What are the causes and treatments of microcytic anemia?

Causes of Microcytic Anemia

The most common causes of microcytic anemia are iron deficiency, anemia of chronic disease, thalassemias, and hemoglobinopathies, with iron deficiency being the most frequent etiology. 1, 2

Primary Causes

Common Etiologies

• Iron deficiency is the most common cause of microcytic anemia, resulting from nutritional deficiency, gastrointestinal blood loss, or malabsorption 2, 3, 4
• Anemia of chronic disease causes functional iron deficiency through iron sequestration rather than true depletion, characterized by elevated ferritin with low serum iron, particularly significant in hospitalized patients and elderly populations 2, 5
• Thalassemias and hemoglobinopathies should be considered when iron studies are normal, particularly in patients with very low MCV and elevated red cell count 1, 4
• NSAID use is a common cause of occult gastrointestinal blood loss leading to iron deficiency 1

Gastrointestinal Sources of Iron Loss

When evaluating iron deficiency in adult men and post-menopausal women, gastrointestinal blood loss is the most common cause and requires investigation to exclude malignancy 1:

• Colonic cancer/polyps, gastric cancer, and angiodysplasia are common sources 1
• Coeliac disease causes malabsorption and should be considered in the diagnostic workup 1
• Previous gastrectomy, gastric atrophy, and bacterial overgrowth impair iron absorption 1

Genetic Disorders of Iron Metabolism and Heme Synthesis

When to Suspect Genetic Causes

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. 2

Specific Genetic Disorders

• Iron-refractory iron-deficiency anemia (IRIDA) presents in childhood with microcytic anemia, remarkably low transferrin saturation, and low-to-normal ferritin, with failure to respond to oral iron 1
• DMT1 deficiency causes anemia with paradoxical systemic iron loading, presenting at birth with microcytic anemia and increased transferrin saturation 2
• SLC25A38 deficiency causes severe congenital sideroblastic anemia, presenting with transfusion-dependent microcytic hypochromic anemia in childhood, with bone marrow showing ring sideroblasts 2
• Congenital erythropoietic porphyria (CEP) presents with combined cutaneous photosensitivity and severe microcytic hypochromic hemolytic anemia 1

Diagnostic Algorithm

Initial Laboratory Assessment

• Serum ferritin is the most powerful test for iron deficiency, with <12 μg/dL diagnostic of iron deficiency 1
• However, ferritin may be elevated above 12-15 μg/dL in patients with concurrent chronic inflammation, malignancy, or hepatic disease; if >100 μg/dL, iron deficiency is almost certainly not present 1
• Transferrin saturation <30% may help confirm diagnosis, but therapeutic response to three weeks of oral iron or bone marrow aspiration are definitive 1
• Red cell distribution width (RDW) appears elevated to a greater extent in iron deficiency than in chronic disease or thalassemia 5

Differential Diagnosis Based on Iron Parameters 1

• Low/normal ferritin with very low transferrin saturation: Consider iron deficiency or IRIDA
• Normal/high ferritin with normal transferrin saturation: Consider anemia of chronic disease or sideroblastic anemia
• High transferrin saturation: Consider genetic disorders with iron loading (DMT1 deficiency, aceruloplasminemia)

Additional Testing for Genetic Causes

When genetic disorders are suspected based on refractory anemia or abnormal iron parameters 1:

• Bone marrow examination for ring sideroblasts
• Genetic testing for TMPRSS6 (IRIDA), SLC11A2 (DMT1), SLC25A38, FECH, ALAS2, UROS, or GATA1 mutations
• Measurement of free protoporphyrin (FPP) and zinc protoporphyrin (ZnPP) in red blood cells
• Urinary uroporphyrin and coproporphyrin levels if photosensitivity is present

Critical Clinical Pitfalls

Red Flags Requiring Further Investigation

• Family history of anemia refractory to iron supplementation, neurologic disease, or skin photosensitivity should raise suspicion for genetic disorders 2
• Do not start empiric oral iron therapy when ferritin is elevated, as this could worsen iron overload in sideroblastic anemia or genetic disorders 2
• Serum ferritin may be elevated in inflammatory conditions despite concurrent iron deficiency, potentially masking true iron depletion 2

Exclude Non-Genetic Causes First

Before pursuing genetic testing, exclude 1:

• Autoimmune atrophic gastritis
• Helicobacter pylori infection
• Celiac disease
• Severe anemia of chronic disease

Treatment Considerations

Iron Deficiency Anemia

• The vast majority of patients respond to oral iron preparations 3
• In cases of malabsorption, losses exceeding maximal oral replacement, or true intolerance, parenteral iron dextran is effective 3
• It is necessary to replete iron stores in addition to correcting the anemia 3

Genetic Disorders

• IRIDA: Case reports indicate response depends on the pathogenicity of the TMPRSS6 defect 1
• CEP: Allogeneic hematopoietic stem cell transplantation should be considered as the only curative treatment 1
• Chronic erythrocyte transfusion is recommended as symptomatic treatment for severe genetic disorders, with iron chelation according to guidelines for chronic transfusions 1