The signs and symptoms of folic acid deficiency are non-specific. Subtle signs such as the development of glossitis and oral sores, grey discoloration of the hair, and in case of children, growth abnormalities may be observed; however, as folic acid deficiency leads to megaloblastic anemia, an anemic presentation is most often seen.

The severity of the symptoms is linked to the degree of the anemia and the general health of the individual; for instance, in old age, the symptoms are often much more marked even with a lower deficiency. The symptoms of anemia include fatigue, shortness of breath (especially on exertion) and palpitations. In severe cases, stable angina and intermittent claudication may also result. On physical examination, the skin and conjunctiva is often pale and the patient has a high volume pulse along with tachycardia. In long standing cases, ankle edema, cardiac murmurs and other signs of heart failure also begin to manifest.

In addition to these general signs and symptoms, the clinical manifestations resulting from the underlying etiology (such as anti-folate drug toxocoty, malabsorption, chronic kidney disease, hemolytic anemias, malignancies and homocysteinuria) may also be observed. Folic acid deficiency in pregnant women can predispose to the development of neural tube defects in the developing fetus (such as anencephaly, spina bifida, etc). Women with documented folic acid deficiency or with a history of bearing one or more child with a neural tube defect carry a particularly high risk. As folic acid is necessary for DNA repair, its deficiency may be associated with the development of certain cancers in the body.

• Fatigue

  Folate-deficiency anemia results in immature, abnormally large red blood cells which can lead into disturbing symptoms such as lose of weight and appetite, forgetfulness, lightheadedness, fatigue, and trouble concentrating. [drugsdb.com]

  If the deficiency progresses then several symptoms may manifest: anemia, fatigue, depression, anorexia, weight loss, diarrhea, forgetfulness, headache, sore and inflamed tongue, heart palpitations, hostility and paranoia. [livestrong.com]

  Signs of early pregnancy are missed menstrual periods, fatigue, breast enlargement, abdominal distention, and nausea. [mountsinai.org]

  They include paleness, fatigue, shortness of breath, and palpitations, or heart fluttering, particularly if you exert yourself. In both disorders, your mouth and tongue may be sore, and your skin may become yellow in color. [revivelifelab.com]

  Fatigue may be the first symptom. [merckmanuals.com]

• Malnutrition

  Abstract Polymorphonuclear leukocyte functions were studied in 92 patients with protein-calorie malnutrition. Serum folic acid levels were higher than 3 ng/ml in 38 patients and 3 ng/ml or less in 54 patients. [ncbi.nlm.nih.gov]

  The oral administration of folic acid produces quick improvement in all symptoms; an adequate diet results in cure in cases due to simple malnutrition . [britannica.com]

  Malnutrition,51. Kwashiorkor,52. Marasmus,53. Obesity,54. Anaemia,55. Epidemic Dropsy,56. Deficiency Diseases,57. Food Hygiene,58. Milk Hygiene,59. Meat Hygiene,60. Fish Hygiene,61. Egg Hygiene,62. Hygiene of Fruits and Vegetables,63. [saraspublication.com]

• Pallor

  On postoperative day 52 it was noted that the patient's tongue was magenta and sore and that she had altered taste, pallor, severe weight loss, diarrhea, and poor appetite and mood. [ncbi.nlm.nih.gov]

  Infants who have a folic acid deficiency may show signs of chronic fatigue, dyspnea, heart palpitations, weakness, glossitis, nausea, low body weight, headache, fainting, irritability, pallor and jaundice, or a yellowing of the skin. [livestrong.com]

  Thus, images shown on the left were taken after 2 months from the start of the pharmacological treatment; at this time, pallor of the optic nerve was still evident for monkeys B and C. [iovs.arvojournals.org]

  Symptoms may include: Fatigue Weakness Headache Pallor Sore mouth and tongue The goal is to identify and treat the cause of the folate deficiency. [medlineplus.gov]

• Chronic Fatigue Syndrome

  Chronic fatigue syndrome. Daily injections of folic acid appear to have no effect on symptoms of chronic fatigue syndrome. Memory and thinking skills in older people. [emedicinehealth.com]

  fatigue syndrome, early Parkinson’s disease, diabetic neuropathy and Alzheimer’s disease. [anhinternational.org]

  Here are nine common signs that you might be suffering from a folate deficiency: Poor immune function; frequently getting sick Chronic low energy (including chronic fatigue syndrome ) Poor digestion; issues like constipation, bloating and IBS Developmental [draxe.com]

• Dyspnea

  Infants who have a folic acid deficiency may show signs of chronic fatigue, dyspnea, heart palpitations, weakness, glossitis, nausea, low body weight, headache, fainting, irritability, pallor and jaundice, or a yellowing of the skin. [livestrong.com]

• Nausea

  Patients should be advised to immediately consult their primary health care provider if they experience extreme nausea and/or vomiting. [pharmacytimes.com]

  Infants who have a folic acid deficiency may show signs of chronic fatigue, dyspnea, heart palpitations, weakness, glossitis, nausea, low body weight, headache, fainting, irritability, pallor and jaundice, or a yellowing of the skin. [livestrong.com]

  Oral use of folic acid can cause: Bad taste in your mouth Nausea Loss of appetite Confusion Irritability Sleep pattern disturbance People with allergies might have a reaction to folic acid supplements. [mayoclinic.org]

  Symptoms of overdose may include: stomach pain, nausea, vomiting, diarrhea. Notes If your doctor has prescribed this medication for you, do not share it with others. [webmd.com]

  Folic Acid Deficiency Anemia Severe fatigue and weakness Paleness (pallor) Shortness of breath Heart palpitations or noticeably rapid heartbeat upon exertion Sore, red, and glazed-looking tongue Loss of appetite leading to weight loss Abdominal swelling Nausea [healthcommunities.com]

• Vascular Disease

  When elevated, it is a marker for heart disease, stroke and peripheral vascular disease.) Folate is especially important during periods of rapid cell division and growth. [smart-publications.com]

  […] stroke, and peripheral vascular disease (fatty deposits in the peripheral arteries). 4 Some researchers consider homocysteine as important a cardiovascular risk factor as low-density lipoprotein (LDL). [lifeextension.com]

  Several recent clinical studies have indicated that mild-to-moderate hyperhomocystinemia is highly associated with atherosclerotic vascular disease such as coronary artery disease (CAD) and stroke. [emedicine.com]

• Oral Ulcers

  The combination of swelling and oral ulcers can lead to discomfort in your mouth, making your tongue feel sore. Folic acid deficiency can be caused by a number of factors, including eating overcooked vegetables and drinking too much alcohol. [livestrong.com]

  In infants and children, folate deficiency can lead to failure to thrive or slow growth rate, diarrhea, oral ulcers, megaloblastic anemia, neurological deterioration. [en.wikipedia.org]

  In addition, it can cause glossitis, angular stomatitis and oral ulcers [2]. [ncbi.nlm.nih.gov]

• Ulcer

  The pigment disappeared with correction of the folate deficiency and healing of the gastric ulcer, suggesting a possible relationship with these entities. [ncbi.nlm.nih.gov]

  In addition to a swollen tongue and mouth sores, you may also become tired, develop gray hair, experience diarrhea, develop peptic ulcers and experience poor growth if you have low folic acid levels. [livestrong.com]

  In infants and children, folate deficiency can lead to failure to thrive or slow growth rate, diarrhea, oral ulcers, megaloblastic anemia, neurological deterioration. [en.wikipedia.org]

  […] thrombocytopenia (a deficiency of platelets ), by ineffective blood formation in the bone marrow, and by progressive gastrointestinal symptoms, such as sore tongue, fissures at the corners of the mouth, diarrhea, inflammation of the pharynx or esophagus, and ulceration [britannica.com]

• Dermatitis

  Patients with neoplastic diseases and such skin diseases as chronic exfoliative dermatitis are also are at risk for folic acid anemia. Folic acid deficiency anemia is common during pregnancy. [innvista.com]

  Risk of folic acid deficiency increases in association with certain skin diseases, including psoriasis and exfoliative dermatitis. [healthcommunities.com]

  […] confusion, insomnia, mental fatigue, depression, and nervous system problems of the hands and legs such as restless leg syndrome 4. problems in cell creation especially those with short life spans such as skin cells, causing skin disorders like seborrheic dermatitis [healthsupplementsnutritionalguide.com]

  […] extremity parasthesias, Chvostek sign, Trousseau sign, muscle cramps, tetany, seizures Vitamin D deficiency, decreased PTH activity, corticosteroid use Serum calcium does not fluctuate with changes in calcium intake Pyridoxine (vitamin B6) Seborrheic dermatitis [ekjm.org]

• Skin Rash

  Warning signs of an allergic reaction include: Skin rash Itching Redness Difficulty breathing Excess folic acid is excreted in urine. A high folate intake can mask vitamin B-12 deficiency until its neurological effects become irreversible. [mayoclinic.org]

The diagnosis of folic acid deficiency is easily made through a careful history and simple physical examination of the individual. A number of simple tests can help confirm the diagnosis. These include the following.

• Hemoglobin level and hematocrit: A reduction in the hemoglobin level below 12.5 in males and 10.5 in females is indicative of anemia. Reduction in the hematocrit also confirms anemia.
• Complete blood count (and peripheral film): Once anemia is confirmed, a complete blood count and/or peripheral film is used to determine the type of anemia. In megaloblastic anemia (as is seen in folic acid deficiency and vitamin B12 deficiency), there is reduction in the total red cell count coupled with an increase in the mean corpuscular volume (MCV). 
• Bone marrow biopsy: This is an invasive procedure and is unnecessary for the diagnosis of folic acid deficiency; however, in certain cases, it may be indicated and will show a megaloblastic picture in the bone marrow.
• Red cell and serum folate levels: It is not possible to differentiate vitamin B12 deficiency and folic acid deficiency on the basis of blood picture alone. For this reason, red cell and serum folate levels are measured and if found to be low, folic acid deficiency is documented.
• Vitamin B12 levels: This test may sometimes be indicated even if red cell and serum folate levels are found to be low. Vitamin B12 deficiency is rare because the human body contains abundant stores of it; however, in case of highly macrocytic picture, co-existing vitamin B12 and folic acid deficiency must be suspected and has to be ruled out. This is necessary because folic acid administration in case of vitamin B12 deficiency can precipitate the neurological features of vitamin B12 deficiency.

• Macrocytic Anemia

  Of 73 anemic FAD patients, three had macrocytic anemia due to FAD, one had pernicious anemia, 14 had iron deficiency anemia, eight had thalassemia trait, and the resting 47 had normocytic anemia. [ncbi.nlm.nih.gov]

  These manifestations may occur in any combination; many patients have the neurologic defects without macrocytic anemia. [mayomedicallaboratories.com]

  Macrocytic anemia of pregnancy responds to treatment with folic acid. [studyandscore.com]

  Macrocytic anemia was not observed and signs of folate deficiency were thought to be completely masked by that of iron deficiency. [jstage.jst.go.jp]

  FOLATE deficiency has been recognized for some time to be the cause of most cases of macrocytic anemia of pregnancy. 1 2 3 The association of megaloblastic anemia with hemorrhage during pregnancy was first noted by Hourihane et al. 4 and by Coyle and [nejm.org]

The treatment of folic acid deficiency is folic acid supplementation which is usually done orally. For mild cases, a diet containing high levels of folate (such as citrus fruits and green, leafy vegetables) can be adequate; however, supplementation using folic acid tablets is usually carried out. The dosage of these supplements depends upon the etiology and the severity of the deficiency. In case of anemia due to folic acid deficiency, a daily dose of 1 to 5 mg is usually administered and the hemoglobin, red cell folate and serum folate levels are repeated after some duration. Once the deficiency has been overcome, a maintenance dose of 5 mg per week is often given.

The dosage and duration of folic acid supplementation in folic acid deficiency due to other etiologies is different. In case of gastrointestinal malignancies, up to 5 mg of folic acid is taken for 3 to 8 years; whereas in other malignancies, doses as high as 40 mg may be taken for the same duration depending upon the severity. Folic acid deficiency resulting from overuse of methotrexate may require doses as high as 20 mg for up to 12 weeks [3] [4] [5]. In chronic kidney disease, supplementation of up to 15 mg is taken on alternate days for several years; whereas in homocysteinuria, up to 5 mg of folic acid is required for 1 to 6 months.

In case of overuse of phenytoin, gum hypertrophy may occur which is treated by supplementation along with the topical application of folic acid over the affected gums [6] [7]. Pregnancy related gum disease is also treated in a similar fashion. Prophylactic folic acid supplementation is recommended to all women of child bearing age. Supplementation starting from 2 months prior to pregnancy and during the first two months of pregnancy is very effective in preventing the development of neural tube defects in the fetus [8].

The prognosis of folic acid deficiency itself is very good; however, the underlying etiology (such as any malignancy) may have a prognosis of its own. In the absence of any pathology, folic acid deficiency is completely reversible and does not carry any permanent effects.

The deficiency of folic acid caused due to poor nutrition, pregnancy or lactation is easily treatable with folic acid supplementation. Similarly, folic acid deficiency resulting from excessive alcohol intake rapidly responds to alcohol withdrawal. Folic acid deficiency due to pathological states responds to folic acid supplementation; however, the recovery is not permanent and the underlying pathology always has to be dealt with. Folic acid deficiency resulting from anti-folate drug use responds to folic acid supplementation and/or drug withdrawal.

Folic acid is not stored in the human body in good amounts due to which a daily intake of folic intake is required. Males require about 400 micrograms of folic acid daily whereas females require 400 to 600 micrograms. Plant sources of folic acid in the human diet include bananas, melons, citrus fruits, green leafy vegetables, tomatoes, peas and mushrooms whereas pork, poultry and kidney and liver meat are the animal sources. By far, the most common cause of folic acid deficiency is dietary deficiency. A diet low in folic acid may lead to folic acid deficiency over the course of a few weeks.

In addition to the consumption of unbalanced diets, dietary deficiency may result from poor intake due to starvation and old age. A number of disease states such as acute hepatitis, depression and anorexia nervosa lead to decreased appetite and can also cause inadequate dietary intake of folic acid. Excessive intake of alcohol interferes with the absorption of folic acid in the gastrointestinal tract and also increases its excretion in the urine. For this reason, folic acid deficiency is common in alcoholics [1]. Folic acid is absorbed from the entire gastrointestinal tract; therefore, malabsorption is a very rare cause of folic acid deficiency. However, a number of gastrointestinal diseases such as celiac disease, Crohn disease and cancers can lead to malabsorption severe enough to cause folic acid deficiency in advanced cases.

Deficiency of folic acid can also occur in certain physiological states involving a high folic acid demand such as pregnancy and lactation. In pregnancy, the growing fetus has many rapidly dividing cells for which folic acid is required in excess. Similarly in lactation, folic acid is secreted into the mother’s milk and excess folic acid is required in the diet to make up for this loss. Up to 200 micrograms of folic acid may be needed in addition to the basal requirement of 400 micrograms.

A number of pathological states also confer a high folic acid demand in the body due to rapid cell turnover. These include hemolytic diseases, malignancies and severe inflammatory diseases. Advanced chronic renal diseases also increase the breakdown of red blood cells and ultimately to folic acid deficiency. High levels of homocysteine (as seen in homocysteinuria) are also known to cause the deficiency of folic acid. The use of certain drugs (such as methotrexate, phenytoin, pyrimethamine, sulfasalazine and trimethoprim) can lead to folic acid deficiency [2]. These drugs are therefore referred to as anti-folate drugs.

Dietary folic acid deficiency is more common in the people belonging to the poor social class, especially in the third world countries where people face starvation and often do not get adequate levels of folic acid in their food.

Deficiency of folic acid is much more common in women due to their increased folic acid demand in pregnancy and lactation. In developed countries, alcohol intake is a very common precipitating cause of folic acid deficiency.

Folic acid is necessary for the synthesis of DNA and RNA; and therefore, the production of new cells. It is also needed for the repair of DNA. All the processes and conditions that require a high cell turnover essentially require folic acid. In case of folic acid deficiency, DNA synthesis and cell division can not take place. The most common physiologic manifestation in adults is the development of megaloblastic anemia.

Consuming a well balanced diet with a good amount of fruits and vegetables is sufficient to prevent the deficiency of folic acid in both genders. Women of childbearing age should take folic acid supplements; especially before and during the first two months of pregnancy [9] [10]. Supplementation should also be taken during the period of lactation. The people suffering from disease conditions that involve a high cellular turn over should consider taking folic acid supplementation prophylactically.

Folic acid is essential for the synthesis of DNA and the division of cells. Deficiency of folic acid usually results from inadequate dietary intake; however, a number of pathological conditions may also precipitate this deficiency. The most common manifestation of folic acid deficiency is megaloblastic anemia. Oral supplements are the mainstay for the management of folic acid deficiency.

The human body essentially requires folic acid for the synthesis of DNA and the formation of new cells. Most commonly, lack of folic acid in the diet leads to folic acid deficiency. The symptoms of folic acid deficiency develop due to reduced number of circulating red blood cells. Supplementation of folic acid using tablets or pills is often sufficient to resolve the deficiency.

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