What lab tests can distinguish between anemia of chronic disease and iron deficiency anemia?

Laboratory Differentiation Between Anemia of Chronic Disease and Iron Deficiency Anemia

Serum ferritin is the most powerful diagnostic test to distinguish between iron deficiency anemia (IDA) and anemia of chronic disease (ACD), with different diagnostic thresholds based on the presence or absence of inflammation. 1

Key Diagnostic Parameters

Initial Laboratory Assessment

• Complete blood count (CBC) with red blood cell indices
• Serum ferritin
• C-reactive protein (CRP) or other inflammatory markers
• Transferrin saturation (TfS)
• Red cell distribution width (RDW)

Interpretation of Results

1. Serum Ferritin

• Without inflammation:

  • Ferritin <30 μg/L: Diagnostic of iron deficiency 1
  • Ferritin <15 μg/L: Highly specific for iron deficiency (specificity 0.99) 1

• With inflammation/chronic disease:

  • Ferritin <100 μg/L: May still indicate iron deficiency 1
  • Ferritin >100 μg/L with TfS <20%: Consistent with ACD 1
  • Ferritin 30-100 μg/L: Likely combined IDA and ACD 1

2. Red Cell Indices

• Mean Corpuscular Volume (MCV):

  • MCV ≤75 μm³: Strong predictor of iron deficiency (83% of cases) 2
  • MCV ≥86 μm³: Very unlikely to be iron deficiency (only 2% of cases) 2
  • In ACD: May be normal or low 1

• Red Cell Distribution Width (RDW):

  • Elevated in iron deficiency
  • High RDW with normal MCV may indicate combined deficiency states 1

3. Transferrin Saturation (TfS)

• TfS <16%: Suggestive of iron deficiency 1
• TfS <20% with ferritin >100 μg/L: Diagnostic of ACD 1

Advanced Diagnostic Tests

Soluble Transferrin Receptor (sTfR)

• Elevated in IDA but not significantly affected by inflammation 3, 4
• Particularly useful when ferritin results are equivocal (30-100 μg/L) 1
• The sTfR/log ferritin ratio provides superior discrimination between IDA and ACD 1, 3

Reticulocyte Parameters

• Reticulocyte hemoglobin content (Ret-Hb):
  • At cutoff of 27 pg/mL: 93.4% sensitivity and 95.8% specificity for IDA 5
  • Early indicator of iron deficiency (changes before RBC parameters) 5
  • Best diagnostic efficiency (AUC 0.96) for differentiating IDA from ACD 5

Diagnostic Algorithm

1. Step 1: Confirm anemia (Hb <12 g/dL in women, <13 g/dL in men) 1

2. Step 2: Check inflammatory markers (CRP, ESR)

   • If elevated: Consider inflammation/chronic disease present
   • If normal: Consider no significant inflammation

3. Step 3: Interpret ferritin based on inflammation status:

   • Without inflammation:
     • Ferritin <30 μg/L → IDA
     • Ferritin >100 μg/L → Not IDA
   • With inflammation:
     • Ferritin <100 μg/L → Possible IDA or mixed IDA/ACD
     • Ferritin >100 μg/L with TfS <20% → ACD
     • Ferritin 30-100 μg/L → Likely combined IDA and ACD 1

4. Step 4: If diagnosis remains unclear, proceed with advanced testing:

   • sTfR and sTfR/log ferritin ratio
   • Reticulocyte hemoglobin content (if available)

Common Pitfalls to Avoid

• Relying solely on MCV: While microcytosis suggests iron deficiency, it can also occur in thalassemia and some cases of ACD 1
• Using serum iron alone: Poor predictor with low specificity 2
• Ignoring inflammatory status: Ferritin is an acute phase reactant and can be falsely elevated in inflammation 1
• Missing combined deficiency states: IDA and ACD frequently coexist, particularly in inflammatory bowel disease 1
• Overlooking non-GI causes: While investigating for GI blood loss is important in IDA, other causes should be considered 1

By following this systematic approach, clinicians can accurately differentiate between IDA and ACD, leading to appropriate treatment decisions that address the underlying cause of anemia.