What causes folic acid deficiency?

Causes of Folic Acid Deficiency

Folic acid deficiency arises from inadequate dietary intake, malabsorption conditions, increased metabolic demands, and medication-induced depletion—with the gastrointestinal tract serving as both the primary site of absorption and a common source of pathology leading to deficiency.

Dietary Insufficiency

Inadequate dietary intake is a fundamental cause of folate deficiency, particularly in populations consuming diets with low vitamin and mineral density 1, 2.

• Natural food folates are approximately 50% less bioavailable than synthetic folic acid, making dietary correction alone challenging without careful food selection 3.
• The bioavailability difference explains why fortification programs (implemented in 1998 in the US with 140 μg synthetic folic acid per 100 grams of enriched grain) were necessary to achieve population-level prevention 3.
• Certain dietary patterns, such as low-carbohydrate diets that restrict fortified grain products, can inadvertently reduce folic acid intake 3.

Malabsorption Disorders

Gastrointestinal diseases directly impair folate absorption, creating a bidirectional relationship where the GI tract is both victim and perpetrator of deficiency 4.

Inflammatory Bowel Disease

• Crohn's disease patients demonstrate 22.3% prevalence of folate deficiency compared to 4.3% in ulcerative colitis, driven by low intake, malabsorption, and excess utilization from mucosal inflammation 3.
• Active intestinal inflammation increases folate consumption, compounding absorption defects 3.
• The small intestine, particularly the proximal portion, is the primary absorption site—any disease affecting this region compromises folate uptake 5.

Celiac Disease and Other Enteropathies

• Celiac disease and other conditions causing villous atrophy impair the enzymatic reduction of naturally occurring conjugated folates to absorbable folic acid 4.
• Bariatric surgery, especially procedures bypassing the proximal small intestine, creates permanent malabsorption risk 1.

Medication-Induced Deficiency

Several commonly prescribed medications directly interfere with folate metabolism or absorption, requiring prophylactic supplementation 3, 1, 5.

Antifolate Medications

• Methotrexate inhibits dihydrofolate reductase, the enzyme converting dihydrofolic acid to tetrahydrofolic acid, blocking folate's metabolic activation 3, 5.
• Sulfasalazine causes direct folate malabsorption in the intestinal tract 3, 1.
• Both medications require routine supplementation: 5 mg folic acid once weekly (24-72 hours post-methotrexate) or 1 mg daily for 5 days per week 3.

Anticonvulsants

• Phenytoin, primidone, and barbiturates interfere with folate metabolism and increase folate loss 5.
• A critical caveat: folic acid antagonizes phenytoin's anticonvulsant action, potentially requiring dose adjustments to prevent breakthrough seizures 5.

Other Medications

• Pyrimethamine and nitrofurantoin contribute to folate depletion 5.
• Azathioprine and 6-mercaptopurine cause macrocytosis through myelosuppressive activity rather than true folate deficiency 3.

Increased Metabolic Demands

Pregnancy dramatically increases folate requirements, with deficiency causing severe fetal consequences 1, 2.

• Neural tube closure occurs within the first 28 days after conception—often before pregnancy recognition—making preconceptional supplementation essential 3.
• Folate deficiency during pregnancy increases risks of preterm delivery, low birth weight, fetal growth retardation, placental abruption, and preeclampsia 2.
• Pregnant women require monitoring of folate levels with supplementation when deficient 3.
• Lactation also increases requirements, though breast milk typically contains adequate amounts for term infants 5.

Alcohol Consumption

Alcoholic cirrhosis and chronic alcohol consumption cause folate deficiency through multiple mechanisms including decreased intake, impaired absorption, and increased hepatic loss 5.

Renal Dialysis

Renal dialysis causes increased folate loss, requiring assessment and potential supplementation 5.

Age-Related Factors

Older age increases folate deficiency risk through decreased dietary intake, polypharmacy, and age-related malabsorption 1.

Critical Diagnostic Pitfall

The most dangerous aspect of folate deficiency is its potential to mask vitamin B12 deficiency 3, 1, 5.

• Folic acid doses above 0.1 mg daily can produce hematologic remission in pernicious anemia while neurologic damage progresses irreversibly 5.
• Always rule out B12 deficiency before treating folate deficiency, as B12 plays a crucial role in folate metabolism 1.
• The FDA label explicitly warns that administering folic acid to patients with undiagnosed anemia risks severe nervous system damage 5.
• Total daily folate intake should not exceed 1000 μg (1.0 mg) unless prescribed by a physician, specifically to avoid masking B12 deficiency 3.

Laboratory Interference

False low serum and red cell folate levels occur in patients taking tetracycline and other antibiotics that suppress Lactobacillus casei growth (used in folate assays) 5.