Diagnosis: Anemia of Chronic Disease (Inflammatory Anemia)
The combination of high serum ferritin with low serum iron indicates anemia of chronic disease (also called anemia of inflammation), where iron is sequestered in storage sites and unavailable for red blood cell production despite adequate—or even elevated—total body iron stores. 1, 2
Understanding the Pathophysiology
The paradoxical pattern of elevated ferritin alongside low serum iron occurs because:
- Inflammatory cytokines (especially IL-6) stimulate hepatic production of hepcidin, which blocks iron release from macrophages, hepatocytes, and enterocytes, creating functional iron deficiency for erythropoiesis despite normal or high iron stores 2, 3
- Ferritin rises as an acute-phase reactant during inflammation, independent of actual iron stores, making it an unreliable marker of iron status in inflammatory states 1, 3
- Iron becomes trapped in the reticuloendothelial system (macrophages and hepatocytes), where it cannot be mobilized for red blood cell production 2, 4
Diagnostic Algorithm
Step 1: Calculate Transferrin Saturation (TSAT)
TSAT = (Serum iron × 100) ÷ Total iron-binding capacity (TIBC) 1
- TSAT <16–20% confirms iron deficiency (absolute or functional) 1
- TSAT <16% with ferritin >100 μg/L defines anemia of chronic disease in the presence of inflammation 1
Step 2: Measure Inflammatory Markers
Check C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to confirm active inflammation 1
- Elevated CRP/ESR with ferritin >100 μg/L and TSAT <16% = anemia of chronic disease 1
- Normal CRP/ESR with low ferritin (<30 μg/L) and TSAT <16% = absolute iron deficiency 1
Step 3: Interpret Ferritin in Context of Inflammation
| Ferritin Level | TSAT | CRP/ESR | Diagnosis |
|---|---|---|---|
| <30 μg/L | <16% | Normal | Absolute iron deficiency [1] |
| 30–100 μg/L | <16% | Elevated | Mixed: iron deficiency + anemia of chronic disease [1] |
| >100 μg/L | <16% | Elevated | Anemia of chronic disease (functional iron deficiency) [1] |
| >500 ng/mL | <25% | Elevated | Severe inflammatory iron block [5] |
Common Underlying Causes to Investigate
Anemia of chronic disease occurs in the setting of:
- Chronic infections (HIV, tuberculosis, endocarditis) 3, 4
- Inflammatory bowel disease (Crohn's disease, ulcerative colitis) 1
- Rheumatologic diseases (rheumatoid arthritis, systemic lupus erythematosus) 3, 4
- Chronic kidney disease (especially in hemodialysis patients) 5, 6
- Malignancy (solid tumors, lymphomas) 3, 4
- Autoimmune diseases 3, 4
Advanced Testing When Diagnosis Is Unclear
If ferritin and TSAT results are discordant or inflammation confounds interpretation:
- Soluble transferrin receptor (sTfR) is elevated in true iron deficiency but remains normal or low in anemia of chronic disease, unaffected by inflammation 1
- Reticulocyte hemoglobin content (CHr or RET-He) directly assesses iron availability to erythropoiesis 1
- sTfR/log ferritin ratio >1.5 indicates iron-deficient erythropoiesis even when ferritin appears normal due to inflammation 1
Management Strategy
Primary Treatment: Address the Underlying Inflammatory Condition
The cornerstone of management is treating the disease causing inflammation, not the elevated ferritin itself 3, 4
- Disease-specific anti-inflammatory therapy for rheumatologic conditions 1
- Antimicrobial therapy for chronic infections 4
- Oncologic treatment for malignancy 4
- Immunosuppression for inflammatory bowel disease 1
Iron Supplementation: When to Avoid and When to Consider
Do NOT administer oral or IV iron in pure anemia of chronic disease (ferritin >100 μg/L, TSAT <20%, elevated CRP) because:
- Iron supplementation will not improve anemia when iron is sequestered by inflammation 4
- Excess iron promotes bacterial growth and tumor proliferation 4
- Iron inhibits T-cell-mediated immunity 4
EXCEPTION: Functional iron deficiency in chronic kidney disease (CKD) patients on erythropoiesis-stimulating agents (ESAs):
- In CKD patients receiving ESAs, ferritin 100–700 ng/mL with TSAT <20% may respond to IV iron therapy despite elevated ferritin 1, 5
- Trial approach: Administer weekly IV iron (50–125 mg) for 8–10 doses; lack of hemoglobin response indicates pure inflammatory block rather than functional iron deficiency 1
Erythropoiesis-Stimulating Agents (ESAs)
Recombinant erythropoietin can be used for prolonged anemia management in chronic disease, though response rates vary 4
Critical Pitfalls to Avoid
- Never diagnose iron deficiency based on low serum iron alone; ferritin and TSAT must be interpreted together with inflammatory markers 1, 3
- Do not assume normal ferritin excludes iron deficiency in inflammatory states; ferritin up to 100 μg/L may still represent depleted stores when inflammation is present 1
- Avoid iron supplementation when ferritin >100 μg/L and TSAT <20% with elevated CRP/ESR, as this represents inflammatory iron block, not true deficiency 4
- Recognize that ferritin >500 ng/mL with TSAT <25% is strongly associated with inflammation rather than iron overload in hemodialysis patients 5
- Do not overlook mixed iron deficiency: ferritin 30–100 μg/L with elevated CRP/ESR indicates coexisting absolute iron deficiency and anemia of chronic disease, requiring treatment of both conditions 1