What are the causes of microcytic anemia in patients with varying demographics and medical histories, including iron deficiency, thalassemia, and chronic disease?

Causes of Microcytic Anemia

Iron deficiency is the most common cause of microcytic anemia, followed by anemia of chronic disease, thalassemias, and rare genetic disorders of iron metabolism or heme synthesis. 1

Primary Causes

Iron Deficiency Anemia (Most Common)

• Nutritional deficiency, gastrointestinal blood loss, and malabsorption are the primary mechanisms leading to iron deficiency anemia 1
• NSAID use is a common cause of occult GI bleeding that leads to iron deficiency 1
• Menstruation, pregnancy, and any source of chronic blood loss disrupt iron homeostasis 2

Anemia of Chronic Disease

• Causes functional iron deficiency through iron sequestration rather than true depletion, mediated by hepcidin upregulation in response to inflammatory cytokines 3
• Associated with cancer, infections, chronic inflammatory conditions, and kidney disease 3
• Particularly significant in hospitalized patients and elderly populations 1
• Inflammatory cytokines reduce ferroportin expression, trapping iron in macrophages and creating functional iron deficiency for erythropoiesis 3

Thalassemias and Hemoglobinopathies

• Should be considered when iron studies are normal, particularly in patients with very low MCV (<70 fL) and elevated red cell count 1, 4
• Thalassemia minor presents with microcytosis disproportionate to the degree of anemia 3
• Do not assume ethnic background explains microcytosis—laboratory confirmation is mandatory 4

Rare Genetic Disorders

Iron-Refractory Iron-Deficiency Anemia (IRIDA)

• Presents in childhood with microcytic anemia, remarkably low transferrin saturation, and low-to-normal ferritin 1
• Fails to respond to oral iron supplementation 1
• Caused by TMPRSS6 gene mutations 1

Sideroblastic Anemias

• Present with elevated ferritin and transferrin saturation even before transfusions 1
• Bone marrow examination shows pathognomonic ring sideroblasts 4
• Unrecognized tissue iron loading leads to severe morbidity and mortality 1

DMT1 Deficiency

• Causes anemia with paradoxical systemic iron loading 1
• Presents at birth with microcytic anemia and increased transferrin saturation 1

Congenital Erythropoietic Porphyria (CEP)

• Presents with combined cutaneous photosensitivity and severe microcytic hypochromic hemolytic anemia 1

Lead Poisoning

• Very rare cause in modern practice 3

Diagnostic Algorithm

Initial Laboratory Evaluation

• Serum ferritin <12 μg/dL is diagnostic of iron deficiency 4
• Ferritin 12-100 μg/dL may still indicate iron deficiency in the presence of inflammation, malignancy, or hepatic disease 4
• If ferritin >100 μg/dL, iron deficiency is almost certainly not present 4
• Transferrin saturation <30% supports iron deficiency diagnosis 4

Distinguishing Iron Deficiency from Other Causes

Red Cell Distribution Width (RDW)

• RDW >14.0% with low MCV indicates iron deficiency anemia 1
• RDW ≤14.0% with low MCV suggests thalassemia minor 1
• RDW is elevated to a greater extent in iron deficiency than in chronic disease or thalassemia 5

Inflammatory Markers

• ESR, ZSR, and CRP are elevated in chronic disease but not in pure iron deficiency, helping differentiate these conditions 1
• Ferritin is an acute phase reactant and can be falsely elevated in inflammation, infection, malignancy, or liver disease 4

Red Cell Count

• Elevated red cell count with microcytosis suggests thalassemia trait rather than iron deficiency 4

Ferritin Interpretation Based on Inflammation Status

Without inflammation:

• Ferritin <30 μg/L is diagnostic of iron deficiency 3

With inflammation:

• Ferritin up to 100 μg/L may still be consistent with iron deficiency 3

Definitive Testing When Doubt Remains

• Therapeutic trial of oral iron for 3 weeks with expected hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency 4
• Bone marrow aspiration showing absent iron stores remains the gold standard 2
• Bone marrow examination can identify ring sideroblasts pathognomonic for sideroblastic anemia 4

Common Pitfalls and Caveats

Do Not Overlook Genetic Disorders

• When ferritin is elevated and/or transferrin saturation is abnormal, or when anemia is refractory to iron supplementation, consider genetic disorders of iron metabolism or heme synthesis 1
• Bone marrow examination is recommended for patients with extreme microcytosis, family history, or unusual presentation 4

Avoid Inappropriate Iron Therapy

• Exact identification of the cause is critical, since inappropriate iron therapy may be useless or even dangerous 6
• Sideroblastic anemias require iron chelation, not iron supplementation 1

Consider Multiple Causes

• Combination of iron deficiency and other causes can occur, particularly in malabsorption syndromes 3