What is the appropriate workup and management for a patient with microcytic anemia?

Workup and Management of Microcytic Anemia

Start with serum ferritin, transferrin saturation, complete blood count with RDW, and peripheral blood smear—these four tests will differentiate iron deficiency from thalassemia trait and guide all subsequent management. 1, 2

Initial Laboratory Evaluation

Order these tests together as your first-line panel:

• Serum ferritin is the single most powerful test for diagnosing iron deficiency 1, 3, 4
• Transferrin saturation (TSAT) to confirm iron deficiency when ferritin may be falsely elevated 1, 2
• Complete blood count with RDW to distinguish iron deficiency (RDW >14%) from thalassemia (RDW ≤14%) 1, 2
• C-reactive protein (CRP) because ferritin is an acute-phase reactant that can mask true iron deficiency in inflammatory states 1, 3
• Peripheral blood smear to assess red cell morphology 2

Interpreting Ferritin Levels

• Ferritin <15 μg/L = absent iron stores with 99% specificity for iron deficiency 1, 2
• Ferritin <30 μg/L = low body iron stores, confirms iron deficiency 1, 2
• Ferritin <45 μg/L = optimal sensitivity and specificity cutoff in clinical practice 1, 2
• Ferritin >100 μg/L = iron deficiency almost certainly not present 1, 3
• Ferritin 12-100 μg/L with inflammation = may still indicate iron deficiency; add TSAT 1, 3

Interpreting Transferrin Saturation

• TSAT <16-20% confirms iron deficiency, especially when ferritin is borderline or elevated by inflammation 1, 2
• TSAT <20% with ferritin >100 μg/L indicates anemia of chronic disease, not iron deficiency 1

Using RDW to Differentiate Causes

• Low MCV + RDW >14% = iron deficiency anemia 1, 2
• Low MCV + RDW ≤14% = thalassemia minor 1, 2
• Elevated RDW with low MCV and low ferritin strongly supports iron deficiency over thalassemia 1, 3

Management Algorithm Based on Laboratory Results

Scenario 1: Ferritin <45 μg/L + RDW >14%

This is iron deficiency anemia—now investigate the source of iron loss before treating. 1, 2

Do not simply prescribe iron without finding the bleeding source, especially in adults. 1

Investigation of Iron Loss

• Adult men with Hb <110 g/L = fast-track GI referral for upper endoscopy and colonoscopy 1
• Non-menstruating women with Hb <100 g/L = fast-track GI referral 1
• All adults with confirmed iron deficiency warrant investigation at any anemia severity 1
• Upper endoscopy with duodenal biopsies to screen for celiac disease (present in 2-3% of iron deficiency cases), gastric cancer, peptic ulcer, NSAID gastropathy 1
• Colonoscopy to detect colonic carcinoma, polyps, angiodysplasia 1
• Premenopausal women = assess menstrual blood loss, but still evaluate GI tract if heavy menses doesn't fully explain severity 1

Treatment of Iron Deficiency

Ferrous sulfate 200 mg (65 mg elemental iron) three times daily for at least 3 months after anemia correction to replenish iron stores. 1, 2

• Alternative formulations: ferrous gluconate or ferrous fumarate if ferrous sulfate not tolerated 1
• Add ascorbic acid to enhance absorption 1
• Expected response: hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency 1
• Expected response: hemoglobin increase ≥2 g/dL within 4 weeks 1, 2

When Oral Iron Fails

Consider intravenous iron if:

• Malabsorption present 1, 2
• Non-compliance 1
• Ongoing blood loss exceeding oral replacement capacity 1, 5
• True intolerance to oral preparations 1, 5

IV iron options: iron sucrose or ferric carboxymaltose, with expected Hb increase ≥2 g/dL within 4 weeks 1, 2

Scenario 2: Ferritin >30 μg/L + RDW ≤14% + Extreme Microcytosis

This suggests thalassemia trait—order hemoglobin electrophoresis for confirmation. 1, 2

Do not give iron supplementation unless concurrent iron deficiency is documented, as this causes harm in thalassemia. 2

• Thalassemia trait management: no iron supplementation; provide genetic counseling 2
• Family screening for hereditary forms 2

Scenario 3: Failure to Respond to Oral Iron Despite Good Compliance

Evaluate for:

• Ongoing blood loss 1
• Malabsorption disorders: celiac disease, H. pylori, autoimmune atrophic gastritis 1
• Genetic disorders of iron metabolism: IRIDA (iron-refractory iron deficiency anemia) 1, 2
• Thalassemia if RDW normal or near-normal 1

Order hemoglobin electrophoresis if:

• Microcytosis persists with normal iron studies 1
• MCV disproportionately low relative to anemia severity 1
• Appropriate ethnic background (African, Mediterranean, Southeast Asian) 1
• Failure to improve after 4 weeks of adequate oral iron 1

Rare Genetic Causes to Consider

Order genetic testing if:

• Extreme microcytosis (MCV <70) 1
• Family history of refractory anemia 1
• Remarkably low TSAT with low-to-normal ferritin 1
• Failure to respond to both oral and IV iron 1

Specific Genetic Disorders

• IRIDA (TMPRSS6 defects): requires IV iron (oral ineffective); ferritin low-to-normal with very low TSAT 1, 2
• X-linked sideroblastic anemia (ALAS2 defects): pyridoxine 50-200 mg daily initially, then 10-100 mg daily lifelong if responsive 1, 2
• SLC25A38 defects: hematopoietic stem cell transplantation is only curative option; symptomatic treatment with transfusions and chelation 1, 2
• Bone marrow examination identifies ring sideroblasts pathognomonic for sideroblastic anemia 3

Monitoring and Follow-Up

• Monitor hemoglobin and red cell indices at 3-month intervals for one year, then annually 1, 2
• Provide additional oral iron if Hb or MCV falls below normal 1
• For patients receiving multiple transfusions: monitor for iron overload with MRI of liver 1
• Iron chelation therapy when phlebotomy not tolerated 2

Critical Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency—anemia of chronic disease, thalassemia, and sideroblastic anemia require different management 1, 2
• Do not rely on ferritin alone in inflammatory states—add TSAT when CRP elevated 1, 3
• Do not use hemoglobin electrophoresis as first-line—only after iron studies are normal or borderline 1
• Do not overlook combined deficiencies—iron deficiency can coexist with B12 or folate deficiency, suggested by elevated RDW 1
• Do not accept upper GI findings (esophagitis, erosions, ulcer) as sole cause without examining lower GI tract—dual pathology present in 10-15% 1
• Do not give empiric iron without confirming iron deficiency—this causes harm in thalassemia and genetic iron disorders 2