What is the most likely cause of normal ferritin and serum iron with low total iron‑binding capacity (TIBC) and low transferrin saturation?

Anemia of Chronic Disease (Functional Iron Deficiency)

The combination of normal ferritin, normal serum iron, low TIBC, and low transferrin saturation indicates anemia of chronic disease (ACD) with functional iron deficiency, where inflammation suppresses transferrin synthesis and traps iron in storage sites, making it unavailable for erythropoiesis despite adequate total body iron stores. 1

Understanding the Laboratory Pattern

• Low TIBC reflects chronic inflammation suppressing hepatic transferrin synthesis, which is the opposite pattern seen in true iron deficiency where TIBC is elevated 2, 3
• Normal ferritin with low transferrin saturation defines functional iron deficiency in inflammatory states, where hepcidin activation blocks iron mobilization from reticuloendothelial stores despite adequate storage 1, 2
• Low transferrin saturation (<20%) indicates iron-deficient erythropoiesis at the bone marrow level, meaning insufficient iron is available for hemoglobin synthesis regardless of total body stores 1
• Normal serum iron in this context reflects the acute-phase response where iron is sequestered intracellularly rather than circulating freely 2

Diagnostic Algorithm

Step 1: Confirm inflammatory state

• Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to document active inflammation 4
• Inflammatory markers will be elevated in ACD, distinguishing it from isolated iron deficiency 4

Step 2: Interpret ferritin in context of inflammation

• In inflammatory conditions, ferritin up to 100 ng/mL may still indicate true iron deficiency despite appearing "normal" 4, 1
• Ferritin >100 ng/mL with TSAT <20% specifically defines functional iron deficiency in chronic disease states 1
• The combination of ferritin 30-100 μg/L with TSAT <20% suggests mixed iron deficiency and ACD 4

Step 3: Identify underlying chronic condition

• Chronic kidney disease (CKD): Calculate eGFR; anemia prevalence increases dramatically when GFR <30 mL/min/1.73m² 1, 5
• Chronic heart failure (CHF): High prevalence of functional iron deficiency defined by ferritin <100 μg/L or TSAT <20% 1
• Inflammatory bowel disease (IBD): Ferritin up to 100 μg/L may still indicate deficiency in active inflammation 4, 1
• Malignancy: Age-appropriate cancer screening is mandatory to exclude occult malignancy 1
• Chronic infection or autoimmune disease: Consider as potential underlying causes 2

Treatment Approach

Intravenous iron is first-line therapy because it bypasses hepcidin-mediated blockade of intestinal iron absorption that occurs in inflammatory states 1

• IV iron formulations: Ferric carboxymaltose, iron sucrose, or low-molecular-weight iron dextran are recommended 1
• Dosing strategy: Weekly IV iron 50-125 mg for 8-10 doses can be administered 1
• Target parameters: Achieve TSAT ≥20% and ferritin ≥100 ng/mL in inflammatory conditions 1, 5

Oral iron is ineffective in functional iron deficiency because hepcidin blocks duodenal iron absorption 1

Erythropoiesis-stimulating agents (ESAs) may be needed if no response to IV iron occurs, particularly in CKD or heart failure 1

• ESAs require continued iron supplementation throughout therapy to optimize response 1
• IV iron combined with ESAs yields 73% hemoglobin response rate versus 45% with oral iron 1

Monitoring Response

• Reticulocytosis occurs 3-5 days after ferric carboxymaltose administration, indicating bone marrow response 1
• Hemoglobin should increase 1-2 g/dL within 4-8 weeks of adequate iron therapy 1
• Repeat iron studies 4-8 weeks after last IV iron infusion; do not measure within 4 weeks as circulating iron interferes with assays 1
• In ongoing inflammation, repeat iron studies every 4-8 weeks to detect and treat iron deficiency before anemia develops 1

Critical Pitfalls to Avoid

• Do not rely on ferritin alone in inflammatory states; it is an acute-phase reactant and can be falsely elevated while true iron deficiency exists 4, 5
• Do not assume normal serum iron excludes iron deficiency; in ACD, iron is trapped in storage sites and unavailable for erythropoiesis despite normal circulating levels 2
• Do not prescribe oral iron for functional iron deficiency; it will not be absorbed due to hepcidin blockade and wastes time 1
• Do not measure iron parameters within 4 weeks of IV iron as falsely elevated results will occur 1
• Do not ignore the underlying chronic disease; treating iron deficiency alone without addressing the inflammatory condition will result in recurrence 1, 2

Special Considerations by Population

Chronic kidney disease patients:

• Absolute iron deficiency in CKD is defined as TSAT ≤20% with ferritin ≤100 μg/L (predialysis/peritoneal dialysis) or ≤200 μg/L (hemodialysis) 1, 5
• Consider nephrology consultation for ESA therapy if IV iron alone is insufficient 1

Heart failure patients:

• IV iron has demonstrated prognostic benefit in meta-analyses for CHF patients with iron deficiency 1
• Treat when NYHA class II-III with ferritin <100 ng/mL or 100-300 ng/mL with TSAT <20% 1

Inflammatory bowel disease patients:

• Active inflammation makes ferritin unreliable; use TSAT <20% as primary diagnostic criterion 4
• IV iron is preferred route due to poor oral absorption and GI side effects 1