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

Workup for Microcytic Anemia

Start with serum ferritin as the single most useful diagnostic test, followed by transferrin saturation, complete blood count with RDW, and peripheral smear examination to differentiate iron deficiency from thalassemia trait and genetic disorders of iron metabolism. 1, 2

Initial Laboratory Testing

First-Line Tests

• Serum ferritin is the most critical initial test: 1, 2

  • <15 μg/L confirms absent iron stores with 99% specificity 1
  • <30 μg/L indicates low body iron stores 1
  • <45 μg/L provides optimal sensitivity and specificity, particularly when inflammatory conditions may be present 1, 2

• Red cell distribution width (RDW) differentiates causes: 1, 2

  • RDW >14.0% with low MCV strongly suggests iron deficiency anemia 1
  • RDW ≤14.0% points toward thalassemia trait 1

• Transferrin saturation (TSAT): 1, 2

  • <30% supports iron deficiency 2
  • Normal or high TSAT with microcytic anemia suggests genetic disorders 3

• Peripheral blood smear examination to identify morphologic clues 1

Diagnostic Algorithm Based on Initial Results

If Ferritin <45 μg/L with Elevated RDW (>14.0%)

• Diagnose iron deficiency anemia 1, 2
• Investigate the source of iron loss immediately: 2
  • In adults, presume gastrointestinal blood loss until proven otherwise 2
  • Perform upper GI endoscopy (reveals cause in 30-50% of cases) with small bowel biopsies to screen for celiac disease 2
  • Proceed with colonoscopy, as dual pathology occurs in 10-15% of patients 2
  • In menstruating women, consider gynecologic sources 4

If Ferritin Normal/High or RDW ≤14.0%

• Measure additional iron parameters: 3, 1

  • Serum iron level
  • Total iron-binding capacity (TIBC)
  • Transferrin saturation

• Consider hemoglobin electrophoresis to evaluate for thalassemia trait (elevated hemoglobin A2 suggests beta-thalassemia trait) 5, 6

If TSAT Very Low with Normal/High Ferritin

• Consider iron-refractory iron deficiency anemia (IRIDA): 3
  • Most patients present in childhood with microcytic anemia and remarkably low TSAT 3
  • Fails to respond to oral iron 3
  • Exclude autoimmune atrophic gastritis, H. pylori infection, or celiac disease 3
  • Confirm diagnosis with TMPRSS6 gene mutation analysis (requires homozygous or compound heterozygous pathogenic mutations) 3

If TSAT Normal/High with Microcytic Anemia

• Evaluate for genetic disorders of heme synthesis: 3
  • Measure free protoporphyrin (FPP) and zinc protoporphyrin (ZnPP) in red blood cells 3
  • Consider bone marrow examination for ring sideroblasts 3

Specific Genetic Disorders to Consider

X-Linked Sideroblastic Anemia (ALAS2 defects)

• Suspect in male patients with microcytic anemia 3
• Confirm with ALAS2 gene mutation analysis 7

Sideroblastic Anemia (SLC25A38 defects)

• Suspect in children with severe unexplained microcytic sideroblastic anemia 3
• Confirm with SLC25A38 gene mutation analysis 3

X-Linked Sideroblastic Anemia with Ataxia (ABCB7 defects)

• Suspect in male patients with mild microcytic anemia AND ataxia 3
• Increased protoporphyrin IX in red blood cells is suggestive 3

DMT1 Deficiency (SLC11A2 defects)

• Suspect in children with microcytic anemia and increased TSAT 3
• Confirm with SLC11A2 gene mutation analysis 3

Aceruloplasminemia (CP defects)

• Suspect with microcytic anemia, low iron binding capacity (low transferrin), and increased ferritin 3
• Measure ceruloplasmin (very low/undetectable) 3
• Confirm with CP gene mutation analysis 3

Hypotransferrinemia (TF defects)

• Suspect with unexplained microcytic anemia, low iron binding capacity, and increased ferritin 3
• Confirm with TF gene mutation analysis 3

Critical Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency—thalassemia and genetic disorders must be considered, especially with extremely low MCV 1

• Do not give iron supplementation empirically without confirming iron deficiency, as this causes harm in thalassemia and genetic iron metabolism disorders 1

• Do not stop at normal ferritin—inflammatory conditions can falsely elevate ferritin; use the 45 μg/L cutoff for optimal accuracy 1, 2

• Do not overlook celiac disease—2-3% of patients with iron deficiency anemia have celiac disease, requiring small bowel biopsies during endoscopy 2

• Do not miss dual pathology—10-15% of patients have lesions in both upper and lower GI tracts, requiring complete evaluation 2

Family Screening Considerations

• For autosomal recessive disorders (IRIDA, SLC25A38, SLC11A2, CP, TF defects): Screen first-degree family members (siblings and parents if of reproductive age) 3, 1

• For X-linked disorders (ALAS2, ABCB7 defects): Inform about inheritance patterns and screen appropriate family members based on the specific genetic defect 3, 7

• Genetic counseling is essential for all hereditary forms of microcytic anemia 1, 7