What is the appropriate diagnostic and treatment approach for a patient with microcytic anemia, indicated by a decreased Mean Corpuscular Volume (MCV)?

Diagnostic and Treatment Approach for Microcytic Anemia (Decreased MCV)

Start oral ferrous sulfate 200 mg three times daily immediately while simultaneously investigating the underlying cause, as iron deficiency is the most common etiology and a therapeutic trial confirms the diagnosis within 2 weeks. 1, 2

Initial Diagnostic Workup

Red Cell Indices Analysis

• RDW >14.0% with low MCV strongly indicates iron deficiency anemia, while RDW ≤14.0% suggests thalassemia minor 1, 3
• Mean corpuscular hemoglobin (MCH) is more reliable than MCV alone because it's less dependent on storage conditions and is reduced in both absolute and functional iron deficiency 1

Serum Ferritin Interpretation

• Ferritin <15 μg/L indicates absent iron stores; <30 μg/L indicates low body iron stores 1, 3
• A cut-off of 45 μg/L provides optimal sensitivity and specificity for iron deficiency in clinical practice 1, 3
• In the presence of inflammation (IBD, chronic disease), ferritin up to 100 μg/L may still be consistent with iron deficiency 4
• Ferritin >150 μg/L makes absolute iron deficiency unlikely 1

Transferrin Saturation

• Add transferrin saturation (TSAT) if ferritin is falsely elevated due to inflammation 1
• TSAT <16% suggests iron deficiency; TSAT <20% with ferritin >100 μg/L indicates anemia of chronic disease 4
• Unexplained microcytic anemia with increased TSAT should prompt consideration of genetic disorders like SLC11A2 defects 3

Investigation of Underlying Cause

Assume Gastrointestinal Blood Loss Until Proven Otherwise

• In men and non-menstruating women with iron deficiency, fast-track GI referral is warranted if Hb <110 g/L (men) or <100 g/L (women) 1
• Perform stool guaiac test for occult blood 2
• Consider upper and lower endoscopy based on severity and risk factors 3

Menstruating Women

• Obtain detailed menstrual history, as heavy menstrual bleeding is the most common cause in premenopausal women 1, 2

Additional Considerations

• Assess dietary iron intake adequacy 2
• Screen for celiac disease if malabsorption suspected 1
• Review medications, particularly NSAIDs 3

First-Line Treatment Protocol

Oral Iron Supplementation

• Ferrous sulfate 200 mg (65 mg elemental iron) three times daily, taken separately from meals 1, 2
• Continue for at least 3 months after hemoglobin normalizes to replenish iron stores 1, 2
• Alternative formulations if ferrous sulfate not tolerated: ferrous gluconate or ferrous fumarate 1, 3
• Add ascorbic acid (vitamin C) to enhance absorption 1, 3

Expected Response

• Hemoglobin should rise ≥10 g/L within 2 weeks if iron deficiency is the cause 1, 2
• Recheck CBC at 2 weeks to confirm response 2
• Expected hemoglobin increase of at least 2 g/dL within 4 weeks confirms diagnosis 1

Monitoring Schedule

• Monitor hemoglobin and red cell indices every 3 months for 1 year, then annually 1, 2
• Provide additional oral iron if hemoglobin or MCV falls below normal 1, 3

When to Consider Intravenous Iron

Switch to IV iron if: 1, 2

• Documented malabsorption (celiac disease, inflammatory bowel disease, post-gastric bypass)
• True intolerance to all oral formulations
• Blood losses exceeding maximal oral replacement capacity
• Expected hemoglobin increase ≥2 g/dL within 4 weeks of IV iron 1, 3

Red Flags Requiring Further Investigation

Failure to Respond to Oral Iron After 4 Weeks

Consider: 1, 3

• Non-compliance
• Ongoing blood loss
• Malabsorption
• Genetic disorders of iron metabolism (IRIDA, SLC11A2 defects)

Hemoglobin Electrophoresis Indications

Order if: 1

• Microcytosis with normal iron studies
• Appropriate ethnic background (Mediterranean, Southeast Asian, African)
• MCV disproportionately low relative to degree of anemia
• Family history of microcytic anemia

Genetic Testing Considerations

Consider genetic testing if: 1, 3

• Extreme microcytosis (MCV <70 fL)
• Family history of refractory anemia
• Normal or elevated ferritin with persistent microcytosis despite treatment
• Unexplained hypochromic microcytic anemia with low iron binding capacity and increased ferritin (hypotransferrinemia)

Specific Genetic Disorders and Their Management

X-Linked Sideroblastic Anemia (ALAS2 Defects)

• Initial treatment: pyridoxine (vitamin B6) 50-200 mg daily 1
• If responsive, continue lifelong supplementation at 10-100 mg daily to avoid neurotoxicity 1

IRIDA (TMPRSS6 Defects)

• Intravenous iron (iron sucrose or iron gluconate) is required, as oral iron is typically ineffective 1, 3
• Monitor ferritin and avoid exceeding 500 mg/L to prevent iron overload, especially in children 1

SLC25A38 Defects

• Hematopoietic stem cell transplantation is the only curative option 1, 3
• Symptomatic treatment includes erythrocyte transfusions and chelation therapy 1

STEAP3 Defects

• Treat with erythrocyte transfusions in combination with erythropoietin (EPO) 1
• Manage systemic iron loading with chelation 1

Critical Pitfalls to Avoid

• Do not stop iron therapy when hemoglobin normalizes—continue for 3 months to replenish stores 2
• Do not overlook combined deficiencies: iron deficiency can coexist with B12 or folate deficiency 1, 3
• Do not assume all microcytic anemia is iron deficiency: anemia of chronic disease, thalassemia, and sideroblastic anemia must be differentiated to avoid unnecessary iron therapy 1
• In anemia of chronic disease with severe microcytosis, do not institute iron therapy without clearly establishing iron deficiency, irrespective of degree of microcytosis 5
• For genetic disorders with iron loading (SLC11A2 defects), normal serum ferritin does not exclude liver iron loading—consider MRI of liver 1, 3