Folate is now added to enriched grain foods in the US and Canada. Folate is also plentiful in various plant foods and meats, particularly raw green leafy vegetables, fruits, organ meats (eg, liver), but its bioavailability is greater when it is in supplements or enriched foods than when it occurs naturally in food (see table ).
Folates are involved in red blood cell maturation and synthesis of purines and pyrimidines. They are required for development of the fetal nervous system. Absorption occurs in the duodenum and upper jejunum. Enterohepatic circulation of folate occurs.
Folate supplements do not protect against coronary artery disease or stroke (even though they lower homocysteine levels); current evidence does not support claims that folate supplementation increases or reduces the risk of various cancers. Any role for using supplemental folate, methyltetrahydrofolate, or L-methylfolate, or for testing for mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene in patients with depression is uncertain at this time.
The upper limit for folate intake is 1000 mcg; higher daily doses (up to 4 mg) are recommended for women who have had a baby with a neural tube defect Overview of Congenital Neurologic Anomalies Congenital brain anomalies usually cause severe neurologic deficits; some may be fatal. Some of the most serious neurologic anomalies (eg, anencephaly, encephalocele, spina bifida) develop in... read more . Folate is essentially nontoxic.
Women taking both oral contraceptives and antiseizure drugs may need to take folate supplements to maintain birth control effectiveness.
(See also Overview of Vitamins Overview of Vitamins Vitamins may be Fat soluble (vitamins A, D, E, and K) Water soluble (B vitamins and vitamin C) The B vitamins include biotin, folate, niacin, pantothenic acid, riboflavin (B2), thiamin (B1)... read more .)
Etiology of Folate Deficiency
The most common causes of folate deficiency are
Inadequate intake (usually in patients with undernutrition Overview of Undernutrition Undernutrition is a form of malnutrition. (Malnutrition also includes overnutrition.) Undernutrition can result from inadequate ingestion of nutrients, malabsorption, impaired metabolism, loss... read more or alcohol use disorder Alcohol Use Disorder and Rehabilitation Alcohol use disorder involves a pattern of alcohol use that typically includes craving and manifestations of tolerance and/or withdrawal along with adverse psychosocial consequences. Alcoholism... read more )
Increased demand (eg, due to pregnancy or lactation)
Impaired absorption Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more (eg, in celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more or due to certain drugs)
Deficiency can also result from inadequate bioavailability and increased excretion (see table ).
Prolonged cooking destroys folate, predisposing to inadequate intake. Intake is sometimes barely adequate (eg, in people with alcohol use disorder). Liver stores provide only a several-month supply.
Alcohol interferes with folate absorption, metabolism, renal excretion, and enterohepatic reabsorption and reduces healthy food intake. 5-Fluorouracil, metformin, methotrexate, phenobarbital, phenytoin, triamterene, and trimethoprim impair folate metabolism.
In the US and Canada, many dietary staples (eg, cereals, grain products) are routinely enriched with folate, tending to reduce risk of deficiency.
Symptoms and Signs of Folate Deficiency
Folate deficiency may cause glossitis, diarrhea, depression, and confusion. Anemia may develop insidiously and, because of compensatory mechanisms, be more severe than symptoms suggest.
Folate deficiency during pregnancy increases the risk of fetal neural tube defects Overview of Congenital Neurologic Anomalies Congenital brain anomalies usually cause severe neurologic deficits; some may be fatal. Some of the most serious neurologic anomalies (eg, anencephaly, encephalocele, spina bifida) develop in... read more and perhaps other brain defects.
Diagnosis of Folate Deficiency
Complete blood count and serum vitamin B12 and folate levels
Complete blood count may indicate megaloblastic anemia Megaloblastic Macrocytic Anemias Megaloblastic anemias result most often from deficiencies of vitamin B12 and folate. Ineffective hematopoiesis affects all cell lines but particularly red blood cells. Diagnosis is usually based... read more indistinguishable from that of vitamin B12 deficiency Vitamin B12 Deficiency Dietary vitamin B12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage... read more .
If serum folate is < 3 mcg/L or ng/mL (< 7 nmol/L), deficiency is likely. Serum folate reflects folate status unless intake has recently increased or decreased. If intake has changed, erythrocyte (red blood cell) folate level better reflects tissue stores. A level of < 140 mcg/L or ng/mL (< 305 nmol/L) indicates inadequate status.
Also, an increase in the homocysteine level suggests tissue folate deficiency (but the level is also affected by vitamin B12 and vitamin B6 levels, renal insufficiency, and genetic factors). A normal methylmalonic acid (MMA) level may differentiate folate deficiency from vitamin B12 deficiency, because MMA levels rise in vitamin B12 deficiency but not in folate deficiency.
Treatment of Folate Deficiency
Supplemental oral folate
Folate 400 to 1000 mcg orally once a day replenishes tissues and is usually successful even if deficiency has resulted from malabsorption. The normal requirement is 400 mcg/day. (CAUTION: In patients with megaloblastic anemia, vitamin B12 deficiency must be ruled out before treating with folate. If vitamin B12 deficiency is present, folate supplementation can alleviate the anemia but does not reverse, and may even worsen, neurologic deficits.)
For pregnant women, the recommended daily allowance (RDA) is 600 mcg/day. For women who have had a fetus or infant with a neural tube defect, the recommended dose is 4000 mcg/day, started 1 month before conception (if possible) and continued until 3 months after conception.
Most commonly, folate deficiency results from reduced intake (eg, due to alcohol use disorder), increased demand (eg, due to pregnancy), or impaired absorption (eg, due to drugs or malabsorption disorders).
Prolonged cooking destroys folate, but many dietary staples are supplemented with folate.
Deficiency causes megaloblastic anemia and sometimes glossitis, diarrhea, depression, and confusion.
Measure serum folate and vitamin B12 levels in patients who have megaloblastic anemia.
To treat deficiency, give patients supplemental folate 400 to 1000 mcg orally once a day.