How do I differentiate between iron deficiency and thalassemia?

Differentiating Iron Deficiency from Thalassemia Trait

Use a systematic approach combining CBC parameters with serum ferritin and hemoglobin electrophoresis to definitively distinguish iron deficiency from thalassemia trait, as both present with microcytic anemia but have fundamentally different iron stores and hemoglobin patterns. 1

Initial Laboratory Workup

The minimum essential tests include:

• Complete blood count with MCV, MCH, and RBC count 1
• Red cell distribution width (RDW) - elevated RDW strongly suggests iron deficiency 1
• Serum ferritin - the most specific test for iron deficiency in the absence of inflammation 1
• Hemoglobin electrophoresis or HPLC - to confirm thalassemia trait by demonstrating elevated HbA2 (>3.5%) 2

Key Distinguishing Features

Iron Deficiency Anemia

• Serum ferritin <30 μg/L (or <15 μg/L for absolute deficiency) 1
• High RDW - indicates variable red cell sizes due to progressive iron depletion 1
• Low transferrin saturation (typically <20%) 2
• Normal or low RBC count 2
• HbA2 levels normal (typically <3.5%) 2, 3

Thalassemia Trait

• Normal to elevated serum ferritin (often >30 μg/L, mean ~87 μg/L) 4, 5
• Normal or only mildly elevated RDW 5
• Elevated RBC count - characteristically increased red cell production with small cell size 2
• MCV disproportionately low relative to degree of anemia 1
• Elevated HbA2 >3.5% on hemoglobin electrophoresis (definitive for beta-thalassemia trait) 2, 3

Diagnostic Algorithm

Step 1: Check serum ferritin first

• Ferritin <30 μg/L strongly indicates iron deficiency 1
• Ferritin >150 μg/L essentially excludes isolated iron deficiency 1

Step 2: Evaluate RBC count and RDW

• Elevated RBC count (>5 million/μL) with low MCV suggests thalassemia trait 2
• High RDW (>15%) favors iron deficiency 1, 5

Step 3: Order hemoglobin electrophoresis when:

• Microcytosis present with normal iron studies 1
• Appropriate ethnic background (Mediterranean, Asian, African descent) 1
• RBC count elevated despite microcytosis 2

Critical Pitfalls to Avoid

Both conditions can coexist - this is a common clinical scenario that confounds diagnosis 2, 3:

• Iron deficiency can mask thalassemia trait by lowering HbA2 levels below the diagnostic threshold of 3.5% 3
• In patients with borderline ferritin (21-34 μg/L) and microcytosis, consider treating iron deficiency first, then repeat hemoglobin electrophoresis after 8-12 weeks 2, 3
• After iron repletion, expect hemoglobin to increase but MCV will remain low if underlying thalassemia trait is present 2

Inflammation affects ferritin interpretation 1:

• Ferritin is an acute phase reactant and can be falsely elevated in inflammatory conditions 1
• In the presence of inflammation, ferritin up to 100 μg/L may still be consistent with iron deficiency 1
• A ferritin cut-off of 45 μg/L provides optimal sensitivity/specificity trade-off in inflammatory states 1

Discriminant Indices (Adjunctive Tools)

While hemoglobin electrophoresis and ferritin are definitive, several mathematical indices can provide rapid screening:

• Mentzer Index (MCV/RBC): <13 suggests thalassemia trait; >13 suggests iron deficiency 5
• CRUISE Index: Recently validated with 90% accuracy and highest area under curve (0.934) for discrimination 5

However, these indices should never replace definitive testing with ferritin and hemoglobin electrophoresis 1, 2

Management Implications

For confirmed iron deficiency:

• Initiate therapeutic iron supplementation (3-6 mg/kg/day elemental iron) 2
• Investigate underlying cause (GI blood loss, menstrual losses, malabsorption) 1

For confirmed thalassemia trait:

• Provide genetic counseling and recommend partner screening if family planning is relevant 2
• Document diagnosis clearly to prevent unnecessary future iron supplementation 2
• Avoid chronic iron therapy beyond correction of any coexisting deficiency, as carriers risk iron overload 2

For coexisting conditions:

• Treat iron deficiency first with 20 weeks of oral iron therapy 3
• Repeat hemoglobin electrophoresis after iron repletion to unmask thalassemia trait 3
• Expect significant improvement in hemoglobin and ferritin but persistent microcytosis if thalassemia trait is present 2, 3