How to manage anemia in a patient with low transferrin saturation, elevated ferritin, and low hemoglobin?

Anemia of Chronic Disease with Functional Iron Deficiency

This patient has anemia of chronic disease (ACD) with functional iron deficiency, requiring intravenous iron therapy as first-line treatment. The combination of low transferrin saturation (10%), elevated ferritin (262 ng/mL), low hemoglobin (9.6 g/dL), and low serum iron (18 μg/dL) is pathognomonic for functional iron deficiency in the setting of inflammation. 1, 2

Diagnostic Interpretation

Your patient's laboratory values definitively establish functional iron deficiency:

• Transferrin saturation of 10% is well below the 16-20% threshold, confirming iron-deficient erythropoiesis regardless of ferritin levels 1, 2
• Ferritin 262 ng/mL is elevated above the 100 ng/mL threshold, indicating inflammation is present and iron stores are sequestered 1, 2
• The combination of TSAT <20% with ferritin 100-300 ng/mL specifically defines functional iron deficiency in chronic disease states, where hepcidin traps iron in storage sites making it unavailable for red blood cell production 2, 3

In inflammatory conditions, ferritin loses reliability as an iron storage marker because it acts as an acute-phase reactant. The ferritin cutoff for diagnosing iron deficiency must be raised to 100 ng/mL in the presence of inflammation. 1, 4

Underlying Cause Investigation

You must identify the source of chronic inflammation causing this pattern:

• Gastrointestinal evaluation is mandatory in men and postmenopausal women to exclude malignancy as a source of chronic blood loss 1, 4
• Test for Helicobacter pylori and celiac disease noninvasively, as both commonly cause iron deficiency anemia 4
• Evaluate for chronic inflammatory conditions including chronic kidney disease (check creatinine/GFR), heart failure, inflammatory bowel disease, and malignancy 1, 5, 6
• In premenopausal women with plausible bleeding source (heavy menstrual bleeding), treat the bleeding and provide iron supplementation without extensive GI investigation 7, 4

Treatment Algorithm

Intravenous iron is the appropriate first-line therapy for this patient:

• IV iron bypasses hepcidin-mediated blockade of intestinal iron absorption that occurs in inflammatory states, directly delivering iron to bone marrow 1, 2
• Oral iron is ineffective in functional iron deficiency because hepcidin blocks GI absorption while simultaneously trapping iron in storage sites 2, 3
• Target TSAT ≥20% after iron repletion to ensure adequate iron availability for erythropoiesis 1, 2

Specific IV Iron Recommendations:

• Administer IV iron formulations (ferric carboxymaltose, iron sucrose, or low molecular weight iron dextran) according to total iron deficit calculation 5
• Expect reticulocytosis at 3-5 days after administration, indicating bone marrow response 2
• Recheck CBC and iron parameters (ferritin, TSAT) 4-8 weeks after the last infusion; do not check within 4 weeks as circulating iron interferes with assays 2
• Hypersensitivity reactions to newer IV iron formulations are rare (<1%) 4

When Oral Iron May Be Considered:

Oral iron (ferrous sulfate 325 mg daily or every other day) is only appropriate if inflammation resolves and TSAT normalizes, or in younger patients with clear bleeding sources and no evidence of chronic disease. 4, 5

Common Pitfalls to Avoid

• Do not withhold iron therapy based on "normal" or elevated ferritin alone in the setting of low TSAT—this is the classic error in diagnosing functional iron deficiency 1, 2
• Do not prescribe oral iron for functional iron deficiency—it will not be absorbed due to hepcidin activation and wastes time while anemia worsens 2, 3
• Do not fail to assess inflammatory status (CRP, ESR) when interpreting iron studies, as this determines which ferritin threshold to apply 1
• Do not rely on hemoglobin screening alone—less than 50% of patients with anemia by hemoglobin criteria actually have iron deficiency in modern populations 2

Monitoring Response

• Evaluate response to IV iron in 2-4 weeks with repeat hemoglobin 4
• If no response occurs, consider erythropoiesis-stimulating agents (ESAs) with continued iron supplementation, particularly if chronic kidney disease or heart failure is present 1, 6
• ESAs require iron supplementation throughout therapy to optimize dose-response and red blood cell production 1

The key principle: functional iron deficiency requires IV iron because the problem is not depleted stores but rather trapped, unavailable iron due to inflammation-induced hepcidin activation. 2, 3