What are the causes and treatments of microcytic anaemia?

Causes of Microcytic Anemia

The most common cause of microcytic anemia is iron deficiency, but you must systematically rule out thalassemia, anemia of chronic disease, and genetic disorders of iron metabolism or heme synthesis to avoid misdiagnosis and inappropriate treatment. 1, 2

Primary Causes

Iron Deficiency Anemia

• This accounts for the vast majority of microcytic anemia cases and results from blood loss (gastrointestinal bleeding, menstruation), increased demand (pregnancy, rapid growth), or rarely inadequate dietary intake. 2, 3
• The body maintains iron homeostasis through recycling, but significant iron loss requires supplementation as physiologic absorption increases are minimal. 2
• Atrophic gastritis (autoimmune or Helicobacter pylori-related) can impair iron absorption and contribute to deficiency. 3

Thalassemia

• Thalassemia presents with MCV disproportionately low relative to the degree of anemia and should be strongly suspected when MCV is extremely low (e.g., <60 fL) with normal or near-normal RDW. 1, 4
• This is particularly important in patients of Mediterranean, African, Middle Eastern, or Southeast Asian ancestry. 4
• Do not give iron supplementation without confirming iron deficiency, as this causes harm in thalassemia. 4

Anemia of Chronic Disease

• This presents as microcytic or normocytic anemia in the setting of chronic inflammatory conditions, chronic kidney disease, or chronic heart failure. 3, 5
• Ferritin is typically normal or elevated (as an acute phase reactant), distinguishing it from iron deficiency. 2

Genetic Disorders of Iron Metabolism or Heme Synthesis

• Iron-Refractory Iron Deficiency Anemia (IRIDA) results from TMPRSS6 mutations and presents with severe microcytic anemia unresponsive to oral iron, requiring repeated intravenous iron. 1, 6, 3
• X-linked Sideroblastic Anemia (ALAS2 defects) responds to pyridoxine (vitamin B6) 50-200 mg daily initially, with lifelong maintenance at 10-100 mg daily. 1, 6
• SLC11A2 (DMT1) defects cause microcytic anemia with systemic iron loading, presenting at birth with increased transferrin saturation and requiring transfusions, with oral iron or EPO showing variable response. 7
• Genetic hypotransferrinemia (TF defects) presents in early life with microcytic hypochromic anemia, low serum iron, high ferritin, and very low or undetectable transferrin levels. 7

Diagnostic Algorithm to Identify the Cause

Step 1: Order Iron Studies and CBC with RDW

• Serum ferritin <15 μg/L confirms absent iron stores; <30 μg/L indicates low stores; use 45 μg/L cutoff for optimal sensitivity/specificity. 1, 6
• Transferrin saturation is more sensitive than hemoglobin alone for detecting iron deficiency. 1, 6
• Low MCV with RDW >14.0% strongly suggests iron deficiency; low MCV with RDW ≤14.0% suggests thalassemia. 1, 4, 6

Step 2: Interpret Results

• If ferritin <45 μg/L with elevated RDW: Diagnose iron deficiency anemia and investigate the source of iron loss (gastrointestinal bleeding, menstruation, malabsorption). 4, 6
• If ferritin normal/elevated (>20 μg/L) with normal RDW: Order hemoglobin electrophoresis immediately to evaluate for thalassemia, especially with appropriate ethnic background or extremely low MCV. 4, 6
• If ferritin elevated with low transferrin saturation: Suspect anemia of chronic disease or genetic disorders of iron metabolism. 1

Step 3: Red Flags for Genetic Disorders

• Family history of anemia, anemia refractory to iron supplementation, neurologic disease, skin photosensitivity, or failure to respond to oral iron within 2-4 weeks mandate investigation for genetic disorders. 1
• In genetic sideroblastic anemias, iron overload is more dangerous than the anemia itself—unrecognized tissue iron loading causes severe morbidity and mortality. 1

Treatment Based on Cause

Iron Deficiency Anemia

• First-line: Ferrous sulfate 200 mg (65 mg elemental iron) three times daily for at least three months after hemoglobin normalizes to replenish iron stores. 1, 6
• Expected hemoglobin rise ≥10 g/L (≥1 g/dL) within 2 weeks confirms diagnosis; expect at least 2 g/dL increase within 4 weeks. 1, 6
• If no response within 2-4 weeks, investigate for genetic disorders, thalassemia, malabsorption, or anemia of chronic disease. 1, 6
• Consider intravenous iron if malabsorption is present or oral iron is not tolerated. 6, 3

Thalassemia

• No iron supplementation unless concurrent iron deficiency is documented. 4
• Provide genetic counseling and monitor for complications. 4
• Iron chelation may be required for transfusion-dependent patients. 8

IRIDA

• Do not use oral iron—it is ineffective and delays appropriate treatment. 1
• Requires intravenous iron (iron sucrose or iron gluconate) repeatedly. 1, 6

X-linked Sideroblastic Anemia

• Pyridoxine (vitamin B6) 50-200 mg daily initially, with lifelong maintenance at 10-100 mg daily if responsive. 1, 6

Critical Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency—failure to consider thalassemia and genetic disorders leads to inappropriate iron therapy and harm. 1, 4
• Do not overlook combined deficiencies—iron deficiency can coexist with B12 or folate deficiency. 1
• Do not give empiric iron without confirming iron deficiency, especially in patients with extremely low MCV or normal RDW. 4
• In adults with confirmed iron deficiency, always investigate the source of iron loss—men with Hb <110 g/L or non-menstruating women with Hb <100 g/L warrant fast-track gastrointestinal referral to detect ulcers or malignancy. 6