Folic Acid Deficiency

Folic Acid  Deficiency

  • The most common cause of folate and riboflavin deficiencies in older people is low dietary intake, whereas low B12 status is primarily associated with food-bound malabsorption.
  • Cancer, Heart attacks, Strokes, Dementia, Depression, Migraines, and Anemia are associated with Folic acid and B-12 deficiency.
  • Most suppressors of inflammation and cancer-protective genes are methylated while inflammatory and cancer producing genes demethylated (without methylation).  
  • Some patients complain of a sore tongue or pain upon swallowing. The tongue may appear swollen, beefy, red, or shiny, usually around the edges and tips initially. Angular stomatitis also may be observed. These oral lesions typically occur at the time when folate depletion is severe enough to cause megaloblastic anemia.


Folate is a water-soluble B vitamin that is naturally present in some foods, added to others, and available as a dietary supplement.

Folate functions as a coenzyme or cosubstrate in single-carbon transfers in the synthesis of nucleic acids (DNA and RNA) and metabolism of amino acids. One of the most important folate-dependent reactions is the conversion of homocysteine to methionine in the synthesis of S-adenosyl-methionine, an important methyl donor. Another folate-dependent reaction, the methylation of deoxyuridylate to thymidylate in the formation of DNA, is required for proper cell division. An impairment of this reaction initiates a process that can lead to megaloblastic anemia, one of the hallmarks of folate deficiency.

Folate and DNA

Chemically speaking, methylation is the process of adding methyl groups to a molecule. A ‘methyl group’ is a chemical structure made of one carbon and three hydrogen atoms. Since methyl groups are chemically inert, adding them to a protein (the process of methylation) changes how that protein reacts to other substances in the body, thus affecting how that protein behaves. Enzymes, hormones, and even some components in genes are proteins and the process of methylation affects them all. In Genes,  this methylation process dictates the active or quiescence state of a gene. Most suppressors of inflammation and cancer-protective genes are methylated while inflammatory and cancer producing genes demethylated (without methylation).  Millions of these reactions occur every millisecond on cells. In some ways, methylation of proteins helps the body detoxify. For example, the methylation process helps convert the toxic amino acid (homocysteine) into a beneficial amino acid (methionine). If your body cannot methylate properly, toxins build up in your bloodstream and will eventually cause disease.

Methylation processes are fundamental in preventing numerous disorders, and folate and B-12 are principal actors in making it possible. Therefore, deficiency of folate and B-12 disrupts the methylation mechanism and as a result, cause disease which includes:

  • Heart Attack
  • Cancer
  • Stroke
  • Dementia
  • Depression
  • Migraines
  • Autism
  • Fertility
  • Anemia
  • Birth defects, and many more.


The total body content of folate is estimated to be 10 to 30 mg; about half of this amount is stored in the liver and the remainder in blood and body tissues. Normal folate levels above 3 nanograms (ng)/mL is adequate.

Plasma homocysteine concentration is a commonly used functional indicator of folate status because homocysteine levels rise when the body cannot convert homocysteine to methionine due to a 5-methyl-THF deficiency. Homocysteine levels, however, are not a highly specific indicator of folate status because they can be influenced by other factors, including kidney dysfunction and deficiencies of vitamin B12 and other micronutrients. The most commonly used cutoff value for elevated homocysteine is 16 micromoles/L.

The Recommended adult  Dietary Allowances (RDAs) for Folate is 400 micrograms. Folate is found naturally in a wide variety of foods, including vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, dairy products, poultry and meat, eggs, seafood, and grains. Spinach, liver, yeast, asparagus, and Brussels sprouts are among the foods with the highest levels of folate. Folic acid is added to enriched bread, cereals, flours, corn meals, pasta, rice, and other grain products

The potential protective roles of folate and the metabolically related B-vitamins (vitamins B12, B6, and riboflavin) in diseases of aging are of increasing research interest. The most common cause of folate and riboflavin deficiencies in older people is low dietary intake, whereas low B12 status is primarily associated with food-bound malabsorption, while sub-optimal vitamin B6 status is attributed to increased requirements in aging. Observational evidence links low status of folate and the related B-vitamins (and/or elevated concentrations of homocysteine) with a higher risk of degenerative diseases including cardiovascular disease (CVD), cognitive dysfunction and osteoporosis. Deficient or low status of these B-vitamins alone or in combination with hereditary disorders, including the common MTHFR 677 C → T polymorphism, could contribute to greater disease risk in aging by causing perturbations in one-carbon metabolism. Moreover, interventions with the relevant B-vitamins to optimize status may have beneficial effects in preventing degenerative diseases. The precise mechanisms are unknown but many have been proposed involving the role of folate and the related B-vitamins as co-factors for one-carbon transfer reactions, which are fundamental for DNA and RNA biosynthesis and the maintenance of methylation reactions.

Patients with Folic acid deficiency presents with a history of excessive alcohol intake with a concurrent poor dietary intake. Other patients may be pregnant or lactating; may take certain drugs, such as phenytoin, sulfonamides, or methotrexate; may have chronic hemolytic anemia, or may have underlying malabsorption.


Some patients complain of a sore tongue or pain upon swallowing. The tongue may appear swollen, beefy, red, or shiny, usually around the edges and tips initially. Angular stomatitis also may be observed. These oral lesions typically occur at the time when folate depletion is severe enough to cause megaloblastic anemia, although, occasionally, lesions may occur before the anemia. Megaloblastic anemia, which is characterized by large, abnormally nucleated erythrocytes, is the primary clinical sign of a deficiency of folate or vitamin B12. Symptoms of megaloblastic anemia include weakness, fatigue, difficulty concentrating, irritability, headache, heart palpitations, and shortness of breath.

Patients may present with gastrointestinal (GI) symptoms, such as nausea, vomiting, abdominal pain, and diarrhea, especially after meals. Anorexia also is common and, in combination with the above symptoms, may lead to marked weight loss. However, be aware that an underlying malabsorption disorder could be causing these symptoms, as well as folate depletion. The lack of folate itself may not be the culprit.

Neurologic presentations include cognitive impairment, dementia, and depression. These manifestations overlap with those of vitamin B-12 deficiency.

Women with insufficient folate intakes are at increased risk of giving birth to infants with neural tube defects (NTDs) although the mechanism responsible for this effect is unknown. Inadequate maternal folate status has also been associated with low infant birth weight, preterm delivery, and fetal growth retardation.

Folate and Cancer

Several epidemiological studies have suggested an inverse association between folate status and the risk of colorectal, lung, pancreatic, esophageal, stomach, cervical, ovarian, breast, and other cancers. Folate might influence the development of cancer through its role in one-carbon metabolism and subsequent effects on DNA replication and cell division.

In a combined analysis of two trials conducted in Norway (where foods are not fortified with folic acid), supplementation with folic acid (800 mcg/day) plus vitamin B12 (400 mcg/day) for a median of 39 months in 3,411 people with ischemic heart disease increased cancer incidence by 21% and cancer mortality by 38% compared with no supplementation. Findings from these Norwegian trials have raised concerns about the potential of folic acid supplementation to raise cancer risk.

The most thorough research has focused on folate’s effect on the development of colorectal cancer and its precursor, adenoma. Several epidemiological studies have found inverse associations between high dietary folate intake and the risk of colorectal adenoma and colorectal cancer. For example, in the NIH-AARP Diet and Health Study, a cohort study of more than 525,000 people aged 50 to 71 years in the United States, individuals with total folate intakes of 900 mcg/day or higher had a 30% lower risk of colorectal cancer than those with intakes less than 200 mcg/day.

These findings, combined with evidence from laboratory and animal studies indicating that high folate status promotes tumor progression, suggest that folate might play dual roles in the risk of colorectal cancer, and possibly other cancers, depending on the dosage and timing of the exposure. Modest doses of folic acid taken before preneoplastic lesions are established might suppress the development of cancer in normal tissues, whereas high doses taken after the establishment of preneoplastic lesions might promote cancer development and progression. This hypothesis is supported by a 2011 prospective study that found an inverse association between folate intake and risk of colorectal cancer only during early preadenoma stages. Also, a study found that folic acid supplementation significantly increased the risk of prostate cancer. Subsequent research has shown an association between increased cancer cell proliferation and higher serum folate concentrations in men with prostate cancer.

Additional research is needed to fully understand the role of dietary folate and supplemental folic acid in colorectal, prostate, and other cancers. Evidence to date indicates that adequate folate intake might reduce the risk of some forms of cancer. However, high doses of supplemental folic acid should be used with caution, especially by individuals with a history of colorectal adenomas.


Folate and Cardiovascular disease and stroke

An elevated homocysteine level has been associated with an increased risk of cardiovascular disease. Folate and other B vitamins are involved in homocysteine metabolism and researchers have hypothesized that they reduce cardiovascular disease risk by lowering homocysteine levels. It does reduce the risk of stroke by 12%. It is not possible to evaluate the impact of folic acid alone from these trials, but little evidence shows that supplemental folic acid with or without vitamin B12 and vitamin B6 can help reduce the risk or severity of cardiovascular disease. B-vitamin supplementation does, however, appear to have a protective effect on stroke.


Folate and Dementia, cognitive function, and Alzheimer’s disease

Most observational studies show positive associations between elevated homocysteine levels and the incidence of both Alzheimer’s disease and dementia

A secondary analysis of a study conducted in Australia (which did not have mandatory folic acid fortification at the time) found that daily supplementation with 400 mcg folic acid plus 100 mcg vitamin B12 for 2 years improved some measures of cognitive function, particularly memory, in 900 adults aged 60 to 74 years who had depressive symptoms.


Folate and Depression

Low folate status has been linked to depression and poor response to antidepressants. In an ethnically diverse population study of 2,948 people aged 1 to 39 years in the United States, serum and erythrocyte folate concentrations were significantly lower in individuals with major depression than in those who had never been depressed. Results from a study of 52 men and women with major depressive disorder showed that only 1 of 14 subjects with low serum folate levels responded to antidepressant treatment compared with 17 of 38 subjects with normal folate levels.

Although supplemental folic acid has not been proposed as a replacement for traditional antidepressant therapy, it might be helpful as an adjuvant treatment.


Neural tube defects (NTDs) result in malformations of the spine (spina bifida), skull, and brain (anencephaly). They are the most common major congenital malformations of the central nervous system and result from a failure of the neural tube to close at either the upper or lower end during days 21 to 28 after conception.

Preterm birth, congenital heart defects, and other congenital anomalies.


Folate Deficiency Treatment

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”



The Dietary Guidelines for Americans describes a healthy eating pattern as one that:

  • Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.

Many fruits and vegetables are good sources of folate. In the United States, bread, cereal, flour, cornmeal, pasta, rice, and other grain products are fortified with folic acid.

  • Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.

Beef liver contains high amounts of folate. Peas, beans, nuts, and eggs also have folate.

  • Limits saturated and transfats, added sugars, and sodium.
  • Stays within your daily calorie needs



The information in this document does not replace a medical consultation. It is for personal guidance use only. We recommend that patients ask their doctors about what tests or types of treatments are needed for their type and stage of the disease. Sources:

  • American Cancer Society
  • The National Cancer Institute
  • National Comprehensive Cancer Network
  • National Institute of Health
  • American Academy of Gastroenterology
  • National Institute of Health
  • MD Anderson Cancer Center
  • Memorial Sloan Kettering Cancer Center
  • American Academy of Hematology






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