What conditions can cause low serum iron but high ferritin levels?

Conditions That Cause Low Serum Iron with High Ferritin

The most common condition causing low serum iron with elevated ferritin is anemia of chronic disease (also called anemia of inflammation), which occurs due to inflammatory conditions that upregulate hepcidin production, blocking iron release from macrophages despite adequate iron stores. 1

Pathophysiology of Iron-Ferritin Discrepancy

Normally, serum iron and ferritin levels correlate with each other. However, several conditions can disrupt this relationship:

Inflammatory Conditions

• Anemia of Chronic Disease/Inflammation
  • Inflammatory cytokines (especially IL-6) increase hepcidin production 1, 2
  • Hepcidin blocks iron release from macrophages, hepatocytes, and enterocytes
  • Results in functional iron deficiency despite normal or elevated iron stores
  • Laboratory findings: low serum iron, low-to-normal transferrin, high-to-normal ferritin, transferrin saturation <16% 1, 2

Specific Inflammatory Conditions Associated with This Pattern

• Chronic infections
• Autoimmune diseases:
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Adult-onset Still's disease (extremely high ferritin levels, averaging 14,242 μg/L) 3, 4
• Malignancies (most frequent cause of markedly elevated ferritin >1000 μg/L) 3
• Chronic kidney disease
• Hemophagocytic lymphohistiocytosis/macrophage activation syndrome 3, 4

Cellular Damage Conditions

• Serum ferritin can be released from damaged cells as a "leakage product" 5
• Liver disease (alcoholic liver disease, chronic hepatitis, NAFLD) 6
• Malignancies (particularly hematologic) 3

Diagnostic Considerations

When encountering low iron with high ferritin:

1. Measure inflammatory markers

   • C-reactive protein (CRP)
   • Erythrocyte sedimentation rate (ESR)
   • Positive inflammatory markers support anemia of chronic disease diagnosis 1

2. Additional laboratory tests to consider

   • Complete blood count with red cell indices
   • Transferrin saturation (key diagnostic marker - will be <16% in anemia of chronic disease) 1
   • Soluble transferrin receptor (sTfR) - helps differentiate between iron deficiency and anemia of chronic disease 1
   • Reticulocyte hemoglobin content - useful for monitoring treatment response 1

3. Diagnostic thresholds

   • Ferritin levels up to 100 μg/L may still represent iron deficiency in inflammatory conditions 1
   • Transferrin saturation <16% with ferritin >100 μg/L is diagnostic of anemia of chronic disease in the presence of inflammation 1

Clinical Pitfalls to Avoid

1. Don't rely solely on ferritin to assess iron status in inflammatory conditions

   • Ferritin is an acute phase reactant that increases with inflammation regardless of iron stores 6, 1
   • A combination of transferrin saturation and ferritin provides better diagnostic accuracy 6

2. Don't miss concurrent true iron deficiency in inflammatory conditions

   • True iron deficiency can coexist with anemia of chronic disease
   • In inflammatory conditions, ferritin cutoffs for iron deficiency should be higher (up to 100 μg/L) 1
   • Bone marrow iron staining remains the gold standard for assessing iron stores in complex cases 7

3. Don't overlook rare but serious causes of extremely high ferritin

   • Adult-onset Still's disease
   • Hemophagocytic lymphohistiocytosis
   • Iron overload syndromes (second most common cause of ferritin >1000 μg/L) 3

4. Consider the severity of ferritin elevation

   • Modest elevation (100-300 μg/L): Often seen in common inflammatory conditions
   • Marked elevation (>1000 μg/L): More concerning for malignancy, hemophagocytic syndromes, or iron overload 3

By understanding these patterns, clinicians can better differentiate between true iron deficiency, anemia of chronic disease, and other conditions that affect iron metabolism.