Microcytic Anemia Causes and Diagnosis

Primary Causes

The American Society of Hematology notes that iron deficiency is the most common cause of microcytic anemia, resulting from nutritional deficiency, gastrointestinal blood loss, or malabsorption 1, 2, 3
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 3
Thalassemias and hemoglobinopathies should be considered when iron studies are normal, particularly in patients with very low MCV and elevated red cell count 1, 2
NSAID use is a common cause of occult gastrointestinal blood loss leading to iron deficiency 4

Serum ferritin is the most powerful test for iron deficiency, with <12 μg/dL diagnostic of iron deficiency 4
Transferrin saturation <30% may help confirm diagnosis, but therapeutic response to three weeks of oral iron or bone marrow aspiration are definitive 4
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, 2, 3

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, 2
DMT1 deficiency causes anemia with paradoxical systemic iron loading, presenting at birth with microcytic anemia and increased transferrin saturation 3
Congenital erythropoietic porphyria (CEP) presents with combined cutaneous photosensitivity and severe microcytic hypochromic hemolytic anemia 1, 2

The American Society of Hematology recommends that IRIDA treatment depends on the pathogenicity of the TMPRSS6 defect 1
CEP treatment involves allogeneic hematopoietic stem cell transplantation as the only curative treatment 1, 2
Chronic erythrocyte transfusion is recommended as symptomatic treatment for severe genetic disorders, with iron chelation according to guidelines for chronic transfusions 1, 2

A low Mean Cell Volume (MCV) with exclusion of lead poisoning, infection, chronic inflammatory disease, and thalassemia minor serves as a specific index for iron-deficiency anemia in adults, with MCV below 80 mcm³ defining microcytic anemia, according to the MMWR Recommendations and Reports 5
Red blood cell distribution width (RDW) >14.0% with low MCV indicates iron-deficiency anemia, whereas RDW ≤14.0% with low MCV suggests thalassemia minor, as recommended by the MMWR Recommendations and Reports 5

The American Academy of Pediatrics and other medical societies imply that erythrocyte sedimentation rate (ESR), zeta-sedimentation rate (ZSR), and C-reactive protein (CRP) are elevated in chronic disease but not in pure iron deficiency, helping differentiate these conditions, although no specific guideline is cited in the provided text, the information is supported by 5

Sideroblastic anemias present with elevated ferritin and TSAT even before transfusions, requiring bone marrow examination showing ring sideroblasts 6
Unrecognized tissue iron loading in sideroblastic anemias leads to severe morbidity and mortality, emphasizing the importance of not overlooking genetic disorders 7

Treatment for sideroblastic anemia includes chronic erythrocyte transfusions with iron chelation 6
Hematopoietic stem cell transplantation is curative for some genetic disorders 6

Anemia of chronic disease causes functional iron deficiency through iron sequestration, rather than true depletion, mediated by hepcidin upregulation in response to inflammatory cytokines, and is associated with cancer, infections, chronic inflammatory conditions, and kidney disease 8
Inflammatory cytokines reduce ferroportin expression, trapping iron in macrophages and creating functional iron deficiency for erythropoiesis, particularly significant in conditions like those described in the Journal of Crohn's and Colitis 8

Without inflammation, ferritin <30 μg/L is diagnostic of iron deficiency, according to guidelines that may be informed by societies such as the American Gastroenterological Association 8
With inflammation, ferritin up to 100 μg/L may still be consistent with iron deficiency, as noted in research published in journals like the Journal of Crohn's and Colitis 8
A combination of iron deficiency and other causes can occur, particularly in malabsorption syndromes, and should be considered in the diagnostic workup 8