In an endurance athlete with low total iron‑binding capacity and normal ferritin, what is the most likely explanation?

Decreased TIBC with Normal Ferritin in an Endurance Runner

The most likely explanation is exercise-induced inflammation causing functional iron dysregulation, where hepcidin elevation and inflammatory processes suppress TIBC while ferritin remains falsely normal or elevated as an acute-phase reactant, masking true iron depletion. 1

Understanding the Atypical Laboratory Pattern

This combination of decreased TIBC with normal ferritin is paradoxical because classic iron deficiency typically elevates TIBC as the body attempts to capture more circulating iron. 1 In endurance athletes, however, several unique mechanisms create this pattern:

Exercise-Induced Inflammation and Hepcidin

• Intense endurance training triggers inflammatory responses that elevate hepcidin, a hormone that blocks iron absorption and sequesters iron in storage sites, preventing its release for erythropoiesis. 2
• Hepcidin levels rise significantly during intensified training periods in long-distance runners, even when dietary iron intake appears adequate. 2
• This inflammatory iron sequestration suppresses the expected compensatory rise in TIBC that would normally occur with iron deficiency. 1

Ferritin as an Unreliable Marker in Athletes

• Ferritin is an acute-phase reactant that becomes falsely elevated during exercise-induced inflammation, stress, or tissue damage, masking underlying iron depletion. 1
• A "normal" ferritin in an endurance athlete may actually represent depleted functional iron stores when inflammation is present. 1
• Athletes with high amounts of repetitive ground strikes (running) are at inherently higher risk for iron deficiency due to antioxidant depletion and erythrocyte damage. 1

Mechanisms Specific to Running

• Repetitive running-associated injury and inflammation can cause defective iron utilization rather than absolute total body iron deficiency, as demonstrated by declining red cell ferritin despite normal serum ferritin. 3
• Endurance training causes antioxidant depletion and erythrocyte damage, contributing to functional iron deficiency. 1
• "Runner's anemia" can develop independently of iron status and iron intake, with reductions in hemoglobin accompanied by reticulocytosis. 4

Diagnostic Algorithm

Step 1: Calculate Transferrin Saturation

• TSAT = (Serum iron × 100) ÷ TIBC
• TSAT <16-20% confirms iron deficiency (absolute or functional) regardless of ferritin level. 1
• Low TSAT with normal/elevated ferritin indicates functional iron deficiency—adequate storage iron but insufficient release for erythropoiesis. 1

Step 2: Measure Inflammatory Markers

• Check CRP and ESR immediately to determine if inflammation is masking true iron deficiency. 1
• Elevated inflammatory markers with normal ferritin and low TIBC confirm exercise-induced functional iron deficiency. 1, 2
• Normal inflammatory markers with this pattern suggest very early absolute iron deficiency before compensatory TIBC elevation. 1

Step 3: Assess Complete Iron Panel

• Obtain complete blood count with reticulocyte count, hemoglobin, hematocrit, MCV, MCH, MCHC, and RDW. 1
• Check serum iron and transferrin saturation to assess iron availability for red blood cell production. 1
• Consider red cell ferritin if available, as it declines into the iron-deficient range in runners even when serum ferritin remains normal. 3

Clinical Significance and Management

Immediate Treatment Recommendations

• Initiate oral iron supplementation immediately with ferrous sulfate 65 mg elemental iron daily or alternate-day dosing (60 mg every other day), which improves absorption by 30-50% and reduces gastrointestinal side effects. 1
• Do not wait for completion of diagnostic workup to begin iron therapy. 1
• Expected response: hemoglobin should rise ≥10 g/L within 2 weeks of starting therapy. 1

Addressing Underlying Causes

• Screen for celiac disease with tissue transglutaminase antibodies, as it accounts for 3-5% of iron deficiency cases and can cause treatment failure. 1
• Test for Helicobacter pylori infection non-invasively (stool antigen or urea breath test), as it impairs iron absorption. 1
• Assess dietary iron intake and consider consultation with a sports dietitian, as athletes with risk factors should consume at least 22 mg/day of iron. 1

When to Consider Intravenous Iron

• Use IV ferric carboxymaltose (15 mg/kg, maximum 1000 mg per dose) if: 1
  • Oral iron intolerance develops
  • Malabsorption is present (celiac disease, inflammatory bowel disease)
  • Ongoing blood loss exceeds oral replacement capacity
  • Lack of hemoglobin response after 8-10 weeks of adequate oral iron
  • Chronic inflammatory conditions are present

Follow-Up and Monitoring

• Repeat CBC and ferritin at 8-10 weeks to assess response to treatment. 1
• Target ferritin >100 ng/mL to fully replenish iron stores and prevent recurrence. 1
• For endurance athletes, schedule ferritin screening every 6-12 months due to ongoing risk. 1

Critical Pitfalls to Avoid

• Never assume normal ferritin excludes iron deficiency in athletes—transferrin saturation is the key parameter for assessing iron availability for erythropoiesis. 1
• Decreased TIBC with normal ferritin may mask underlying chronic inflammatory conditions or malignancy—checking CRP/ESR helps uncover hidden pathology. 1
• Iron supplementation during periods of very high training intensity and elevated hepcidin may be ineffective because transferrin saturation is also very high, preventing absorption of dietary iron. 5
• Do not overlook celiac disease screening—its 3-5% prevalence in iron deficiency can lead to treatment failure if missed. 1