What is the clinical significance of ferritin as an acute phase reactant?

Clinical Significance of Ferritin as an Acute Phase Reactant

Ferritin is a critical acute phase reactant that can be significantly elevated in inflammatory conditions, making its interpretation challenging when assessing iron status, as elevated levels may not accurately reflect iron stores during inflammation.

Understanding Ferritin's Dual Role

Ferritin serves two primary functions in the body:

1. Iron Storage Marker: Under normal circumstances, ferritin accurately reflects body iron stores
2. Acute Phase Reactant: During inflammation, infection, or malignancy, ferritin levels increase independently of iron status

Physiological Mechanism

• Ferritin is produced in response to inflammatory cytokines
• During inflammation, proinflammatory cytokines trigger increased hepcidin expression
• Hepcidin restricts dietary iron uptake and promotes iron sequestration within storage sites 1
• This leads to restricted iron availability for erythropoiesis despite normal or elevated ferritin levels

Clinical Implications

Diagnostic Challenges

• Standard ferritin thresholds for iron deficiency (<30 μg/L) do not apply in inflammatory states 1
• Ferritin can be markedly elevated in various conditions:
  • Chronic kidney disease
  • Inflammatory bowel disease
  • Chronic heart failure
  • Infections (including COVID-19)
  • Autoimmune disorders (e.g., Adult-onset Still's disease)
  • Malignancies

Extreme Elevations

• In Adult-onset Still's disease, ferritin can reach extraordinarily high levels (4,000-30,000 ng/mL or even as high as 250,000 ng/mL) 2
• Severe COVID-19 has been associated with hyperferritinemia, suggesting ferritin may play a pathogenetic role beyond being just an acute phase reactant 3

Diagnostic Approach in Inflammatory Conditions

Combined Assessment

• Always interpret ferritin with other markers of inflammation and iron status:
  • C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to assess inflammation 4
  • Transferrin saturation (TSAT) to evaluate iron availability 4

Modified Diagnostic Thresholds

• In inflammatory conditions, consider these diagnostic criteria for iron deficiency:
  • Serum ferritin <100 μg/L OR
  • TSAT <20% regardless of ferritin level
  • If ferritin is 100-300 μg/L, TSAT <20% is required to confirm iron deficiency 1

Additional Helpful Tests

• Soluble transferrin receptor (sTfR): Remains mostly normal in functional iron deficiency but elevates in true iron deficiency, even with inflammation 2
• Reticulocyte hemoglobin content (RetHb): Provides insight into adequacy of iron supply to developing red cells 2
• Glycosylated ferritin fraction: In healthy subjects, 50-80% of ferritin is glycosylated; in inflammatory diseases, this drops to 20-50%; in Adult-onset Still's disease, it often falls below 20% 2

Clinical Applications

Iron Deficiency Anemia Diagnosis

• In patients with chronic kidney disease, ferritin levels should be interpreted in the context of underlying inflammatory states 2
• A ferritin level <45 ng/mL typically indicates iron deficiency anemia, but this threshold may be too low in inflammatory conditions 2

Monitoring Treatment Response

• Ferritin levels correlate with disease activity in inflammatory conditions like Adult-onset Still's disease 2
• Ferritin often normalizes when inflammation resolves
• However, glycosylated ferritin remains low for many months after disease remission and cannot be used for monitoring 2

Common Pitfalls to Avoid

1. Misdiagnosing iron deficiency in inflammatory states by using standard ferritin cutoffs
2. Missing iron deficiency in patients with inflammatory conditions who have "normal" ferritin levels
3. Failing to measure TSAT alongside ferritin in patients with suspected inflammation
4. Overlooking other causes of hyperferritinemia such as hemochromatosis, liver disease, or malignancy
5. Initiating iron therapy based solely on ferritin levels without considering inflammatory markers

Practical Approach to Hyperferritinemia

1. Check inflammatory markers (CRP, ESR)
2. Assess iron availability (TSAT)
3. Consider additional tests (sTfR, RetHb) in unclear cases
4. Use higher ferritin thresholds for diagnosing iron deficiency in inflammatory states
5. Monitor both ferritin and TSAT during treatment of iron deficiency in inflammatory conditions

By understanding ferritin's role as an acute phase reactant, clinicians can more accurately assess iron status and avoid diagnostic errors that could lead to inappropriate treatment decisions affecting patient morbidity and mortality.