What is the most likely cause of a normocytic anemia with normal serum iron, normal total iron‑binding capacity, and low transferrin saturation, and how should it be evaluated and managed?

Anemia of Chronic Disease with Functional Iron Deficiency

This presentation—normocytic anemia with normal serum iron, normal TIBC, normal transferrin, but low transferrin saturation—indicates anemia of chronic disease (ACD) with functional iron deficiency, where inflammation traps iron in storage sites making it unavailable for erythropoiesis despite adequate total body iron stores. 1

Understanding the Paradox

• Low TSAT (<20%) with normal iron parameters reflects iron-deficient erythropoiesis, meaning the bone marrow lacks sufficient available iron to produce hemoglobin even though total body iron may be adequate. 1

• In inflammatory states, hepcidin is activated and blocks iron mobilization from storage sites while simultaneously preventing intestinal iron absorption, creating a functional iron deficiency where iron exists but cannot be accessed. 1

• Normal serum iron and TIBC distinguish this from classic iron deficiency anemia, where you would expect low serum iron with elevated TIBC as the body attempts to capture more iron. 2

• The normal transferrin level confirms this is not absolute iron deficiency, which typically shows elevated transferrin production. 3

Diagnostic Workup

Minimum essential tests:

• Serum ferritin to distinguish absolute from functional iron deficiency—expect ferritin 30-300 ng/mL in functional deficiency versus <30 ng/mL in absolute deficiency. 3, 1

• Inflammatory markers (CRP, ESR) to confirm the presence of chronic inflammation driving hepcidin activation. 3, 2

• Complete blood count with MCV and reticulocyte count to assess severity and bone marrow response—expect normal or low-normal reticulocytes indicating suppressed erythropoiesis. 3

Extended evaluation to identify the underlying chronic disease:

• Renal function (creatinine, eGFR) because chronic kidney disease is a leading cause, with anemia prevalence increasing dramatically when GFR <30 mL/min/1.73m². 1

• Age-appropriate cancer screening (colonoscopy if >50 years, especially in men and postmenopausal women) to exclude malignancy as the underlying cause. 1, 4

• Evaluation for chronic heart failure, inflammatory bowel disease, or other chronic inflammatory conditions based on clinical context. 1

Interpretation Algorithm

Step 1 – Confirm functional iron deficiency:

• TSAT <20% = iron-deficient erythropoiesis confirmed. 1
• Ferritin 30-100 μg/L with TSAT <20% = combination of true iron deficiency and ACD. 3
• Ferritin 100-300 ng/mL with TSAT <20% = pure functional iron deficiency. 1

Step 2 – Identify the inflammatory driver:

• Elevated CRP/ESR confirms active inflammation. 3
• Screen systematically for CKD, CHF, IBD, malignancy, autoimmune disease. 1

Step 3 – Rule out ongoing blood loss:

• Gastrointestinal evaluation is mandatory in men and postmenopausal women to exclude malignancy, even with confirmed inflammation. 1
• Fecal occult blood testing and endoscopy (colonoscopy first if >50 years) should be performed. 4

Management Strategy

Intravenous iron is first-line therapy:

• IV iron bypasses hepcidin-mediated blockade of intestinal absorption that occurs in inflammatory states, directly delivering iron to bone marrow. 1

• Oral iron is ineffective in functional iron deficiency because hepcidin blocks duodenal iron absorption—do not waste time with oral supplementation. 1

• Preferred IV formulations include ferric carboxymaltose, iron sucrose, or low-molecular-weight iron dextran, typically dosed as 50-125 mg weekly for 8-10 doses. 1

Treatment targets:

• Achieve TSAT ≥20% to ensure adequate iron availability for erythropoiesis. 1

• Target ferritin ≥100 ng/mL in inflammatory conditions (versus ≥30 ng/mL in non-inflammatory states). 1

• Expect hemoglobin increase of 1-2 g/dL within 4-8 weeks if iron therapy is effective. 1, 4

Monitoring response:

• Recheck iron parameters (ferritin, TSAT) 4-8 weeks after the last IV iron infusion—do not measure within 4 weeks as circulating iron interferes with assays. 1

• Reticulocytosis should occur at 3-5 days after IV iron administration, indicating bone marrow response. 1

If no response to IV iron:

• Consider erythropoiesis-stimulating agents (ESAs) with continued iron supplementation, particularly if CKD or heart failure is present. 1

• ESAs require ongoing iron supplementation to optimize dose-response—IV iron yields 73% hemoglobin response rate versus 45% with oral iron when combined with ESAs. 1

• Coordinate with nephrology or cardiology for ESA dosing and management decisions. 1

Common Pitfalls to Avoid

• Do not rely on ferritin alone in inflammatory states—ferritin can be falsely elevated by inflammation, masking true iron deficiency. 3, 1

• Do not prescribe oral iron for functional iron deficiency—it will not work because hepcidin blocks absorption. 1

• Do not measure iron parameters within 4 weeks of IV iron infusion—results will be falsely elevated and misleading. 1

• Do not assume normal serum iron excludes iron deficiency—in CKD and chronic disease, low serum iron with normal TSAT can still indicate risk for anemia. 5

• Do not skip cancer screening in appropriate patients—9% of patients >65 years with iron deficiency anemia have gastrointestinal malignancy. 4