are widely used in the United States, and reports of toxicity from iron overload are very rare.17
And finally, the commentary on this question of iron levels and risk of heart attack presented by Dr. Michael Murray in his book, Encyclopedia of Nutritional Supplements, further helps to put the concern over excess iron into proper perspective:
“Recent news accounts highlight the possible relationship of elevated iron levels and the risk for heart attacks. The articles in the popular press are based on several scientific studies. However, the news accounts do not provide all the information. For example, let's look at the study published in the medical journal Circulation. In this study of Finnish men, researchers demonstrated that high stored-iron levels produced by a diet of excess meat is associated with excess risk of heart attack, Although iron was singled out, the study also demonstrated an increased risk for a heart attack when LDL-cholesterol levels were elevated. In other words, the strongest link between increased stored iron levels and risk for a heart attack was found in men with LDL-cholesterol levels greater than 193 milligrams per deciliter. Furthermore, the strongest dietary link to an increased risk for a heart attack in the study was meat intake. Meat intake was also linked to increased LDL-cholesterol levels and increased dietary intake of saturated fats.
Another way of expressing the results of the study would be to simply state that Finnish men eating more meat have an increased risk for heart attacks, elevated LDL-cholesterol levels, and elevated iron stores. Therefore, the study simply provided additional evidence that high meat intake increases the risk of heart attack. This is nothing new; it is just a different way in which high meat intake can lead to premature death.
Elevated levels of iron may lead to an increased risk of heart disease by spinning off free radicals in the blood and either damaging cholesterol or the artery walls directly. Antioxidants like vitamin C and vitamin E protect against iron-induced oxidative damage.”18Conclusion
For people who are not in the high risk group for iron deficiency (menstruating women, dieters, pregnant women, endurance athletes, strict vegetarians, infants and children), it is prudent to moderate or reduce iron supplement intake. This would include men, especially heavy meat eaters.
Some experts indeed claim that “adult men who eat well-balanced diets of 2,000 calories or more do not need iron supplements..”17 This may be true, but the same can be said for all vitamins and minerals, depending on your viewpoint. The problem, of course, is that so few of us can claim to eat a well-balanced diet. More realistic, in my opinion, is to reduce the amount of iron to a more prudent level.
A level of less than 10 mg in a balanced multivitamin would be appropriate. It is important to utilize a multivitamin with a full spectrum of antioxidants, to ensure, in addition to all the many benefits antioxidants provide, that the iron does not function as a pro-oxidant. An additional antioxidant blend is usually desirable in any case.
Those who feel that they might for any reason be in danger of too much stored iron should have the appropriate blood tests run to determine whether or not they have a valid reason for concern. The proper test for this purpose would be a serum ferritin test, which measures how much iron is stored in the body.
If there is insufficient reason to request a serum ferritin test, then I suggest that there is insufficient reason to totally eliminate iron from the daily supplement program. The importance of adequate iron levels should dictate the inclusion of a moderate level in the daily supplement program.
The realization that genetic iron overload disease is a more common disorder than was one thought is not to be interpreted as justification for depriving otherwise healthy adults of the benefits of iron supplementation. Instead, it should be considered basis for increased emphasis on blood test screening so that those individuals can be properly identified.
There is no basis for totally restricting iron supplementation in the absence of such clinical testing. As explained above, the value of iron is too great to risk a deficiency. While elderly men can be thought to be more likely to have adequate iron stores, it should be remembered that elderly men are at the same time more likely to have difficulty absorbing iron due to reduced levels of hydrochloric acid in the stomach.
It should also be kept in mind that the actual amount of iron absorbed from a supplement is small. This is especially true when the supplement contains a large amount of calcium.16 Just as calcium interferes with the absorption of lead, it interferes with the absorption of iron.
The general rule of thumb, in fact, is that only about 10% of iron is absorbed. The actual estimated requirement for iron for adult men is 0.65 to 1.3 mg. This leads to a Recommended Daily Allowance of 10 mg (National Research Council). The Food and Drug Administration, in adopting the “US RDA” or “Percent Daily Value” for label purposes, increased the level to 18 mg. A level of 10 mg, therefore, is more in keeping with the level recommended for men over the age of 19, and women over the age of 51.
For those in the other category, where there is little question but that there is need additional iron supplementation, an additional supplement and/or increased dietary heme iron intake is necessary. This would include, of course, adolescents, premenopausal women, pregnant and lactating women, those with anemia, dieters, “and the elderly with poor dietary habits over long periods of time.”17Special Note: Willvite
In the product Willvite, a total multivitamin-multimineral supplement formulated by Willner Chemists, the amount of iron present is 9 mg, per four tablets, which represents 50% of the “Percent Daily Value” as mandated by the FDA. As explained above, for most people, we feel this represents an appropriate compromise. In addition, the type of iron used is a form bound to fumaric acid, the chelated ferrous fumarate. This form, especially in the presence of a balanced array of antioxidants, is considered safe and effective. (For iron deficiency, for example, Dr. Michael Murray18 recommends “iron bound to either succinate or fumarate”).References
1. Univ. of California at Berkeley Wellness Letter. The New Wellness Encyclopedia. Houghton Mifflen Co. 1995.
2. Holford, Patrick. The Optimum Nutrition Bible. The Crossing Press, 1999.
3. Atkins, M.D., Robert. Dr. Atkins’ Vita-Nutrient Solution. Simon & Schuster, 1998.
4. Lavie, Rebecca. Iron and Copper Overload. Consumer Health Newsletter. 21.6, 1198.
5. Salonen JU, Nyyssonen K, Korpela H, et al. High stored iron levels associated with excess risk of myocardial infarction in western Finnish men. Circulation 1992; 86:803-11.
6. Sempos CT, Looker AC, Gillum RF, Makuc DM. Body iron stores and the risk of coronary heart disease. N Engl J Med 1994; 330:1119-24.
7. Baer DM, Tekawa IS, Hurley LB. Iron stores are not associated with acute myocardial infarction. Circulation 1994; 89:2915-8.
8. Kechl S, Willeit J, Egger G, et al. Body iron stores and the risk of carotid atherosclerosis. Circulation 1997; 96:3300-307.
9. Austin, Steve. "Is Iron Getting a Bad Rap?" Yes - And Well It Should! Quarterly Review of Natural Medicine 03-31-98 p. 44
10. Tzonou A, Lagiou P, Trichopoulou A, et al. Dietary iron and coronary heart disease risk: a study from Greece. Am J Epidemiol 1998; 147:161-6
11. Proulx, William R.; Weaver, Connie M. Ironing Out Heart Disease: Deplete or Not Deplete? Nutrition Today 02-28-95 V.30; N.1 p. 16-23
12. Lieberman, PhD, Shari and Bruning, Nancy. The Real Vitamin & Mineral Book, 2nd Ed., Avery Publishing Group, 1997.
13. Murray, Frank. The Big Family Guide to All the Minerals. Keats Publishing. 1995.
14. Kirschmann, Gayla and John. Nutrition Almanac, 4th Ed. McGraw Hill 1996
15. Somer, Elizabeth. The Essential Guide to Vitamins and Minerals. Health Media of America. Harper Perennial. 1992.
16. Courtenay, Gary and Smith, Catherine Joy. 100 Years Young. Apple Publishing. 1997
17. Hendler, Sheldon Saul. The Doctor’s Vitamin and Mineral Encyclopedia. Fireside, Simon & Schuster. 1991.
18. Murray, Michael. Encyclopedia of Nutritional Supplements. Prima Publishing. 1996.
Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 1993;90:7915-22.
Aronow WS. Serum ferritin is not a risk factor for coronary artery disease in men and women aged _62 years. Am J Cardiol 1993;72:347-8.
Aruoma OL, Bomford A, Poison RJ, Halliwell B. Nontransferrin-bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy. Blood 1988;72:1416-19.
Ascherio A, Wilier CW, Rimm EB, Giovannucci EL, Stampfer MJ. Dietary iron intake and risk of coronary heart disease among men. Circulation 1994;89:969 -74.
Babbs CF. Role of iron in the genesis of reperfusion injury following successful cardiopulmonary resuscitation: preliminary data and a biochemical hypothesis. Ann Emerg Med 1985;14: 777-83.
Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM. Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 1992;267:18148-53.
Baer DM, Tekawa IS, Hurley LB. Iron stores are not associated with acute myocardial infarction. Circulation 1994;89:2915-18.
Beard JL. Are we at risk for heart disease because of normal iron status? Nutr Rev 1993;51:112-15.
Beard J, Borel M. Iron deficiency and thermoregulation. Nutr Today 1988;23:41-5.
Bernier M, Hearse DJ, Manning AS. Reperfusioninduced arrhythmia's and oxygen-derived free radical interventions and free-radical generating system in the isolated perfused rat heart. Circ Res 1986;58:331.
Colditz GA, Willet WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987;316:1105-10.
Cook JD, Finch GA, Smith NJ. Evaluation of the iron status of a population. Blood 1976;48:44955.
Dallman PR. Biochemical basis for the manifestations of iron deficiency. Ann Rev Nutr 1986;6:1340.
Fairbanks VF. Iron in medicine and nutrition. In: Shils M, Olson J, Shike M, eds. Modern nutrition in health and disease. 8th ed. Philadelphia: Lea & Febiger, 1994;185-213.
Finch CA, Bellotti V, Stray S, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986;145:657- 63.
Frassinelli-Gunderson EP, Margen S, Brown JR. Iron stores in users of oral contraceptive agents. Am J Clin Nutr 1985;41:703-12.
Garry PJ, Wayne SJ, Koehler KM, Pathak DR, Baumgartner RN, Simon TL. Prediction of iron absorption based on iron status of female blood donors. Am J Clin Nutr 1992;56:691-8.
Gavin MW, McCarthy DM, Garry PJ. Evidence that iron stores regulate iron absorption: a set point theory. Am J Clin Nutr 1994;59:1376-80.
Gilligan DM, Badar DM, Panza JA, Quyyumi AA, Cannon RO. Acute vascular effects of estrogen in postmenopausal women. Circulation 1994;90: 786-91.
Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med 1978; 89:157-61.
Green A, Bain C. Epidemiological overview of oestrogen replacement therapy and cardiovascular disease. Baillieres Clin Endrocinol Metab 1993;7:95-112.
Gutteridge JMC, Quinlan GJ. Antioxidant protection against organic and inorganic oxygen radicals by normal human plasma: the important primary role for iron-binding and iron-oxidizing proteins. Biochem Biophys Acta 1993;1156: 144-50.
Halliwell B, Gutteridge JM. Free radicals in biology and medicine. 2nd ed. Oxford: Clarendon Press, 1989.
Herbert V. Does mega-C do more good than harm, or more harm than good? Nutr Today 1993;28: 28-32.
Herbert V. Everyone should be tested for iron disorders. J Am Diet Assoc 1992;92:1502-9.
Ihanainen M, Salonen R, Seppanen R, Salonen JT. Nutrition collection in the Kuopio Ischemic Heari Disease Risk Factor Study: nutrient intake of middle-aged eastern Finnish men. Nutr Res 1989;9:597-604.
Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1976;85:447-52.
Kehrer JP. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 1993;23:21-48.
Keys A. Seven countries: a multivariate analysis of death and coronary disease. Cambridge, MA: Harvard University Press, 1980.
Larsson G, Milsom I, Lindstedt G, Rybo G. The influence of a low-dose combined oral contraceptive on menstrual blood loss and iron status. Contraception 1992;46:327-34.
Li R, Chen X, Yah H, Durenberg P, Garby L, Hautrast J. Functional consequences of iron supplementation in iron-deficient female cotton mill workers in Beijing, China. Am J Clin Nutr 1994;59:908-13.
Liao Y, Cooper RS, McGee DL. Iron status and coronary heart disease: negative findings from the NHANES 1 epidemiotogic follow-up study. Am J Epidemiol 1994;139:704-12.
Lin P, Frid D, McGee M, Currie K, Pierce C, Rittenhouse L, Bales C. Iron (Fe) and lipid status in patients with coronary artery disease (CAD): iron is not related to extent of disease. Exp Biol 1994(abstr)8:A713.
Lozoff B, Jimenez E, Wolf AW. Long-term developmental outcome of infants with iron deficiency. N Engl J Med 1991;325:687-94.
MacDougall LG, Anderson R, McNab GM, Katz J. The immune response in iron-deficient children: impaired cellular defense mechanisms with altered humoral components. J Pediatr 1975;86: 833-43.
Magnusson MK, Sigfusson N, Sigvaldson H, Johannesson GM, Magnusson S, Thorgeirsson G. Low iron-binding capacity as a risk factor for myocardial infarction. Circulation 1994;89:102-8.
Manolio TA, Furberg CD, Shemanski L, Psaty BM, O'Leary DH, Tracy RP, Bush TL. Post-menopausal estrogen use and carotid atherosclerosis in older women. Circulation 1993;87(abstr):14.
Mann JI, Doll R, Thorogood M, Vessey MP, Waters WE. Risk factors for myocardial infarction in young women. Br J Prev Soc Med 1976;30:94-100.
Manson JE, Gaziano JM, Jonas MA, Hennekens CH. Antioxidants and cardiovascular disease: a review. J Am Coll Nutr 1993;12:426-32.
Mant D, Vilard-Mackintosh L, Vessey MP, Yeates D. Myocardial infarction and angina pectoris in young women. J Epidemiol Community Health 1987;41:215-19.
Manttari M, Manninen V, Huttunen JK, Heinonen OP, Frick MH. Serum ferritiu and ceruloplasmin as coronary risk factors: a nested case control study in the Helsinki Heart Study population. Circulation 1993;88(abstr):1-70.
Mathews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989;321:641 - 6.
McCord JM. Free radicals and prooxidants in health and nutrition. Food Technol May 1994; 106-11.
McCord JM. Is iron sufficiency a risk factor in ischemic heart disease? Circulation 1991;83:111214.
Miller M, Hutchins GM. Is iron overload a risk factor for coronary artery disease? Circulation 1993;88(abstr):1-636.
Munro H. The ferritin genes: their response to iron status. Nutr Rev 1993;51:65-73.
Negre-Salvayre A, Pieraggi MT, Mabile L, Salvayre R. Protective effect of 17 beta-estradiol against the cytotoxicity of minimally oxidized LDL to cultured bovine aortic endothilial cells. Atherosclerosis 1993;99:207-17.
Oski FA. Iron deficiency in infancy and childhood. N Engl J Med 1993;329:190-93.
Palmer JR, Rosenberg L, Shapiro S. Reproductive factors and risk of myocardial infarction. Am J Epidemiol 1992;136:408-16.
Pollitt E. Iron deficiency and cognitive function. Ann Rev Nutr 1993;13:521-37.
Porter JB, Hunter JR, Jick H, Stergachis A. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66:1-4.
Porter JB, Jick H, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70: 29-32.
Regnstrom J, Tornvall P, Kallner A, Nilsson J, Hamsten A. Stored iron levels and myocardial infarction at young age [letter]. Atherosclerosis 1994;106:123-5.
Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Giovannucci E, Willet WC. Dietary iron intake and risk of coronary disease among men. Circulation 1993;87(abstr):P22.
Rouault TA. Hereditary hemochromatosis. I Am Med Assoc 1993;269:3152-4.
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.
Sempos CT, Looker AC, Gillum RF, Makuc DM. Body iron stores and the risk of coronary heart disease. N Engl J Med 1994;330:1119-24.
Seppanen R, Hasunen K, Pekkarinen M. The food consumption and nutrient intake in Finland from 1973 to I976. Helsinki, Finland: Publications of the Social Insurance Institution, ML:22, 1981.
Slone D, Shapiro S, Kaufman DW, Rosenberg L, Miettinen OS, Stolley PD. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Engl J Med 1981;305:420-4.
Stampfer M, Grodstein F, Rosenberg I, Willet W, Hernekens C. A prospective study of plasma ferritin and risk of myocardial infarction in US physicians. Circulation 1993;688(abstr):P7.
Stampfer MJ, Colditz GA, Willet WC, Manson JE, Rosner B, Spiezer FE, Hennekens CH. Post-menopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurse's Health Study. N Engl J Med 1991;325:756-62.
Stampfer MJ, Willet WC, Colditz GA, Spiezer FE, Hennekens CH. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl] Med 1988;319: 1313-17.
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-24.
Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293-4.
Sullivan JL. Stored iron and ischemic heart disease: empirical support for a new paradigm. Circulation 1992;86:803-4.
Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J 1989;117:1177-88.
Uusitalo U, Pietinen P, Leino U. Food and nutrient intake among adults in east and southwest Finland -- a dietary survey of the Finmonica Project in 1982. Helsinki, Finland: Publications of the National Public Health Institute, B1, 1987.
Welch S. Transferrin: the iron carrier. Boca Raton: CRC Press 1987;1992:1-23.
Williams RE, Zweier JL, Flaherty JT. Treatment with deferoxamine during ischemia improves functional and metabolic recovery and reduces reperfusion-induced oxygen radical generation in rabbit hearts. Circulation 1991;83: 1006-14.
Wolf PH, Madans JH, Finucane FF, Higgins M, Kleinman JC. Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort. Am J Obstet Gynecol 1991;164: 489-94.