What are the causes of an elevated serum folate level?

Causes of Elevated Serum Folate

Elevated serum folate is most commonly caused by excessive folic acid supplementation (particularly doses >1 mg/day) and cumulative exposure from fortified foods, which often contain 50% more folic acid than labeled amounts. 1, 2

Primary Etiologies

Supplementation-Related Causes

• High-dose folic acid supplements exceeding 1 mg/day represent the single most common cause of elevated serum folate, as the body's capacity to metabolize folic acid becomes saturated at these levels 1, 2
• Therapeutic supplementation in patients receiving methotrexate or sulfasalazine (typically 5 mg weekly or daily) frequently produces elevated serum folate 2
• Therapeutic folate given for active inflammatory bowel disease can elevate serum levels 2

Dietary Fortification

• Fortified grain products (flour, cornmeal, rice, bread, pasta) contribute substantially to baseline folate exposure, with approximately 70% of North Americans receiving significant folate from fortification alone before any supplementation 2
• The actual folic acid content in fortified foods is approximately 50% higher than labeled amounts, leading to unintended excessive intake 1, 2
• Combined exposure from fortified foods plus supplements is the most frequent real-world scenario causing elevated folate, as this dual exposure routinely exceeds safe upper intake thresholds 2

Physiological Factors Affecting Folate Metabolism

• Saturable dihydrofolate reductase (DHFR) capacity limits the body's ability to convert folic acid to active forms, causing accumulation when intake is high 3
• Age-related changes in intestinal pH and enzyme activity affect folic acid reduction capacity 3
• Genetic polymorphisms in folate-metabolizing enzymes, particularly the 19 bp deletion in the DHFR gene, can impair folic acid metabolism and contribute to elevated levels 4

Critical Clinical Pitfall: Masked B12 Deficiency

When you encounter elevated folate, immediately measure vitamin B12 status—this is a medical emergency for neurological function. 1, 2

• Elevated folate can correct the megaloblastic anemia of B12 deficiency while allowing irreversible neurological damage to progress unchecked 2
• The combination of high folate with concurrent low B12 is particularly dangerous in elderly patients (>65 years), who face the highest risk for masked B12 deficiency and undiagnosed pernicious anemia 1, 5
• If B12 is low or borderline (<148 pmol/L) with elevated folate, stop all folic acid supplementation immediately and initiate urgent B12 replacement with 1,000 µg intramuscular injection every other day for one week, followed by monthly injections for life 2

Diagnostic Workup Algorithm

When elevated folate is detected:

1. Measure serum vitamin B12 immediately 1, 5
2. If B12 is borderline or low, check methylmalonic acid (MMA) for functional confirmation of B12 deficiency (elevated MMA confirms functional deficiency) 1, 2
3. Assess homocysteine levels (>15 µmol/L serves as an additional functional marker, though affected by B2, B6, B12, and renal function) 1, 2
4. Evaluate renal function, as impaired kidney clearance affects folate metabolism and homocysteine interpretation 1, 5
5. Review supplementation history: document all folic acid supplements and assess fortified food intake 2

Additional Populations at Risk

• Pregnant women with high folate and low B12 have offspring with increased risk of insulin resistance, obesity, wheezing, and respiratory tract infections 2, 4
• Elderly individuals with high folate and low B12 develop anemia and cognitive impairment 2, 4
• Women homozygous for the 19 bp DHFR deletion who take folic acid supplements during pregnancy have a 4-fold higher risk of unilateral retinoblastoma in offspring 4

Management Based on B12 Status

If B12 is low or borderline with elevated folate:

• Discontinue all folic acid supplementation immediately 1, 2
• Initiate urgent B12 replacement as outlined above 2

If B12 is adequate:

• Reduce total folic acid intake to ≤1 mg/day 1, 2
• Target maintenance levels of approximately 330 µg DFE daily for adults and 500-600 µg DFE for pregnant/lactating women 1, 5
• Reassess necessity of supplementation entirely 2