A BRIEF REVIEW: THE IMPLICATIONS OF IRON SUPPLEMENTATION FOR MARATHON RUNNERS ON HEALTH AND PERFORMANCE MICHAEL C. ZOURDOS,1 MARCOS A. SANCHEZ-GONZALEZ,2,3
AND
SARA E. MAHONEY4
1
Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida; 2Department of Biomedical Sciences, Larking Health Sciences Institute, South Miami, Florida; 3Larkin Community Hospital, South Miami, Florida; and 4Department of Exercise Science, Bellarmine University, Louisville, Kentucky
ABSTRACT Zourdos, MC, Sanchez-Gonzalez, MA, and Mahoney, SE. A brief review: the implications of iron supplement for marathon runners on health and performance. J Strength Cond Res 29(2): 559– 565, 2015—The marathon is considered one of the most demanding endurance events, imposing an enormous amount of physiological stress on bodily structures, the metabolic machinery, and organ systems. Scientific evidence has conclusively shown that marathoners are in need of special nutritional strategies to maintain performance and health. Indeed, among competitive athletes, marathoners are at greater risk to develop anemia, bone mineral density loss, immunosuppression, and other clinical syndromes that may affect performance. Inadequate dietary intake of the micronutrient iron has been identified as one key factor in the development of the above mentioned anomalies. In fact, iron is one of the few nutrients recommended as a supplement by the American College of Sports Medicine (ACSM), the Academy of Nutrition and Dietetics (AND), and Dietitians of Canada. Therefore, the aim of this review article is to discuss the role of iron on the marathoner’s health and performance. Special emphasis will be given to the physiological mechanisms accounting for the additional iron need in this group of athletes and the nutritional strategies intended to counteract iron deficiency.
KEY WORDS iron supplementation, marathon, running performance
INTRODUCTION
T
he 42.2-km (26.2-mile) distance run known as the marathon is commonly recognized as one of the most physically demanding endurance events. Throughout marathon training and competition, an enormous amount of physiological stress is imposed over
Address correspondence to Michael C. Zourdos, [email protected]. 29(2)/559–565 Journal of Strength and Conditioning Research Ó 2015 National Strength and Conditioning Association
bodily structures, the metabolic machinery, and to various organ systems (50). For years, scientific evidence has consistently shown that marathoners are in need of rigorous training and specifically designed nutritional strategies to maintain good health and support peak performance. In fact, among competitive athletes, marathoners are at a greater risk of developing anemia, bone mineral density loss, and immunosuppression because of the prolonged and high-intensity training hours typically required for this sport (6,15,19,37,41,51). Because of these significant training strategies, appropriate nutrient intake may be a vital component to avoid clinical disorders and ultimately augment performance and maintain health. Accordingly, recent studies seem to suggest that a deficiency of the micronutrient iron may significantly impact the development of various clinically relevant syndromes that may in turn impair marathon performance and overall health. The physiological importance of iron is remarkable in view of the fact that those with iron deficiency (ID) are known to have inefficient oxygen transport capacity, which affects energy use; this leads to a plethora of adverse health disorders such as immunosuppression and lack of bone strength (6,28,37,39). Moreover, ID has been associated with impaired performance in marathon runners (8,27,28), possibly because of inefficient oxygen transport. Although the typical marathoner’s diet is high in caloric content (;3,750 kcal$d21), it is not often rich in iron (13.6 g$d21) (63), and thereby, may not be adequate to satisfy the recommended dietary allowance (RDA) (60,63) and might accelerate ID. In addition, marathoners are known to have high erythrocyte fragility along with an augmented erythrocyte turnover (19,61); therefore, physiological iron requirements for marathoners are likely higher than those specified by the RDA. Moreover, there is a significantly increased demand of iron use among marathon runners. Therefore, it is reasonable to justify supplementation of the micronutrient iron in this particular athletic group (13,36,45,46,52,66). In fact, iron is one of the few nutrients recommended as a dietary supplement, for endurance athletes, by The American College of Sports Medicine (ACSM), the Academy of Nutrition and Dietetics (AND), and Dietitians of Canada (53,54). VOLUME 29 | NUMBER 2 | FEBRUARY 2015 |
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Iron Supplementation, Health, and Performance The appropriate use of supplemental iron involves a high degree of complexity and a certain level of expertise partly because of its potential cardiovascular toxic effects (26,57). The sports dietitian who may implement this supplementation must be aware of individual variations and genderspecific factors, which modulate iron homeostasis and metabolism. When considering supplementation, gender differences are of particular importance because women are at a higher risk of developing ID, because of limited iron storage, augmented gastrointestinal iron loss (37,38), and the ID in premenopausal women being also associated with menstrual iron loss (;1.4–1.6 mg$d21) (29,70). Because of these genders-specific factors, in addition to the increased iron demand and use associated with the marathon run, female runners must be closely monitored to establish a successful training and dietary program. Because iron is important for preserving health and optimizing performance in marathoners, it is imperative to understand its physiological and nutritional implications. Therefore, the aim of this review is to discuss the role of iron on the marathoner runner’s health and the possible impact of ID on endurance performance. Special emphasis will be given to the physiological mechanisms to account for the additional iron requirements in this group of athletes and the nutritional strategies intended to counteract ID. Additionally, gender-specific differences that may affect iron status will also be considered.
PHYSIOLOGY
OF
IRON
For a 70-kg male individual, the total body iron is approximately 3.5 g (50 mg$kg21); this makes iron the most abundant trace element present in the human body (67). Most of the body’s iron is found in blood (2,400 mg) and is distributed within erythrocytes as a component of the oxygen transport protein hemoglobin (Hb). Approximately 350 mg is located within muscle fibers and other tissues, such as enzymes and cytochromes, where iron is involved in oxygen storage (myoglobin) and metabolic processes, respectively. The remaining body iron is stored as ferritin bound in the liver (400 mg), in macrophages of the reticuloendothelial system (500 mg), in bone marrow (150 mg), and is transported by the protein transferrin (4 mg) (25,38). A typical diet contains approximately 15–20 mg of iron; however, the body is able to absorb only a small portion of the ingested amount (1–2 mg$d21) (1). In foods, iron adopts 2 different ionic forms known as heme (10%) and nonheme (90%). Because most of the nonheme iron primarily exists in a nonbioavailable oxidized Fe3+ form, it must be reduced to Fe2+ to be properly absorbed from the apical surface of duodenal enterocytes (1,2). Interestingly, the body has no effective mechanisms for excreting excessive iron (.1 mg$d21); thus, regulation of absorption from the duodenum plays a pivotal role in iron homeostasis (38). Considering these factors (i.e., low absorption rates and heme and nonheme iron), the composition of an athlete’s diet is quite important for maintaining iron status. Thus, and an endurance
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athlete who typically consumes a lower amount of iron from heme sources may need to consider iron supplementation. In terms of bodily movement, iron is transferred across intestinal epithelial cells via the transport protein: divalent metal transporter 1. Ultimately, iron in the epithelial cells or enterocytes is released into the blood by ferroportin, and is then bound to transferrin in the bloodstream (21). The regulation of iron homeostasis has been associated with multiple factors including absorption, excretion, and use. Factors that may enhance iron duodenal absorption, including ascorbic acid, are known to have a positive influence on iron status (2). Conversely, those factors that evoke a high iron demand (hemolysis and hematopoiesis) may negatively influence iron status (2,58). Thereby, iron status must be consistently monitored to prevent the development of ID especially in populations at a high risk of developing iron imbalances such as marathoners (10,13,40). Although there are several blood markers available for monitoring iron status, the specificity and clinical relevance of each marker are different. Widely used measurements include, but are not limited to, erythrocyte size, serum ferritin and transferrin concentration, plasma ascorbate, and the most recently developed soluble transferrin receptor (sTfr) expression and the hepcidin peptide assay (5,12,46,61). Interestingly, sTfr has been shown to be very sensitive for detecting and monitoring the iron status in marathon runners (61). In addition, ID in female runners may be caused by elevated hepcidin levels (12,42). The potential mechanisms that explain the correlation between ID and increased hepcidin levels are based on the fact that after an acute bout of endurance exercise (60–120 minutes), iron is retained by macrophages in response to fluctuating hepcidin levels (55,63). When properly conducted, laboratory tests may be valuable in determining iron status that may ultimately help in the prevention of ID in both male and female runners.
EFFECTS
OF
MARATHON RUN
ON
IRON HOMEOSTASIS
After a high-intensity endurance run, such as the marathon, iron dynamics are significantly altered as a result of the strenuous effort characteristic of the event. In fact, serum iron concentration may be unchanged or increased immediately after a race and may remain elevated for as long as 2 weeks (10,45). However, a decline in erythrocytes, Hb, and hematocrit has been detected between the second and the ninth day after a marathon (45,55). Additionally, various markers of oxidative stress, such as homocysteine, DNA damage, antioxidant capacity in lymphocytes, and plasma and ferritin levels, are increased in response to a long distance run (7,19,61,69). Some reports have shown that the high-intensity marathon run may cause hemoglobinuria (high levels of free plasma Hb), pulmonary hemorrhage, gastrointestinal blood loss, and most importantly foot strike associated hemolysis (16,24,33,68). In fact, the forces that promote hemolysis owing to foot strikes is considered
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Journal of Strength and Conditioning Research a pivotal factor associated with iron imbalance in marathon runners, independent of gender (46). Although exercise-induced hemolysis (the rupturing and subsequent loss of erythrocytes) has been described in the literature in regard to swimmers, cyclists, and marathoners, the underlying mechanisms that may explain the development of this specific hemolysis have not yet been fully elucidated (46,48,52). However, some of the potential factors associated with erythrocyte destruction in runners may include, but are not limited to, increased mechanical load, elevated intramuscular pressure, and the pounding of feet on solid surfaces (14,16). Running is considered as a high impact exercise in view of the fact that the body weight is considerably amplified at the time the foot hits the ground. Indeed, the mechanical energy that is imposed on the heel may increase from 0.24 J (walking) to 3.99 J (running) while causing a transient but significant deformation of the foot (14). In addition, intramuscular pressure has been reported to reach values .300 mm Hg, which are likely generated by local muscle tissue deformations in response to muscle force development or impact force absorption (3). These mechanical deformations may increase the susceptibility of hemolysis because red blood cells of marathon runners have high osmotic fragility resulting from reduced concentration of the protein spectrin within the cell membrane (30,71). Interestingly, the rate of hemolysis is more reliant on the running speed and exercise intensity than the running surface itself (46). Taken together, these acute responses seem to suggest that high-intensity aerobic exercise along with the mechanical loads imposed during a marathon race are important stressors that may induce organ damage. Given that the extreme efforts associated with a marathon alter the iron balance toward deficiency (30,62), an increased iron homeostasis may place marathoners at an increased risk of developing anemia. Anemia is a clinical syndrome characterized by an impaired systemic oxygen-carrying capacity because of a reduced erythrocyte mass and/or Hb deficiency (17). Although the development of anemia in runners may be attributed to blood volume expansion (dilutional anemia), ID anemia is the most prevalent regardless of age or gender (20). In marathon runners, ID anemia has been implicated as a causative factor of immunosuppression and high incidence of upper respiratory tract infections (30,37). Moreover, it is important to consider the fact that if the iron status of the runner is not monitored regularly, the likelihood of ID anemia may be increased. Therefore, a runner with ID anemia may compromise his or her maximal aerobic capacity, and this can consequently result in deleterious effects on endurance running performance (8).
IRON SUPPLEMENTATION AND RUNNING PERFORMANCE The use of iron supplementation with the intent to increase aerobic capacity has been studied for many years. Early studies showed that after intervention using iron supple-
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mentation, patients who were previously anemic were able to improve their Hb levels and erythrocyte mass (22). A study conducted by Schoene et al. (59) demonstrated that discrete reductions in iron and Hb levels may induce significant reductions in maximal aerobic capacity. In addition Lyle et al. (34) showed that a diet high in meat was as effective as a 50-mg$d21 oral iron supplement in protecting the ferritin status in iron-deficient (serum ferritin level of 25 mg$L21), previously sedentary, young women. Interestingly, those participants that did not receive the iron treatment and performed moderate aerobic exercise during the 12-week period significantly decreased their iron and Hb levels (34). Long-term studies ($3 months) have shown that a treatment with 100 mg of ferrous iron per day is sufficient to significantly increase the values of serum ferritin from 34 to 54 mg$L21 and liver iron from 105 to 227 mg$g21 of liver (13,27). These studies were critical in supporting the theory that exercise performance, which requires a high oxygen delivery, is significantly affected by an individual’s Hb level, while at the same time iron supplementation is needed to overcome such reductions (Table 1). Several of the studies designed to test the effect of iron supplementation on parameters related to physical fitness have produced mixed results. In most cases, runners with ID anemia or poor iron status improve performance in response to the supplement intervention. For example, iron supplementation improves iron status and endurance capacity in iron-deficient, nonanemic male and female runners (28). Further, individuals with abnormally high sTfr (.8.0 mg$L21) improved 15-km time trial performance, work rate, and max_ O2max) after 4 weeks of iron imal oxygen consumption (V supplementation (8). Additionally, in slightly anemic women, iron supplementation has been shown to improve V_ O2max, and to reduce blood lactate concentration after submaximal endurance exercise (32). Iron supplementation may also improve performance parameters that are specific to long distance runs including improved energy efficiency and reduced respiratory exchange ratio (28). These results seem to suggest that in iron-deficient athletes both with and without anemia may benefit from iron supplementation as an effective way to augment performance. It is also worth mentioning that female runners are likely better responders to iron supplements than are male runners; however, the exact mechanisms require further investigation. Conversely, iron supplementation in athletes without ID seems to be ineffective for improving athletic performance (18,39,49). If these findings are conclusive, they may represent an argument in opposition to the use of iron supplementation in marathon runners without any ID. Further, the risk of developing hemochromatosis along with iron toxicity and even cancer may be increased by the excessive use of iron supplements (57,64,65,70). Therefore, although iron supplementation may be beneficial in certain situations, the incorrect or unsupervised use of iron supplementation may be harmful and may result in serious health complications. VOLUME 29 | NUMBER 2 | FEBRUARY 2015 |
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Iron Supplementation, Health, and Performance
TABLE 1. A collection of previous results of iron supplementation for health and endurance performance.* Study
Deficiency
Supplementation protocol
Results
LaManca (32)
20 Moderately trained female athletes
Low serum ferritin (,20 ng$ml21)
8 wks; 100 mg$d21 iron
Klingshirm (31)
18 Female distance runners
Low serum ferritin (,20 mg$L21), nonanemic (Hb .12 g$dL21)
8 wks
Hinton et al. (27)
42 Female athletes
Low serum ferritin (,16 mg$L21), nonanemic (Hb .12 g$dl21)
6 wks; 100 mg ferrous sulfate per day
Brutsaert (9)
21 Female athletes
4 wks; 10 mg ferrous sulfate, twice per day
Dressendorfer et al. (18)
15 Male runners
36 mg$d21; no placebo control
Hb decreased independent of iron intake
Newhouse et al. (39)
40 Female runners
Low serum ferritin (,20 mg$L21) nonanemia (Hb .12 g$dl21) Normal Hb, tested after 20 d of high mileage training Low serum ferritin (,20 mg$L21)
Increased serum ferritin (22.5 6 3.4 vs. 14.3 6 2.2 ng$ml21), Hb (12.8 6 0.4 to 14.1 6 0.2 g$dl21), and V_ O2max (p # 0.05); TTE increased (38%, n.s.); reduced blood lactate postexercise (5.03 6 0.44 to 3.85 6 0.6 m$Ml21) Increased serum ferritin (23.4 vs. 15.7 ng$ml21); no change in TTE; no change in lactate concentration or V_ O2max Increased serum ferritin (8.11 6 0.90 vs. 14.52 6 1.5), decreased transferrin receptors (7.93 6 0.77 vs. 6.78 6 0.42); decreased 15k time (30.3 6 0.7 vs. 29.6 6 0.6) Increased MVC after 6-min fatiguing protocol (26% increase)
8 wks; 320 mg ferrous sulfate per day
Rowland et al. (56)
14 Adult runners
Low serum ferritin (,20 mg$L21), nonanemic
4 wks; 975 mg ferrous sulfate per day
Powell and Tucker (49)
10 Female distance runners
2 wks; 650 mg ferrous sulfate and 130 mg iron per day
Matter et al. (35)
85 Female marathon runners 15 Female athletes
Low serum ferritin (,20 ng$ml21) nonanemia (Hb .12 g$dl21) 16% Were deficient in serum ferritin Low Fe/TIBC, ferritin, and minimally decreased Hb values
Increased serum ferritin (17.2 6 8.9 vs. 19.7 ng$ml21); no change in work capacity and in Hb Serum ferritin increased (8.6 vs. 26.6 ng$ml21); treadmill endurance time increased (1.30 vs. 1.92 min); no change in V_ O2max or heart rate max No change in blood iron indices; no change in metabolic data
Normal iron status
50 mg$d21 (High supplementation); 10 mg$d21 (low supplementation); high iron diet
Shoene (59)
Lyle et al. (34)
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47 Sedentary female athletes beginning aerobic training program
11 wks; 50 mg elemental iron Not reported
No change in performance measures: V_ O2max, treadmill time, peak lactate No change in exercise performance, but blood lactate levels reduced at max exercise after supplementation (10.3 6 0.6 vs. 8.42 6 0.7 mmol$L21) Improved blood iron indices in 50 mg$d21 and high iron diet group, no performance measures reported
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Hinton and Sinclair (28)
20 Recreationally trained men and women
Normal Hb, low serum ferritin (,16 mg$L21)
30 mg$d21 Ferrous sulfate for 6 wks
Brownlie et al. (8)
41 Untrained females
Nonanemic, iron depleted
100 mg Ferrous sulfate for 6 wks
Peeling et al. (44)
16 Adult athletes
Injection of 100 mg of elemental iron for 20 d
Garvican (23)
27 Highly trained adult distance runners
Iron deficient (serum ferritin ,35 mg$L21), nonanemic (Hb .115 g$L21) Low serum ferritin (,35 mg$L21) or suboptimal serum ferritin (,65 mg$L21)
Intravenous (ferrous carboxymaltose) or oral supplement (ferrous sulfate)
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Improved serum ferritin (15.18 6 12.23 vs. 20.82 6 11.60 ng$ml21), increase in gross energetic efficiency (16.5 6 6.0 vs. 17.5 6 6.6%), and heart rate (153 6 15 vs. 149 6 13 b$min21) Improved 15k time trial (32.6 6 1.2 vs. 30.0 6 0.6 min), work rate (116 6 11 vs. 117 6 7 W), and V_ O2max (78.2 6 4.3 vs. 83.9 6 2.4%) in those with sTRc .8 mmol Improved serum ferritin (19 6 3 to 65 6 11 to 57 6 12 mg$L21), no change in V_ O2max, heart rate, or lactate Hb mass increased in IV-LOW group (4.9%); V_ O2max increased in IV-LOW group (3.3%)
*Hb = hemoglobin; TTE = total time to exhaustion; MVC = maximal voluntary contraction; TIBC = total iron-binding capacity.
IRON DIETARY GUIDELINES
AND
RECOMMENDATIONS
The decision to use iron supplementation in marathoners should be based on carefully performed and analyzed laboratory tests. It is commonly recommended to proceed with supplementation in athletes with basal serum ferritin concentrations of ,35 mg$L21 (53). The measurement of serum ferritin level should be made once or twice per year, and supplementation should aim to restore the serum ferritin level to a target value of approximately 60 mg$L21 (45). Most studies have shown that 100 mg$d21 of heme iron is an adequate amount to replenish iron stores within 2–3 months (11,28,37,44). Although iron supplementation has not been shown to be effective in athletes without ID, controlled supplementation may be helpful to prevent ID. Moreover, dietary sources of heme iron, such as meat products along with ascorbic acid, facilitate iron absorption and iron bioavailability (47). Finally, it has been reported that women (43) may consume a lower than normal amount of heme iron and that vegetarians (4) may have an increased affinity for ID as a result of decreased levels of heme iron intake. Therefore, monitoring iron status is of greater importance in the case of women and vegetarians, and iron supplementation may become an attractive strategy.
PRACTICAL APPLICATIONS Running the distance of a marathon and marathon-type training is known to evoke responses, which may eventually lead to improper iron balance and consequentially to ID.
These responses that may lead to disruption of iron homeostasis include mechanical, hematological, and musculoskeletal damage. Moreover, female runners are particularly susceptible to iron imbalance because of increased gastrointestinal and menstrual blood losses, and abnormally high hepcidin levels after exercise. Additionally, nutritional considerations may further contribute to ID; therefore, marathon runners should monitor heme iron intake in an effort to consume enough iron in the diet. Marathoners, coaches, and sport dietitians should be attentive to serum markers of iron status such as ferritin, Hb, and sTrf to avoid the development of ID anemia. Ultimately, iron supplementation can be used as a preventative strategy against ID and in some cases has been shown to improve performance. In fact, iron is even a supplement recommended by the ACSM, AND, and the Dietitians of Canada. Prospective studies should consider variations in iron status throughout a racing season in an attempt to understand iron dynamics so as to properly adjust dietary intakes, if necessary. In conclusion, the marathoner may experience beneficial effects from the supplemental use of iron, which are not only related to performance but are also associated with the maintenance of an adequate health status.
ACKNOWLEDGMENTS No funding was received for the preparation of this article. The authors have no professional relationships to disclose. The authors would like to thank Alex Klemp for his revisions to this manuscript. VOLUME 29 | NUMBER 2 | FEBRUARY 2015 |
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Journal of Strength and Conditioning Research 41. Ostojic, SM and Ahmetovic, Z. Weekly training volume and hematological status in female top-level athletes of different sports. J Sports Med Phys Fitness 48: 398–403, 2008. 42. Pasricha, SR, Low, M, Thompson, J, Farrell, A, and De-Regil, LM. Iron supplementation benefits physical performance in women of reproductive age: A systematic review and meta-analysis. J Nutr 144: 906–914, 2014. 43. Pasricha, SR, McQuilten, Z, Westerman, M, Keller, A, Nemeth, E, Ganz, T, and Wood, E. Serum hepcidin as a diagnostic test of iron deficiency in premenopausal female blood donors. Haematologica 96: 1099–1105, 2011. 44. Peeling, P, Blee, T, Goodman, C, Dawson, B, Claydon, G, Beilby, J, and Prins, A. Effect of iron injections on aerobic-exercise performance of iron-depleted female athletes. Int J Sport Nutr Exerc Metab 17: 221–231, 2007. 45. Peeling, P, Dawson, B, Goodman, C, Landers, G, Wiegerinck, ET, Swinkels, DW, and Trinder, D. Cumulative effects of consecutive running sessions on hemolysis, inflammation and hepcidin activity. Eur J Appl Physiol 106: 51–59, 2009. 46. Peeling, P, Dawson, B, Goodman, C, Landers, G, Wiegerinck, ET, Swinkels, DW, and Trinder, D. Training surface and intensity: Inflammation, hemolysis, and hepcidin expression. Med Sci Sports Exerc 41: 1138–1145, 2009. 47. Pe´neau, S, Dauchet, L, Vergnaud, AC, Estaquio, C, Kesse-Guyot, E, Bertrais, S, Latino-Martel, P, Hercberg, S, and Galan, P. Relationship between iron status and dietary fruit and vegetables based on their vitamin C and fiber content. Am J Clin Nutr 87: 1298–1305, 2008. 48. Pizza, FX, Flynn, MG, Boone, JB, Rodriguez-Zayas, JR, and Andres, FF. Serum haptoglobin and ferritin during a competitive running and swimming season. Int J Sports Med 18: 233–237, 1997. 49. Powell, PD and Tucker, A. Iron supplementation and running performance in female cross-country runners. Int J Sports Med 12: 462–467, 1991. 50. Reid, SA, Speedy, DB, Thompson, JM, Noakes, TD, Mulligan, G, Page, T, Campbell, RG, and Milne, C. Study of hematological and biochemical parameters in runners completing a standard marathon. Clin J Sport Med 14: 344–353, 2004. 51. Robertson, JD, Maughan, RJ, and Davidson, RJ. Faecal blood loss in response to exercise. Br Med J (Clin Res Ed) 295: 303–305, 1987. 52. Robinson, Y, Cristancho, E, and Boning, D. Intravascular hemolysis and mean red blood cell age in athletes. Med Sci Sports Exerc 38: 480–483, 2006. 53. Rodriguez, NR, DiMarco, NM, and Langley, S. American college of sports medicine position stand nutrition and athletic performance. Med Sci Sports Exerc 41: 709–731, 2009. 54. Rodriguez, NR, DiMarco, NM, and Langley, S; American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine Nutrition, and Athletic Performance. Position of the American Dietetic Association, Dietitians of Canada, and the American College of Sports Medicine: Nutrition and Athletic performance. J Am Diet Assoc 109: 509–527, 2009. 55. Roecker, L, Meier-Buttermilch, R, Brechtel, L, Nemeth, E, and Ganz, T. Iron-regulatory protein hepcidin is increased in female athletes after a marathon. Eur J Appl Physiol 95: 569–571, 2005.
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56. Rowland, TW, Deisroth, MB, Green, GM, and Kelleher, JF. The effect of iron therapy on the exercise capacity of nonanemic irondeficient adolescent runners. American Journal of Diseases of Children 142: 165–169, 1988. 57. Salonen, JT, Nyyssonen, K, Korpela, H, Tuomilehto, J, Seppanen, R, and Salonen, R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 86: 803–811, 1992. 58. Schmid, A, Jakob, E, Berg, A, Russmann, T, Konig, D, Irmer, M, and Keul, J. Effect of physical exercise and vitamin C on absorption of ferric sodium citrate. Med Sci Sports Exerc 28: 1470–1473, 1996. 59. Schoene, RB, Escourrou, P, Robertson, HT, Nilson, KL, Parsons, JR, and Smith, NJ. Iron repletion decreases maximal exercise lactate concentrations in female athletes with minimal iron-deficiency anemia. J Lab Clin Med 102: 306–312, 1983. 60. Schroder, S, Fischer, A, Vock, C, Bohme, M, Schmelzer, C, Dopner, M, Hulsmann, O, and Doring, F. Nutrition concepts for elite distance runners based on macronutrient and energy expenditure. J Athl Train 43: 489–504, 2008. 61. Schumacher, YO, Schmid, A, Konig, D, and Berg, A. Effects of exercise on soluble transferrin receptor and other variables of the iron status. Br J Sports Med 36: 195–199, 2002. 62. Simpson, RJ, Florida-James, GD, Whyte, GP, Middleton, N, Shave, R, George, K, and Guy, K. The effects of marathon running on expression of the complement regulatory proteins CD55 (DAF) and CD59 (MACIF) on red blood cells. Eur J Appl Physiol 99: 201– 204, 2007. 63. Sinclair, LM and Hinton, PS. Prevalence of iron deficiency with and without anemia in recreationally active men and women. J Am Diet Assoc 105: 975–978, 2005. 64. Stevens, RG, Jones, DY, Micozzi, MS, and Taylor, PR. Body iron stores and the risk of cancer. N Engl J Med 319: 1047–1052, 1988. 65. Swanson, CA. Iron intake and regulation: Implications for iron deficiency and iron overload. Alcohol 30: 99–102, 2003. 66. Tomten, SE and Hostmark, AT. Serum vitamin E concentration and osmotic fragility in female long-distance runners. J Sports Sci 27: 69– 76, 2009. 67. Vellar, OD. Studies on sweat losses of nutrients. I. Iron content of whole body sweat and its association with other sweat constituents, serum iron levels, hematological indices, body surface area, and sweat rate. Scand J Clin Lab Inves 21: 157–167, 1968. 68. Weight, LM, Byrne, MJ, and Jacobs, P. Haemolytic effects of exercise. Clin Sci (Lond) 81: 147–152, 1991. 69. Wu, HJ, Chen, KT, Shee, BW, Chang, HC, Huang, YJ, and Yang, RS. Effects of 24 h ultra-marathon on biochemical and hematological parameters. World J Gastroenterol 10: 2711–2714, 2004. 70. Yokoi, K. Numerical methods for estimating iron requirements from population data. Biol Trace Elem Res 95: 155–172, 2003. 71. Yusof, A, Leithauser, RM, Roth, HJ, Finkernagel, H, Wilson, MT, and Beneke, R. Exercise-induced hemolysis is caused by protein modification and most evident during the early phase of an ultraendurance race. J Applied Physiol 102: 582–586, 2007.
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AND
SARA E. MAHONEY4
1
Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida; 2Department of Biomedical Sciences, Larking Health Sciences Institute, South Miami, Florida; 3Larkin Community Hospital, South Miami, Florida; and 4Department of Exercise Science, Bellarmine University, Louisville, Kentucky
ABSTRACT Zourdos, MC, Sanchez-Gonzalez, MA, and Mahoney, SE. A brief review: the implications of iron supplement for marathon runners on health and performance. J Strength Cond Res 29(2): 559– 565, 2015—The marathon is considered one of the most demanding endurance events, imposing an enormous amount of physiological stress on bodily structures, the metabolic machinery, and organ systems. Scientific evidence has conclusively shown that marathoners are in need of special nutritional strategies to maintain performance and health. Indeed, among competitive athletes, marathoners are at greater risk to develop anemia, bone mineral density loss, immunosuppression, and other clinical syndromes that may affect performance. Inadequate dietary intake of the micronutrient iron has been identified as one key factor in the development of the above mentioned anomalies. In fact, iron is one of the few nutrients recommended as a supplement by the American College of Sports Medicine (ACSM), the Academy of Nutrition and Dietetics (AND), and Dietitians of Canada. Therefore, the aim of this review article is to discuss the role of iron on the marathoner’s health and performance. Special emphasis will be given to the physiological mechanisms accounting for the additional iron need in this group of athletes and the nutritional strategies intended to counteract iron deficiency.
KEY WORDS iron supplementation, marathon, running performance
INTRODUCTION
T
he 42.2-km (26.2-mile) distance run known as the marathon is commonly recognized as one of the most physically demanding endurance events. Throughout marathon training and competition, an enormous amount of physiological stress is imposed over
Address correspondence to Michael C. Zourdos, [email protected]. 29(2)/559–565 Journal of Strength and Conditioning Research Ó 2015 National Strength and Conditioning Association
bodily structures, the metabolic machinery, and to various organ systems (50). For years, scientific evidence has consistently shown that marathoners are in need of rigorous training and specifically designed nutritional strategies to maintain good health and support peak performance. In fact, among competitive athletes, marathoners are at a greater risk of developing anemia, bone mineral density loss, and immunosuppression because of the prolonged and high-intensity training hours typically required for this sport (6,15,19,37,41,51). Because of these significant training strategies, appropriate nutrient intake may be a vital component to avoid clinical disorders and ultimately augment performance and maintain health. Accordingly, recent studies seem to suggest that a deficiency of the micronutrient iron may significantly impact the development of various clinically relevant syndromes that may in turn impair marathon performance and overall health. The physiological importance of iron is remarkable in view of the fact that those with iron deficiency (ID) are known to have inefficient oxygen transport capacity, which affects energy use; this leads to a plethora of adverse health disorders such as immunosuppression and lack of bone strength (6,28,37,39). Moreover, ID has been associated with impaired performance in marathon runners (8,27,28), possibly because of inefficient oxygen transport. Although the typical marathoner’s diet is high in caloric content (;3,750 kcal$d21), it is not often rich in iron (13.6 g$d21) (63), and thereby, may not be adequate to satisfy the recommended dietary allowance (RDA) (60,63) and might accelerate ID. In addition, marathoners are known to have high erythrocyte fragility along with an augmented erythrocyte turnover (19,61); therefore, physiological iron requirements for marathoners are likely higher than those specified by the RDA. Moreover, there is a significantly increased demand of iron use among marathon runners. Therefore, it is reasonable to justify supplementation of the micronutrient iron in this particular athletic group (13,36,45,46,52,66). In fact, iron is one of the few nutrients recommended as a dietary supplement, for endurance athletes, by The American College of Sports Medicine (ACSM), the Academy of Nutrition and Dietetics (AND), and Dietitians of Canada (53,54). VOLUME 29 | NUMBER 2 | FEBRUARY 2015 |
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Iron Supplementation, Health, and Performance The appropriate use of supplemental iron involves a high degree of complexity and a certain level of expertise partly because of its potential cardiovascular toxic effects (26,57). The sports dietitian who may implement this supplementation must be aware of individual variations and genderspecific factors, which modulate iron homeostasis and metabolism. When considering supplementation, gender differences are of particular importance because women are at a higher risk of developing ID, because of limited iron storage, augmented gastrointestinal iron loss (37,38), and the ID in premenopausal women being also associated with menstrual iron loss (;1.4–1.6 mg$d21) (29,70). Because of these genders-specific factors, in addition to the increased iron demand and use associated with the marathon run, female runners must be closely monitored to establish a successful training and dietary program. Because iron is important for preserving health and optimizing performance in marathoners, it is imperative to understand its physiological and nutritional implications. Therefore, the aim of this review is to discuss the role of iron on the marathoner runner’s health and the possible impact of ID on endurance performance. Special emphasis will be given to the physiological mechanisms to account for the additional iron requirements in this group of athletes and the nutritional strategies intended to counteract ID. Additionally, gender-specific differences that may affect iron status will also be considered.
PHYSIOLOGY
OF
IRON
For a 70-kg male individual, the total body iron is approximately 3.5 g (50 mg$kg21); this makes iron the most abundant trace element present in the human body (67). Most of the body’s iron is found in blood (2,400 mg) and is distributed within erythrocytes as a component of the oxygen transport protein hemoglobin (Hb). Approximately 350 mg is located within muscle fibers and other tissues, such as enzymes and cytochromes, where iron is involved in oxygen storage (myoglobin) and metabolic processes, respectively. The remaining body iron is stored as ferritin bound in the liver (400 mg), in macrophages of the reticuloendothelial system (500 mg), in bone marrow (150 mg), and is transported by the protein transferrin (4 mg) (25,38). A typical diet contains approximately 15–20 mg of iron; however, the body is able to absorb only a small portion of the ingested amount (1–2 mg$d21) (1). In foods, iron adopts 2 different ionic forms known as heme (10%) and nonheme (90%). Because most of the nonheme iron primarily exists in a nonbioavailable oxidized Fe3+ form, it must be reduced to Fe2+ to be properly absorbed from the apical surface of duodenal enterocytes (1,2). Interestingly, the body has no effective mechanisms for excreting excessive iron (.1 mg$d21); thus, regulation of absorption from the duodenum plays a pivotal role in iron homeostasis (38). Considering these factors (i.e., low absorption rates and heme and nonheme iron), the composition of an athlete’s diet is quite important for maintaining iron status. Thus, and an endurance
560
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athlete who typically consumes a lower amount of iron from heme sources may need to consider iron supplementation. In terms of bodily movement, iron is transferred across intestinal epithelial cells via the transport protein: divalent metal transporter 1. Ultimately, iron in the epithelial cells or enterocytes is released into the blood by ferroportin, and is then bound to transferrin in the bloodstream (21). The regulation of iron homeostasis has been associated with multiple factors including absorption, excretion, and use. Factors that may enhance iron duodenal absorption, including ascorbic acid, are known to have a positive influence on iron status (2). Conversely, those factors that evoke a high iron demand (hemolysis and hematopoiesis) may negatively influence iron status (2,58). Thereby, iron status must be consistently monitored to prevent the development of ID especially in populations at a high risk of developing iron imbalances such as marathoners (10,13,40). Although there are several blood markers available for monitoring iron status, the specificity and clinical relevance of each marker are different. Widely used measurements include, but are not limited to, erythrocyte size, serum ferritin and transferrin concentration, plasma ascorbate, and the most recently developed soluble transferrin receptor (sTfr) expression and the hepcidin peptide assay (5,12,46,61). Interestingly, sTfr has been shown to be very sensitive for detecting and monitoring the iron status in marathon runners (61). In addition, ID in female runners may be caused by elevated hepcidin levels (12,42). The potential mechanisms that explain the correlation between ID and increased hepcidin levels are based on the fact that after an acute bout of endurance exercise (60–120 minutes), iron is retained by macrophages in response to fluctuating hepcidin levels (55,63). When properly conducted, laboratory tests may be valuable in determining iron status that may ultimately help in the prevention of ID in both male and female runners.
EFFECTS
OF
MARATHON RUN
ON
IRON HOMEOSTASIS
After a high-intensity endurance run, such as the marathon, iron dynamics are significantly altered as a result of the strenuous effort characteristic of the event. In fact, serum iron concentration may be unchanged or increased immediately after a race and may remain elevated for as long as 2 weeks (10,45). However, a decline in erythrocytes, Hb, and hematocrit has been detected between the second and the ninth day after a marathon (45,55). Additionally, various markers of oxidative stress, such as homocysteine, DNA damage, antioxidant capacity in lymphocytes, and plasma and ferritin levels, are increased in response to a long distance run (7,19,61,69). Some reports have shown that the high-intensity marathon run may cause hemoglobinuria (high levels of free plasma Hb), pulmonary hemorrhage, gastrointestinal blood loss, and most importantly foot strike associated hemolysis (16,24,33,68). In fact, the forces that promote hemolysis owing to foot strikes is considered
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Journal of Strength and Conditioning Research a pivotal factor associated with iron imbalance in marathon runners, independent of gender (46). Although exercise-induced hemolysis (the rupturing and subsequent loss of erythrocytes) has been described in the literature in regard to swimmers, cyclists, and marathoners, the underlying mechanisms that may explain the development of this specific hemolysis have not yet been fully elucidated (46,48,52). However, some of the potential factors associated with erythrocyte destruction in runners may include, but are not limited to, increased mechanical load, elevated intramuscular pressure, and the pounding of feet on solid surfaces (14,16). Running is considered as a high impact exercise in view of the fact that the body weight is considerably amplified at the time the foot hits the ground. Indeed, the mechanical energy that is imposed on the heel may increase from 0.24 J (walking) to 3.99 J (running) while causing a transient but significant deformation of the foot (14). In addition, intramuscular pressure has been reported to reach values .300 mm Hg, which are likely generated by local muscle tissue deformations in response to muscle force development or impact force absorption (3). These mechanical deformations may increase the susceptibility of hemolysis because red blood cells of marathon runners have high osmotic fragility resulting from reduced concentration of the protein spectrin within the cell membrane (30,71). Interestingly, the rate of hemolysis is more reliant on the running speed and exercise intensity than the running surface itself (46). Taken together, these acute responses seem to suggest that high-intensity aerobic exercise along with the mechanical loads imposed during a marathon race are important stressors that may induce organ damage. Given that the extreme efforts associated with a marathon alter the iron balance toward deficiency (30,62), an increased iron homeostasis may place marathoners at an increased risk of developing anemia. Anemia is a clinical syndrome characterized by an impaired systemic oxygen-carrying capacity because of a reduced erythrocyte mass and/or Hb deficiency (17). Although the development of anemia in runners may be attributed to blood volume expansion (dilutional anemia), ID anemia is the most prevalent regardless of age or gender (20). In marathon runners, ID anemia has been implicated as a causative factor of immunosuppression and high incidence of upper respiratory tract infections (30,37). Moreover, it is important to consider the fact that if the iron status of the runner is not monitored regularly, the likelihood of ID anemia may be increased. Therefore, a runner with ID anemia may compromise his or her maximal aerobic capacity, and this can consequently result in deleterious effects on endurance running performance (8).
IRON SUPPLEMENTATION AND RUNNING PERFORMANCE The use of iron supplementation with the intent to increase aerobic capacity has been studied for many years. Early studies showed that after intervention using iron supple-
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mentation, patients who were previously anemic were able to improve their Hb levels and erythrocyte mass (22). A study conducted by Schoene et al. (59) demonstrated that discrete reductions in iron and Hb levels may induce significant reductions in maximal aerobic capacity. In addition Lyle et al. (34) showed that a diet high in meat was as effective as a 50-mg$d21 oral iron supplement in protecting the ferritin status in iron-deficient (serum ferritin level of 25 mg$L21), previously sedentary, young women. Interestingly, those participants that did not receive the iron treatment and performed moderate aerobic exercise during the 12-week period significantly decreased their iron and Hb levels (34). Long-term studies ($3 months) have shown that a treatment with 100 mg of ferrous iron per day is sufficient to significantly increase the values of serum ferritin from 34 to 54 mg$L21 and liver iron from 105 to 227 mg$g21 of liver (13,27). These studies were critical in supporting the theory that exercise performance, which requires a high oxygen delivery, is significantly affected by an individual’s Hb level, while at the same time iron supplementation is needed to overcome such reductions (Table 1). Several of the studies designed to test the effect of iron supplementation on parameters related to physical fitness have produced mixed results. In most cases, runners with ID anemia or poor iron status improve performance in response to the supplement intervention. For example, iron supplementation improves iron status and endurance capacity in iron-deficient, nonanemic male and female runners (28). Further, individuals with abnormally high sTfr (.8.0 mg$L21) improved 15-km time trial performance, work rate, and max_ O2max) after 4 weeks of iron imal oxygen consumption (V supplementation (8). Additionally, in slightly anemic women, iron supplementation has been shown to improve V_ O2max, and to reduce blood lactate concentration after submaximal endurance exercise (32). Iron supplementation may also improve performance parameters that are specific to long distance runs including improved energy efficiency and reduced respiratory exchange ratio (28). These results seem to suggest that in iron-deficient athletes both with and without anemia may benefit from iron supplementation as an effective way to augment performance. It is also worth mentioning that female runners are likely better responders to iron supplements than are male runners; however, the exact mechanisms require further investigation. Conversely, iron supplementation in athletes without ID seems to be ineffective for improving athletic performance (18,39,49). If these findings are conclusive, they may represent an argument in opposition to the use of iron supplementation in marathon runners without any ID. Further, the risk of developing hemochromatosis along with iron toxicity and even cancer may be increased by the excessive use of iron supplements (57,64,65,70). Therefore, although iron supplementation may be beneficial in certain situations, the incorrect or unsupervised use of iron supplementation may be harmful and may result in serious health complications. VOLUME 29 | NUMBER 2 | FEBRUARY 2015 |
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Iron Supplementation, Health, and Performance
TABLE 1. A collection of previous results of iron supplementation for health and endurance performance.* Study
Deficiency
Supplementation protocol
Results
LaManca (32)
20 Moderately trained female athletes
Low serum ferritin (,20 ng$ml21)
8 wks; 100 mg$d21 iron
Klingshirm (31)
18 Female distance runners
Low serum ferritin (,20 mg$L21), nonanemic (Hb .12 g$dL21)
8 wks
Hinton et al. (27)
42 Female athletes
Low serum ferritin (,16 mg$L21), nonanemic (Hb .12 g$dl21)
6 wks; 100 mg ferrous sulfate per day
Brutsaert (9)
21 Female athletes
4 wks; 10 mg ferrous sulfate, twice per day
Dressendorfer et al. (18)
15 Male runners
36 mg$d21; no placebo control
Hb decreased independent of iron intake
Newhouse et al. (39)
40 Female runners
Low serum ferritin (,20 mg$L21) nonanemia (Hb .12 g$dl21) Normal Hb, tested after 20 d of high mileage training Low serum ferritin (,20 mg$L21)
Increased serum ferritin (22.5 6 3.4 vs. 14.3 6 2.2 ng$ml21), Hb (12.8 6 0.4 to 14.1 6 0.2 g$dl21), and V_ O2max (p # 0.05); TTE increased (38%, n.s.); reduced blood lactate postexercise (5.03 6 0.44 to 3.85 6 0.6 m$Ml21) Increased serum ferritin (23.4 vs. 15.7 ng$ml21); no change in TTE; no change in lactate concentration or V_ O2max Increased serum ferritin (8.11 6 0.90 vs. 14.52 6 1.5), decreased transferrin receptors (7.93 6 0.77 vs. 6.78 6 0.42); decreased 15k time (30.3 6 0.7 vs. 29.6 6 0.6) Increased MVC after 6-min fatiguing protocol (26% increase)
8 wks; 320 mg ferrous sulfate per day
Rowland et al. (56)
14 Adult runners
Low serum ferritin (,20 mg$L21), nonanemic
4 wks; 975 mg ferrous sulfate per day
Powell and Tucker (49)
10 Female distance runners
2 wks; 650 mg ferrous sulfate and 130 mg iron per day
Matter et al. (35)
85 Female marathon runners 15 Female athletes
Low serum ferritin (,20 ng$ml21) nonanemia (Hb .12 g$dl21) 16% Were deficient in serum ferritin Low Fe/TIBC, ferritin, and minimally decreased Hb values
Increased serum ferritin (17.2 6 8.9 vs. 19.7 ng$ml21); no change in work capacity and in Hb Serum ferritin increased (8.6 vs. 26.6 ng$ml21); treadmill endurance time increased (1.30 vs. 1.92 min); no change in V_ O2max or heart rate max No change in blood iron indices; no change in metabolic data
Normal iron status
50 mg$d21 (High supplementation); 10 mg$d21 (low supplementation); high iron diet
Shoene (59)
Lyle et al. (34)
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Sample
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47 Sedentary female athletes beginning aerobic training program
11 wks; 50 mg elemental iron Not reported
No change in performance measures: V_ O2max, treadmill time, peak lactate No change in exercise performance, but blood lactate levels reduced at max exercise after supplementation (10.3 6 0.6 vs. 8.42 6 0.7 mmol$L21) Improved blood iron indices in 50 mg$d21 and high iron diet group, no performance measures reported
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Hinton and Sinclair (28)
20 Recreationally trained men and women
Normal Hb, low serum ferritin (,16 mg$L21)
30 mg$d21 Ferrous sulfate for 6 wks
Brownlie et al. (8)
41 Untrained females
Nonanemic, iron depleted
100 mg Ferrous sulfate for 6 wks
Peeling et al. (44)
16 Adult athletes
Injection of 100 mg of elemental iron for 20 d
Garvican (23)
27 Highly trained adult distance runners
Iron deficient (serum ferritin ,35 mg$L21), nonanemic (Hb .115 g$L21) Low serum ferritin (,35 mg$L21) or suboptimal serum ferritin (,65 mg$L21)
Intravenous (ferrous carboxymaltose) or oral supplement (ferrous sulfate)
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Improved serum ferritin (15.18 6 12.23 vs. 20.82 6 11.60 ng$ml21), increase in gross energetic efficiency (16.5 6 6.0 vs. 17.5 6 6.6%), and heart rate (153 6 15 vs. 149 6 13 b$min21) Improved 15k time trial (32.6 6 1.2 vs. 30.0 6 0.6 min), work rate (116 6 11 vs. 117 6 7 W), and V_ O2max (78.2 6 4.3 vs. 83.9 6 2.4%) in those with sTRc .8 mmol Improved serum ferritin (19 6 3 to 65 6 11 to 57 6 12 mg$L21), no change in V_ O2max, heart rate, or lactate Hb mass increased in IV-LOW group (4.9%); V_ O2max increased in IV-LOW group (3.3%)
*Hb = hemoglobin; TTE = total time to exhaustion; MVC = maximal voluntary contraction; TIBC = total iron-binding capacity.
IRON DIETARY GUIDELINES
AND
RECOMMENDATIONS
The decision to use iron supplementation in marathoners should be based on carefully performed and analyzed laboratory tests. It is commonly recommended to proceed with supplementation in athletes with basal serum ferritin concentrations of ,35 mg$L21 (53). The measurement of serum ferritin level should be made once or twice per year, and supplementation should aim to restore the serum ferritin level to a target value of approximately 60 mg$L21 (45). Most studies have shown that 100 mg$d21 of heme iron is an adequate amount to replenish iron stores within 2–3 months (11,28,37,44). Although iron supplementation has not been shown to be effective in athletes without ID, controlled supplementation may be helpful to prevent ID. Moreover, dietary sources of heme iron, such as meat products along with ascorbic acid, facilitate iron absorption and iron bioavailability (47). Finally, it has been reported that women (43) may consume a lower than normal amount of heme iron and that vegetarians (4) may have an increased affinity for ID as a result of decreased levels of heme iron intake. Therefore, monitoring iron status is of greater importance in the case of women and vegetarians, and iron supplementation may become an attractive strategy.
PRACTICAL APPLICATIONS Running the distance of a marathon and marathon-type training is known to evoke responses, which may eventually lead to improper iron balance and consequentially to ID.
These responses that may lead to disruption of iron homeostasis include mechanical, hematological, and musculoskeletal damage. Moreover, female runners are particularly susceptible to iron imbalance because of increased gastrointestinal and menstrual blood losses, and abnormally high hepcidin levels after exercise. Additionally, nutritional considerations may further contribute to ID; therefore, marathon runners should monitor heme iron intake in an effort to consume enough iron in the diet. Marathoners, coaches, and sport dietitians should be attentive to serum markers of iron status such as ferritin, Hb, and sTrf to avoid the development of ID anemia. Ultimately, iron supplementation can be used as a preventative strategy against ID and in some cases has been shown to improve performance. In fact, iron is even a supplement recommended by the ACSM, AND, and the Dietitians of Canada. Prospective studies should consider variations in iron status throughout a racing season in an attempt to understand iron dynamics so as to properly adjust dietary intakes, if necessary. In conclusion, the marathoner may experience beneficial effects from the supplemental use of iron, which are not only related to performance but are also associated with the maintenance of an adequate health status.
ACKNOWLEDGMENTS No funding was received for the preparation of this article. The authors have no professional relationships to disclose. The authors would like to thank Alex Klemp for his revisions to this manuscript. VOLUME 29 | NUMBER 2 | FEBRUARY 2015 |
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