Folate is an essential water-soluble vitamin, naturally present in food, especially in fruits, green leafy vegetables, and liver. Folic acid is the synthesized form of folate present in fortified foods and supplements and has a higher bioavailability than naturally occurring folate. Folate has been added to grains in the United States, to prevent congenital disabilities, especially neural tube defects, as it is necessary for the formation of several coenzymes in many metabolic systems and maintenance in erythropoiesis.

The most common cause of folic acid deficiency is inad­equate dietary intake. Alcoholic or anorectic patients, persons who do not eat fresh fruits and vegetables, and those who overcook their food are candidates for folic acid deficiency. Reduced folic acid absorption is rarely seen, since absorption occurs from the entire gastrointestinal tract. However, medications such as phenytoin, trimethoprim-sulfamethoxazole, or sulfasalazine may interfere with its absorption. Folic acid absorption is poor in some patients with vitamin B12 deficiency due to gastrointestinal mucosal atrophy. Folic acid requirements are increased in pregnancy, hemolytic anemia, and exfoliative skin disease, and in these cases the increased requirements (5 to 10 times normal) may not be met by a normal diet.


Megaloblastic anemia is identical to anemia resulting from vitamin B12 deficiency. A red blood cell folic acid level below 150 ng/mL (340 nmol/L) is diagnostic of folic acid deficiency. Whether to order a serum or a red blood cell folate level remains unsettled since there are few, if any, data to support one test over the other. Usually, the serum vitamin B12 level is normal, and it should always be mea­sured when folic acid deficiency is suspected. In some instances, folic acid deficiency is a consequence of the gastrointestinal mucosal megaloblastosis from vitamin B12 deficiency.

Differential Diagnosis

The megaloblastic anemia of folic acid deficiency should be differentiated from vitamin B12 deficiency by the finding of a normal vitamin B12 level and a reduced red blood cell (or serum) folic acid level. Alcoholic patients, who often have nutritional deficiency, may also have anemia of liver dis­ease. Pure anemia of liver disease causes a macrocytic ane­mia but does not produce megaloblastic morphologic changes in the peripheral blood; rather, target cells are pres­ent. Hypothyroidism is associated with mild macrocytosis and also with pernicious anemia.

Folic acid deficiency is treated with daily oral folic acid (1 mg). The response is similar to that seen in the treatment of vitamin B12 deficiency, with rapid improvement and a sense of well-being, reticulocytosis in 5–7 days, and total correction of hematologic abnormalities within 2 months. Large doses of folic acid may produce hematologic responses in cases of vitamin B12 deficiency, but permit neurologic damage to progress; hence, obtaining a serum vitamin B12 level in suspected folic acid deficiency is paramount.


Untreated folic acid deficiency can lead to megaloblastic anemia and pancytopenia. In addition, it can cause glossitis, angular stomatitis, and oral ulcers. Neuropsychiatric manifestations, including depression, irritability, insomnia, cognitive decline, fatigue, and psychosis, are also known to occur with folic acid deficiency

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