Preface: Confronting Ferrotoxic Disease

By Leo Zacharski, M.D.

In “Dumping Iron”, Dennis Mangan has provided the reader access to a massive scientific data pool linking body iron overload to major diseases of mankind.

Iron, in excess of requirements for normal respiration, generates highly toxic hydroxyl radicals contributory to “inflammation and oxidative stress responsible for the grand global health challenges: diabetes, cancer, neurodegenerative disorders, hypertension and cardiovascular disease.”¹i The very thought that so pedestrian and easily controlled a culprit might be linked to premature suffering and death may explain partly why the concept of “ferrotoxic disease” has been embraced reluctantly or not at all².ii Among well-documented health hazards, iron excess must remain one of the world’s best kept secrets.

Using masterful prose, Mangan has outlined the magnitude of the problem and described factors responsible for “iron blindness” among health care providers and within the general public. This volume can claim status as an iron nutrition owner’s manual.

The degree to which iron is noxious is determined by the dose times the duration: the more iron on-board and the longer it remains, the greater the risk. “Normal” iron levels represented by ferritin are those levels associated with minimum disease risk and maximum longevity.

Several epidemiological studies have shown increased longevity associated with ferritin below an upper threshold of about 80 to 90 ng/ml, the plateau in post-menopausal women (shown in the first figure in this book) that is also conducive to older age in men – those with higher levels have dropped out of the population by dying. Plots of paired values for the ferritin and h³emoglobin obtained from a large clinical trial of iron reduction showed that rising ferritin levels up to about 80 ng/ml are associated with rising hemoglobin levels within the normal range, indicating use of iron for red cell oxygen transport. Above the 80 ng/ml cut-off, ferritin levels continue to rise but without physiologic correspondence.

Ferritin levels are a continuum and susceptibility to iron toxicity thus may commence at ferritin levels mistakenly considered to be within the “reference range” used commonly. This explains why much higher ferritin levels are more clearly disease-associated while levels in the 100 to 150 ng/ml range “mysteriously” appear in some, but not all, studies as disease-associated.iii⁴⁵⁶

The tragedy of ferrotoxic disease is compounded by unnecessary ingestion of highly absorbable iron supplements by an unwary public, for a disease that most people do not have (iron deficiency), and without their knowledge or consent. Recommendations for “minimum daily requirements” for iron used to justify supplementation are based on estimates applied blindly to a popul⁷ation without consideration of existing body iron levels.iv Iron supplementation has also been justified based on the existence of “small pale red cells” in populations only a small fraction of which have iron deficiency. Thus, Blacks may appear to have iron deficiency based on red cell morphology but they do not; they have genetically-determined variant red cell hemoglobinization and iron excess.v Oriental populations commonly have thalassemia or hemoglobin E resulting in similar red cell morphology, but also have iron excess rather than deficiency. Supplement use in such populations has no effect on hemoglobin levels but rather drives up ferritin levels increasing risk of ferrotoxicity.vi

Note in the first graph in this book that low risk ferritin levels in young adult males and pre-menopausal females rise into the at-risk range in middle-aged males and post-menopausal females. The imperceptibly slow rise in ferritin levels of about 3 to 5 ng/ml per year could easily be accounted for by ubiquitous but inappropriate iron supplementation of processed foods.vii This increase need not occur.

Pharmaceutical companies have no incentive to test treatment hypotheses with no prospect of payback. Federal funding agencies have shown little interest in studying the therapeutic/preventive value of shifting potentially noxious excess iron out of storage sites into a physiologic (red cell) compartment, as is achieved with phlebotomy. Potent pharmaceutical iron binding drugs (chelators) do not distinguish between physiologic and unphysiologic (excessive) iron, and their use may be accompanied by significant toxicity.

I submit that “Dumping Iron” should be required reading in science and nutrition for high school and above. The ultimate triumph of “Dumping Iron” might be an informed public that will increasingly access ferritin test screening, and health care providers better prepared to interpret tests of iron status, particularly the ferritin level. Acknowledgment of risks of iron overload and proper product labeling might lead to reduced public iron intoxication and improved population health to a degree that would be no less than monumental!

Dr. Leo Zacharski is Professor of Medicine, Geisel School of Medicine at Dartmouth College, and manages an iron overload clinic at the Hitchcock Hospital, Lebanon, NH.