What to do if ferritin (iron storage protein) and vitamin B12 levels are elevated but all other lab results are normal?

Elevated Ferritin and B12: Investigation and Management

When ferritin and vitamin B12 are both elevated with otherwise normal labs, investigate for iron overload disorders (hemochromatosis), inflammatory conditions, malignancy, and liver disease—ferritin is an acute-phase protein that rises with inflammation, while elevated B12 typically reflects excess supplementation, liver disease, or hematologic disorders. 1, 2

Initial Diagnostic Approach

Evaluate the Ferritin Elevation

Ferritin serves dual roles: it reflects iron stores AND acts as an acute-phase reactant during inflammation or malignancy. 1, 2

• Check inflammatory markers (CRP, ESR) to determine if ferritin elevation is inflammatory versus true iron overload 1
• If inflammation is present: Ferritin >100 μg/L may be falsely elevated and not reflect true iron stores 1, 3
• If no inflammation: Elevated ferritin likely indicates iron overload requiring further workup 1, 2

Assess for Iron Overload

Order transferrin saturation and consider genetic testing for hemochromatosis (HFE gene mutations, particularly C282Y homozygosity). 1

• Transferrin saturation >45% suggests true iron overload rather than inflammatory hyperferritinemia 1
• Hemochromatosis is the primary concern when ferritin is elevated without inflammation 1
• Iron overload can cause pruritus, liver disease, diabetes, cardiomyopathy, and arthropathy 1, 4

Investigate the B12 Elevation

Elevated B12 is less commonly pathologic than low B12, but warrants investigation for specific conditions. 5

Common causes include:

• Excessive supplementation (most common benign cause) 5
• Liver disease (impaired B12 storage and release) 1
• Myeloproliferative disorders (polycythemia vera, leukemia) 1
• Renal failure (decreased clearance)

Specific Clinical Scenarios

If Hemochromatosis is Confirmed

Initiate therapeutic phlebotomy when ferritin is elevated, targeting a ferritin level of 50-100 μg/L. 1, 4

• Remove 1 unit (450-500 mL) of blood weekly until ferritin reaches 50-100 μg/L 1, 4
• Monitor hemoglobin/hematocrit before each phlebotomy; postpone if anemia develops 1
• Check ferritin every 10-12 phlebotomies during depletion phase 1
• Maintenance therapy: Continue phlebotomy every 3-6 months to maintain ferritin 50-100 μg/L 1
• Avoid vitamin C supplements and iron-fortified foods (vitamin C enhances iron absorption) 1, 4
• Avoid uncooked seafood due to Vibrio vulnificus risk in iron overload 1, 4

If Inflammatory/Malignant Cause is Suspected

Pursue age-appropriate cancer screening and evaluate for chronic inflammatory conditions. 1, 2

• Ferritin >1000 μg/L raises concern for malignancy or severe inflammation 2
• Consider hematologic malignancies (lymphoma, leukemia, myeloma) if other features present 1
• Evaluate liver function tests for hepatic disease 1, 2

If Polycythemia Vera is Considered

Check complete blood count for elevated hemoglobin/hematocrit and consider JAK2 mutation testing. 1

• Polycythemia vera commonly presents with pruritus (especially aquagenic) and elevated ferritin 1
• Both elevated ferritin and B12 can occur in myeloproliferative disorders 1

Key Pitfalls to Avoid

• Do not assume elevated ferritin always means iron overload—inflammation is a common confounder requiring CRP/ESR assessment 1, 3, 2
• Do not ignore ferritin >1000 μg/L—this warrants liver biopsy consideration and aggressive investigation for underlying disease 1
• Do not start phlebotomy without confirming true iron overload via transferrin saturation and excluding inflammatory causes 1
• Do not overlook liver disease—it can cause both elevated ferritin and elevated B12 1, 2
• Transferrin saturation >800 μg/L is toxic and should be avoided during iron replacement in other contexts 1

Monitoring Strategy

Once the underlying cause is identified, establish regular monitoring intervals based on the specific diagnosis. 1

• For confirmed hemochromatosis: Monitor ferritin every 3-6 months during maintenance 1
• For inflammatory causes: Treat underlying condition and recheck ferritin after inflammation resolves 1, 2
• For unexplained elevations: Consider hepatology or hematology referral for liver biopsy or bone marrow evaluation 1, 2