Causes of Low Folic Acid
Low folic acid levels result primarily from inadequate dietary intake, malabsorption conditions, certain medications, and increased physiological demands, with dietary insufficiency being the most common cause in the general population. 1
Primary Causes
Inadequate Dietary Intake
- The most common cause of folate deficiency is insufficient consumption of folate-rich foods, including pulses (legumes), leafy green vegetables, eggs, nuts, and whole grain products 1
- Natural food folates have lower bioavailability than synthetic folic acid, requiring larger quantities from diet alone to meet requirements 1
- In Ireland, 13% of women have inadequate folate intakes, with 2-15% showing deficient folate status depending on the population studied 1
Malabsorption Conditions
- Bariatric surgery patients are at particularly high risk due to altered gastrointestinal anatomy and reduced absorptive capacity 1
- Atrophic gastritis, affecting up to 20% of older adults, impairs folate absorption 1
- Any condition causing malabsorption should trigger investigation if folate deficiency persists despite oral supplementation 1
Medication Interactions
- Anticonvulsants (phenytoin, primidone, barbiturates) significantly interfere with folate metabolism 1, 2
- Sulfasalazine and methotrexate (folic acid antagonists) directly affect folate levels 1
- Proton pump inhibitors contribute to malabsorption, though their effect is more pronounced on vitamin B12 1
- Pyrimethamine and nitrofurantoin can cause folate depletion 2
Increased Physiological Demands
- Pregnancy and lactation approximately double folate requirements (from 330 μg to 600-800 μg DFE daily) 1
- Renal dialysis causes increased folate loss 2
- Chronic alcoholism, particularly alcoholic cirrhosis, depletes folate stores through multiple mechanisms 2
Special Populations at Risk
Older Adults:
- Lower dietary intake due to reduced food consumption and limited access to fresh produce 1, 3
- Polypharmacy increasing drug-nutrient interactions 1
- Age-related changes in absorption capacity 3
Post-Bariatric Surgery Patients:
- Non-adherence with daily multivitamin supplementation is a common cause 1
- Anatomical changes reducing absorptive surface area 1
Assessment Considerations
Laboratory Markers
- Serum/plasma folate reflects recent dietary intake and is the earliest indicator of altered folate exposure 1
- Red blood cell folate is the preferred marker for long-term status, reflecting folate accumulation over the preceding 3 months and tissue stores 1
- Serum folate should be ≥10 nmol/L and RBC folate ≥340 nmol/L 1
- Plasma homocysteine can serve as a functional marker but is also affected by vitamins B2, B6, and B12 status, as well as renal function 1
Critical Diagnostic Pitfall
- Always exclude vitamin B12 deficiency before treating folate deficiency, as folic acid supplementation can mask the hematologic manifestations of B12 deficiency while allowing neurologic damage to progress 1, 2
- This is particularly important in older adults where B12 deficiency affects 12% of the population 1
- Normal cobalamin and methylmalonic acid (MMA) levels help differentiate isolated folate deficiency from combined deficiencies 1
False Laboratory Results
- Antibiotic use (particularly tetracycline) can cause falsely low serum and RBC folate levels by suppressing Lactobacillus casei growth in microbiological assays 2
- Pre-analytical precautions are essential as folate is susceptible to degradation by light, temperature, pH, and oxygen 1
Management Approach
For confirmed folate deficiency after excluding B12 deficiency:
- Oral folic acid 5 mg daily for a minimum of 4 months 1
- If malabsorption is suspected and oral therapy fails, further investigation is warranted 1
- Address underlying causes: optimize diet, review medications, treat malabsorption conditions 1
Dietary optimization should include: