Buy the Book PDA Download

Update Me E-mail alerts The Merck Manual Minute

Print This Topic Email This Topic

Folate (folic acid) is now added to enriched grain foods in the US. Folate is also plentiful in various plant foods and meats, but its bioavailability is greater when it is in supplements or enriched foods than when it occurs naturally in food.

Folates are involved in RBC 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 (by lowering homocysteine levels); their role in reducing the risk of various cancers is unclear. The upper limit for folate intake is 1000 μg; higher doses (up to 5 mg) are recommended for women who have had a baby with a neural tube defect. Folate is essentially nontoxic.

Folate Deficiency

Folate deficiency is common. It may result from inadequate intake, malabsorption, or use of various drugs. Deficiency produces megaloblastic anemia (indistinguishable from that due to vitamin B₁₂ deficiency). Maternal deficiency increases the risk of neural tube birth defects. Diagnosis requires laboratory testing to confirm. Measurement of neutrophil hypersegmentation is sensitive and readily available. Treatment with oral folate is usually successful.

Etiology and Pathophysiology

The most common causes are inadequate intake (usually in patients with undernutrition or alcoholism), increased demand (eg, due to pregnancy or lactation), and impaired absorption (eg, in tropical sprue or due to certain drugs). Deficiency can also result from inadequate bioavailability and increased excretion (see Table 4: Vitamin Deficiency, Dependency, and Toxicity: Causes of Folate Deficiency).

Table 4
Causes of Folate Deficiency Cause Source Inadequate intake Diet lacking fresh, green vegetables or enriched grains; chronic alcoholism; TPN Impaired absorption Celiac disease, sprue, other malabsorption syndromes, certain drugs ( phenytoin Some Trade Names DILANTIN Click for Drug Monograph , primidone Some Trade Names MYSOLINE Click for Drug Monograph , barbiturates), congenital or acquired folate malabsorption Inadequate utilization Folate antagonists ( methotrexate Some Trade Names RHEUMATREX Click for Drug Monograph , triamterene Some Trade Names DYRENIUM Click for Drug Monograph , trimethoprim Some Trade Names PROLOPRIM TRIMPEX Click for Drug Monograph ), anticonvulsants, congenital or acquired enzyme deficiency, alcoholism Increased demand Pregnancy, lactation, infancy, increased metabolism Increased excretion Renal dialysis (peritoneal or hemodialysis)

Prolonged cooking destroys folate, predisposing to inadequate intake. Intake is sometimes barely adequate (eg, in alcoholics). Liver stores provide only a several month supply.

Alcohol interferes with folate absorption, metabolism, renal excretion, and enterohepatic reabsorption, as well as intake. 5- Fluorouracil Some Trade Names
ADRUCIL
Click for Drug Monograph
, metformin Some Trade Names
GLUCOPHAGE
Click for Drug Monograph
, methotrexate Some Trade Names
RHEUMATREX
Click for Drug Monograph
, phenobarbital Some Trade Names
LUMINAL
Click for Drug Monograph
, phenytoin Some Trade Names
DILANTIN
Click for Drug Monograph
, sulfasalazine Some Trade Names
AZULFIDINE
Click for Drug Monograph
, triamterene Some Trade Names
DYRENIUM
Click for Drug Monograph
, and trimethoprim Some Trade Names
PROLOPRIM
TRIMPEX
Click for Drug Monograph
impair folate metabolism.

In the US, many dietary staples (eg, cereals, grain products) are routinely enriched with folate, tending to reduce risk of deficiency.

Symptoms and Signs

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 and perhaps other brain defects (see Congenital Neurologic Anomalies: Introduction).

Diagnosis

• CBC and plasma vitamin B₁₂ and folate levels

CBC may indicate megaloblastic anemia indistinguishable from that of vitamin B₁₂ deficiency. If serum folate is < 3 μg/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 (RBC) folate level better reflects tissue stores. A level of < 140 μg/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

• Supplemental oral folate

Folate 400 to 1000 μg po once/day replenishes tissues and is usually successful even if deficiency has resulted from malabsorption. The normal requirement is 400 μg/day. (Caution: In patients with megaloblastic anemia, vitamin B ₁₂ deficiency must be ruled out before treating with folate. If vitamin B ₁₂ 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 μg/day. For women who have had a fetus or infant with a neural tube defect, the recommended dose is 1000 to 5000 μg/day.

Last full review/revision April 2007 by Larry E. Johnson, MD, PhD

Content last modified April 2007