Iron deficiency is common – very common. Estimates of the prevalence of iron deficiency in the U.S. vary depending on the age of the population studied and co-morbidities. In the National Health and Nutrition Examination Survey (NHANES III) iron deficiency was present in 1-2% of adults (1). Iron deficiency without anemia was more common, occurring in up to 11 percent of women (most often premenopausal) and 4 percent of men. The prevalence of iron deficiency anemia was significantly higher in older adults, being between 12 and 17 percent in persons 65 years and older (2, 3). An astonishing 35% of the adults, age 65 and older, had unexplained anemia (3). Of those with iron deficiency, only 50% normalized their hemoglobin in response to oral iron replacement.
Two studies (one recent and one not-so-recent) shed light on what I think is a fascinating and under-recognized consequence of iron deficiency. The morbidity associated with iron deficiency is not due just to anemia. In fact, the symptoms associated with iron deficiency may have less to do with the anemia itself and much more to do with iron deficiency and its impact on iron dependent cellular metabolism.
The FAIR-HF trial published in the New England Journal (4) randomized 459 patients with chronic heart failure and iron deficiency to receive either placebo or intravenous iron (ferric carboxymaltose). Fifty percent of the treatment group reported being much or moderately improved on the self-reported Patient Global Assessment tool with improvement in NYHA functional class, six-minute walk test, and other outcome measures. Importantly, the iron deficient patients treated with intravenous iron showed improved functional status regardless of whether their starting hemoglobin was greater than or less than 12 g/dl when enrolled in the study. Could iron deficiency itself, rather than anemia be the more important contributor to the signs and symptoms of anemia?
An animal studied published in 1976 by the University of Washington School of Medicine offers insight into this question (5). In this study rats were made anemic, iron deficient, or both, and their running ability measured using a small animal treadmill. As expected, the rats that were severely anemic with hemoglobin less than 6 g/dl had severely impaired running ability regardless of iron status. However, there was an impressive difference between iron replete and iron deficient rats when the hemoglobin was increased to a level consistent with moderate anemia (10 g/dl). Again, iron deficient animals showed a very limited ability to run. However, there was rapid reversibility of this dysfunction (3-4 days) when iron deficiency was corrected even when the hemoglobin was maintained at only 10g/dl. This correlated with normalization of oxidative phosphorylation in mitochondria prepared from the skeletal muscle of the study animals.
The lesson: transfusion is almost never the treatment of choice in iron deficiency anemia. These two studies teach us that the treatment for iron deficiency is iron! Iron replacement can be done quickly, easily and safely with intravenous iron in patients with symptomatic iron deficiency (with or without anemia) with rapid clinical and symptomatic improvement of the iron deficient patient.
1) JAMA 1997;277:973
2) Blood. 2004;104(8):2263
3) Blood Cells Mol Dis. 2011;46(2):159
4) N Engl J Med 2009;361:2436
5) Journal Clin Invest. Vol. 58 August 1976.447
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