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Bench to Bedside

Too much iron?
By Leo R. Zacharski, M.D.

We are barraged today with iron in vitamin and mineral preparations and in all manner of iron-supplemented foods, yet too much iron in our diet can be dangerous and may increase the risk of cardiovascular disease. In fact, most of us take in several times more iron than we need to replace the trace amounts that we lose in urine and in cells that are shed from our skin and intestinal tract.

In 1981, Jerome Sullivan, then a pathologist at the University of South Florida, observed a correlation between increased levels of iron and ageand gender-related heart-attack rates in the general population. He published his hypothesis— that body iron stores might contribute over time to vascular disease—in the Lancet. Sullivan's hypothesis was controversial because hormone levels or other factors were considered to be more likely contributors to heart disease risk. But more recent epidemiological evidence has discounted the role of hormones and has supported Sullivan's findings.

Excess: The key is in deciphering what levels of iron might be toxic. Amounts of iron are assessed by measuring serum levels of two iron-binding proteins—transferrin, made by the liver, and ferritin, made by all the cells in the body. Transferrin picks up iron from the intestines and from storage sites, and delivers it to cells where the iron reacts with oxygen for respiration and supports DNA synthesis. Only a tiny fraction of total body iron is bound to transferrin. However, all cells are programmed to anticipate damage from too much iron and to produce ferritin to capture excess iron. Excess iron can be tracked because leftover iron-protein complexes have nowhere to go and break down to form microscopically detectable deposits—that look like purple blobs in stained tissue—called hemosiderin. Hemosiderin is deposited throughout the body in the reticuloendothelial system, the inflammatory cell network that defends against outside threats and serves as the body's "toxic waste dump."

Too much iron in our diet can be dangerous. Will cereal manufacturers soon label their products "no iron added"?
Illustration: Suzanne DeJohn

Levels: Ferritin levels vary dramatically between males and females and with age. The normal range for ferritin—15 to 300 nanograms per milliliter (ng/ml) of serum—represents a whopping 20-fold spread that is far greater than the range for virtually any other blood measurement. Ferritin levels in children, menstruating women, and athletes average about 25 ng/ml. In children, there's less apt to be excess iron because growing muscles use so much of it. Menstruating women— and blood donors—shed excess iron in the blood they lose. In males, ferritin levels begin rising in the late teens. In females, the levels don't increase until after menopause. It was because of this disparity that Sullivan was able to correlate ferritin levels with coronary risk.

How can an essential mineral like iron be toxic in excess? We know that as iron atoms lose or gain electrons, they become highly reactive free radicals that can damage lipids and cells. The more iron, the more free radicals; the more damage, the more disease. Too much iron activates platelets, increases the cellular trigger for blood clotting, and decreases levels of nitric oxide, the molecule that causes blood vessels to relax. But when the amount of iron is decreased, the levels of nitric oxide and "good" cholesterol increase, and the level of "bad" cholesterol decreases.

In 1993, we began testing the iron hypothesis in patients at the VA Medical Center in White River Junction, Vt. We confirmed that ferritin levels vary with age and that they are different in males and females. We also noticed that in blacks (compared to whites and Hispanics), there's an exaggerated rise in ferritin with age for both genders. We found that iron stores can be reduced—by calibrated blood removal—to ferritin levels typical in children and premenopausal women. Then, in 1999, we began a controlled study to examine the long-term effects of reducing iron stores in patients with vascular disease. Enrollment has been completed, with 1,350 patients entered from 24 VA hospitals. We already know that high ferritin levels predict coronary risk, adverse stroke outcome, atherosclerosis, and increased thickness of the carotid artery wall, as well as poor blood flow through the heart muscle. Our study is designed to determine whether purposely reducing iron stores will alter long-term patient outcomes. Time will tell.

Beware: How will policy-makers, and those concerned with environmental toxins and "natural" foods, view the results? The FDA allows sale of over-the-counter iron preparations ad lib for self-treatment, and the Centers for Disease Control and Prevention has taken a "wait-and-see" attitude. But vitamin manufacturers recognize the problem—they already make iron-free products for men and for senior citizens. Will cereal manufacturers soon label their products "no iron added"? For now, individuals are advised to consult with their physicians, get tested, and heed the advice "Consumer beware!"

At the very least, this hypothesis signals a special interdependence between humans and the environment and a possible new way for individuals to participate in their own health maintenance. The implications of finding a low cost, low-tech, non-toxic, drugless method for disease containment continue to challenge the imagination.

"Bench to Bedside" explores the research underlying advances in clinical medicine. Zacharski is a professor of medicine at Dartmouth Medical School and associate chief of staff for research at the VA Medical Center in White River Junction, Vt.

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