How to diagnose Anemia of Chronic Disease (ACD) with a normal Red Blood Cell (RBC) count?

Diagnosing Anemia of Chronic Disease with Normal RBC Count

The diagnosis of Anemia of Chronic Disease (ACD) with normal RBC count requires evaluation of iron studies, inflammatory markers, and soluble transferrin receptor levels, with serum ferritin >100 μg/L and transferrin saturation <20% in the presence of inflammation being diagnostic for ACD. 1, 2

Diagnostic Approach

Key Laboratory Parameters

• Complete blood count with differential
• Reticulocyte count (normal or low in ACD)
• Iron studies:
  • Serum iron (low in ACD)
  • Serum ferritin (elevated in ACD)
  • Transferrin saturation (low in ACD, typically <16-20%)
  • Total iron binding capacity (normal or low in ACD)
• Inflammatory markers:
  • C-reactive protein (CRP)
  • Erythrocyte sedimentation rate (ESR)

Diagnostic Criteria for ACD with Normal RBC

1. In the presence of inflammation:

   • Serum ferritin >100 μg/L AND
   • Transferrin saturation <20% 1

2. For mixed ACD and iron deficiency:

   • Serum ferritin between 30-100 μg/L AND
   • Transferrin saturation <16% 1

Advanced Diagnostic Tests

• Soluble transferrin receptor (sTfR): Normal or low in isolated ACD, elevated in iron deficiency 1, 3
• sTfR/log ferritin index: Superior to sTfR alone for differential diagnosis 3
  • Cutoff value: 14 (using nmol/L) or 1.03 (using mg/L)
  • Values above cutoff suggest iron deficiency component
  • Values below cutoff suggest pure ACD

Clinical Considerations

Underlying Conditions to Evaluate

• Chronic infections
• Autoimmune disorders (e.g., rheumatoid arthritis)
• Malignancies
• Chronic kidney disease
• Inflammatory bowel disease 2

Pitfalls to Avoid

1. Relying solely on ferritin: In inflammation, ferritin acts as an acute phase reactant and may be falsely elevated despite iron deficiency 1
2. Overlooking mixed deficiency: ACD frequently coexists with true iron deficiency, making diagnosis complex 1, 3
3. Ignoring inflammatory status: Evaluation of anemia is incomplete without clearly defining inflammatory status 1
4. Missing other causes: Normal RBC count with anemia may represent early stages of disease or compensated hemolysis 2

Diagnostic Algorithm

1. Confirm anemia: Low hemoglobin despite normal RBC count
2. Assess inflammation: Check CRP and/or ESR
3. If inflammation present:
   • Check iron studies (ferritin, transferrin saturation)
   • If ferritin >100 μg/L and transferrin saturation <20% → ACD 1
   • If ferritin 30-100 μg/L and transferrin saturation <16% → Mixed ACD and iron deficiency 1
4. If diagnosis unclear:
   • Measure sTfR and calculate sTfR/log ferritin index
   • Index >14 (or >1.03 using mg/L) suggests iron deficiency component 3
   • Index <14 (or <1.03 using mg/L) suggests pure ACD 3

Treatment Implications

• Treatment should target the underlying inflammatory condition 2
• Avoid iron supplementation alone in active inflammation unless concurrent true iron deficiency is confirmed 2, 4
• For persistent symptomatic anemia despite treating the underlying condition, consider erythropoiesis-stimulating agents 2

Using this comprehensive approach with both standard and advanced markers significantly improves diagnostic accuracy, with the combination of ferritin, sTfR, and sTfR Index more than doubling the detection of iron deficiency compared to using ferritin alone (92% vs 41%) 3.