How to manage anemia with normal iron levels?

Management of Anemia with Normal Iron Levels

When anemia is present but iron studies are normal (ferritin >35-45 μg/L and normal transferrin saturation), you must systematically investigate alternative causes rather than defaulting to iron supplementation. 1

Initial Diagnostic Approach

Confirm true iron sufficiency first, as ferritin can be falsely elevated in inflammatory conditions, malignancy, or hepatic disease even when iron deficiency exists. 1

• In patients with chronic inflammation or malignancy: Ferritin levels between 45-100 μg/L may still represent functional iron deficiency despite appearing "normal." Check transferrin saturation (<20% suggests iron deficiency), soluble transferrin receptor, or reticulocyte hemoglobin equivalent for confirmation. 1, 2

• In chronic kidney disease (CKD): Different thresholds apply—absolute iron deficiency is defined as transferrin saturation ≤20% with ferritin ≤100 μg/L (predialysis/peritoneal dialysis) or ≤200 μg/L (hemodialysis patients). 1

Investigate Alternative Causes of Anemia

Screen for Vitamin Deficiencies

• Measure vitamin B12 and folate levels: Combined deficiencies are common, particularly in elderly patients where multiple causes often coexist. 1
• Check for elevated red cell distribution width (RDW): This suggests combined deficiency (e.g., folate plus iron). 1

Screen for Celiac Disease

• All patients with unexplained anemia should undergo celiac disease screening with tissue transglutaminase antibody (IgA type) and total IgA testing, as celiac disease causes iron malabsorption and can present with normal ferritin if inflammation is present. 1, 3

Evaluate for Hemoglobinopathies

• Obtain hemoglobin electrophoresis in patients of African, Mediterranean, or Southeast Asian ancestry with microcytosis, as thalassemia minor or sickle cell trait can cause anemia unresponsive to iron therapy. 1
• Check red cell count: Thalassemia typically shows elevated red cell count despite microcytosis. 1

Consider Chronic Disease and Inflammation

• Anemia of chronic disease can present with normal or elevated ferritin but low transferrin saturation due to impaired iron utilization. 1
• Measure inflammatory markers (CRP, ESR) to identify underlying chronic inflammatory conditions. 3

Assess for Chronic Kidney Disease

• Check glomerular filtration rate (GFR): CKD is a potential cause when GFR <60 mL/min/1.73m², especially likely when GFR <30 mL/min/1.73m². 1
• Functional iron deficiency is common in advanced CKD despite normal ferritin, requiring specialized management per NICE and Renal Association guidelines. 1

Evaluate for Gastrointestinal Pathology (If Appropriate)

• In men and postmenopausal women with unexplained anemia: Even with normal iron studies, consider bidirectional endoscopy (gastroscopy and colonoscopy) if other causes are excluded, as occult GI bleeding or malabsorption may be present. 1, 3
• Screen for Helicobacter pylori: Eradication may improve anemia in patients with recurrent unexplained anemia. 1

Management Based on Identified Cause

If Functional Iron Deficiency in Inflammatory Conditions

• In inflammatory bowel disease with active inflammation: Use intravenous iron therapy as oral absorption is compromised. 1
• Treat underlying inflammation effectively to enhance iron absorption and reduce iron depletion. 1

If Vitamin Deficiency Identified

• Supplement appropriately: Vitamin B12 (if deficient) and/or folate replacement as indicated by laboratory results. 1

If Celiac Disease Confirmed

• Ensure strict adherence to gluten-free diet to improve iron absorption before considering supplementation. 1

If Chronic Kidney Disease

• Consider erythropoiesis-stimulating agents (ESAs) only when hemoglobin is appropriately low and after correcting iron deficiency, using the lowest dose to avoid transfusions (target hemoglobin should NOT exceed 11 g/dL due to increased cardiovascular risks and mortality). 4
• Maintain iron repletion during ESA therapy. 4

If Hemoglobinopathy

• No iron supplementation is indicated unless true iron deficiency coexists. 1
• Refer to hematology for specialized management. 1

Critical Pitfalls to Avoid

• Do not empirically treat with iron when ferritin is normal without confirming true iron deficiency, as this provides no benefit and may delay diagnosis of serious underlying conditions. 1, 5
• Do not assume dietary insufficiency alone explains anemia in men or postmenopausal women—these patients warrant thorough investigation for GI pathology. 1
• Do not overlook functional iron deficiency in patients with chronic inflammation, where ferritin may be misleadingly normal or elevated. 1
• Do not target high hemoglobin levels (>11 g/dL) with ESAs in CKD patients, as this increases mortality, cardiovascular events, and stroke risk. 4