Folate - Kresser Institute Membership Site

Marker Name: Folate

REFERENCE RANGES FOR SERUM FOLATE:

Laboratory reference range: > 3 μg/L

Functional range: > 8 μg/L

DESCRIPTION:

Folate is a coenzyme that participates in single-carbon transfers during nucleic acid and amino acid metabolism.¹ Specifically, folate is a cofactor in purine biosynthesis, thymidylate biosynthesis, and synthesis of methionine from homocysteine.² Folate also generates the single-carbon molecule formate, which participates in various one-carbon reactions. Folate converts various amino acids (e.g., histidine) to glutamate.¹ Taken together, folate is a critical cofactor in the synthesis of DNA and protein metabolism.

Folate is sometimes used interchangeably with the term folic acid; however, this is not technically accurate. Folic acid is the most oxidized form of folate and is often found in supplements, but it occurs rarely in food.¹ Folate is a broad term that applies to many molecules that have folate-like activity.

Humans derive folate from dietary sources. Naturally occurring “food” folates have up to six additional glutamate molecules in a peptide polymer linkage.³ These food folates are hydrolyzed to form monoglutamate prior to absorption in the gut.¹ The resulting monoglutamate is further reduced to form either methyl- or formyl-tetrahydrofolate, though the main form of folate in the plasma is 5-methyltetrahydrofolate.⁴ Folate is freely filtered by the glomerulus, but most is reabsorbed in the proximal tubule of the nephron.¹ Whole-body folate turnover occurs via catabolism into cleavage products.¹

Enzymatic processes that use folate are intimately related to those that use vitamin B12. In fact, vitamin B12 deficiency can be masked by sufficient levels of folate. In vitamin B12 deficiency, folate levels tend to accumulate in the serum and decrease the enzymatic activity of vitamin B12-dependent methyltransferases.⁵ One way to distinguish between folate and vitamin B12 deficiency is to simultaneously assay serum concentrations of homocysteine and methylmalonic acid. Serum homocysteine and methylmalonic acid levels will be elevated in vitamin B12 deficiency, whereas folate deficiency will only increase homocysteine levels in the serum, not methylmalonic acid levels.⁶

High serum folate levels usually represent excessive dietary consumption, usually through consumption of fortified foods and supplements. There are no known negative clinical consequences of an abnormally high folate level, and maximum daily intake is unlikely to cause adverse events.^1,4,7 On the other hand, an abnormally high serum folate level may indicate the presence of disease, such as vitamin B12 deficiency or pernicious anemia. In the setting of vitamin B12 deficiency, for example, abnormally high serum folate can worsen anemia and cognitive disturbances in some individuals.⁸

A low serum folate level is usually due to decreased intake or absorption of the vitamin.⁹ Decreased intake usually results from overcooking food, which can destroy folate, or in the context of general malnutrition. Normal pregnancy and lactation increase metabolic demands on the mother, which can lead to lower folate levels when intake isn’t properly increased. Diseases affecting the intestines, such as celiac sprue and inflammatory bowel disease, can interfere with the absorption of folate. Several genetic conditions may lead to chronically low folate levels; perhaps most notable among these is methylenetetrahydrofolate reductase (MTHFR) deficiency.⁹ Methotrexate, trimethoprim, and phenytoin are well known to reduce serum folate levels.

Folate is measured with serum vitamin B12. A workup of folate deficiency may include a serum homocysteine level and a serum methylmalonic acid level.⁶ Serum folate is quite sensitive to recent dietary intake and thus may be inadequate to determine chronic folate deficiency. The folate found within red blood cells, however, provides a better estimate of long-term body folate status.^4,6

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^3,5

Excessive intake
Vitamin B12 deficiency
Pernicious anemia

Low in:^9,10

Normal pregnancy
Normal lactation
Nutritional deficiency
- Poor dietary intake
- Overcooked foods
- Alcohol
- Substance abuse
Malabsorption
- Celiac disease
- Inflammatory bowel disease
- Infiltrative bowel disease
- Short bowel syndrome
Chronic hemolysis
Exfoliative dermatitis
Genetic causes
- Methylenetetrahydrofolate reductase (MTHFR) deficiency
- Hereditary folate malabsorption
- Glutamate formiminotransferase deficiency
- Functional methionine synthase deficiency
Drugs
- Methotrexate
- Trimethoprim
- Phenytoin
- Pyrimethamine
- Alcohol

FUNCTIONAL RANGE INDICATIONS:

High in:

Low in:

Folate deficiency

References: