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Folate deficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Editor : L.Farrukh​

Synonyms and keywords: Folic acid deficiency

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Folate deficiency is the deficiency of folic acid, which is a necessary compound for the normal production of red blood cells. Folic acid is part of the vitamin B complex, also called vitamin B9 or pteroylglutamic acid. The recommended daily amount of folate for adults is 400 micrograms (mcg). Adult women who are planning pregnancy or could become pregnant should be advised to get 400 to 800 mcg of folic acid a day. The deficiency of folic acid is associated with a type of anemia, characterized by enlarged blood corpuscles, called megaloblastic anemia.The anemia is thought to be due to problems in the synthesis of DNA precursors, specifically in the synthesis of thymine, which is required for normal erythropoesis and dependent on products of the MTR reaction. Other cell lines such as white blood cells and platelets are also found to be low due to impaired division of the precursor cells. Bone marrow examination may show megaloblastic hemopoiesis. The anemia is easy to cure with folic acid supplementation.[1]

Historical Perspective

Folate deficiency was first discovered by Lucy Wills, an English hematologist, in 1931 while conducting seminal work in India in the late 1920s and early 1930s on macrocytic anemia of pregnancy.[2]

Classification

There is no established system for the classification of Folate deficiency. However, it can be classified into different categories,based on the causative factors.[3]

Pathophysiology

Folate (also called vitamin B9 or pteroylglutamic acid) is a water soluble vitamin, cannot be synthesized by the human body, however can be obtained from the diet like green leafy vegetables and liver.In the human body folic acid serves a number of functions which include the following :

  • Production and maintenance of new cells
  • DNA and RNA synthesis
  • Carrying one-carbon groups for various methylation reactions
  • Preventing changes to DNA, therefore, for preventing cancer

Causes

Common causes of folate deficiency include gastrointestinal conditions, including malabsorption syndrome and other diseases obstructing folate absorption. Oncological causes, including leukemia, stomach cancer, and liver cancer are life threatening and should be promptly differentiated and diagnosed.

Differentiating Folate deficiency from Other Diseases

Folate deficiency must be differentiated from other diseases associated with the Macrocytic anemia such as Vitamin B12 deficiency, Alcoholic liver disease, Hypothyroidism, Myelodysplasia and Aplastic anemia.

Epidemiology and Demographics

The prevalence of folate deficiency is quite variable across the world.Patients of all age groups may develop folate deficiency however primary age groups affected by Folate deficiency include preschool children, pregnant women and older people.

Risk Factors

Several factors may put a person at risk for developing Folate deficiency.These include the presence of congenital defect, malabsorptive disorder and alcohol abuse. Certain medications use are also associated with higher risk for developing Folate deficiency.

Screening

Screening for Folate deficiency anemia is usually not routinely recommended for asymptomatic patients.

Natural History, Complications, and Prognosis

The symptoms of folate deficiency are very non specific and subtle.It can present with the features of anemia and can lead to severe complications if not treated.[4][5]

Prognosis

Prognosis of patients with folate deficiency is generally good and clinical and hematological parameters usually reverses after 8 weeks of treatment.

Diagnosis

Diagnostic Study of Choice

There is no single diagnostic study of choice or gold standard test for the diagnosis of folate deficiency.

History and Symptoms

History plays an important role in folate deficiency as the signs and symptoms associated with it are subtle and non specific.

Physical Examination

Patients with folate deficiency may appear normal in some cases but usually if anemia is moderate or severe, the patient would appear pale,malnourished or underdeveloped. All organ systems can be involved by the effects of anemia.[6]

Laboratory Findings

Laboratory tests used to diagnose Folate deficiency include complete blood count, peripheral smear, serum LDH level, serum indirect biluribin level, serum folate level, RBC folate level, plasma or serum homocysteine level.

Imaging Findings

There are no other imaging findings associated with Folate deficiency.

Other Diagnostic Studies

Bone marrow biopsy, although not done routinely but sometimes can be useful in supporting the diagnosis.[7]

Treatment

Medical Therapy

Treatment of folate deficiency includes folic acid supplementation and treating the cause of the folate deficiency.Standard dosing of oral folic acid is 1 to 5 mg/day orally for 1 to 4 months, or until complete hematologic recovery occurs. The oral route is sufficient even in those with malabsorption.

Vitamin B12 deficiency must be ruled out, and treated if present, before giving folic acid to a patient with megaloblastic anemia, since administration of folic acid may worsen neurologic complications of untreated vitamin B12 deficiency.[8]

Surgery

There is no surgical treatment available for folate deficiency.

Prevention

Maintaining adequate folate level in the body, is the most effective approach to prevent folate deficiency in states of increased demand such as pregnancy.The source of folic acid to the body is diet. Consuming folic acid rich food will prevent folate deficiency.[9]

References

  1. ↑ “StatPearls”. 2018. PMID 30570998.
  2. ↑ THOMSON DL (1947). “The folic acid story”. Can Med Assoc J. 56 (4): 432–5. PMC 1591988. PMID 20286957.
  3. ↑ “StatPearls”. 2018. PMID 30570998.
  4. ↑ Pieroth R, Paver S, Day S, Lammersfeld C (2018). “Folate and Its Impact on Cancer Risk”. Curr Nutr Rep. 7 (3): 70–84. doi:10.1007/s13668-018-0237-y. PMC 6132377. PMID 30099693.
  5. ↑ Green R, Miller JW (1999). “Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status”. Semin Hematol. 36 (1): 47–64. PMID 9930568.
  6. ↑ Koike H, Takahashi M, Ohyama K, Hashimoto R, Kawagashira Y, Iijima M; et al. (2015). “Clinicopathologic features of folate-deficiency neuropathy”. Neurology. 84 (10): 1026–33. doi:10.1212/WNL.0000000000001343. PMID 25663227.
  7. ↑ Aslinia F, Mazza JJ, Yale SH (2006). “Megaloblastic anemia and other causes of macrocytosis”. Clin Med Res. 4 (3): 236–41. PMC 1570488. PMID 16988104.
  8. ↑ Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology (2014). “Guidelines for the diagnosis and treatment of cobalamin and folate disorders”. Br J Haematol. 166 (4): 496–513. doi:10.1111/bjh.12959. PMID 24942828.
  9. ↑ US Preventive Services Task Force. Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW; et al. (2017). “Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement”. JAMA. 317 (2): 183–189. doi:10.1001/jama.2016.19438. PMID 28097362.

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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Folate deficiency was first discovered by Lucy Wills, an English hematologist, in 1931 while conducting seminal work in India in the late 1920s and early 1930s on macrocytic anemia of pregnancy.[1][2]

Historical Perspective

Discovery

  • Folate deficiency was first discovered by Lucy Wills, an English hematologist, in 1931 while conducting seminal work in India in the late 1920s and early 1930s on macrocytic anemia of pregnancy. During her study, she found that this nutrient was needed to prevent the anemia of pregnancy. Dr. Wills demonstrated that this condition could be reversed with brewer’s yeast.
  • It was in the later 1930’s that folate, the naturally occurring form of folic acid, was isolated from brewer’s yeast and folic acid was identified in the pathogenesis of anemia in pregnant women.
  • In 1941, it was first extracted by Mitchell and others.
  • In 1941, Folic acid received its name, when it was isolated from spinach ( folium= leaf) and was shown to be a growth factor for Streptococcus Lactis R( S.Faecalis)
  • In August 1943,Bob Stokstad, Lederle Laboratory scientist, isolated the pure folate crystals form, from one and half tons of liver,determined its structure and synthesized it.
  • In 1945, soon after the synthesis of folic acid, it was realized that it is effective in the treatment of megaloblastic anemia particularly related to pregnancy, lactation and malabsorption syndrome.
  • In 1963,Bob Stokstad, along with his colleagues at Berkeley, were first to isolate,purify and characterize many of the mammalian enzymes involved in the metabolism of folate.
  • During research on folate and folic acid, it was found that overexposure of folate therapy led the growth of tumors.
  • In 1948, G.H. Hitchings and G.B. Elion started research at the laboratories of Nobel Laureates on folate antagonists or anti-folates.  This was significant because aminopterin was discovered by Sydney Farber which led to several anti-cancer agents being developed that could inhibit normal metabolic reactions.

References

  1. ↑ Hoffbrand, A. V.; Weir, D. G. (2001). “The history of folic acid”. British Journal of Haematology. 113 (3): 579–589. doi:10.1046/j.1365-2141.2001.02822.x. ISSN 0007-1048.
  2. ↑ THOMSON DL (1947). “The folic acid story”. Can Med Assoc J. 56 (4): 432–5. PMC 1591988. PMID 20286957.

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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

There is no established system for the classification of Folate deficiency. However, it can be classified into different categories,based on the causative factors.

Classification

There is no established system for the classification of Folate deficiency. However, it can be classified as follows :[1]

Some situations that increase the need for folate, may lead to folate deficiency in the body. These include:

Medication induced Folate Deficiency:

Medications can interfere with folate utilization, including:

Genetic or Metabolic disorder:

  • Defects in folate metabolism
  • Defects in folate absorption

Dietary Deficiency:

  • A diet low in fresh fruits, vegetables, and fortified cereals
  • superoxides can inactivate folate

Folate deficiency due to increased loss:

  • Vitamin B12 deficiency causes “folate trap” and inhibits the utilization of folate in the body
  • Chronic alcoholism leads to increased excretion of folate into bile
  • Excessive urinary excretion as in chronic dialysis

Endocrine causes of folate deficiency:

  • Hypothyroidism which leads to decreased hepatic levels of the enzyme dihydrofolate reductase

Folate deficiency due to malabsorption:

References

  1. ↑ “StatPearls”. 2018. PMID 30570998.
  2. ↑ Varghese JS, Swaminathan S, Kurpad AV, Thomas T (2019). “Demand and supply factors of iron-folic acid supplementation and its association with anaemia in North Indian pregnant women”. PLoS One. 14 (1): e0210634. doi:10.1371/journal.pone.0210634. PMID 30699167.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Larabe Farrukh

Overview

Folate (also called vitamin B9 or pteroylglutamic acid) is a water soluble vitamin, cannot be synthesized by the human body, however can be obtained from the diet like green leafy vegetables and liver.In the human body folic acid serves a number of functions which include the following :

  • Production and maintenance of new cells
  • DNA and RNA synthesis
  • Carrying one-carbon groups for various methylation reactions
  • Preventing changes to DNA, therefore, for preventing cancer

Pathophysiology

Folate (also called vitamin B9 or pteroylglutamic acid) is a water soluble vitamin, cannot be synthesized by the human body, however can be obtained from the diet like green leafy vegetables and liver.

Physiology:

  • In the human body folic acid serves a number of functions which include the following
    • Production and maintenance of new cells
    • DNA and RNA synthesis
    • Carrying one-carbon groups for various methylation reactions
    • Preventing changes to DNA, therefore, for preventing cancer

Dietary sources:

  • Folate naturally occurs in a variety of foods, including dark green leaf vegetables, fruits , nuts, soybeans, dairy products, poultry, eggs, seafood, grains, and some beers.[+https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/+ “Folate — Health Professional Fact Sheet”] Check |url= value (help).
  • Avocado, beetroot, spinach, liver, yeast, asparagus, kale, and Brussels sprouts are among the foods that contain the highest levels of folate.
  • Folate, found in food is susceptible to high heat, UV light and may also be susceptible to damage by oxidation.[1]
  • Folic acid is also added to grain products and these fortified products make up a significant source of the population’s folate intake.
    • For example enriched flour and fortified rice typically contain folate. In adults, normal total body folate is between 10,000–30,000 micrograms (µg) with blood levels of greater than 7 nmol/L (3 ng/mL).

Absorption and Bioavailability

  • Natural folates are quite unstable and they lose their vitamin activity during food processing. In vegetables, the folates can be destroyed by cooking and in grains/cereals folates can be broken down during milling and baking. Folates exist as polyglutamates in the diet and need to be enzymatically converted into monoglutamate forms by folate reductase. This takes place in the jejunum where the absorption of folate also occurs.
  • Folate itself is not biologically active, but is converted into dihydrofolate, by the enzyme dihydrofolate synthetase, in the liver. This is then converted into tetrahydrofolate (THF) by dihydrofolate reductase.Tetrahydrofolate is converted into 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase. Tetrahydrofolate and its methylated forms then play a crucial role as methyl donors in different reactions that occur throughout the body.
  • Folate deficiency can occur when the body’s need for folate is increased, when dietary intake or absorption of folate is inadequate, or when the body loses more folate than it acquires from the diet.
  • Absolute folate deficiency is usually associated with dietary insufficiency but may it also be caused by impairment in the folate absorption.
  • Folate is absorbed in the small intestine, mainly in the Jejunum, after binding to specific receptor proteins.Absorption is optimal at slightly acidic pH.[2][3][4]
  • This can occur due to Inflammatory or degenerative changes in the small intestine, such as Crohn’s disease, chronic enteritis, Celiac disease, that may reduce the folate uptake, which gives rise to folate deficiency or due to certain genetic defects that impair the absorption in the gastrointestinal tract. Other causes may include mutations causing impaired activity of the enzymes involved in folate metabolism. Low levels of blood folate can lead to increased plasma homocysteine, impaired DNA synthesis and DNA repair and may promote the development of some forms of cancers as well.
  • Certain medications (e.g Anticonvuslants, Methotrexate, Sulfasalazine) can also interfere with the folate metabolism in our body.
  • The deficiency is more common among pregnant women, infants, children, and adolescents.
  • Poor diet and chronic alcoholism is also an important cause of folate deficiency.
  • Moreover, a defect in homocysteine methyltransferase or a deficiency of cobalamine (B-12) may lead to “folate trap“.
  • In vitamin B12 deficiency, the utilization of Methyl THF in the B-12 dependent methylation of homocysteine to methionine is impaired.
  • THF is converted to methyl-THF which cannot be further metabolized, and serves as a sink of THF that leads to a subsequent deficiency in folate.
  • Thus, a deficiency in B-12 can generate a large pool of methyl-THF that is unable to undergo reactions and resembles folate deficiency.[5]

References

  1. ↑ Borradale, David C; Kimlin, Michael G (2012). “Folate degradation due to ultraviolet radiation: possible implications for human health and nutrition”. Nutrition Reviews. 70 (7): 414–422. doi:10.1111/j.1753-4887.2012.00485.x. ISSN 0029-6643.
  2. ↑ Moestrup SK (2006). “New insights into carrier binding and epithelial uptake of the erythropoietic nutrients cobalamin and folate”. Curr Opin Hematol. 13 (3): 119–23. doi:10.1097/01.moh.0000219654.65538.5b. PMID 16567952.
  3. ↑ Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E; et al. (2006). “Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption”. Cell. 127 (5): 917–28. doi:10.1016/j.cell.2006.09.041. PMID 17129779.
  4. ↑ Zhao R, Matherly LH, Goldman ID (2009). “Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues”. Expert Rev Mol Med. 11: e4. doi:10.1017/S1462399409000969. PMC 3770294. PMID 19173758.
  5. ↑ Tefferi A, Pruthi RK (1994). “The biochemical basis of cobalamin deficiency”. Mayo Clin Proc. 69 (2): 181–6. PMID 8309270.

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Differentiating Folate deficiency from other Diseases

Differentiating Folate deficiency from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Folate deficiency must be differentiated from other diseases associated with the Macrocytic anemia such as Vitamin B12 deficiency, Alcoholic liver disease, Hypothyroidism, Myelodysplasia and Aplastic anemia.

Differential Diagnosis

Differentiating Folate deficiency from other Diseases:

CONDITIONS SIGNS/SYMPTOMS INVESTIGATIONS
Vitamin B12 deficiency Associated with neurologic and neuropsychiatric symptoms. e.g. decreased vibration sense, peripheral neuropathy, gait abnormalities.
  • Serum vitamin B12 levels are low.
  • Both homocysteine and methylmalonic acid are elevated.
Alcoholic liver disease Nutritional deficiencies and macrocytic anemia may be the presenting features. History reveals alcohol abuse.
  • Elevated liver enzymes e.g. ALT and AST
  • Liver biopsy shows fatty liver or cirrhosis.
Hypothyroidism Associated with constipation, weight gain, cold intolerance, hoarse voice, bradycardia, dry skin, delayed tendon reflexes.
  • Elevated TSH, low T4, and low T3.
  • Serum folate level is normal. Homocysteine is often elevated
Myelodysplastic syndrome Gradual-onset fatigue often present. Patients may have splenomegaly.
  • Macrocytic anemia may be associated with neutropenia and thrombocytopenia.
  • Peripheral smear may suggestive of large, hypogranular platelets; hypogranulated, hyposegmented neutrophils with Dohle bodies; and circulating myeloblasts.
  • Bone marrow findings include dyserythropoiesis; hypogranulated, hyposegmented granulocytic precursors; increased myeloblasts; and megakaryocytes showing fewer or disorganized nuclei. Ringed sideroblasts can also be seen
  • Cytogenetic analysis and fluorescence in-situ hybridization can identify specific chromosomal abnormalities.
Aplastic anemia Hx of recent viral illness, chemical exposure, or drug use.

Bleeding and symptoms of infection are usually present. Ecchymosis and signs of infection may be present.

  • Macrocytic anemia, neutropenia, thrombocytopenia, and reticulocytopenia are present.
  • Bone marrow aspirate and biopsy show decreased cellularity and paucity of all 3 lineage precursor cells.
Drug-induced macrocytosis Hx of intake of certain drugs, such as DNA synthesis-inhibiting drugs, immunosuppressive drugs, anticonvulsants, and antiviral medications.
  • Serum folate level is normal.
Diphyllobothriasis Associated with abdominal discomfort, diarrhea, vomiting, weakness, weight loss, and occasionally acute abdominal pain due to intestinal obstruction, cholangitis, or cholecystitis. Other features are megaloblastic anemia and neurologic abnormalities secondary to vitamin B12 (cobalamin) deficiency.
  • Identification of the operculated eggs in the stool
  • Polymerase chain reaction (PCR)
  • Megaloblastic anemia with low vitamin B12 level

Differentiating Macrocytic Anemia from Other Diseases

To review the differential diagnosis of anemia, click here.

Disease Genetics Clinical manifestation Lab findings
History Symptoms Signs Hemolysis Intrinsic/Extrinsic Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Iron studies Specific finding on blood smear
Serum iron Serum Tfr level Transferrin or TIBC Ferritin Transferrin saturation
Folate deficiency[3]
  • Impaired DNA synthesis
 − − Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑
Vitamin B12 deficiency[4] − − Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑
Orotic aciduria[5]
  • Neurological manifestation
 − − Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑ NA
Fanconi anemia[6]
  • Significant for bilateral short thumbs
 − − Anisochromic Macrocytic ↑ ↓ Nl Nl ↑ ↑ ↓ ↑ ↑
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/Extrinsic Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear
Diamond-Blackfan anemia[7] Mutations in:
  • RPL5
  • RPL11
  • RPL35A
  • RPS7
  • RPS10
  • RPS17
  • RPS19
  • RPS24
  • RPS26
 − − Anisochromic Macrocytic Nl ↓ Nl Nl ↑ ↑ ↓ ↑ ↑ NA
Liver disease[8] −
  • Hepatitis
  • Binge drinking
  • Gall bladder disease
 − − Anisochromic Macrocytic ↑ ↑ Nl Nl ↑ ↑ ↓ ↑ ↑
Alcoholism[9] − − − Anisochromic Macrocytic ↑ ↑ Nl Nl ↑ ↑ ↓ ↑ ↑
Disease Genetics History Symptoms Signs Hemolysis Intrinsic/Extrinsic Hb concentration MCV RDW Reticulocytosis Haptoglobin levels Hepcidin Serum iron Serum Tfr level IBC Ferritin Transferrin saturation Specific finding on blood smear

References

  1. ↑ Snow CF (1999). “Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician”. Arch Intern Med. 159 (12): 1289–98. PMID 10386505.
  2. ↑ Nagao, Takayo; Hirokawa, Makoto (2017). “Diagnosis and treatment of macrocytic anemias in adults”. Journal of General and Family Medicine. 18 (5): 200–204. doi:10.1002/jgf2.31. ISSN 2189-7948.
  3. ↑ Koike H, Takahashi M, Ohyama K, Hashimoto R, Kawagashira Y, Iijima M, Katsuno M, Doi H, Tanaka F, Sobue G (March 2015). “Clinicopathologic features of folate-deficiency neuropathy”. Neurology. 84 (10): 1026–33. doi:10.1212/WNL.0000000000001343. PMID 25663227.
  4. ↑ Hunt A, Harrington D, Robinson S (September 2014). “Vitamin B12 deficiency”. BMJ. 349: g5226. PMID 25189324.
  5. ↑ Grohmann K, Lauffer H, Lauenstein P, Hoffmann GF, Seidlitz G (April 2015). “Hereditary orotic aciduria with epilepsy and without megaloblastic anemia”. Neuropediatrics. 46 (2): 123–5. doi:10.1055/s-0035-1547341. PMID 25757096.
  6. ↑ Alter BP (2014). “Fanconi anemia and the development of leukemia”. Best Pract Res Clin Haematol. 27 (3–4): 214–21. doi:10.1016/j.beha.2014.10.002. PMC 4254647. PMID 25455269.
  7. ↑ Vlachos A, Blanc L, Lipton JM (June 2014). “Diamond Blackfan anemia: a model for the translational approach to understanding human disease”. Expert Rev Hematol. 7 (3): 359–72. doi:10.1586/17474086.2014.897923. PMID 24665981.
  8. ↑ Marks PW (July 2013). “Hematologic manifestations of liver disease”. Semin. Hematol. 50 (3): 216–21. doi:10.1053/j.seminhematol.2013.06.003. PMID 23953338.
  9. ↑ Yokoyama A, Yokoyama T, Brooks PJ, Mizukami T, Matsui T, Kimura M, Matsushita S, Higuchi S, Maruyama K (May 2014). “Macrocytosis, macrocytic anemia, and genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2 in Japanese alcoholic men”. Alcohol. Clin. Exp. Res. 38 (5): 1237–46. doi:10.1111/acer.12372. PMID 24588059.

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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The prevalence of folate deficiency is quite variable across the world.Patients of all age groups may develop folate deficiency however primary age groups affected by Folate deficiency include preschool children, pregnant women and older people.

Epidemiology and Demographics

  • The prevalence of folate deficiency is quite variable across the world.
  • The deficiency is more commonly seen in countries without folic acid fortification of cereal-grain products.
  • Folate deficiency can be a public health problem, revealed in one of the survey conducted in several countries.
  • Folate deficiency affects 5% of total US population.
  • In the US, folate deficiency was present in school-age children (2.3% of the folate-deficient population), adults (24.5%), and older people (10.8%) before folic acid fortification was introduced.
  • In 1998, the FDA has required folic acid fortification of all enriched cereal-grain products in the U.S to to explore the changes in serum and erythrocyte folate status of the adult U.S. population following folic acid fortification of enriched cereal-grain products.
  • Subsequent surveys have shown that serum and RBC folate concentrations have increased in the general population of all age and sex groups.[1]
  • National Health and Nutrition Examination Survey conducted during 1999-2000 shows that the prevalence of low serum folate concentrations (<6.8 nmol/L) decreased from 16% before to 0.5% after fortification.[2]

DEMOGRAPHICS

Each year in the United States

  • There are 3,000 pregnancies affected by neural tube defects (NTDs) caused by the incomplete closing of the spine and skull.
  • About 1,300 babies are born without a neural tube defect since folic acid fortification.
  • Many, but not all, neural tube defects could be prevented if women took 400 mcg of folic acid daily, before and during early pregnancy.
  • Folate deficiency complicates between 1% and 4% of pregnancies in the United States and affects approximately one-third of pregnancies worldwide.
  • Many epidemiologic studies indicate that higher intakes of folate, either from dietary sources or from supplements may lower the risk of colorectal adenoma and cancer.[3]
  • In US, patients with previous history of child with neural tube defect, the recurrence risk is 2% to 3% in subsequent pregnancies.The Medical Research Council Vitamin Study Group reported the results of a trial of folic acid supplementation for the prevention of NTDs in pregnancies of women who had a previous child with an NTD and the CDC published its recommendations.
  • Later on, The National Health and Nutrition Examination Survey conducted a study to determine differences in dietary and total folate intake, for age and racial-ethnic groups by sex and prevalence of inadequate and excessive intakes is presented as well and it was concluded that measures need to be made both to monitor for over-supplementation in certain groups and to target increased supplementation in the groups at risk for deficiency like women of child bearing age and non-Hispanic black women.[4]

Hispanic/Latina Women

  • Have the highest rate among women having a child affected by these birth defects.
  • Have lower blood folate levels and are less likely to consume foods fortified with folic acid.
  • Are less likely to have heard about folic acid, or take vitamins containing folic acid before pregnancy.

Use of Supplements Containing Folic Acid Among Women of Childbearing Age — United States

2007 Survey Data

Among all women of childbearing age:

  • 40% reported taking folic acid daily.
  • 81% reported awareness of folic acid.
  • 12% reported knowing that folic acid should be taken before pregnancy.

Women of childbearing age who were aware of folic acid reported hearing about it from:

  • Health care provider (33%)
  • Magazine or newspaper (31%)
  • Radio or television (23%)
  • Women aged 18-24 years were more likely to hear about folic acid from a magazine or newspaper (25%) or school or college (22%) than from their health care provider (17%). Whereas 37% of women aged 25-34 years and 36% of women 35-45 years reported hearing about folic acid from their health care provider.

Among women who reported not taking a vitamin or mineral supplement on a daily basis, the most common reasons were:

  • “Forgetting” (33%)
  • “No need” (18%)
  • “No reason” (14%)
  • “Already get balanced nutrition” (12%)
2005 Survey Data

Among all women of childbearing age:

  • 33% reported taking folic acid daily.
  • 84% reported awareness of folic acid.
  • 7% reported knowing that folic acid should be taken before pregnancy.

Among women who reported not taking a vitamin or mineral supplement on a daily basis, the most common reasons were:

  • Forgetting to take supplements (28%)
  • Perceiving they do not need them (16%)
  • Believing they get needed nutrients and vitamins from food (9%)

When asked, “For what specific need would you start taking a vitamin or mineral supplement?” The most common reported needs were:

  • Being sick or in poor health (20%)
  • A doctor’s recommendation (20%)
  • The need for energy (9%)
  • Being pregnant (8%)
  • Being deficient in any vitamins or minerals (7%)
  • Balancing the diet (6%)
  • Keeping bones strong (6%)
  • In addition, 11% cited no specific need that would motivate them to begin taking a vitamin or supplement. Among women who reported not consuming a vitamin or mineral supplement daily, 31% indicated they had received a doctor’s recommendation.

Economic Cost

  • The annual medical care and surgical costs for people with spina bifida exceed $200 million.
  • The total lifetime cost of care for a child born with spina bifida is estimated to be $791,900.

Age

  • Patients of all age groups may develop folate deficiency however primary age groups affected by Folate deficiency include preschool children, pregnant women and older people.
  • Pregnant women are at higher risk of developing folate deficiency because of increased requirements. Upto 20% of the pregnant women are folate deficient because of five fold increased daily requirement of folate during pregnancy
  • Elderly people may be more susceptible to folate deficiency, as a result of their predisposition to mental health status, social isolation, low dietary intake, malnutrition, and co morbid medical conditions.
  • According to the department of the health and social security survey approximately 15% of elderly people living in the community are likely to be deficient in folate.

Race

  • The prevalence has reported to be higher in African and Asian population.

Gender

  • National Health and Nutrition Examination Survey shows that women of childbearing age were at high risk of folic acid deficiency due to an inadequate folic acid intake

Region

  • There is no evidence that prevalence is associated with the level of development or the geographical location.

References

  1. ↑ Dietrich M, Brown CJ, Block G (2005). “The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States”. J Am Coll Nutr. 24 (4): 266–74. PMID 16093404.
  2. ↑ Pfeiffer CM, Caudill SP, Gunter EW, Osterloh J, Sampson EJ (2005). “Biochemical indicators of B vitamin status in the US population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000”. Am J Clin Nutr. 82 (2): 442–50. doi:10.1093/ajcn.82.2.442. PMID 16087991.
  3. ↑ Giovannucci, Edward (2002). “Epidemiologic Studies of Folate and Colorectal Neoplasia: a Review”. The Journal of Nutrition. 132 (8): 2350S–2355S. doi:10.1093/jn/132.8.2350S. ISSN 0022-3166.
  4. ↑ Bailey, Regan L; Dodd, Kevin W; Gahche, Jaime J; Dwyer, Johanna T; McDowell, Margaret A; Yetley, Elizabeth A; Sempos, Christopher A; Burt, Vicki L; Radimer, Kathy L; Picciano, Mary Frances (2010). “Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006”. The American Journal of Clinical Nutrition. 91 (1): 231–237. doi:10.3945/ajcn.2009.28427. ISSN 0002-9165.

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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Several factors may put a person at risk for developing Folate deficiency.These include the presence of congenital defect, malabsorptive disorder and alcohol abuse. Certain medications use are also associated with higher risk for developing Folate deficiency.

Risk Factors

Several factors may put a person at risk for developing Folate deficiency.These include the presence of congenital defect, malabsorptive disorder and alcohol abuse. Certain medications use are also associated with higher risk for developing Folate deficiency.

Common Risk Factors[1][2]

  • Common risk factors in the development of Folate deficiency include:
    • Low dietary folate intake
    • Age >65 years
    • Alcoholism
    • Pregnant or lactating mothers
    • Prematurity
    • Intestinal malabsorptive disorders e.g. celiac disease, tropical sprue, jejunal resection, inflammatory bowel diseases.
    • Use of drugs e.g. trimethoprim, methotrexate, anticonvulsants, sulfasalazine, or pyrimethamine
    • Infantile intake of goats’ milk which is low in folate content
    • States of increased cell turnover e.g. chronic hemolysis

Less Common Risk Factors

  • Less common risk factors in the development of Folate deficiency include:
    • Congenital defects in folate absorption and metabolism
    • Intake of special diet
    • Chronic dialysis

References

  1. ↑ Shahab-Ferdows, Setareh; Engle-Stone, Reina; Hampel, Daniela; Ndjebayi, Alex O; Nankap, Martin; Brown, Kenneth H; Allen, Lindsay H (2015). “Regional, Socioeconomic, and Dietary Risk Factors for Vitamin B-12 Deficiency Differ from Those for Folate Deficiency in Cameroonian Women and Children”. The Journal of Nutrition. 145 (11): 2587–2595. doi:10.3945/jn.115.210195. ISSN 1541-6100.
  2. ↑ Metz, Jack (1999). “Results: Appropriate use of tests for folate and vitamin B12 deficiency”. Australian Prescriber. 22 (1): 16–18. doi:10.18773/austprescr.1999.010. ISSN 0312-8008.

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Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Screening for Folate deficiency is usually not routinely recommended for asymptomatic patients.

Screening

References

  1. ↑ Clarke R, Refsum H, Birks J, Evans JG, Johnston C, Sherliker P; et al. (2003). “Screening for vitamin B-12 and folate deficiency in older persons”. Am J Clin Nutr. 77 (5): 1241–7. doi:10.1093/ajcn/77.5.1241. PMID 12716678.
  2. ↑ Metz, Jack (1999). “Results: Appropriate use of tests for folate and vitamin B12 deficiency”. Australian Prescriber. 22 (1): 16–18. doi:10.18773/austprescr.1999.010. ISSN 0312-8008.

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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The symptoms of folate deficiency are very non specific and subtle.It can present with the features of anemia and can lead to severe complications if not treated. Prognosis of patients with folate deficiency is generally good and clinical and hematological parameters usually reverses after 8 weeks of treatment.

Natural History

Natural History

  • The symptoms of folate deficiency are very non specific and subtle.It can present with the features of anemia and can lead to severe complications if not treated.
  • Depending upon the baseline stores, Folate deficiency develops rapidly within weeks to months and become rapidly depleted during normal cell division, as compared to the Vitamin b12 deficiency that develops over the course of years, as total body stores are large.
  • Although asymptomatic initially, anemia, neurocognitive and other changes have been reported with folate deficiency at the later stage.

Complications

Some of the common complications include :[1]

  • Hematologic deficits : Inadequately treated or untreated patients will develop megaloblastic anemia, leukopenia, and thrombocytopenia.
  • Neural tube defects : Folate deficiency in pregnant women increases the incidence of neural tube defects in their fetuses. This can be effectively prevented by increasing folic acid intake preconceptually and during pregnancy.[2]
  • Neuropathy : Initiation of folic acid therapy may lead to progression of neuropathy and cognitive impairment in underlying vitamin B12 deficiency. This can be prevented by prompt diagnosis and treatment of vitamin B12 deficiency before instituting folic acid therapy.
  • Cardiovascular disease : Moderate elevation of plasma homocysteine is an independent risk factor for cardiovascular disease, stroke, and venous thrombosis[3]
  • Colorectal cancer : High folate levels inhibit malignant transformation, but high folate levels may also enhance the growth of established malignancies. Some studies have suggested a possible link between low folate status and colorectal cancer .However, scientific evidence is not sufficiently clear to recommend increased folate intake for populations at risk for developing colorectal cancer.[4][5]
  • Toxicity : Evidence is emerging of possible toxicities associated with excess folate intake as a result of folic acid food fortification and use of dietary supplements containing folic acid. Toxicities include progressive neurologic damage, cognitive impairment (particularly in individuals with concomitant vitamin B12 deficiency), and enhanced growth of malignant tumors (specifically colonic tumors). Large doses of intravenous folic acid have been reported to exacerbate seizures in patients with underlying seizure disorders.
  • Fertility : Folate deficiency can also affect fertility. However, the effects are only temporary and can be reversed by using vitamin supplements.
  • Premature birth : As well as affecting your baby’s growth, a lack of folate during your pregnancy may also increase the risk of your baby being born prematurely (before week 37 of the pregnancy).

Prognosis

Prognosis of patients with folate deficiency is generally good, if folic acid supplementations are started early and clinical and hematological parameters usually reverses after 8 weeks of treatment.Body stores can be replenished with additional folic acid supplements for 1 month.

References

  1. ↑ Miller, J.W. (2013). “Folic Acid”: 262–269. doi:10.1016/B978-0-12-375083-9.00111-2.
  2. ↑ Reynolds EH (2014). “The neurology of folic acid deficiency”. Handb Clin Neurol. 120: 927–43. doi:10.1016/B978-0-7020-4087-0.00061-9. PMID 24365361.
  3. ↑ Green R, Miller JW (1999). “Folate deficiency beyond megaloblastic anemia: hyperhomocysteinemia and other manifestations of dysfunctional folate status”. Semin Hematol. 36 (1): 47–64. PMID 9930568.
  4. ↑ Choi SW, Mason JB (2000). “Folate and carcinogenesis: an integrated scheme”. J Nutr. 130 (2): 129–32. doi:10.1093/jn/130.2.129. PMID 10720158.
  5. ↑ Pieroth R, Paver S, Day S, Lammersfeld C (2018). “Folate and Its Impact on Cancer Risk”. Curr Nutr Rep. 7 (3): 70–84. doi:10.1007/s13668-018-0237-y. PMC 6132377. PMID 30099693.

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Treatment

Treatment

Cost-Effectiveness of Therapy

Cost-Effectiveness of Therapy

According to a study, the greatest benefits from fortification were predicted in MI prevention, with 16,862 and 88,172 cases averted per year in steady state for the 140-mcg and 700-mcg fortification levels, respectively. These projections were 6,261 and 38,805 for colon cancer and 182 and 1,423 for Neural tube defects , while 15 to 820 additional B-12 cases were predicted. Compared with no fortification, all post-fortification strategies provided QALY gains and cost savings for all subgroups, with predicted population benefits of 266,649 QALYs gained and $3.6 billion saved in the long run by changing the fortification level from 140-mcg/100-g enriched grain to 700-mcg/100-g.

This study indicates that the health and economic gains of folic acid fortification far outweigh the losses for the U.S. population, and that increasing the level of fortification deserves further consideration to maximize net gains.

Future or Investigational Therapies

Future or Investigational Therapies

Reticulocytosis can be assessed at the end of the first week of therapy. It is important to determine completeness of response after 8 weeks of therapy, when blood counts should have normalized. Homocysteine levels can be used to monitor response. Inadequate response indicates a coexisting cause of anemia, such as iron deficiency or vitamin B12 (cobalamin) deficiency.                                                                                    

Case Studies

Case Studies

Case #1

Case presentation

A year 30 year old woman (gravida 4, para 3) was admitted at 33 weeks gestation with worsening fatigue and shortness of breath on exertion over a month. Recently she noticed occasional gum bleeding and easy bruising. She reported that her appetite had decreased and attributed this to pregnancy related nausea. She denied any fever or night sweats. There was no history of alcohol abuse or dietary restriction. She had no history of any medication and all her previous pregnancies had been uneventful.

Examination

She was pale with few petechiae seen on the buccal mucosa. Her blood pressure was 120/80 mm Hg with a trace of protein detected on urine dipstick. There was no lymphadenopathy or splenomegaly palpable. The remainder of the clinical examination was unremarkable.

Investigations

A full blood count revealed a macrocytosis with a severe pancytopenia. Haemoglobin of 70 g/L with a MCV of 105 fL , platelets were decreased 14×109/L and neutrophils were also low 0.5×109/L (1.7–7.5×109). Her last recorded haematological profile 5 months ago was within normal limits. Reticulocyte count was decreased 8×109/L. RFTs, LFTs and coagulation screen were normal. A blood film showed macrocytes. Hypersegmented neutrophils and thrombocytopenia were also seen. Ferritin and vitamin B12 level were normal. Serum folate was subtherapeutic at 2.5 ng/mL (4.6–18.7 ng/mL). An autoimmune screen was unremarkable. Antitransglutaminase antibodies were also negative.A bone marrow aspirate was hypercellular with megaloblastoid features. Early erythroid precursors and giant metamyelocytes were seen.

Treatment

She was transfused with two units packed red cells and one adult dose of platelets. She was then started on folic acid 5 mg daily. A single dose of 1 mg hydroxycobalamin was also administered. A week later, the neutrophil count had recovered (1.5×109/L) with an increase in platelet count (25×109/L)

Outcome and follow-up

Her counts normalized and she gave birth to a healthy male baby. His full blood count was normal and there were no signs of neurological compromise.

Discussion

Folate deficiency is a cause of macrocytosis in pregnancy. If left untreated, it could progress to severe megaloblastic anaemia with pancytopenia. Peripheral blood film may reveal macrocytic anaemia and hyper-segmented neutrophils. Bone marrow examination could demonstrate megaloblastic changes reflecting ineffective haematopoiesis and resultant bone marrow failure.

In the majority of developed countries, folic acid supplementation (at least 400 µg) is recommended for 2–3 months prior to conception and throughout pregnancy into the postpartum period. This been adopted as a worldwide strategy to reduce the incidence of fetal neural tube defects (NTD) such as anencephaly, spina bifida and meningomyelocele. This may also lower the risk of other congenital anomalies and adverse pregnancy outcomes such as pontaneous abortions, placental abruption and low birth weight.

Folate deficiency is most often a result of poor dietary intake either alone or in combination with malabsorption or increased utilisation. Excess cell turnover may be physiological such as in pregnancy and lactation or pathological such as in haemolysis or chronic inflammatory disorders. Other causes of folate deficiency include excess urinary loss, drugs, long-term dialysis and alcoholism. While there is no requirement to measure serum folate routinely in pregnancy, testing should be sought in those with a history of poor or inadequate diet, any symptoms of malabsorption and those with an unexplained macrocytic anaemia. Hyperemesis during pregnancy and multiparity are also recognised as risk factors prompting investigation.


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