What are the differences between macrocytic and microcytic anemia in terms of causes, diagnosis, and treatment?

Macrocytic vs Microcytic Anemia: Key Differences

Fundamental Distinction

Microcytic anemia (MCV <80 fL) and macrocytic anemia (MCV >100 fL) represent fundamentally different pathophysiologic processes requiring distinct diagnostic and therapeutic approaches. 1, 2

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Microcytic Anemia (MCV <80 fL)

Primary Causes

• Iron deficiency anemia is the most common cause of microcytic anemia, resulting from inadequate iron stores for hemoglobin synthesis 3, 4
• Thalassemia trait presents with microcytosis, typically with elevated red cell count and RDW ≤14.0% 1, 4
• Anemia of chronic disease can present with microcytosis, though more commonly normocytic 3, 4
• Sideroblastic anemia represents genetic disorders of heme synthesis with characteristic ring sideroblasts on bone marrow examination 5

Diagnostic Algorithm for Microcytic Anemia

Step 1: Serum Ferritin Assessment

• Ferritin <12 μg/dL is diagnostic of iron deficiency 5
• Ferritin 12-100 μg/dL may still indicate iron deficiency if inflammation, malignancy, or liver disease present 5
• Ferritin >100 μg/dL essentially excludes iron deficiency 5
• Optimal cut-off of 45 μg/L provides best sensitivity and specificity in practice 1, 6

Step 2: RDW Analysis

• Low MCV with RDW >14.0% strongly suggests iron deficiency anemia 1, 6
• Low MCV with RDW ≤14.0% suggests thalassemia minor 1, 6
• This combination is more reliable than MCV alone for distinguishing these conditions 1

Step 3: Transferrin Saturation

• TSAT <30% supports iron deficiency diagnosis 5
• TSAT is more sensitive than hemoglobin alone for detecting iron deficiency 1, 6
• Add TSAT if ferritin is potentially falsely elevated by inflammation 1

Step 4: Confirmatory Testing

• Therapeutic trial of oral iron for 3 weeks with expected hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency 1, 5
• Bone marrow examination remains definitive, showing absent iron stores in iron deficiency or ring sideroblasts in sideroblastic anemia 5, 3
• Hemoglobin electrophoresis if microcytosis with normal iron studies or disproportionately low MCV suggests thalassemia 1

Treatment of Microcytic Anemia

First-Line: Oral Iron Supplementation

• Ferrous sulfate 200 mg three times daily for at least three months after anemia correction to replenish stores 1, 6
• Alternative formulations (ferrous gluconate, ferrous fumarate) if intolerance occurs 1, 6
• Adding ascorbic acid enhances absorption 1, 6
• Expected response: hemoglobin rise ≥10 g/L within 2 weeks confirms diagnosis 1, 6

Second-Line: Intravenous Iron

• Consider IV iron if malabsorption present, with expected hemoglobin increase ≥2 g/dL within 4 weeks 1, 6
• Required for IRIDA (iron-refractory iron deficiency anemia) as oral iron typically ineffective 1

Genetic Disorders Require Specialized Treatment:

• ALAS2 defects (X-linked sideroblastic anemia): pyridoxine 50-200 mg daily initially, then 10-100 mg daily lifelong 1
• SLC25A38 defects: hematopoietic stem cell transplantation is only curative option 1
• STEAP3 defects: erythrocyte transfusions with EPO, chelation for iron overload 1

Monitoring:

• Check hemoglobin and red cell indices at 3-month intervals for one year, then annually 1, 6
• Provide additional oral iron if hemoglobin or MCV falls below normal 1, 6
• Monitor for iron overload in patients receiving multiple transfusions or long-term therapy 1

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Macrocytic Anemia (MCV >100 fL)

Primary Causes

• Megaloblastic anemia from vitamin B12 or folate deficiency causes impaired DNA synthesis 2
• Nonmegaloblastic causes include myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, and certain medications 2
• Marked macrocytosis is characteristic of vitamin B12 and folate deficiencies, certain medications, and primary bone marrow disorders 4

Diagnostic Approach for Macrocytic Anemia

Critical Caveat: MCV-guided classification has significant limitations—in one study, 90% of macrocytic patients had anemia etiologies not in accordance with expected causes based on MCV alone 7

Essential Testing:

• Vitamin B12 and folate levels to identify megaloblastic causes 8, 2
• Peripheral blood smear examination for hypersegmented neutrophils (megaloblastic) vs other morphologic features 4, 2
• Reticulocyte count to assess bone marrow response 8
• Liver function tests, thyroid function, and medication review for nonmegaloblastic causes 2
• If MDS suspected (especially with cytopenias), hematology consultation and bone marrow examination indicated 2

Treatment of Macrocytic Anemia

• Cause-specific therapy is crucial—differentiate megaloblastic from nonmegaloblastic anemia first 2
• Vitamin B12 or folate replacement for deficiency states 2
• Address underlying conditions (liver disease, hypothyroidism, alcohol cessation) for nonmegaloblastic causes 2
• MDS and myeloid neoplasms require specialized hematologic management, potentially including lenalidomide for 5q- MDS or azacitidine for high-risk MDS 8

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Critical Pitfalls to Avoid

• Do not rely solely on MCV for classification—85% of anemic patients have MCV within normal range, and MCV-guided classification can incorrectly rule out diagnoses 7
• Do not assume all microcytic anemia is iron deficiency—thalassemia, anemia of chronic disease, and sideroblastic anemia must be differentiated to avoid unnecessary iron therapy 1
• Ferritin is an acute phase reactant—can be falsely elevated in inflammation, infection, malignancy, or liver disease, potentially masking concurrent iron deficiency 5
• Do not overlook combined deficiencies—iron deficiency can coexist with B12 or folate deficiency 1, 6
• In adults with iron deficiency, investigate the source of blood loss—men with Hb <110 g/L or non-menstruating women with Hb <100 g/L warrant fast-track GI referral 1
• Do not assume ethnicity explains microcytosis—hemoglobinopathies must be confirmed by laboratory testing, not presumed based on ethnic background 5