Folic Acid (Folate) Deficiency

Article Author:
Kashif Khan
Article Editor:
Ishwarlal Jialal
12/17/2018 8:53:30 PM
PubMed Link:
Folic Acid (Folate) Deficiency


Folate is an essential water-soluble vitamin, naturally present in food, especially in fruits,  green leafy vegetables, and liver[1][2] 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, particularly for purine and pyrimidine synthesis, nucleoprotein synthesis and maintenance in erythropoiesis[1]. Folate like Vitamin B12 is a provider of 1-Carbon residues for DNA and RNA synthesis. The potent form of folic acid is tetrahydrofolate.


Folic acid deficiency can arise from multiple causes including inadequate dietary intake. Heating during cooking destroys folic acid. Folate is absorbed in the jejunum by active and passive transport mechanisms across the intestinal wall. Hence, diseases such as celiac disease, tropical sprue, short bowel syndrome, amyloidosis, gastric bypass or mesenteric vascular insufficiency can inhibit folate absorption resulting in a deficiency. Elevated pH as occurs in achlorhydria can also lead to poor folate absorption. Drugs such as methotrexate, phenytoin, sulfasalazine, and trimethoprim can antagonize folate utilization, inhibit its absorption or conversation to its active form resulting in folate deficiency. Congenital deficiencies of enzymes required in folate metabolism can lead to folate deficiency.  Folic acid deficiency can occur subsequent to vitamin B-12 deficiency due to an impairment of methionine synthase resulting in the trapping of folate as methyltetrahydrofolate whereby methylene THFA accumulates in serum leading to folate trap phenomenon and increased urinary excretion of folate. Alcoholism is a significant cause of folate deficiency. Pregnancy, hemolytic anemia, and dialysis can also result in folate deficiency.


A study in the National Health and Nutrition Examination Survey (NHANES) identified that women of childbearing age and non-black Hispanic women were at high risk of folic acid deficiency due to an inadequate folic acid intake.[3] Most developed nations have mandatory folic acid flour fortifications, and most European countries recommend folic acid supplementation before conception and up to first three months of pregnancy. Individuals with low socio-economic status and institutionalized elderly population are also at an increased risk of folic acid deficiency due to inadequate intake of green leafy vegetables, malnutrition and mental status changes.[4]


Folate is present in abundance in green leafy vegetables, citrus fruits, and animal products. Folate is poorly stored, and deficiency can develop in weeks to months in persons with folate deficient diets. Most of the serum folate is present in the inactive 5-methyltetrahydrofolate (5-methyl THFA) form. Upon entering cells, 5-methyl THFA demethylates to THFA, the biologically active form involved in folate-dependent enzymatic reactions. Cobalamin (B-12) serves as a co-factor for this demethylation to occur and in its absence, folate is “trapped” inside cells as 5-methyl THFA. THFA is involved in the formation of many coenzymes in metabolic systems, particularly for purine and pyrimidine synthesis, nucleoprotein synthesis and maintenance in erythropoiesis.[1] Deficiency of folate, as a result, leads to impairment of cell division, accumulation of toxic metabolites and impartment of methylation reactions required for regulation of gene expression.

History and Physical

Several important clues from a patient’s history may point to the underlying reason for the deficiency. Dietary history, drug history, and alcohol intake may point towards the cause. Pregnant or lactation, patients with hemolytic anemia or certain exfoliative dermatological conditions may have increased requirements. Those on certain medications such as methotrexate, phenytoin, trimethoprim can have folate deficiency. Most of these symptoms overlap with symptoms of vitamin B-12 deficiency except for the classical neurological features of B12 deficiency.


Patients being evaluated for folic acid deficiency should also be evaluated for Vitamin B12 deficiency as both cause macrocytic anemia. Initial laboratory tests should include a complete blood count (CBC) and a peripheral smear (PS). Laboratory tests in folic acid deficiency would reveal anemia, manifesting as a decrease in hemoglobin and hematocrit levels. The mean corpuscular volume (MCV) would be increased to a level greater than 100 consistent with a diagnosis of macrocytic anemia. In addition, a PS would show macrocytic red blood cells (RBCs)and/or megaloblasts and hypersegmented neutrophils. Ordering a serum vitamin b12 and folate levels can help differentiate between the two.

Generally, serum folate levels <2 ng/mL are considered deficient, while levels > 4ng/ml are considered as normal. Borderline levels between 2 to 4 ng/mL warrant further confirmation by measurement of Methyl Malonic acid (MMA) and homocysteine levels. Folate deficiency can be confirmed with a normal B12 and  MMA level and elevated homocysteine levels while vitamin B12 deficiency can be confirmed with an elevated MMA and homocysteine levels and low B12 levels [1]. RBC folate levels are a very useful index of body stores and can help access duration of deficiency.[5][6]. Bone marrow evaluation is not required for evaluation of Vitamin B12 or folate deficiency, but if done for other reasons in patients with folate deficiency may show hypercellularity with a megaloblastic erythroid hyperplasia of cells. Future deficiencies can be prevented by identifying an underlying and addressing an underlying cause of folic acid deficiency. 

Treatment / Management

All patients with folate deficiency should be offered supplemental folic acid for correction of deficiency. Typically, oral folic acid (1 to 5mg daily) suffices to treat folate deficiency [1]. Intravenous, subcutaneous or intramuscular formulations of folic acid can be used for patients unable to tolerate oral medications. Folinic acid (also called leucovorin), a reduced form of folate, is primarily used to prevent toxicities of methotrexate. Duration of therapy depends on whether the cause of initial deficiency persists. Patients with malabsorption or short gut syndromes may typically require long-term treatment. 

In patients who have concomitant vitamin B12 deficiency, it is imperative to replete vitamin B12 as well. Folate treatment alone does not improve neurological symptoms and signs due to B12 deficiency which, if untreated, may likely progress and cause permanent neurological damage [5].

Differential Diagnosis

Vitamin B12 deficiency, alcohol liver disease, hypothyroidism, aplastic anemia.


Prognosis is favorable with treatment and generally reverses most clinical and biochemical abnormalities seen with folic acid deficiency. 


Untreated folic acid deficiency can lead to megaloblastic anemia and pancytopenia. In addition, it can cause glossitis, angular stomatitis and oral ulcers [2]. Neuropsychiatric manifestations including depression, irritability, insomnia, cognitive decline, fatigue and psychosis are also known to occur with folic acid deficiency [3][4][5][6].

Deterrence and Patient Education

Patients with folic acid deficiency should be encouraged to eat a diet rich in green leafy vegetables and fruits. Folic acid supplementation at a dose of 1mg daily is usually sufficient to prevent folic acid deficiency in certain high-risk patient populations (bariatric surgery, malnutrition, chronic alcohol use, chronic hemolytic anemia and conditions with high cell turnover). It is strongly recommended that women of childbearing age, eat folate-rich foods and receive at least 0.4mg per day of supplemental folic acid to prevent pregnancy-related complications and fetal abnormalities including neural tube defects [7]. Routine supplementation of folic acid other the in conditions mentioned above is not indicated.

Pearls and Other Issues

Food fortification programs have been implemented in a majority of western countries and have shown to decrease incidence of folate deficiency. According to World Health Organization (WHO) along with Food and Agriculture Organization (FAO) the recommended nutrient intake (RNI) for folate is 400mcg per day [8].

Excess intake of folate produces another set of problems, especially in the elderly population. Higher levels of folate have historically been seen to worsen anemia and cognition while masking low levels of vitamin B. Excess folate intake is also known to have a controversial and complex dual role in colorectal cancer. While some studies have found folate to be protective in risk of colorectal cancer, other studies have found folate supplementation to be potentially cancer-promoting [12][9].

Enhancing Healthcare Team Outcomes

Folic acid deficiency is an easily treatable nutritional deficiency, but if left untreated, can lead to multiple serious complications. In most cases, dietary counseling can prevent development of deficiency and supplementing folic acid to high-risk individuals. Folic acid deficiency is ideally managed with an extraprofessional team including primary care physicians, internists, obstetricians, gastroenterologists, dietician, pharmacist and nurse. The focus is on prevention of development of deficiency. Primary care physicians, internists, obstetricians and nurses can identify patients at high risk, educate them and treat consultation with a dietician and a pharmacist. Women of childbearing age, patients with malabsorption syndromes or those with bowel resections are at increased risks of developing folic acid deficiency and should be provided with folic acid supplements.


[1] Green R,Datta Mitra A, Megaloblastic Anemias: Nutritional and Other Causes. The Medical clinics of North America. 2017 Mar     [PubMed PMID: 28189172]
[2] Attia AAA,Amer MAEM,Hassan M,Din SFG, Low serum folic acid can be a potential independent risk factor for erectile dysfunction: a prospective case-control study. International urology and nephrology. 2018 Dec 13     [PubMed PMID: 30547361]
[3] Lever EG,Elwes RD,Williams A,Reynolds EH, Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment. Journal of neurology, neurosurgery, and psychiatry. 1986 Oct     [PubMed PMID: 3783183]
[4] Green R,Miller JW, Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status. Seminars in hematology. 1999 Jan     [PubMed PMID: 9930568]
[5] Okada A,Koike H,Nakamura T,Watanabe H,Sobue G, Slowly progressive folate-deficiency myelopathy: report of a case. Journal of the neurological sciences. 2014 Jan 15     [PubMed PMID: 24215944]
[6] Reynolds EH, The neurology of folic acid deficiency. Handbook of clinical neurology. 2014     [PubMed PMID: 24365361]
[7] Wilson RD,Wilson RD,Audibert F,Brock JA,Carroll J,Cartier L,Gagnon A,Johnson JA,Langlois S,Murphy-Kaulbeck L,Okun N,Pastuck M,Deb-Rinker P,Dodds L,Leon JA,Lowel HL,Luo W,MacFarlane A,McMillan R,Moore A,Mundle W,O'Connor D,Ray J,Van den Hof M, Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2015 Jun     [PubMed PMID: 26334606]
[8] Watson J,Lee M,Garcia-Casal MN, Consequences of Inadequate Intakes of Vitamin A, Vitamin B{sub}12{/sub}, Vitamin D, Calcium, Iron, and Folate in Older Persons. Current geriatrics reports. 2018     [PubMed PMID: 29721404]
[9] Mason JB,Tang SY, Folate status and colorectal cancer risk: A 2016 update. Molecular aspects of medicine. 2017 Feb     [PubMed PMID: 27890600]
[10] Oakley GP Jr, Inertia on folic acid fortification: public health malpractice. Teratology. 2002 Jul;     [PubMed PMID: 12115780]