Causes of Folate Deficiency
Folate deficiency results from four primary mechanisms: inadequate dietary intake, intestinal malabsorption, increased metabolic utilization (particularly during inflammation), and medication-induced interference with folate metabolism.
Dietary and Absorption Causes
- Low dietary intake is the most common cause of folate deficiency, particularly from insufficient consumption of green leafy vegetables, legumes, and liver 1, 2.
- Malabsorption occurs in gastrointestinal diseases where the small intestine's ability to absorb folate is compromised 1, 3.
- Celiac disease and other malabsorptive conditions can significantly impair folate absorption, as the gastrointestinal tract serves as both the site of absorption and a potential victim of folate deficiency 3.
Medication-Induced Folate Deficiency
Medications represent a critical and often overlooked cause of folate deficiency through two distinct mechanisms:
Direct Enzyme Inhibition
- Methotrexate causes folate deficiency by inhibiting dihydrofolate reductase, the enzyme that converts dihydrofolic acid to the active tetrahydrofolic acid form 1.
- Anticonvulsants (phenytoin, primidone, barbiturates) interfere with folate metabolism and can antagonize folate's effects 4, 5.
- Pyrimethamine and trimethoprim act as folate antagonists through enzyme inhibition 5.
Impaired Absorption
- Sulfasalazine causes folate deficiency through direct interference with intestinal folate absorption 1.
- Nitrofurantoin can interfere with folate metabolism 4.
- Alcohol consumption, especially in alcoholic cirrhosis, significantly impairs folate status 4, 5.
Myelosuppressive Effects
- Azathioprine and 6-mercaptopurine induce macrocytosis through myelosuppressive activity rather than direct folate antagonism 1.
Disease-Related Causes
Inflammatory Bowel Disease
- Excess folate utilization occurs due to active mucosal inflammation in IBD, with prevalence of folate deficiency reaching 22.3% in Crohn's disease patients 1.
- Multiple concurrent factors often combine in IBD: low intake, malabsorption, inflammation-driven utilization, and medication effects 1.
Post-Bariatric Surgery
- Malabsorption following bariatric surgery can lead to folate deficiency, particularly when combined with poor adherence to multivitamin supplementation 1.
Increased Physiological Demands
- Pregnancy markedly increases folate requirements, and deficiency during pregnancy results in fetal damage and increased risk of neural tube defects 4.
- Lactation similarly increases folate requirements, though breast milk typically contains adequate amounts for term infants 4.
High-Risk Populations
- Older adults (≥65 years) face increased risk due to age-related physiological changes, reduced food intake, limited dietary variety, and polypharmacy 2.
- Lower socioeconomic status reduces access to fresh, nutrient-dense foods and limits dietary variety 2.
- Patients with chronic gastrointestinal disorders, cancer, or diabetes have altered nutrient absorption and metabolism 2.
Critical Clinical Pitfall
A major danger exists when administering folic acid to patients with undiagnosed vitamin B12 deficiency: Folic acid in doses above 0.1 mg daily may mask pernicious anemia by correcting hematologic manifestations while allowing neurologic complications to progress, potentially resulting in severe irreversible nervous system damage 4. Always exclude B12 deficiency before initiating folate supplementation 1, 4.