What are the causes of folate and vitamin B12 deficiency in adults, particularly the elderly?

Causes of Folate and Vitamin B12 Deficiency in Adults and the Elderly

The most common causes of vitamin B12 deficiency in adults, particularly the elderly, are food-bound cobalamin malabsorption due to gastric atrophy (affecting up to 20% of older adults) and low dietary intake of animal-source foods, while folate deficiency primarily results from inadequate consumption of green leafy vegetables and legumes, though this is increasingly rare in fortified populations. 1, 2

Vitamin B12 Deficiency Causes

Malabsorption (Most Common in Elderly)

• Food-bound cobalamin malabsorption is the predominant cause in older adults, resulting from gastric atrophy that impairs the release of vitamin B12 from food proteins despite intact intrinsic factor production 1, 3
• Helicobacter pylori infection contributes to gastric atrophy and subsequent malabsorption 1
• Pernicious anemia (autoimmune destruction of gastric parietal cells) eliminates intrinsic factor production, requiring lifelong intramuscular B12 replacement 4
• Bariatric surgery reduces hydrochloric acid and intrinsic factor availability, causing malabsorption that requires indefinite supplementation 4
• Ileal resection >20 cm removes the primary B12 absorption site, necessitating lifelong monthly intramuscular injections 5
• Crohn's disease affecting the terminal ileum impairs B12 absorption 5

Dietary Insufficiency

• Low intake of animal-source foods is the primary dietary cause, as vitamin B12 exists naturally only in animal products (meat, dairy, eggs, fish, shellfish) 1, 6, 2
• Strict vegetarians (vegans) face inevitable deficiency without supplementation or fortified foods 1, 6
• Lacto-ovo vegetarians with minimal dairy/egg consumption develop depletion over time 1
• Populations in less-industrialized countries with limited animal food access show high deficiency rates 1

Medication-Induced Deficiency

• Metformin use >4 months significantly increases B12 deficiency risk through impaired intestinal absorption 4, 5
• Proton pump inhibitors (PPIs) and H2 receptor antagonists used >12 months reduce gastric acid needed to release food-bound B12 5, 2
• Colchicine, anticonvulsants, phenobarbital, and pregabalin interfere with B12 absorption or utilization 5

Genetic and Metabolic Factors

• Polymorphisms in transcobalamin genes (TCN2, MMACHC, MMADHC, MTRR, MTR) affect plasma B12 concentrations and intracellular metabolism 1, 5
• These genetic variants may cause elevated methylmalonic acid despite normal serum B12 levels 5

Age-Related Considerations

• Elderly adults (>60 years) experience reduced gastric acid secretion and intrinsic factor production 6, 2
• Metabolic B12 deficiency affects 10.6% of adults overall and 18.1% of those >80 years, even with "normal" serum levels 4, 5
• Vitamin B12 stores last 2-3 years, so deficiency presents gradually in at-risk populations 5

Folate Deficiency Causes

Dietary Insufficiency (Primary Cause)

• Low intake of folate-rich foods (green leafy vegetables, citrus fruits, legumes, nuts) is the predominant cause 4, 2
• Natural food folates are approximately 50% less bioavailable than synthetic folic acid, making dietary correction challenging without careful food selection 7
• Low-carbohydrate diets restricting fortified grain products inadvertently reduce folic acid intake 7
• In fortified populations like the United States (mandatory fortification since 1998), folate deficiency is virtually nonexistent 6, 7

Malabsorption Conditions

• Crohn's disease demonstrates 22.3% folate deficiency prevalence (versus 4.3% in ulcerative colitis) due to low intake, malabsorption, and excess utilization from mucosal inflammation 7
• Active intestinal inflammation increases folate consumption, compounding absorption defects 7
• Bariatric surgery impairs folate absorption, requiring monitoring and supplementation 4, 7
• Celiac disease and other small bowel disorders reduce folate absorption 7

Medication-Induced Deficiency

• Methotrexate inhibits dihydrofolate reductase, blocking folate's metabolic activation and requiring routine supplementation (5 mg weekly, 24-72 hours post-dose) 4, 7
• Sulfasalazine causes direct intestinal folate malabsorption, requiring 1 mg daily supplementation for 5 days weekly 4, 7
• Anticonvulsants (phenytoin, phenobarbital) interfere with folate metabolism 4
• Azathioprine and 6-mercaptopurine cause macrocytosis through myelosuppression rather than true folate deficiency 7

Increased Metabolic Demands

• Pregnancy and lactation dramatically increase folate requirements, with deficiency causing neural tube defects and fetal growth retardation 7, 1, 6
• Preconceptional supplementation (400-800 mcg daily, or 4 mg for women with prior neural tube defect-affected pregnancy) is essential 7
• Alcoholism increases folate deficiency risk through poor intake, malabsorption, and increased urinary excretion 1

Functional Interdependence with B12

• Vitamin B12 deficiency leads to functional folate deficiency because B12-dependent methionine synthase is required to convert 5-methyltetrahydrofolate to tetrahydrofolate 4, 2
• This "methyl-folate trap" causes folate accumulation in an unusable form despite adequate total folate levels 4
• The functional interdependence explains why B12 status must always be assessed before treating folate deficiency 4, 7

Critical Clinical Pitfall: The Folate-B12 Interaction

Never initiate folic acid supplementation without first excluding or treating vitamin B12 deficiency, as folate can mask the megaloblastic anemia of B12 deficiency while allowing irreversible neurological damage (subacute combined degeneration of the spinal cord) to progress unchecked. 4, 7, 3

• High-dose folic acid (>5 mg/day) or elevated serum folate during B12 deficiency may exacerbate (not just mask) anemia and worsen cognitive symptoms by depleting serum holotranscobalamin, the active form of B12 3, 8, 9
• Total daily folate intake should not exceed 1000 mcg (1 mg) unless prescribed by a physician, specifically to avoid masking B12 deficiency 7
• This interaction is particularly dangerous in elderly populations not routinely screened for B12 deficiency, where neurological effects become irreversible at advanced stages 4