What are the differences between folate (vitamin B9) and ferritin regarding the nutrients they assess, the type of anemia they cause, and the appropriate supplementation treatment?

Folate vs Ferritin: Key Differences in Assessment and Management

What Each Biomarker Measures

Folate (vitamin B9) assesses folate stores and recent dietary intake, while ferritin measures iron stores in the body. 1 Folate can be measured as serum folate (reflecting recent intake) or red blood cell (RBC) folate (indicating long-term folate status), analogous to serum iron versus ferritin measurements. 1 Ferritin is the primary storage protein for iron and serves as the most reliable indicator of total body iron stores, though it is also an acute-phase reactant that rises during inflammation. 2

Type of Anemia Each Deficiency Causes

Folate Deficiency

• Folate deficiency produces megaloblastic, macrocytic anemia characterized by elevated mean corpuscular volume (MCV) and large, immature red blood cells. 1
• The anemia results from impaired DNA synthesis in rapidly dividing cells, including erythroid precursors in the bone marrow. 1
• Folate deficiency may also cause neurological symptoms, though these are less severe than those seen with vitamin B12 deficiency. 1

Iron Deficiency (Low Ferritin)

• Iron deficiency causes microcytic, hypochromic anemia with low MCV and pale red blood cells due to inadequate hemoglobin synthesis. 2
• Ferritin <30 μg/L in the absence of inflammation confirms iron deficiency anemia. 2
• In inflammatory states, ferritin up to 100 μg/L may still represent true iron deficiency when transferrin saturation (TSAT) is <20%. 2, 3

Diagnostic Thresholds and Interpretation

Folate

• Serum folate deficiency is defined as <6.8 nmol/L, though RBC folate is a superior marker of long-term folate status. 1, 4
• Folate deficiency prevalence ranges from 23-26% in women of childbearing age in various populations. 4, 5
• Testing for folate should be reserved for patients with macrocytic anemia, neurological symptoms, or high clinical suspicion, as deficiency is rare in countries with grain fortification programs. 1

Ferritin

• Ferritin <15 μg/L has 99% specificity for absolute iron deficiency, while ferritin <30 μg/L is the recommended threshold in non-inflammatory states. 2
• Ferritin <45 μg/L provides optimal sensitivity-specificity balance for diagnosing iron deficiency anemia in clinical practice. 2
• When inflammation is present (elevated CRP/ESR), ferritin 30-100 μg/L with TSAT <20% indicates coexisting iron deficiency and anemia of chronic disease. 2, 3
• Ferritin >100 μg/L with TSAT <20% and elevated inflammatory markers defines anemia of chronic disease with functional iron deficiency. 2, 3

Critical Diagnostic Pitfalls

Folate Assessment

• Vitamin B12 deficiency must be excluded before treating folate deficiency, as folate supplementation can mask severe B12 depletion while allowing irreversible neurological damage to progress. 1
• Serum folate fluctuates with recent dietary intake, making RBC folate a more reliable indicator of true folate stores. 1

Ferritin Assessment

• Never rely on ferritin alone when inflammation is present; always calculate TSAT because functional iron deficiency can exist with high ferritin but low TSAT (<20%). 2
• Ferritin is falsely elevated in chronic inflammation, malignancy, and hepatic disease despite true iron deficiency. 2
• Using the traditional ferritin cutoff of <15 μg/L misses the majority of iron deficiency cases due to poor sensitivity. 2

Appropriate Supplementation Treatment

Folate Deficiency

• For confirmed folate deficiency, prescribe oral folic acid 1-5 mg daily for a minimum of 3-4 months. 1
• Reassess folate levels after 3 months to confirm correction. 1
• Always treat vitamin B12 deficiency immediately before initiating folic acid supplementation. 1

Iron Deficiency

• For iron deficiency with ferritin 30-100 μg/L and TSAT <20%, initiate oral iron therapy promptly while concurrently treating any underlying inflammatory condition. 2
• In anemia of chronic disease (ferritin >100 μg/L, TSAT <20%, elevated CRP/ESR), the primary intervention is aggressive management of the underlying inflammatory disease rather than iron supplementation. 2, 3
• Intravenous iron formulations (iron dextran, iron sucrose, sodium ferric gluconate, or ferric carboxymaltose) are preferred when oral iron is not tolerated or ineffective. 1

Coexistence and Interaction

• Both folate and iron deficiency can coexist, particularly in women of childbearing age, with iron deficiency being the most important contributor to anemia. 6, 4
• In populations studied, 44-51% of women had deficiency in at least one B vitamin or iron. 4, 5
• Iron deficiency was independently associated with anemia (adjusted OR 6.4), while folate deficiency showed weaker associations. 4
• Elevated red cell ferritin can occur in untreated megaloblastic anemia due to B12 or folate deficiency, potentially confusing iron status interpretation. 7

Special Population Considerations

Inflammatory Bowel Disease

• In IBD patients in remission, ferritin <30 μg/L reliably indicates iron deficiency; during active inflammation, use ferritin <100 μg/L with TSAT <20% as diagnostic criteria. 2
• Monitor iron status every 6-12 months in remission and at least every 3 months in active disease. 1

Cancer Patients

• Folate deficiency prevalence is <1% in cancer patients due to grain fortification; reserve testing for high clinical suspicion cases. 1
• Iron deficiency prevalence ranges from 29-60% in cancer patients, with approximately 63% having low TSAT and ferritin. 1