What is the likely diagnosis and appropriate management for anemia with ferritin 210 ng/mL, transferrin 219 mg/dL, serum iron 46 µg/dL, and transferrin saturation 17%?

Functional Iron Deficiency in the Setting of Inflammation

This laboratory pattern—ferritin 210 ng/mL, transferrin saturation 17%, serum iron 46 µg/dL, transferrin 219 mg/dL—defines functional iron deficiency in a chronic inflammatory state, where iron is sequestered in storage sites but unavailable for erythropoiesis despite seemingly adequate ferritin levels. 1

Understanding the Laboratory Pattern

• Transferrin saturation of 17% falls below the critical 20% threshold, confirming iron-deficient erythropoiesis regardless of the ferritin level 1
• The ferritin of 210 ng/mL is elevated above normal ranges (135 µg/L for men, 43 µg/L for women) but does not indicate iron overload—it reflects both stored iron and acute-phase inflammation 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 1
• Low serum iron (46 µg/dL) combined with the low TSAT confirms insufficient iron delivery to bone marrow for hemoglobin synthesis 1

Immediate Diagnostic Work-Up

Confirm Inflammatory State

• Measure C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to document chronic inflammation that is driving the hepcidin-mediated iron sequestration 1
• Elevated inflammatory markers will confirm that ferritin is artificially raised by inflammation rather than reflecting true iron overload 1, 3

Assess Anemia Severity

• Obtain complete blood count (hemoglobin, hematocrit, MCV, reticulocyte count) to determine if functional iron deficiency has progressed to anemia 1
• MCV may be normal (normocytic) or low (microcytic) depending on whether absolute iron deficiency coexists 1

Evaluate Underlying Chronic Conditions

The most common causes of functional iron deficiency with this laboratory pattern include:

• Chronic kidney disease: Check serum creatinine and estimated GFR; anemia prevalence increases dramatically when GFR <30 mL/min/1.73m² 1
• Chronic heart failure: Prevalence of iron deficiency (defined by ferritin <100 µg/L or TSAT <20%) is high in CHF patients 1, 3
• Inflammatory bowel disease: Ferritin up to 100–300 µg/L may still indicate deficiency in active IBD 1, 3
• Malignancy: Age-appropriate cancer screening is mandatory, as occult malignancy can present with this pattern 1

Rule Out Gastrointestinal Blood Loss

• In men and postmenopausal women, bidirectional endoscopy is mandatory to exclude malignancy as a source of chronic blood loss 1
• Screen for celiac disease with tissue transglutaminase antibodies (present in 3–5% of iron deficiency cases) 1
• Test for Helicobacter pylori non-invasively (stool antigen or urea breath test) 1

Treatment Algorithm

First-Line: Intravenous Iron Therapy

Oral iron is ineffective in functional iron deficiency because hepcidin blocks intestinal iron absorption; intravenous iron bypasses this blockade and directly delivers iron to bone marrow. 1

Specific indications for IV iron in this scenario:

• Chronic kidney disease with eGFR <30 mL/min/1.73m² 1
• Heart failure (NYHA class II–III) with ferritin 100–300 ng/mL and TSAT <20% 1
• Active inflammatory bowel disease 1
• Chronic inflammatory conditions (cancer, CKD, CHF) where TSAT <20% confirms functional deficiency 1, 3

Recommended IV iron formulations:

• Ferric carboxymaltose 15 mg/kg (maximum 1000 mg per dose) 1
• Iron sucrose or low-molecular-weight iron dextran are alternatives 1
• Reticulocytosis occurs within 3–5 days after administration, indicating bone marrow response 1

Treatment Targets After Iron Repletion

• Target TSAT ≥20% to ensure adequate iron availability for erythropoiesis 1
• Target ferritin ≥100 ng/mL in the setting of chronic inflammation to ensure true iron repletion 1

Monitoring Response to IV Iron

• Do NOT measure iron parameters within 4 weeks of IV iron infusion because circulating iron interferes with assay accuracy and produces falsely elevated results 1
• Re-evaluate CBC and iron parameters (ferritin, TSAT) 4–8 weeks after the last infusion 1
• Expected response: hemoglobin should increase by 1–2 g/dL within 4–8 weeks of treatment 1

If No Response to IV Iron: Consider Erythropoiesis-Stimulating Agents

• If hemoglobin fails to rise despite IV iron, consider ESAs with continued iron supplementation, particularly if CKD or heart failure is present 1
• ESAs require ongoing iron supplementation throughout therapy; maintaining TSAT >20% is essential for optimal ESA response 1
• In CKD patients receiving ESAs, target ferritin >200 ng/mL and TSAT >20% to optimize hemoglobin response and reduce ESA requirements 1

Critical Diagnostic Pitfalls

Pitfall #1: Misinterpreting Elevated Ferritin as Iron Overload

• Ferritin 210 ng/mL in an inflammatory state reflects iron sequestration, NOT iron overload 1, 3
• True iron overload concerns arise only when ferritin chronically exceeds 1000 ng/mL 1
• TSAT is more reliable than ferritin in inflammatory states because it is less affected by inflammation 1, 3

Pitfall #2: Attempting Oral Iron in Functional Iron Deficiency

• Oral iron cannot overcome hepcidin-mediated blockade of intestinal absorption when inflammation is present 1
• Continuing oral iron provides no therapeutic benefit and exposes patients to unnecessary gastrointestinal side effects 1

Pitfall #3: Relying Solely on Ferritin Without TSAT

• Ferritin alone provides an incomplete picture; both ferritin and TSAT must be interpreted together 1, 3
• Failing to calculate TSAT can lead to missed diagnoses of functional iron deficiency 1

Pitfall #4: Measuring Iron Studies Too Early After IV Iron

• Iron parameters measured within 4 weeks of IV infusion yield falsely elevated results 1
• Adhere to the 4–8 week re-testing interval to obtain accurate assessment 1

Distinguishing Functional Iron Deficiency from Inflammatory Iron Block

When ferritin is 100–700 ng/mL and TSAT <20%, distinguishing functional iron deficiency from pure inflammatory block can be challenging. 1

Trial of IV iron can differentiate the two:

• Administer weekly IV iron 50–125 mg for 8–10 doses 1
• If hemoglobin rises, functional iron deficiency was present and iron therapy is effective 1
• If no erythropoietic response occurs, inflammatory iron block predominates and ESAs may be required 1

Long-Term Management

• Treat the underlying inflammatory condition to reduce hepcidin activation and improve iron mobilization 1
• Repeat iron studies every 4–8 weeks in patients with ongoing chronic inflammation to detect and treat iron deficiency before anemia develops 1
• Coordinate with nephrology, cardiology, or gastroenterology for management of the underlying chronic disease 1