When endurance running leads to functional iron deficiency

In this issue of Blood Advances, the findings of Tobiasch et al¹ suggest that extreme long-distance trail running at higher elevations induces functional iron deficiency through rather complex interactions among inflammatory, hemolytic, and hypoxic responses.

In 7 elite athletes participating in the 86.9-km “Trail Long” race of the World Mountain and Trail Running Championships, the authors measured serum biomarkers and peripheral blood mononuclear cell (PBMC) transcriptional responses before and immediately after competition. The physiologic stress was substantial: more than 6500 m of ascent, up to 2400 m of elevation, prolonged exertion for a median of 12 hours, and increases in muscle injury markers, renal dysfunction markers, and core body temperature.

Increases in plasma C-reactive protein, interleukin-6 (IL-6), and neopterin concentrations during the long-distance trail run indicated a proinflammatory response, whereas the increase in IL-10 level suggested a compensatory anti-inflammatory response.^2,3 Increases in lactate dehydrogenase and bilirubin levels were compatible with hemolysis, with declines in haptoglobin and hemopexin concentrations indicating the scavenging of free hemoglobin and heme.⁴ Increases in erythropoietin (EPO) and transferrin levels were consistent with a hypoxic response.⁵

Hepcidin, the master regulator of iron metabolism, increased during the long-distance run. Previous studies have shown transient post-exercise increase in hepcidin level,^6,7 but this study extends those findings to ultradistance mountain running at higher altitudes.¹ Hepcidin is a hepatic peptide that inhibits the absorption of iron by enterocytes and the release of iron from macrophages through the degradation of ferroportin in the cellular membrane. Hepcidin is upregulated in response to higher iron stores and plasma iron concentrations, as reflected by serum ferritin and transferrin saturation, and inflammation, as reflected by elevated IL-6 concentration; however, it is downregulated by increased erythropoiesis, as reflected in higher EPO and erythroferrone levels, and decreased iron availability, as reflected in elevated transferrin concentration and low transferrin saturation. Elevations in EPO and transferrin levels can both be reflective of a hypoxic response.⁵

Iron is essential not only for hemoglobin synthesis but also for many other cellular processes. In athletes, causes of iron deficiency may include march hemoglobinuria (foot-strike hemolysis),⁴ gastrointestinal bleeding, and menstruation. But the findings of Tobiasch et al indicate that a single episode of extreme endurance exercise with higher-elevation exposure results in increased hepcidin level and functional iron deficiency, in which iron stores are present but have reduced availability. In this case, an inflammatory increase in IL-6 level stimulates hepcidin production with the resultant degradation of ferroportin and retention of iron within macrophages and enterocytes, limiting delivery to erythroid precursors and peripheral tissues.^2,3 In this study, the tendency of the hypoxic response to increase EPO and transferrin levels and thereby reduce hepcidin production was overshadowed by the tendency of the inflammatory response to increase hepcidin production. Furthermore, elevated EPO level was not accompanied by an increased concentration of erythroferrone, which mediates the effect of EPO in the suppression of hepcidin.

Functional iron deficiency was manifested by declines in serum iron concentration and transferrin saturation and an increase in transferrin level at the same time that there were significant increases in hepcidin and ferritin concentrations (see figure). Increases in IL-6 and C-reactive protein levels support inflammation because they are the dominant drivers of decrease in serum iron and increase in ferritin levels. The increase in IL-10 concentration suggests a concurrent anti-inflammatory response as well. Hepcidin likely mediated hypoferremia by restricting intestinal iron absorption and promoting macrophage iron retention by inhibiting the iron exporter ferroportin. The fact that hepcidin levels rose rather than declined, despite significant increases in EPO and transferrin concentrations, may be partially explained by the lack of a corresponding rise in erythroferrone level, which is the mediator of EPO’s suppressive effect on hepcidin production. Perhaps the 12-hour race window was extremely short for the marrow to mount an erythroferrone-mediated response or it may be that the surge in IL-6 level acted as a dominant molecular “override,” driving hepcidin level upward and effectively silencing the signals that would otherwise promote iron availability.

Extreme endurance exercise at higher altitude induces IL-6–driven inflammation and mild intravascular hemolysis, leading to increased hepcidin production, macrophage iron sequestration, reduced circulating iron level and transferrin saturation, and ultimately functional iron deficiency with intracellular low iron concentration despite normal or elevated ferritin levels. A concurrent hypoxic response leads to increased EPO and transferrin levels, but their potential effect on decreasing hepcidin concentration is overshadowed by the effect of IL-6. Hb, hemoglobin; Tf, transferrin; Tsat, transferrin saturation.

The observations of Tobiasch et al support the concept of “foot-strike hemolysis,” which may occur in endurance athletes.⁴ Although hemolysis releases hemoglobin and heme, with the expected effects of iron release and hepcidin suppression, rapid sequestration by haptoglobin and hemopexin may limit heme-driven inflammation and promote anti-inflammatory signaling, including IL-10 production.⁸

Of the 4 significant PBMC transcriptional changes during the extreme long-distance run, decrease in the ferroportin level was especially interesting because it is consistent with the predominant IL-6–mediated increase in hepcidin concentration, a major finding of this study. This pattern resembles an intracellular iron-deficiency response: cells increase import and reduce export when iron becomes scarce. In effect, although plasma ferritin level increased, PBMCs behaved as though they were iron-deprived.¹

These findings suggest that iron deficiency matters even before anemia develops, with the possibility that tissue iron restriction can impair cellular function and exercise performance. Previous studies in women with iron depletion but without anemia showed that iron supplementation enhances favorable physiologic adaptations to endurance training, thereby increasing endurance capacity.⁹

Several limitations deserve attention. The study is necessarily small, with only 7 elite athletes, and immediate post-race sampling cannot determine the duration of these abnormalities. Whether changes resolve within hours, persist for days, or accumulate across repeated training cycles is unknown. It was only possible to observe genetic activity in PBMCs.

The clinical implications are significant. Serum ferritin concentration should not be interpreted in isolation after strenuous exercise, particularly in endurance athletes. Elevated ferritin level may reflect inflammation and hemolysis rather than iron sufficiency. The timing of blood collection relative to exercise may be important. Tobiasch et al remind us that iron metabolism is dynamic and that exercise can at least briefly reproduce the biology of inflammation-associated iron restriction.

Conflict-of-interest disclosure: The authors declare no competing financial interests.