Folate is an essential water-soluble vitamin, naturally present in foods, especially fruits, green leafy vegetables and liver .
Folic acid is the synthesized form of folate present in fortified foods and supplements and has greater bioavailability than natural folate. In the US, folate has been added to cereals to prevent congenital disabilities, especially neural tube defects, as it is required for the formation of several coenzymes in many metabolic systems, particularly for the synthesis of purines, pyrimidines, and nucleoproteins. , and the maintenance of erythropoiesis.
Folate, like vitamin B12, is a provider of 1-carbon residues for DNA and RNA synthesis. The potent form of folic acid is tetrahydrofolate. Some of the latest research reveals that due to folic acid deficiency:
1. There may be a link between elevated homocysteine (a marker of increased risk for arteriosclerosis) and folate deficiency.
2. Correcting hyperhomocysteinemia with folic acid may reduce the risk of stroke but not adverse cardiac events.
3. Folic acid supplements during pregnancy reduce the incidence of neural tube defects.
4. Lack of folic acid during pregnancy may increase the risk of congenital disabilities and autism associated with diabetes.
5. Maternal folic acid during pregnancy may reduce the risk of childhood leukemia.
6. Folic acid supplementation may increase the risk of cancer.
| Etiology |
Folic acid deficiency can arise from multiple causes, including inadequate dietary intake. Heating during cooking destroys folic acid. Folate is absorbed in the jejunum through active and passive transport mechanisms, through the intestinal wall. Therefore, diseases such as celiac disease, tropical disease, short bowel syndrome, amyloidosis, gastric bypass or mesenteric vascular insufficiency can inhibit folate absorption and cause folate 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, in folate deficiency, convert it to its active form.
Congenital deficiencies of the enzymes required in folate metabolism can lead to its deficiency. Folic acid deficiency may occur after vitamin B-12 deficiency due to an impairment of methionine synthase resulting in the capture of folate as methyltetrahydrofolate, whereby methylene THFA accumulates in the serum, causing the phenomenon folate capture with increased urinary excretion.
Alcoholism is a major cause of folate deficiency. Pregnancy, hemolytic anemia, and dialysis can also cause it.
| Epidemiology |
A study from the National Health and Nutrition Examination Survey (NHANES) identified that women of childbearing age and non-African American Hispanic women were at elevated risk of folic acid deficiency due to inadequate folic acid intake.
Most developed countries make flour fortification with folic acid mandatory , and most European countries recommend folic acid supplementation before conception and up to the first 3 months of pregnancy.
People with low socioeconomic status and the institutionalized elderly population are also at increased risk of folic acid deficiency due to inadequate intake of green leafy vegetables, malnutrition, and changes in mental status. A recently noted feature is that the individual who consumes too much folate appears to have an elevated risk of developing malignant tumors.
| Pathophysiology |
Folate is present in abundance in green leafy vegetables, citrus fruits and animal products. Folate is poorly stored, and in people on folate-deficient diets, deficiency can develop over weeks or months. Most serum folate is present in the inactive form 5-methyltetrahydrofolate (5-methyl THFA). Upon entry into cells, 5-methyl THFA is demethylated to THFA, the biologically active form involved in folate-dependent enzymatic reactions.
Cobalamin (B-12) serves as a cofactor for this demethylation to occur, and in its absence, folate becomes “trapped” inside cells as 5-methyl THFA. THFA participates in the formation of many coenzymes in metabolic systems, in particular in the synthesis of purines, pyrimidines and nucleoproteins, and the maintenance of erythropoiesis.
Folate deficiency, as a result, leads to impairment of cell division, accumulation of toxic metabolites, and impartation of methylation reactions necessary for the regulation of gene expression. The body has about 1,000 to 20,000 mcg of folate stores, and adults need about 400 mcg/day to replace daily losses. Folate deficiency can take between 8 and 16 weeks to manifest.
| History and physical examination |
Several essential clues from a patient’s history can point to the underlying reason for the deficiency. Dietary, drug, and alcohol consumption history may point to the cause. Pregnant or lactating women, patients with hemolytic anemia or certain exfoliative dermatological conditions may have higher requirements.
Those taking certain medications, such as methotrexate, phenytoin, trimethoprim, may have folate deficiency. Most of these symptoms overlap with the symptoms of vitamin B-12 deficiency, except for the classic neurological features of B12 deficiency.
Physical examination may reveal a red, fleshy, and painful tongue. There may be signs of anorexia, and neurological examination may reveal cognitive impairment, depression, and dementia.
| Assessment |
Patients 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 and peripheral blood smear.
Laboratory analyzes in folic acid deficiency reveal anemia, which manifests itself as a decrease in hemoglobin and hematocrit levels. The mean corpuscular volume increases to a level >100 consistent with a diagnosis of macrocytic anemia. On the other hand, a smear may show macrocytic red blood cells and/or megaloblasts and hypersegmented neutrophils.
Serum levels of vitamin B12 and folate should be determined, as it can help differentiate between the two deficiencies. In general, serum folate levels <2 ng/ml are considered deficient, while levels >4 ng/ml are considered normal. Levels between 2 and 4 ng/m warrant further confirmation by measuring methylmalonic acid and homocysteine levels.
Folate deficiency can be confirmed in the presence of a normal level of B12 and methylmalonic acid, and elevated levels of homocysteine, while vitamin B12 deficiency can be confirmed if there are elevated levels of methylmalonic acid and homocysteine and low levels of B12. Folate levels in red blood cells are a very useful index of body stores and can help determine the duration of deficiency.
Bone marrow testing is not necessary to evaluate for vitamin B12 or folate deficiency, but if performed for other reasons in patients with folate deficiency, it may show hypercellularity with hyperplasia of megaloblastic erythroid cells. Future deficiencies can be prevented by identifying and treating the underlying cause.
| Treatment/Management |
All patients with folate deficiency should be offered supplemental folic acid to correct the deficiency.
Typically, 1-5 mg/day of oral folic acid is sufficient to treat folate deficiency. For patients who cannot tolerate oral medications, intravenous, subcutaneous, or intramuscular formulations of folic acid can be used.
Folinic acid (also called leucovorin), a reduced form of folate, is primarily used to prevent methotrexate toxicity. The duration of therapy depends on whether or not the cause of the initial deficiency persists.
Patients with malabsorption or short bowel syndromes usually require prolonged treatment. In those with a concomitant vitamin B12 deficiency, it is also very important to replenish vitamin B12.
Folate treatment alone does not improve neurological symptoms and signs caused by vitamin B12 deficiency, which, if left untreated, is likely to progress and cause permanent neurological damage. All patients should be encouraged to follow a diet rich in fruits and vegetables.
| Differential diagnosis |
Vitamin B12 deficiency, alcoholic liver disease, hypothyroidism and aplastic anemia
| Forecast |
The prognosis is favorable with treatment and generally reverses most of the clinical and biochemical abnormalities seen with folic acid deficiency. However, lack of folate can cause macrocytic anemia. It also raises homocysteine levels, which is associated with atherosclerotic disease.
Lack of folate causes a number of pregnancy-related complications, including placental abruption, miscarriage, neural tube defects, and severe language deficiencies in offspring.
| Complications |
Untreated folic acid deficiency can lead to megaloblastic anemia and pancytopenia.
On the other hand, it can cause glossitis, angular stomatitis and oral ulcers. Neuropsychiatric manifestations also occur, such as depression, irritability, insomnia, cognitive impairment, fatigue, and psychosis.
| Patient Feedback and Education |
Patients with folic acid deficiency should be advised to consume a diet rich in fruits and green leafy vegetables. Supplementation with 1 mg/day of folic acid is usually sufficient to prevent deficiency in certain high-risk patient populations (bariatric surgery, malnutrition, chronic alcohol consumption, 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 0.4 mg/day of supplemental folic acid to prevent pregnancy-related complications and fetal anomalies, including neural tube defects.
Routine folic acid supplementation other than the conditions mentioned above is not indicated.
| Miscellany |
Food fortification programs have been implemented in most Western countries and have been shown to decrease the incidence of folate deficiency. According to the WHO, together with the FAO (Food and Agriculture Organization), the recommended folate nutrient intake is 400 mcg/day.
Excessive folate consumption produces another set of problems, especially in the elderly. Historically, higher levels of folate have been found to worsen anemia and cognition, while masking low levels of vitamin B. Furthermore, excessive folate consumption has a controversial and complex dual role in cancer colorectal.
While some studies have found that folate protects against the risk of colorectal cancer, other studies have found that folate supplementation is potentially cancer-promoting.
| Improving healthcare team outcomes |
Folic acid deficiency is an easily treatable nutritional deficiency, but if left untreated, it can lead to multiple serious complications. Folic acid deficiency is a public health problem and public education is vital. Clinicians at all levels should encourage patients to consume diets rich in fruits and vegetables.
The pharmacist should educate the patient about consuming natural foods instead of consuming supplements. It is noted that there is literature suggesting that excessive consumption of folate supplements may lead to an increased risk of cancer.
It is necessary to recommend abstinence from alcohol. In most cases, dietary counseling can prevent the development of deficiency and supplement folic acid in high-risk individuals. Folic acid deficiency is ideally managed with an interdisciplinary team, including primary care physicians, internists, obstetricians, gastroenterologists, dieticians, pharmacists, and nurses.
The focus is on preventing the development of the deficiency. Primary care physicians, internists, obstetricians, and nurses can identify high-risk patients, educate them, and treat them in consultation with a dietitian and pharmacist.
Women of childbearing age, patients with malabsorption syndromes or those with intestinal resections are at greater risk of developing folic acid deficiency and should be supplemented. Finally, all doctors should keep in mind that failure to educate pregnant women about the importance of folic acid can result in medical malpractice litigation if the baby is born with a neural tube defect.
| Results |
If folic acid deficiency is corrected, the results are excellent for most patients.
