Folate and Vitamin B12

Folate and vitamin B12 are 2 of the most clinically important water-soluble vitamins. Deficiencies can present with megaloblastic anemia, GI symptoms, neuropsychiatric symptoms, and adverse pregnancy complications, including neural tube defects. Deficiencies are more likely to occur in specific patient populations, especially B12 deficiencies, which are more common in patients on vegan diets and in those with conditions related to the stomach and/or terminal ileum that affect absorption. These vitamins generally do not cause toxicity when consumed in excess amounts, even in supplemental form, as they are effectively excreted by the kidneys.

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Folate refers to the group of compounds occurring naturally in foods as well as folic acid, which is commonly used in supplements. Folate deficiency can result in megaloblastic anemia and, if the deficiency occurs in pregnant women, neural tube defects in their infants.


  • A coenzyme involved in the synthesis of nucleic acids (required for DNA and RNA)
  • Involved in the conversion of homocysteine to methionine
  • Required for cell division, especially during pregnancy and infancy
  • Required for the production of RBCs (as hematopoietic precursors are some of the most rapidly dividing cells in the body and are sensitive to abnormal DNA synthesis)

Absorption, metabolism, transport, and storage

  • Folates ingested as food are typically in tetrahydrofolate (THF) form.
  • THF is hydrolyzed to a monoglutamate form in the gut.
  • Colonic microbes can also synthesize folate.
  • Absorbed via active transport primarily in the jejunum (passive transport also occurs at pharmacologic doses)
  • Dihydrofolate reductase in the intestinal mucosa cells reduces the folic acid to THF, which is then methylated prior to secretion into the blood.
  • The primary form of folate in the blood is 5-methyl-THF
  • About 50% of folate is stored in the liver and 50% in the blood and body tissues.
Role of vitamin B12 and folic acid in DNA synthesis

Role of vitamin B12 and folic acid in DNA synthesis (from the bottom):
Dietary folate is absorbed in the intestine in the form of 5-methyl-tetrahydrofolate (THF). Vitamin B12–dependent methionine synthetase converts 5-methyl-THF to THF. The same process generates methionine from homocysteine, and this methionine converts to S-adenosylmethionine (SAM; also necessary for DNA methylation). The THF produced is converted to 5,10-methylene-THF. A methyl group is donated from methylene-THF to the 5-carbon of uridylate to form thymidylate. As a consequence of donating the methyl group, methylene-THF becomes dihydrofolate. Dihydrofolate is reduced by reductase to re-generate tetrahydrofolate.

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Daily requirement

  • Infants: 65–80 μg/day 
  • Children 1–13 years of age: 150–300 μg daily, based on age
  • People ≥ 14 years of age: 400 μg daily, higher in pregnancy and lactation
  • Green leafy vegetables:
    • Spinach
    • Broccoli
    • Brussel sprouts
    • Romaine lettuce
    • Asparagus
  • Legumes:
    • Black-eyed peas
    • Kidney beans
    • Green peas
    • Peanuts
  • Fruits:
    • Avocados
    • Bananas
    • Papayas
    • Cantaloupe
  • Fortified cereals, breads, and formula

Dietary sources

Vitamin B12: Cobalamin

Vitamin B12 is important in the formation of RBCs, and its deficiency is associated with megaloblastic anemia.


Vitamin B12 is required for:

  • Production of RBCs (as hematopoietic precursors are some of the most rapidly dividing cells in the body and are sensitive to abnormal DNA synthesis)
  • DNA synthesis
  • Conversion of homocysteine to methionine
  • Nerve cell function (exact mechanisms unknown)

Absorption, metabolism, transport, and storage

  • Vitamin B12 is protein-bound in food.
  • Saliva releases vitamin B12 from these proteins.
  • In the duodenum, B12 combines with intrinsic factor (IF) secreted by the parietal cells in the stomach.
  • The B12–IF complex is absorbed by receptor-mediated endocytosis in the terminal ileum.
  • B12 is secreted into the blood by active transport, where it binds to transcobalamin.
  • The B12 is taken up by receptor-mediated endocytosis in cells throughout the body (especially the liver and bone marrow), where it is converted into methyl-cobalamin or adenosyl-cobalamin.
  • Unlike other water-soluble vitamins, B12 can be stored in the liver for months or years.

Daily requirement

  • Infants: 0.4–0.5 μg/day 
  • Children aged 1–13 years: Requirement increases from 0.9 μg/day up to 1.8 μg/day.
  • People ≥ 14 years of age: 2.4 μg/day (more in pregnancy and lactation)

Dietary sources

  • Fish and clams
  • Meat and poultry
  • Dairy
  • Eggs
  • Fortified cereals and nutritional yeasts
  • Not present in plants

Folate and Vitamin B12 Deficiencies


Folate deficiency can result from:

  • Insufficient dietary intake (most common)
  • Liver disease, including alcohol abuse
  • Increased needs during pregnancy
  • Medications: 
    • Antiepileptic medications 
    • Methotrexate (a dihydrofolate reductase inhibitor) used in rheumatic diseases 
  • Jejunal malabsorption (e.g., celiac disease)

Causes of B12 deficiency include:

  • Insufficient intake: vegan diet
  • Certain types of GI surgery, including gastrectomy and resection of the ileum
  • Autoimmune destruction of gastric parietal cells→ ↓ intrinsic factor → ↓ B12 absorption → pernicious anemia
  • Small-bowel disease affecting the terminal ileum (e.g., Crohn disease, celiac disease)
  • Pancreatic insufficiency
  • Antacids that impair absorption (e.g., proton pump inhibitors, histamine II receptor antagonists)
  • Increased utilization of B12 in pregnancy and lactation

Clinical presentation

Folate and vitamin B12 deficiencies present similarly. Although both may cause neuropsychiatric findings, only B12 deficiency is associated with symptoms related to subacute spinal cord degeneration. 

  • Can be asymptomatic and discovered on routine lab testing
  • Megaloblastic anemia on CBC
  • Symptoms of megaloblastic anemia: 
    • Fatigue
    • Shortness of breath
    • Tachycardia
    • Pallor
    • Sore tongue with shallow ulcerations
    • Changes in skin, hair and/or fingernail pigmentation
  • Glossitis of the tongue
  • Symptoms of peripheral neuropathy:
    • Numbness in the hands and feet (which can be irreversible)
    • Impaired position and/or vibration sense
    • Muscle weakness
    • Ataxia
  • Psychiatric manifestations:
    • Depression or irritability
    • Dementia
    • Psychosis
  • In pregnancy, deficiencies of folate and B12 can lead to harmful effects on the fetus:
    • Neural tube defects (both, but especially folate)
    • Preterm delivery
    • Low-birth-weight infant
    • Developmental delay
    • Failure to thrive

Therapeutic Uses and Clinical Relevance


  • Folate is used to treat megaloblastic anemia due to folate deficiency. 
  • Prenatal vitamins contain folate to decrease the risk of neural tube defects.
  • MTX is a folate antagonist:
    • Patients taking MTX for rheumatologic disease should take folate supplements to minimize side effects.
    • Patients taking MTX for cancer treatments should consult their oncologist, as folate may reduce the efficacy of their treatment.
  • Folate interacts with some antiepileptic medications.
  • People with a homozygous methylenetetrahydrofolate reductase (MTHFR) mutation have an impaired ability to convert folic acid to its active form:
    • Leads to elevated homocysteine levels
    • These patients are susceptible to folate deficiency.
    • Clinical relevance is still under investigation.

Vitamin B12

  • Symptoms of B12 deficiency can take several years to appear due to body stores.
  • Some patients with barriers to absorption (e.g., Crohn disease, gastric surgery, or pernicious anemia) must be treated with injectable B12 preparations.
  • Prevention of B12 deficiency with oral supplementation is important in:
    • Patients with a vegan diet
    • Pregnant women
    • Neonates born to B12–deficient women


  • Not an issue with dietary consumption of folate and B12
  • With excess supplementation:
    • Folate: Effects are under investigation.
    • B12: no toxic effects identified
  • Concern that folate supplementation will mask a B12 deficiency by correcting megaloblastic anemia without correcting the B12 deficiency.


  1. National Institutes of Health Office of Dietary Supplements. (2021). Folate: Fact sheet for health professionals. Retrieved June 6, 2021, from 
  2. National Institutes of Health Office of Dietary Supplements. (2021). Vitamin B12: Fact sheet for health professionals. Retrieved June 6, 2021, from 
  3. Means, R.T., Fairfield, K.M. (2020). Causes and pathophysiology of vitamin B12 and folate deficiencies. In Tirnauer, J.S. (Ed.), UpToDate. Retrieved June 6, 2021, from 
  4. Means, R.T., Fairfield, K.M. (2021). Clinical manifestations and diagnosis of vitamin B12 and folate deficiencies. In Tirnauer, J.S. (Ed.), UpToDate. Retrieved June 6, 2021, from 

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