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| {{Infobox_Disease | | | {{Infobox_Disease | |
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| '''For patient information click [[Folate deficiency (patient information)|here]]''' | | '''For patient information click [[Folate deficiency (patient information)|here]]''' |
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| {{CMG}} | | {{CMG}} '''Editor''' : [https://www.wikidoc.org/index.php?title=L.Farrukh&action=edit&redlink=1 L.Farrukh] |
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| {{SK}} Folic acid deficiency | | {{SK}} Folic acid deficiency |
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| ==[[Folate deficiency overview|Overview]]== | | ==[[Folate deficiency overview|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. 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.
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| 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 which is 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.
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| ==[[Folate deficiency historical perspective|Historical Perspective]]== | | ==[[Folate deficiency historical perspective|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, 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 occuring form of folic acid, was isolated from brewer's yeast and folic acid was identified in the pathogenesis of anemia in pregnant women.
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| ==[[Folate deficiency classification|Classification]]== | | ==[[Folate deficiency classification|Classification]]== |
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| ==[[Folate deficiency pathophysiology|Pathophysiology]]== | | ==[[Folate deficiency pathophysiology|Pathophysiology]]== |
| 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. 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. | | ==[[Folate deficiency differential diagnosis|Differentiating Folate deficiency from other Diseases]]== |
| | ==[[Folate deficiency epidemiology and demographics|Epidemiology and Demographics]]== |
| | ==[[Folate deficiency risk factors|Risk Factors]]== |
| | ==[[Folate deficiency screening|Screening]]== |
| | ==[[Folate deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| | ==Treatment== |
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| 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. Folate is absorbed in the small intestine, mainly in the Jejunum, after binding to specific receptor proteins. Inflammatory or degenerative changes in the small intestine, such as [[Crohn's disease]], chronic enteritis, [[Celiac disease]], may reduce the folate uptake, which gives rise to folate deficiency.
| | ==[[Folate deficiency 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. |
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| === Physiology ===
| | 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. |
| In human body folic acid serves a lot of functions such as :
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| * Production and maintenance of new cells
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| * DNA and RNA synthesis
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| * Carrying one-carbon groups for various methylation reactions
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| * Preventing changes to DNA, therefore, for preventing cancer
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| 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).
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| === Dietary sources === | | ==[[Folate deficiency future or investigational therapies|Future or Investigational Therapies]]== |
| 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. 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. 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.
| | 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. |
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| === Absorption and Bioavailability === | | ==Case Studies== |
| 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. 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.
| | [[Folate deficiency case study one|Case #1]] |
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| 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 occurthroughout the body. | |
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| Absolute folate deficiency is usually associated with dietary insufficiency but may it also be caused by impairment in the folate absorption. This can occur due to gastrointestinal diseases or 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.
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| ==[[Folate deficiency causes|Causes]]== | | ===Case presentation=== |
| * Inadequate intake of folate containing foods e.g. chronic alcoholism, psychiatric causes, elderly patients.
| | 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. |
| * Impaired absorption in the gastrointestinal tracts e.g. celiac disease, tropical sprue, achlorhydria, anticonvulsant therapy, bacterial overgrowth in blind loops, strictures, adhesions, diverticula
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| * Impaired metabolism leading to inability to utilize folate in the body e.g. methotrexate and trimethoprim (folate antagonists) inhibit the enzyme dihydrofolate reductase involved in the formation of Tetrahydrofolate (active form of folate in the body)
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| * Hypothyroidism which leads to decreased hepatic levels of the enzyme dihydrofolate reductase
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| * Congenital deficiency of enzymes of folate metabolism
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| * Increased requirement e.g during infancy, pregnancy, lactation, malignancy, chronic hemolytic states (increased hematopoiesis), hemodialysis, peritoneal dialysis, inflammation.
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| * Increased loss e.g. 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
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| * Increased destruction e.g. superoxides can inactivate folate
| | =====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. |
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| ==[[Folate deficiency differential diagnosis|Differentiating Folate deficiency from other Diseases]]== | | ===Investigations=== |
| {| class="wikitable"
| | 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. |
| !CONDITIONS
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| !SIGNS/SYMPTOMS
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| !INVESTIGATIONS
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| |Vitamin B12 (cobalamin) deficiency
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| |May be associated with neurologic and neuropsychiatric manifestations: specifically, decreased vibration sense, peripheral neuropathy, gait abnormalities, dementia, depression, and visual impairment.
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| Clinical and hematologic response to treatment confirms diagnosis.
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| |Serum vitamin B12 levels are low.
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| Both homocysteine and methylmalonic acid are elevated.
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| |Thiamine-responsive megaloblastic anemia
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| |Diabetes mellitus and sensorineural deafness are present in addition to megaloblastic anemia.
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| Megaloblastic anemia and diabetes mellitus respond partially to thiamine therapy.
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| |Ringed sideroblasts are seen in the bone marrow.
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| Serum folate level is normal.
| | ===Treatment=== |
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| | 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) |
| |Alcoholic liver disease
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| |Nutritional deficiencies and macrocytic anemia may be the presenting features. History reveals alcohol abuse.
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| |Elevated liver enzymes.
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| Liver biopsy shows fatty liver, inflammation, and/or cirrhosis.
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| |Hypothyroidism
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| |Constipation, weight gain, cold intolerance, hoarse voice, bradycardia, dry/rough skin, delayed tendon reflexes.
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| |Elevated TSH, low T4, and low T3. Serum folate level is normal. Homocysteine levels are often elevated
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| |[[Hereditary orotic aciduria]]
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| |Growth retardation, neurologic abnormalities, and obstructive uropathy are associated with hypochromic megaloblastic anemia, with or without congenital malformations and immune deficiency.
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| Replacement of uridine corrects anemia, reduces orotic crystalluria, and improves other sequelae.
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| |Orotic acid crystalluria is present.
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| Serum folate level is normal.
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| |Myelodysplastic syndrome
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| |Gradual-onset fatigue often present, and 20% of patients have splenomegaly. May be associated with prior chemotherapy or radiation exposure.
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| |Macrocytic anemia may be associated with neutropenia and thrombocytopenia.
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| Peripheral smear findings include dimorphic anemia; large, hypogranular platelets; hypogranulated, hyposegmented neutrophils with Dohle bodies; and circulating myeloblasts.
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| Bone marrow shows dyserythropoiesis; hypogranulated, hyposegmented granulocytic precursors; increased myeloblasts; and megakaryocytes showing fewer or disorganized nuclei. Ringed sideroblasts are seen in the bone marrow in certain subtypes of myelodysplastic syndrome.
| | ===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. |
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| Cytogenetic analysis and fluorescence in-situ hybridization can identify specific chromosomal abnormalities.
| | ===Discussion=== |
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| | 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. |
| |Aplastic anemia
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| |History of prior viral illness, chemical exposure, or drug use may be present.
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| Bleeding, lassitude, and symptoms of infection are usually present. Ecchymosis and signs of infection may be present in addition to pallor.
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| |Macrocytic anemia, neutropenia, thrombocytopenia, and reticulocytopenia are present. Absence of GPI-anchored proteins, when associated with paroxysmal nocturnal hemoglobinuria.
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| Bone marrow aspirate and biopsy show decreased cellularity and paucity of all 3 lineage precursors. | |
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| |Drug-induced macrocytosis
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| |Associated with intake of certain drugs, such as DNA synthesis-inhibiting drugs, immunosuppressive drugs, anticonvulsants, and antiviral medications.
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| |Usually a clinical diagnosis.
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| Serum folate level is normal.
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| |Diphyllobothriasis
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| |Presents with abdominal discomfort, diarrhea, vomiting, weakness, weight loss, and occasionally acute abdominal pain due to intestinal obstruction, cholangitis, or cholecystitis. Additional features are megaloblastic anemia and neurologic abnormalities secondary to vitamin B12 (cobalamin) deficiency.
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| |Stool exam reveals characteristic eggs of the fish tapeworm Serum vitamin B12 levels are low.
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| Serum folate is normal.
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| Macrocytosis is defined as a MCV (mean corpuscular volume) greater than 100 fL. It can be divided into megaloblastic and non-megaloblastic types. Following are the causes of '''Non-megaloblastic anemia''' i.e. MCV >100 fL without DNA replication problems and megaloblastic changes.
| | 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. |
| * Alcoholism : This is a result of dietary lack, a weak antifolate action and due to a direct toxic effect of alcohol on the bone marrow.
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| * Hypothyroidism : Macrocytosis is found in up to 55% patients with hypothyroidism and may result from the insufficiency of the thyroid hormones themselves and also due to 20 times increased risk of pernicious anemia in people with hypothyroidism
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| * Aplastic anemia : Mild macrocytosis can be observed in association with stress erythropoiesis and elevated fetal hemoglobin levels in aplastic anemia.
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| * Reticulocytosis : Commonly due to hemolysis or a recent history of blood loss. This is due to increased hematopoeisis and rapid release of immature RBCs from the bone marrow to replace the blood loss.
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| * Liver disease : Liver enzymes play an important role in the process of normal erythropoiesis
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| * Myeloproliferative diseas and Myelodysplastic syndromes : due to bone marrow dysfunction
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| * Chronic exposure to benzene and drugs like 5- Fluorouracil.
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| Folate and Vitamin B12 deficiencies : These are the two most important causes of '''Megaloblastic macrocytic anemia''' associated with impaired DNA synthesis and megaloblastic changes like hypersegmented neutrophils and glossitis. History and physical examination, vitamin B<sub>12</sub> level, reticulocyte count, and a peripheral smear are helpful in delineating the underlying cause of megaloblastosis. A measurement of methylmalonic acid in the blood or urine, can provide an indirect method for partially differentiating Vitamin B<sub><small>12</small></sub> and folate deficiencies. The level of methylmalonic acid is not elevated in folic acid deficiency while it is raised in Vitamin B12 (cobalamin) deficiency. Direct measurement of blood cobalamin and folate is the gold standard to differentiate between the two causes.
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| ==[[Folate deficiency epidemiology and demographics|Epidemiology and Demographics]]==
| | 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. |
| The prevalence of folate deficiency across the world is quite variable. The deficiency is more common in countries without folic acid fortification of cereal-grain products and rarely in countries with folic acid fortification. National surveys conducted in several countries show that without fortification, folate deficiency can be a public health problem. The primary age groups affected include preschool children (33.8% of the folate-deficient population in Venezuela), pregnant women (48.8% in Costa Rica and 25.5% in Venezuela), and older people (15% in the UK). 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. Mandatory folic acid fortification of enriched cereal-grain products was initiated in the US in 1996 and Canada in 1998. Subsequent surveys of regional and nationally representative populations have shown that serum and RBC folate concentrations have increased in the general population in these countries.
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| ==[[Folate deficiency risk factors|Risk Factors]]==
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| Strong risk factors include :
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| * Low dietary folate intake
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| * Age >65 years
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| * Alcoholism
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| * Pregnant or lactating mothers
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| * Prematurity
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| * Intestinal malabsorptive disorders e.g. celiac disease, tropical sprue, jejunal resection, inflammatory bowel diseases.
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| * Use of dtugs e.g. trimethoprim, methotrexate, anticonvulsants, sulfasalazine, or pyrimethamine
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| * Infantile intake of goats' milk which is low in folate content
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| * Congenital defects in folate absorption and metabolism
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| Weaker risk factors inlcude :
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| * States of increased cell turnover e.g. chronic hemolysis
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| * Intake of special diet
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| * Chronic dialysis
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| ==[[Folate deficiency screening|Screening]]==
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| ==[[Folate deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
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| ==Diagnosis==
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| [[Folate deficiency history and symptoms|History and Symptoms]] | [[Folate deficiency physical examination|Physical Examination]] | [[Folate deficiency laboratory findings|Laboratory Findings]] | [[Folate deficiency imaging findings|Imaging Findings]] | [[Folate deficiency other diagnostic studies|Other Diagnostic Studies]]
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| ==Treatment==
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| [[Folate deficiency medical therapy|Medical Therapy]] | [[Folate deficiency primary prevention|Primary Prevention]] | [[Folate deficiency secondary prevention|Secondary Prevention]] | [[Folate deficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Folate deficiency future or investigational therapies|Future or Investigational Therapies]]
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| ==Case Studies==
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| [[Folate deficiency case study one|Case #1]]
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For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Editor : L.Farrukh
Synonyms and keywords: Folic acid deficiency
Treatment
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.
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 #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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