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'''For patient information click [[Folate deficiency (patient information)|here]]'''
'''For patient information click [[Folate deficiency (patient information)|here]]'''


{{CMG}}
{{CMG}} '''Editor''' : [https://www.wikidoc.org/index.php?title=L.Farrukh&action=edit&redlink=1 L.Farrukh]​


{{SK}} Folic acid deficiency
{{SK}} Folic acid deficiency


==[[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.
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.


==[[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.


==[[Folate deficiency classification|Classification]]==
==[[Folate deficiency classification|Classification]]==
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==[[Folate deficiency screening|Screening]]==
==[[Folate deficiency screening|Screening]]==
==[[Folate deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
==[[Folate deficiency natural history, complications and prognosis|Natural History, Complications and Prognosis]]==
=== Diagnosis ===
[[Folate deficiency history and symptoms|History and Physical Examination]]
Common diagnostic factors include the following :
* shortness of breath
* dizziness, headache
* pallor
* tachycardia, tachypnea
* history of prolonged diarrhea
* loss of appetite and weight loss
* fatigue
* heart murmur
* signs of heart failure
* history of chronic alcohol abuse
* signs of hemolytic anemia
* signs of exfoliative dermatitis
* glossitis
* angular stomatitis
*
[[Folate deficiency laboratory findings|Laboratory Findings]]
First line investigations include the following:
* Examination of peripheral blood smear : Macrocytic anemia and hypersegmented neutrophils are classically seen in folate deficiency. Anisocytosis and poikilocytosis can also be observed.
* Complete Blood Count : Low hemoglobin, elevated MCV and MCH, thrombocytopenia, neutropenia.
* Reticulocyte count : Low corrected reticulocyte count which indicates decreased production by the bone marrow.
[[Folate deficiency other diagnostic studies|Other Diagnostic Studies]]
Other investigations and confirmatory tests include the following :
* serum folate
* RBC folate
* serum vitamin B12
* serum iron panel
* plasma or serum methylmalonic acid
* plasma homocysteine
* bone marrow biopsy
* serum LDH
* serum unconjugated bilirubin
==Treatment==
==Treatment==
[[Folate deficiency medical therapy|Medical Therapy]]
'''During pregnancy or lactation'''
* low risk : 0.4 to 0.8 mg orally once daily starting 1-3 months before pregnancy and continuing until 6 weeks postpartum or the end of lactation
* medium risk: 1 mg orally once daily starting 1-3 months before pregnancy and continuing through the first 12 weeks of pregnancy, followed by 0.4 to 1 mg once daily from week 13 of pregnancy and continuing until 6 weeks postpartum or the end of lactation
* high risk: 4 mg orally once daily starting 1-3 months before pregnancy and continuing through the first 12 weeks of pregnancy, followed by 0.4 to 1 mg once daily from week 13 of pregnancy and continuing until 6 weeks postpartum or the end of lactation
==== Malabsorption or chronic hemolysis ====
* Correction of underlying disorder and oral folic acid supplementation (1mg orally once daily)
==== Congenital folate metabolism defect ====
* Treatment of children with inborn errors of folate metabolism requires extremely large doses of folic acid given parenterally.
==== Congenital folate malabsorption ====
* Folic acid or leucovorin (3-6 mg intramuscularly once daily)
==== Macrocytic anemia and pancytopenia ====
* folic acid with vitamin B9 : 1 mg orally once daily ; adults: 1-5 mg orally once daily
* Ruling out vitamin B12 deficiency is important because initiation of folic acid therapy may aggravate underlying neurologic manifestations due to vitamin B12 deficiency.
[[Folate deficiency primary prevention|Primary Prevention]]
Folic acid supplementation can prevent folate deficiency in states of increased demand (e.g., pregnancy and lactation) and in conditions with folate malabsorption (e.g., celiac disease) or loss (e.g., chronic hemolytic disorder). Preconception folic acid supplementation in women can also prevent fetal neural tube defects.
Folic acid supplementation during pregnancy reduces megaloblastic anemia in mothers, but there is no conclusive evidence to suggest any beneficial effect on pregnancy outcomes e.g. preventing premature birth, stillbirth, neonatal mortality, or miscarriage.
There is conclusive evidence that use of folic acid supplementation preconceptually and during pregnancy can prevent fetal NTDs. Therefore, preconception folic acid supplementation is recommended at a dose of 400-800 micrograms/day for women who are planning to or are capable of becoming pregnant, with higher doses (up to 4 mg/day) recommended for certain risk groups.
[[Folate deficiency secondary prevention|Secondary Prevention]]
Continued folic acid supplementation is necessary in certain conditions with poor folate absorption or ongoing losses (e.g., celiac disease, chronic hemolytic disease) and states of increased demand (e.g., pregnancy, lactation, prematurity). National food fortification can prevent folate deficiency on a larger scale. This can positively affect the folate status of the population at large especially for the high risk groups such as pregnant and lactating women and older people.
[[Folate deficiency cost-effectiveness of therapy|Cost-Effectiveness of Therapy]]


==[[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.
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.
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.


[[Folate deficiency future or investigational therapies|Future or Investigational Therapies]]
==[[Folate deficiency 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.                                                                                    
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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[[Folate deficiency case study one|Case #1]]
[[Folate deficiency case study one|Case #1]]


=== Case presentation ===
===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.
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 =====
=====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.
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 ===
===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.
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 ===
===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)
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 ===
===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.
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 ===
===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.
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.



Latest revision as of 15:16, 6 September 2020

Folate deficiency
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Folic acid (B9)
ICD-10 D52 E53.8
ICD-9 266.2
DiseasesDB 4894
MedlinePlus 000354
MeSH D005494

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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

Historical Perspective

Classification

Pathophysiology

Differentiating Folate deficiency from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Treatment

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

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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