What is the role of vitamin B12 and folate in iron deficiency?

Role of Vitamin B12 and Folate in Iron Deficiency

Vitamin B12 and folate deficiencies should not be routinely tested for in all cases of iron deficiency anemia, but should be evaluated in patients over 60 years of age or when clinical suspicion exists, as these deficiencies can coexist with or mask iron deficiency. 1

Relationship Between B12, Folate, and Iron Deficiency

Coexistence of Deficiencies

• Low vitamin B12 levels are found in approximately 18% of patients with iron deficiency anemia 1
• Combined deficiencies are particularly important to recognize because:
  • Iron deficiency can mask the macrocytosis typically seen in B12/folate deficiency 1
  • B12 deficiency in doses above 10 mcg daily may produce hematologic responses in patients with folate deficiency 2
  • Folate in doses above 0.1 mg daily may obscure B12 deficiency by correcting hematologic abnormalities while allowing neurologic complications to progress 3

Metabolic Interactions

• Iron deficiency appears to affect multiple metabolic pathways, including those involving B12 and folate 4
• Treatment of iron deficiency with iron supplementation has been shown to significantly increase serum folate and vitamin B12 levels 4
• Even in patients with initially low B12 levels (≤200 pmol/L), iron therapy alone can normalize B12 levels 4

Diagnostic Approach

When to Test for B12 and Folate

1. Age-based approach: Test for B12 deficiency in iron deficiency anemia patients over 60 years (91% sensitivity for identifying combined deficiency) 1
2. Clinical suspicion: Test when symptoms suggest possible B12/folate deficiency:
   • Neurological symptoms (for B12) 2, 3
   • Macrocytosis or dimorphic anemia on blood smear 5
   • Malabsorption syndromes or other risk factors 6

Diagnostic Tests

• Initial testing for vitamin B12 deficiency should use either total B12 (serum cobalamin) or active B12 (serum holotranscobalamin) 7
• For indeterminate B12 results (180-350 ng/L), measuring serum methylmalonic acid (MMA) can help confirm deficiency 7
• Complete blood count, iron studies, B12, folate, and homocysteine levels may be needed for comprehensive evaluation 7

Treatment Considerations

Iron Deficiency with B12/Folate Deficiency

• Treat the underlying iron deficiency first, as this may improve B12 and folate levels 4
• For confirmed B12 deficiency:
  • Oral vitamin B12 supplementation at 1500-2000 mcg daily for 3 months 7
  • Alternative: Intramuscular vitamin B12 injections of 1000 mcg every other day for a week, then monthly 7
• For folate deficiency: 1-5 mg oral folate daily for 90 days 6

Important Warnings

• Critical warning: Folate supplementation in undiagnosed B12 deficiency can mask hematologic symptoms while allowing neurological damage to progress 2, 3
• Untreated vitamin B12 deficiency may cause permanent degenerative lesions of the spinal cord 2
• Vitamin B12 deficiency that progresses for longer than three months may produce permanent neurological damage 2

Special Considerations

• Monitor response to treatment by checking hematologic parameters and vitamin levels after 3 months 7
• In critical care settings, no specific recommendations exist for B12/folate supplementation to reduce transfusion requirements or improve outcomes related to anemia 6
• The prevalence of folate deficiency has decreased significantly since food fortification began in 1998 6
• Consider underlying causes of deficiencies, including malabsorption syndromes, medications (metformin, anticonvulsants), and dietary factors 7

By understanding these complex interactions and following appropriate diagnostic and treatment protocols, clinicians can effectively manage cases where iron deficiency coexists with B12 and/or folate deficiencies.