What causes elevated serum iron levels with low ferritin?

High Serum Iron with Low Ferritin: Causes and Clinical Approach

Direct Answer

The combination of elevated serum iron with low ferritin is an uncommon pattern that most commonly indicates rare genetic disorders of iron metabolism, particularly atransferrinemia, DMT1 deficiency, or early-stage iron deficiency with laboratory artifact. 1

Primary Causes

Genetic Disorders of Iron Metabolism

Atransferrinemia (Transferrin Deficiency)

• This rare autosomal recessive disorder causes defective transferrin production, leading to paradoxically high serum iron despite iron-deficient erythropoiesis 1
• Key laboratory pattern: Low to undetectable transferrin levels (0-20% of normal), fully saturated transferrin, low serum iron concentration but high non-transferrin-bound iron, and elevated ferritin 1
• Patients present with microcytic hypochromic anemia in early life, failure to thrive, and signs of systemic iron overload in non-hematopoietic tissues despite bone marrow iron depletion 1
• The mechanism involves increased intestinal iron absorption due to strongly reduced hepatic hepcidin production 1

DMT1 Deficiency (SLC11A2 Defects)

• Defects in the divalent metal transporter 1 cause impaired enterocyte and erythroid iron uptake 1
• Laboratory findings: Elevated transferrin saturation at presentation, with ferritin levels ranging from low to moderately increased 1
• Seven patients from six families have been described, with 4 of 7 presenting at birth with microcytic anemia and increased transferrin saturation 1
• Liver iron loading develops despite normal or mildly elevated ferritin in some cases 1

Laboratory and Technical Considerations

Timing of Measurement

• Iron parameters should not be evaluated within 4 weeks of total dose iron infusion, as circulating iron interferes with assays leading to spurious results 1
• Serum iron has significant diurnal variation and can be transiently elevated 1

Inflammatory Confounding

• While ferritin is typically elevated in inflammation, the iron content within ferritin protein differs based on the cause of hyperferritinemia 2, 3
• Ferritin generated during inflammation contains much less iron (typically <15% iron by weight) compared to ferritin reflecting true iron stores (>15% iron by weight in iron overload) 2
• The iron content of serum ferritin (ICF) correlates with tissue cell damage independent of inflammatory and body iron status 3

Diagnostic Approach

Initial Laboratory Evaluation

• Measure transferrin saturation (TSAT): Calculate from serum iron divided by total iron-binding capacity 1
• Obtain complete blood count to assess for microcytic hypochromic anemia 1
• Measure transferrin levels directly to identify atransferrinemia 1
• Check inflammatory markers (CRP, ESR) to assess for acute phase reaction 1, 4

Interpretation Algorithm

1. If transferrin is undetectable or <20% of normal: Consider atransferrinemia with genetic testing 1
2. If TSAT is markedly elevated (>45%) with low ferritin: Evaluate for DMT1 deficiency or other rare iron transport disorders 1
3. If inflammatory markers are elevated: The low ferritin may represent true iron deficiency masked by acute phase ferritin elevation, while elevated serum iron could reflect acute phase changes 1
4. If recent IV iron administration: Repeat testing after 4-8 weeks as current values are unreliable 1

Advanced Testing When Indicated

• Genetic testing for SLC11A2, TF, or other iron metabolism genes if clinical presentation suggests hereditary disorder 1
• Bone marrow examination showing reduced iron stores with decreased myeloid:erythroid ratio supports iron-deficient erythropoiesis 1
• Liver MRI or biopsy to assess for tissue iron loading in suspected genetic disorders 1

Critical Clinical Pitfalls

Do Not Assume Iron Overload from Elevated Serum Iron Alone

• Serum iron reflects circulating iron, not total body stores 1
• Ferritin remains the best indicator of iron stores in the absence of inflammation, with 1 μg/L ferritin corresponding to approximately 10 mg stored iron 4

Recognize That Low Ferritin (<50 ng/mL) Indicates Depleted Iron Stores

• A ferritin of 21 ng/mL represents early iron store depletion regardless of serum iron level 4
• Traditional cutoff of ≤15 μg/L for definite iron deficiency has 75% sensitivity but 98% specificity 4
• In the presence of inflammation, iron deficiency may exist with ferritin up to 50-100 μg/L 4

Consider Measurement Artifacts

• Hemolyzed samples can falsely elevate serum iron 1
• Non-fasting samples may show variability, though fasting is no longer absolutely required for transferrin saturation 1

Management Principles

For Genetic Disorders

• Atransferrinemia may require plasma infusions or recombinant transferrin (investigational) 1
• DMT1 deficiency patients may respond to oral iron supplementation in some cases, though this can worsen liver iron loading 1
• Erythropoietin therapy has been attempted with variable success 1

For True Iron Deficiency with Laboratory Discordance

• If TSAT <20% confirms functional iron deficiency despite elevated serum iron, treat the underlying iron deficiency 1, 4
• Oral iron (ferrous sulfate 200 mg three times daily) for three months after anemia correction to replenish stores 4
• Investigate and address underlying causes of iron loss or malabsorption 1