What does a low total iron‑binding capacity with elevated ferritin indicate, and what is the appropriate work‑up and management?

Low TIBC with High Ferritin: Anemia of Chronic Disease

The combination of low TIBC with elevated ferritin indicates anemia of chronic disease (ACD), where inflammation suppresses transferrin synthesis and sequesters iron in storage sites, making it unavailable for red blood cell production despite adequate or elevated iron stores. 1, 2

Understanding the Laboratory Pattern

• Low TIBC reflects chronic inflammation suppressing transferrin synthesis, not iron deficiency—this is the opposite pattern seen in true iron deficiency, where TIBC rises compensatorily 1, 2
• Elevated ferritin (typically >100 ng/mL) indicates both inflammation and iron sequestration in the reticuloendothelial system, where hepcidin activation traps iron in storage sites 1, 2
• This pattern defines functional iron deficiency: adequate iron stores exist but cannot be mobilized for erythropoiesis due to inflammatory blockade 1, 2

Immediate Diagnostic Work-Up

Calculate Transferrin Saturation (TSAT)

• TSAT = (serum iron ÷ TIBC) × 100% to determine iron availability for red cell production 2
• TSAT <20% confirms iron-deficient erythropoiesis regardless of ferritin level, indicating the bone marrow lacks sufficient available iron for hemoglobin synthesis 1, 2
• TSAT <20% with ferritin 100–300 ng/mL specifically defines functional iron deficiency in chronic disease states 1, 2

Measure Inflammatory Markers

• Check CRP and ESR immediately to confirm active inflammation driving the iron sequestration 1
• Elevated inflammatory markers with this iron pattern confirm ACD rather than simple iron deficiency 1

Assess Anemia Severity

• Obtain complete blood count including hemoglobin, MCV, and reticulocyte count to determine severity and red cell indices 3, 1
• MCV may be normal or low in ACD; normocytic anemia is common, but microcytosis can occur when ACD coexists with true iron deficiency 3

Investigation of Underlying Chronic Conditions

The priority is identifying the inflammatory condition driving iron sequestration:

• Chronic kidney disease: Check serum creatinine and eGFR; anemia prevalence increases dramatically when GFR <30 mL/min/1.73m² 1
• Chronic heart failure: Assess for clinical signs; iron deficiency is highly prevalent in CHF and defined by ferritin <100 μg/L or TSAT <20% 1
• Inflammatory bowel disease: Evaluate for GI symptoms; ferritin up to 100 μg/L may still indicate deficiency in active IBD 3, 1
• Malignancy: Perform age-appropriate cancer screening in men and postmenopausal women to exclude occult malignancy as the underlying cause 1
• Chronic infection or autoimmune disease: Consider based on clinical context and elevated inflammatory markers 4

Treatment Algorithm

When TSAT <20% with Ferritin 100–300 ng/mL (Functional Iron Deficiency)

Intravenous iron is first-line therapy because it bypasses hepcidin-mediated intestinal blockade:

• Administer IV ferric carboxymaltose (15 mg/kg, maximum 1000 mg per dose) or iron sucrose as preferred formulations 1
• Oral iron is ineffective in functional iron deficiency because hepcidin blocks intestinal absorption; do not waste time with oral supplementation 1, 2
• IV iron produces reticulocytosis within 3–5 days and yields mean hemoglobin increase of ≈8 g/L over 8 days 1

Specific Indications for IV Iron

Clinical Condition	Rationale	Citation
CKD with eGFR <30 mL/min/1.73m²	Hepcidin elevation and impaired erythropoietin production	[1]
Heart failure (NYHA II–III) with ferritin <100 ng/mL or ferritin 100–300 ng/mL + TSAT <20%	Improves functional status and quality of life	[1]
Active inflammatory bowel disease	Inflammation blocks oral absorption	[3,1]
Malignancy with anemia	Cytokine-mediated iron sequestration	[1]

When to Add Erythropoiesis-Stimulating Agents (ESAs)

• If no hemoglobin response to IV iron after 8–10 weeks, consider ESAs with continued iron supplementation, particularly in CKD or heart failure 1
• Maintain TSAT >20% throughout ESA therapy to optimize dose-response and red blood cell production 1, 2
• IV iron combined with ESAs yields 73% hemoglobin response rate vs 45% with oral iron plus ESAs 1

Monitoring Response to Treatment

• Do NOT recheck iron parameters within 4 weeks of IV iron infusion because circulating iron interferes with assays and produces falsely elevated results 1, 2
• Optimal timing for reassessment is 4–8 weeks after the last IV iron dose to evaluate CBC and iron parameters (ferritin, TSAT) 1, 2
• Target TSAT ≥20% after iron repletion to ensure adequate iron availability for erythropoiesis 1, 2
• Expected hemoglobin rise is 1–2 g/dL within 4–8 weeks of adequate treatment 1

Critical Pitfalls to Avoid

• Do not assume elevated ferritin means iron overload—in inflammatory states, ferritin reflects inflammation-driven iron sequestration, not excess total body iron 1, 2
• Do not prescribe oral iron for functional iron deficiency—it provides no therapeutic benefit and exposes patients to unnecessary GI side effects because hepcidin blocks intestinal absorption 1, 2
• Do not rely on ferritin alone—TSAT is more reliable than ferritin in inflammatory states and must be interpreted together with ferritin to distinguish functional from absolute iron deficiency 1, 2
• Do not overlook the underlying chronic disease—treating iron deficiency without addressing the inflammatory condition (e.g., uncontrolled IBD, untreated malignancy) will result in treatment failure 3, 1
• Do not measure iron studies too early after IV iron—wait the full 4–8 weeks to avoid falsely elevated results that misguide management 1, 2