Can a patient with elevated ferritin levels still be iron deficient?

Iron Deficiency with Elevated Ferritin Levels

Yes, a patient can absolutely have iron deficiency despite elevated ferritin levels, particularly in the presence of inflammation, infection, or chronic disease. 1

Understanding Ferritin in Different Clinical Contexts

Ferritin is an acute-phase reactant that increases during inflammation, complicating the diagnosis of iron deficiency. The traditional threshold for iron deficiency (<30 μg/L) does not apply in inflammatory conditions, and higher thresholds must be considered 1, 2.

Diagnostic Criteria Based on Inflammatory Status:

• Without inflammation:

  • Serum ferritin <30 μg/L indicates iron deficiency 1, 3
  • Transferrin saturation (TSAT) <16% 1

• With inflammation/chronic disease:

  • Serum ferritin up to 100 μg/L may still be consistent with iron deficiency 1
  • If ferritin is between 30-100 μg/L with inflammation, a combination of true iron deficiency and anemia of chronic disease is likely 1
  • TSAT <20% is required to confirm iron deficiency when ferritin is 100-300 μg/L 2

Types of Iron Deficiency with Elevated Ferritin

1. Functional Iron Deficiency:

   • Occurs when there is a need for greater iron for hemoglobin synthesis than can be released from stores
   • Often seen in patients receiving erythropoietin therapy
   • TSAT decreases to levels consistent with iron deficiency despite normal or elevated ferritin 1
   • Patients may demonstrate improved hemoglobin when IV iron is administered 1

2. Iron Deficiency in Inflammatory Conditions:

   • Chronic kidney disease, inflammatory bowel disease, heart failure, and other inflammatory conditions can present with elevated ferritin despite iron deficiency 2, 4
   • Proinflammatory cytokines trigger increased hepcidin, which restricts dietary iron uptake and promotes iron sequestration 2
   • Results in restricted iron availability for erythropoiesis despite normal or high ferritin levels 4

Distinguishing Iron Deficiency from Inflammatory Iron Block

A common clinical challenge is differentiating between functional iron deficiency and inflammatory iron block:

• Both conditions may present with:

  • TSAT <20%
  • Ferritin 100-700 ng/mL (or higher in severe inflammation) 1

• Distinguishing features:

  • In functional iron deficiency: Serial ferritin levels decrease during treatment but remain elevated (>100 ng/mL)
  • In inflammatory iron block: Abrupt increase in ferritin with sudden drop in TSAT 1

Diagnostic Approach

1. Assess inflammatory status:

   • Check inflammatory markers (CRP, ESR, leukocyte count)
   • Look for clinical evidence of inflammation (symptoms, endoscopic findings) 1

2. Evaluate iron parameters:

   • Serum ferritin
   • Transferrin saturation (TSAT)
   • Complete blood count with MCV and reticulocytes 1, 3

3. Consider additional tests when available:

   • Soluble transferrin receptor (sTfR) - high in iron deficiency, normal/low in anemia of chronic disease
   • Percent of hypochromic red blood cells - values exceeding 10% are compatible with iron deficiency 1

Common Pitfalls

• Relying solely on ferritin levels without considering inflammatory status can lead to missed diagnoses of iron deficiency 2, 5
• Using inappropriate cutoffs - a study found that using ferritin ≤50 μg/L as cutoff in inflammatory conditions had only 22% negative predictive value 5
• Failing to recognize functional iron deficiency in patients receiving erythropoietin therapy 1
• Not considering a therapeutic trial of iron in unclear cases - weekly IV iron (50-125 mg) for 8-10 doses can help distinguish functional iron deficiency from inflammatory block 1

In summary, elevated ferritin levels do not exclude iron deficiency, especially in inflammatory states. A comprehensive assessment including TSAT, inflammatory markers, and clinical context is essential for accurate diagnosis and appropriate treatment.