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I attended remotely the American College of Cardiology’s (ACC) Care of the Athletic Heart Conference (June 12-14, 2025). Before attending I had started drafting this post with this introduction:
“I love sports cardiology conferences, but I cannot remember ever hearing a lecture of iron (Fe) deficiency in athletes at these sessions. Every clinician knows that Fe deficiency is critical in red cell production and can cause Fe deficiency anemia. What is not appreciated is that Fe deficiency can cause decreased exercise performance without “anemia”, and that endurance training can decrease Fe absorption.”
I started this post partly because of an excellent review of Fe deficiency in JAMA from March 2025 (1), but I wrote too soon because on the last day of the three-day ACC meeting, Shannon Grappe, MSN, APRN, from Dr. Ben Levine’s group in Dallas, gave an excellent presentation on Fe deficiency in athletes. Nevertheless, and for those who missed the session, here is a review of what general cardiologists, sports cardiologists and other clinicians should know about Fe deficiency in active people.
One of my sports cardiology colleagues at Hartford HealthCare, Dr. Antonio Fernandez, recently saw a college 800 m runner whose 800 m times had decreased from the 2:10s per race to the 2:20s. His hematocrit / hemoglobin were normal at 43% (nl - 40 – 50) and 13.9 g/dL (nl – 13.5-17.5). His Fe and percent saturation were 35 (nl - 50-105 mcg/dL) and 8 (nl - 20-48%), respectively. A ferritin value was ordered, but not performed. Many of his red cell values were low normal, but normal. Despite his ”normality”, he improved remarkably within weeks of oral Fe therapy. We don’t yet have repeat blood values and performance times because he left school and track for the summer.
I am not a hematologist, and my comments are based on the observations of a cardiologist who occasionally uncovers anemia and/or Fe deficiency as the cause of decreased exercise tolerance and who is interested in hemochromatosis. (2) But I have always been impressed that patients with Fe deficiency anemia are often symptomatic at higher hematocrit values than are patients with other types of anemia, such as those with B12 deficiency. I have seen several patients with B12 deficiency who had few symptoms despite hematocrits below 10%. In contrast, patients with Fe deficiency are often symptomatic once their hematocrit dips below 30%.
What Antonio’s patient and the JAMA review indicate is that patients can have Fe deficiency despite not being anemic. I often ask an expert to review my blog pieces before I publish them. So I asked Randy Eichner, MD, to review this post for me. Randy is a friend, former physician for the University of Oklahoma football team, and has been called “the father of sports hematology”. Randy’s opinion is that there is really no such thing as non-anemic Fe deficiency. He thinks that these athletes have an anemia for them, even if it doesn’t reach the definition of anemia. He thinks this because virtually all the studies that show increased performance with Fe supplementation also show an increase in the subject’s hemoglobin/hematocrit values. Randy’s thoughts are summarized elsewhere. (3)
The mechanism for this intolerance of mild anemia with Fe deficiency and for developing symptoms without “anemia” may be Fe’s role in muscle metabolism. We know that Fe is required to bind oxygen to hemoglobin for oxygen transport , but Fe is also important in myoglobin function. Both hemoglobin and myoglobin are globins. In fact, myoglobin also binds oxygen and facilitates the transport of oxygen into the muscle. The oxygen bound by myoglobin is also used for muscle metabolism in the first seconds of exercise. Fe also is required for electron transport in the mitochondria.
And here is a key point, Fe deficiency can exist with normal hematocrits. (1) Fe deficiency probably causes exercise intolerance with normal hematocrits and Fe values because of Fe’s role in muscle energy metabolism, and because athletes are sensitive to even mild Fe deficiency.
Normal healthy athletes can develop anemia from several mechanisms, not related to Fe. Endurance exercise training increases plasma volume. The expanded plasma volume probably occurs because renal perfusion is decreased during vigorous exercise because of vasoconstriction of blood flow to the renal and splanchnic circulations so that blood can go where it’s needed to exercise, the skeletal muscle. The decreased renal perfusion activates the renin-aldosterone-angiotensin pathway ultimately leading to increased aldosterone levels and volume retention.
Peter Herbert, MD, and I in the 1980s made radio-labelled HDL and injected it into distance runners (including me - Peter was a control) to determine HDL survival in the circulation. We demonstrated that HDL lasts longer in the athletes, but by measuring the radio-labelled HDL concentration 10 minutes after injection, we were able to measure plasma volume. We demonstrated that plasma volume was 500 (4) to 800 (5) ml larger in the runners despite the fact that the runners had much smaller body sizes. This volume expansion dilutes the red blood cell concentration and produces a hematocrit about 10% lower than it would be in not-endurance-trained individuals. The 10% comes from the fact that normal plasma volume is around 5 L, so that 500 ml more volume would produce about a 10% dilution. We also think that this volume expansion partly explains why endurance athletes have about a 10% lower LDL because within 48 hours of stopping distance runners from running, they lost 5% of their plasma volume (6) and increased their LDL 10%. ( 7) Volume expansion also partly explains why menstruating woman have their lowest LDL levels shortly before menstruation, something we also demonstrated years ago. (8)
But dilution as a cause of low hematocrits should always be a diagnosis of exclusion. I once made that diagnosis of “runner’s anemia” in a runner in the early 1980s before ferritin levels were readily available, only to have him come back 2 weeks later with a seriously bleeding, duodenal ulcer. So, believer beware.
In addition to the expanded plasma volume, endurance athletes might develop anemia from “foot strike hemolysis”. This was first reported in the 1890s, and was also called “march hemoglobinuria” because it was observed in soldiers after marching. It has primarily been attributed to red cell compression and destruction, but Dr. Eichner has also reported hemolysis in swimmers after workouts so the hemolysis might also be related to shear forces placed on red cells during exercise. (9)
Neither plasma volume expansion nor foot strike hemolysis should be severe enough to cause Fe deficiency, so what causes the Fe deficiency in athletes?
Sweat contains some Fe, so sweating could contribute to Fe deficiency in athletes as can a no-meat diet, celiac disease, heavy menses, and proton pump inhibitors, which reduce the acidification of Fe reducing absorption as we have discussed before.(2) But I suspect the real culprit is hepcidin.
Fe is absorbed in the duodenum by ferroportin, which transports Fe from the duodenum to the circulation. Hepcidin regulates Fe absorption by binding to ferroportin. Hepcidin’s binding to ferroportin reduces Fe transfer from the duodenum to the circulation. Therefore, if hepcidin levels are high, Fe absorption is reduced. Inflammation increases hepcidin levels, thereby reducing Fe absorption. We summarized years ago that exercise produces an acute inflammatory response, even though inflammatory markers in athletes are chronically lower. (10) So it is possible that the acute inflammation from frequent exercise sessions increases hepcidin levels which reduce Fe absorption.
Whatever the cause, Fe deficiency is common in endurance athletes. An abstract report of 277 participants in running races of 21 or 42 km defined severe iron deficiency as ferritin under 15 ng/mL or ferritin under 35 ng/mL and an iron saturation under 16%. (10) Clinical iron deficiency was defined as a ferritin <30 ng/mL, or a ferritin under 100 ng/mL and an Fe saturation under 20%. Severe Fe deficiency was present in 15% of the women and 3% of men. Clinical Fe deficiency was present in 48% of the women and 15% of the men.
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At the ACC Athletic Heart Program, Andre La Gerche MD, PhD, a prominent exercise cardiologist from Australia, noted that he has seen some female athletes with neurocardiogenic syncope and Fe deficiency who improved with Fe replacement. So, Fe deficiency should be kept in the differential for more than just decreased exercise tolerance in athletes.
Replacement therapy can be done orally or intravenously. I am not expert at either. But oral Fe should be given usually in the morning with an acidic substance such as orange juice since the Fe+3 absorbs more readily than the Fe+2. Oral Fe replacement often causes nausea, but can be given several times weekly instead of daily. Actually, intermittent Fe may be preferrable because daily iron dosing increases hepcidin and thereby reduces Fe absorption. Intravenous iron can be used if the athlete cannot tolerate oral replacement, or for more rapid resolution of symptoms. There are at least six intravenous iron preparations, but clinicians dealing with athletes should be aware that the ferric carboxymaltose formulation can produce low phosphate levels which can produce fatigue, cramps and muscle weakness so may not be the best choice for athletes. (1)
So, the rules are:
- Exclude Fe deficiency in athletes with decreased exercise performance even if the hematocrit is normal because that hematocrit may not be normal for them.
- Include Fe deficiency in the differential diagnosis of multiple other cardiovascular complaints in athletes. Fe deficiency may not be the cause of the symptoms, but it may, especially if an athlete's hematocrit increases with Fe supplementation.
1. Auerbach M, DeLoughery TG, Tirnauer JS. Iron Deficiency in Adults: A Review. JAMA. 2025 May 27;333(20):1813-1823.PMID: 40159291
2. https://pauldthompsonmd.substack.com/p/do-antacids-treat-hemochromatosis
3. Eichner ER. Athletes, Anemia, and Iron Redux. Curr Sports Med Rep. 2021 Jul 1;20(7):335-336. PMID: 34234086
4. P D Thompson 1, E M Cullinane, S P Sady, M M Flynn, C B Chenevert, P N Herbert. High density lipoprotein metabolism in endurance athletes and sedentary men. Circulation. 1991 Jul;84(1):140-52. PMID: 2060090
5. P N Herbert, D N Bernier, E M Cullinane, L Edelstein, M A Kantor, P D Thompson. High-density lipoprotein metabolism in runners and sedentary men. JAMA. 1984 Aug;252(8):1034-7. PMID: 6748208
6. Cullinane EM, Sady SP, Vadeboncoeur L, Burke M, Thompson PD. Cardiac size and VO2max do not decrease after short-term exercise cessation.Med Sci Sports Exerc. 1986 Aug;18(4):420-4. PMID: 3747802
7. Thompson PD, Cullinane EM, Eshleman R, Sady SP, Herbert PN. The effects of caloric restriction or exercise cessation on the serum lipid and lipoprotein concentrations of endurance athletes. Metabolism. 1984 Oct;33(10):943-50..PMID: 6482736
8. Cullinane EM, Yurgalevitch SM, Saritelli AL, Herbert PN, Thompson PD. Variations in plasma volume affect total and low-density lipoprotein cholesterol concentrations during the menstrual cycle. Variations in plasma volume affect total and low-density lipoprotein cholesterol concentrations during the menstrual cycle. Metabolism. 1995 Aug;44(8):965-71. PMID: 7637653
9. G B Selby, E R Eichner. Endurance swimming, intravascular hemolysis, anemia, and iron depletion. New perspective on athlete's anemia. Am J Med. 1986 Nov;81(5):791-4. PMID: 3776985
10. Christos Kasapis 1, Paul D Thompson. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review., J Am Coll Cardiol. 2005 May 17;45(10):1563-9. PMID: 15893167
12. Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, Melse-Boonstra A, Brittenham G, Swinkels DW, Zimmermann MB. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015 Oct 22;126(17):1981-9. PMID: 26289639
Antonio Fernandez, MD and Randy Eichner, MD provided advice on this blog, but I am solely responsible for the final publication.
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