Authors: Sarah M.E. McErlean, Loba Alam, Aaron L. Baggish, Eugene H. Chung, Timothy W. Churchill, Gianmichel D. Corrado, Noah D.H. Lewis, Erin E. Orchard, Katie M. Stewart, James Sawalla Guseh
Categories: Heatlth Promotion and Preventive Cardiology, exercise intolerance, female athlete, iron deficiency, peak Vo2
Source: JACC Case Reports
Authors: Sarah M.E. McErlean, Loba Alam, Aaron L. Baggish, Eugene H. Chung, Timothy W. Churchill, Gianmichel D. Corrado, Noah D.H. Lewis, Erin E. Orchard, Katie M. Stewart, James Sawalla Guseh
Exercise intolerance in athletes is often attributed to cardiopulmonary or autonomic causes; however, nonanemic iron deficiency is a common and under-recognized contributor that may hinder aerobic adaptation. Ferritin thresholds used in general populations do not reflect athletes' higher physiological iron requirements.
A 21-year-old collegiate gymnast presented with exertional intolerance, positional lightheadedness, and tachycardia. Cardiopulmonary exercise testing showed reduced aerobic capacity (peak oxygen 25.5 mL/kg/min; 67% predicted). Iron studies revealed marked deficiency (ferritin: 15 μg/L, transferrin 13%) despite normal hemoglobin (14.1 g/dL). She was treated with intravenous iron; 5 months later, iron normalized, symptoms improved, and peak oxygen consumption increased to 31.2 mL/kg/min (81% predicted).
This case highlights that nonanemic iron deficiency can mimic deconditioning and dysautonomia yet is fully reversible when identified early. Physiological evidence supports using ferritin <50 μg/L to detect clinically relevant deficiency in athletes.
Iron deficiency without anemia should be considered early in athletes with unexplained exercise intolerance.
Exercise intolerance is a common yet diagnostically challenging complaint in athletes. Although cardiovascular, pulmonary, and skeletal muscle causes have prominent etiologic roles, iron deficiency is an important and under-recognized contributor to consider. Iron's role in oxygen transport, mitochondrial respiration, and energy metabolism is central and even in the absence of anemia, low iron stores may greatly affect physical performance.^1^ Despite this, iron deficiency is frequently overlooked as a potential cause of unexplained fatigue, reduced exercise capacity, and presyncope, which complicates the diagnostic evaluation of athletes.
Female endurance athletes are particularly vulnerable to iron depletion due to menstrual blood loss, dietary restriction, hemolysis, gastrointestinal microtrauma, and sweat-mediated losses.^1^ Conventional laboratory cutoffs for iron deficiency (<30 μg/L) tend to underestimate the higher physiological iron requirements in athletes. New physiological evidence suggests that the cutoffs should be closer to 50 μg/L, as that is when the gastrointestinal tract begins to increase iron absorption. These higher thresholds are associated with improved aerobic performance and reduced exercise intolerance in women.^2^
We present a case of a collegiate gymnast with exertional intolerance and orthostatic symptoms in whom iron repletion led to restoration of aerobic capacity and resolution of symptoms. This draws attention to the fact that iron deficiency is a reversible contributor to impaired performance, even in the absence of anemia, and underscores the need for clinicians to consider it when evaluating unexplained exercise intolerance.
A 21-year-old collegiate gymnast presented with concerns of postural orthostatic tachycardia syndrome, reporting episodes of positional lightheadedness inducing several falls, associated with tachycardia and shortness of breath. These symptoms appeared during everyday activities such as walking or stair climbing. She denied any vertigo or vision changes and confirmed the absence of true syncope.
Her physical examination was normal. An active standing test revealed a blood pressure of 124/77 mm Hg and a resting heart rate of 57 beats/min while sitting. On standing, the heart rate spiked to 110 beats/min and was associated with lightheadedness. The heart rate quickly normalized (80 beats/min) after 1 minute. Blood pressure stayed normal throughout the test.
She was known to have exercise-induced asthma and had undergone recent shoulder labral surgery, followed by a period of reduced physical activity.
Given the recent postoperative inactivity, deconditioning was considered. However, iron deficiency was strongly suspected, as reduced iron availability directly impairs oxygen transport, mitochondrial efficiency, and skeletal muscle energetics, producing symptoms that can mimic deconditioning or mild autonomic dysfunction, suggestive of early postural orthostatic tachycardia syndrome.
Electrocardiogram showed normal sinus rhythm. The axis was normal, and there were no other ST-segment or T-wave abnormalities. Iron studies revealed low serum iron (49 μg/dL), low transferrin saturation (13%), and low ferritin (15 μg/L) with a normal-high total iron-binding capacity (370 μg/dL), consistent with iron deficiency without anemia (Table 1). On cardiopulmonary exercise test (CPET), the patient demonstrated markedly reduced exercise capacity, with a peak oxygen consumption (Vo2) of 25.5 mL/kg/min, corresponding to 67% of the predicted value (Table 2). Ventilatory and hemodynamic responses were otherwise normal, and no ischemia or arrhythmia was observed. Ambulatory rhythm monitoring was normal.Table 1Laboratory Values Before and After IV Iron InfusionReference RangeBefore IV IronAfter IV IronFerritin, μg/L10-20015185Serum iron, μg/L30-16049128Iron saturation, %14-501341Total iron binding capacity, μg/dL230-404370313Hemoglobin, g/dL12-1614.113.7Comparison of iron studies and hemoglobin levels before and after IV iron therapy. Normal reference ranges used at our institution at the time of the study are included. Ferritin reference ranges at our institution have since been updated to 30 to 200 μg/L; at the time of this study, 10 μg/L was considered the lower limit of normal.IV = intravenous.Table 2Changes in Absolute and Weight-Adjusted Vo2 Before and After Intravenous Iron InfusionBefore IV IronAfter IV IronAbsolute Vo2, L/min1.51.8Weight-Adjusted Vo2, mL/kg/min25.531.2% predicted Vo2, %6781Absolute Vo2 and weight-adjusted Vo2 measured before and after IV iron therapy. Values demonstrate an increase in both raw oxygen consumption and normalized oxygen uptake after iron repletion within a 3-month period.IV = intravenous; Vo2 = oxygen consumption.
Based on these results, intravenous iron and low-intensity steady-state exercise were prescribed. She received 750 mg of intravenous iron administered as a single infusion. Propranolol (60 mg daily) was started for orthostatic tachycardia and discontinued once symptoms resolved after iron repletion.
Five months later, laboratory studies confirmed iron repletion with marked improvements in ferritin, transferrin saturation, and serum iron (Table 1). Symptoms improved soon after the infusion. Repeat CPET demonstrated an increase in peak Vo2 from 25.5 to 31.2 mL/kg/min (Figure 1, Table 2). The magnitude of improvement exceeded what would ordinarily be expected from low-intensity retraining alone, supporting a physiological benefit from iron repletion and the removal of a constraint on aerobic training adaptation. Despite a beta-blocker–related reduction in peak heart rate, the follow-up study showed higher aerobic capacity and an augmented oxygen pulse, consistent with improved stroke volume and/or peripheral oxygen extraction.Figure 1Cardiopulmonary Exercise Testing Before and After Intravenous Iron Repletion(A and B) (Oxygen Pulse): before treatment (A), oxygen pulse demonstrated a blunted augmentation pattern, failing to rise appropriately with increasing workload. After intravenous iron repletion (B), oxygen pulse rose proportionately with workload, reflecting normalization of stroke volume augmentation and improved aerobic efficiency. (C and D) (Peak Vo2): before treatment (C), peak Vo2 was 1.5 L/min (25.5 mL/kg/min adjusted; 67% predicted), consistent with reduced aerobic capacity. After repletion (D), peak Vo2 increased to 1.8 L/min (31.2 mL/kg/min adjusted; 81% predicted), indicating normalization toward expected aerobic capacity. peak Vo2 = peak oxygen consumption.
Iron deficiency—particularly in the absence of anemia—is widely under-recognized in athletic populations for 3 key reasons. First, traditional ferritin cutoffs are derived from general population reference ranges rather than the higher physiological iron requirements of athletes, leading to systematic underdiagnosis. Second, the earliest manifestations of impaired oxygen transport and mitochondrial dysfunction occur well before anemia develops; however, these symptoms are frequently misattributed to deconditioning or autonomic dysfunction. Third, conventional laboratory thresholds (<15-30 μg/L) represent statistical norms rather than physiological adequacy, analogous to outdated “normal” cholesterol ranges used decades ago. Together, these limitations result in delayed recognition of a reversible, performance-limiting condition. Although the prevalence of iron-deficiency anemia among US females aged 12 to 21 years between 2003 and 2020 is 6.3% (95% CI, 5.2%-7.4%), the prevalence of iron deficiency alone without anemia approximates 4 in 10 females.^3^ The high prevalence of iron deficiency in young females without associated iron-deficiency anemia highlights the fact that current guidelines may overlook many individuals with clinically relevant iron deficiency without anemia.
Multiple lines of evidence support defining clinically relevant iron deficiency in athletes at ferritin levels <50 μg/L:•Symptoms occur with ferritin <50 μg/L despite normal hemoglobin. Fatigue, cognitive impairment, diminished exercise capacity, and impaired thermoregulation occur within this range.^4^^,^^5^•Iron supplementation benefits nonanemic women with ferritin <50 μg/L. Randomized controlled trials demonstrate improvements in fatigue and increases in peak Vo2.4, 5, 6•Gastrointestinal iron absorption rises as ferritin falls below ∼50 μg/L and returns to baseline once this level is restored.^7^•Hepcidin and soluble transferrin receptor (biomarkers of iron homeostasis) normalize at ferritin levels of ∼50 μg/L indicating adequate iron availability for erythropoiesis and mitochondrial function.^8^
Similar physiological reasoning supports higher ferritin targets in some contexts—such as restless legs syndrome and altitude training—where higher ferritin levels and sufficient iron stores have been advocated to support increased iron demands (eg, erythropoiesis, acclimatization).^9^^,^^10^ Although endurance training may be associated with dilutional reductions in hemoglobin and ferritin described as “sports anemia,” this phenomenon has traditionally been viewed as a training-related or adaptive response rather than a clear pathologic cause of impaired performance.^11^ In contrast, the present case demonstrates symptomatic nonanemic iron deficiency with preserved hemoglobin, objective impairment in aerobic capacity, and clear physiological reversibility after iron repletion.
Iron is central to each domain of the oxygen cascade including hemoglobin-dependent oxygen transport, myoglobin-mediated intramuscular storage, mitochondrial oxidative phosphorylation, and neuromuscular energetics (Figure 2: Wasserman diagram). As iron stores decline, the body prioritizes erythropoiesis by diverting iron from skeletal muscle and mitochondrial reserves. This leads to early reductions in oxidative capacity, increased perceived exertion, and diminished endurance long before anemia emerges.Figure 2Iron's Integrated Role in the Oxygen CascadeIron supports oxygen transport and utilization at multiple levels. It is required for hemoglobin synthesis, and arterial oxygen content falls only when iron deficiency progresses to anemia. Even before anemia develops, iron is essential for myoglobin-mediated intracellular oxygen movement and for the iron-sulfur cluster and cytochrome enzymes that drive mitochondrial oxidative phosphorylation. Accordingly, nonanemic iron deficiency can still lower peak Vo2 by impairing skeletal muscle oxygen extraction and mitochondrial energy production, despite preserved cardiopulmonary function and normal arterial oxygen content. Vo2 = oxygen consumption.
Athletes operate near their physiological limits; small reductions in iron availability can produce measurable impairments in peak Vo2, ventilatory efficiency, lactate handling, and recovery. This case illustrates both the magnitude of functional limitation attributable to nonanemic iron deficiency and the scale of improvement achievable with repletion. Iron deficiency occurs in athletes due to numerous etiologies including redistribution (plasma volume expansion), increased iron demands (tissue remodeling), reduced absorption (gastrointestinal blood flow redistribution), sequestration (inflammation/sweating), and loss (hematuria, trauma, hemolysis), among other mechanisms. Data demonstrate that hepcidin levels are significantly increased in athletes after intense exercise as part of an acute phase inflammatory response further hindering iron absorption.^12^ Specifically, hepcidin binds to and degrades the iron regulatory protein ferroportin, which exacerbates iron deficiency by causing increased iron sequestration and decreased gastrointestinal iron absorption.Visual SummaryNonanemic Iron Deficiency and Reversible Exercise Intolerance in an AthleteA collegiate gymnast presented with exertional intolerance, lightheadedness, and tachycardia. Cardiopulmonary exercise testing showed reduced aerobic capacity (peak Vo2: 25.5 mL/kg/min; 67% predicted) with normal ventilatory and hemodynamic responses. Laboratory evaluation demonstrated marked nonanemic iron deficiency (ferritin: 15 μg/L; transferrin 13%) despite normal hemoglobin. Intravenous iron repletion and low-intensity steady-state training led to normalization of iron stores and improvement in peak Vo2 to 31.2 mL/kg/min (81% predicted), with complete resolution of symptoms. Nonanemic iron deficiency is a reversible and commonly overlooked cause of reduced cardiorespiratory fitness in athletes, warranting evaluation when unexplained performance decline is present. CPET = cardiopulmonary exercise test; Vo2 = oxygen consumption.
This case demonstrates that iron deficiency without anemia can meaningfully impair exercise tolerance and mimic autonomic dysfunction in athletes. A ferritin threshold of <50 μg/L is physiologically justified and clinically relevant. Iron deficiency should be incorporated early into the evaluation of unexplained exercise intolerance, particularly in female athletes.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.Take-Home Messages•Iron deficiency without anemia is a common, reversible, and often overlooked cause of exercise intolerance in athletes.•Ferritin <50 μg/L should prompt evaluation and treatment, especially when CPET shows unexplained reductions in aerobic capacity.