Folate deficiency: Difference between revisions

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==[[Folate deficiency differential diagnosis|Differentiating Folate deficiency from other Diseases]]==
==[[Folate deficiency differential diagnosis|Differentiating Folate deficiency from other Diseases]]==
==[[Folate deficiency epidemiology and demographics|Epidemiology and Demographics]]==
==[[Folate deficiency epidemiology and demographics|Epidemiology and Demographics]]==
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. 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, pregnant women and older people.  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 cereal-grain products was initiated in the US in 1996. Subsequent surveys have shown that serum and RBC folate concentrations have increased in the general population.
==[[Folate deficiency risk factors|Risk Factors]]==
==[[Folate deficiency risk factors|Risk Factors]]==
Strong risk factors include :
Strong risk factors include :

Revision as of 19:27, 20 May 2018

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

Folate deficiency Microchapters

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Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Folate deficiency from other Diseases

Epidemiology and Demographics

Risk Factors

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Natural History, Complications and Prognosis

Diagnosis

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Secondary Prevention

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Case #1

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

Synonyms and keywords: Folic acid deficiency

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.

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.

Classification

Pathophysiology

Differentiating Folate deficiency from other Diseases

Epidemiology and Demographics

Risk Factors

Strong risk factors 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
  • Congenital defects in folate absorption and metabolism

Weaker risk factors inlcude :

  • States of increased cell turnover e.g. chronic hemolysis
  • Intake of special diet
  • Chronic dialysis

Screening

Screening for folate deficiency is not routinely recommended. However, early detection can lead to folic acid supplementation, which is a simple treatment of the underlying cause. can reduce the risk of anemia certain conditions such as fetal neural tube defects in newborns.

High risk populations

  • Older people (Age >65)
  • Alcohol abusers
  • Pregnant or lactating women
  • Preterm infants
  • Lower socioeconomic groups
  • Patients with intestinal malabsorption
  • Patients with conditions with increased cell turnover states
  • Patients on special diets, and infants given goats' milk
  • Chronic dialysis patients.

Screening tests

CBC may show increased MCV i.e. MCV > 100fL with or without low hemoglobin.Further testing includes serum folate level (Adults: 2-20 ng/mL). High risk populations are tested for folate deficiency if their CBC is abnormal.

Natural History, Complications and Prognosis

  • Hematologic deficits : Inadequately treated or untreated patients will have 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.
  • Neuropathy due to folic acid therapy in vitamin B12 deficiency: 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
  • 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.
  • 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:

Therapy often consists of giving oral folic acid, which is simple and inexpensive. Even in patients with malabsorptive disorders, folic acid is better absorbed than natural folate present in food. Hematologic parameters usually normalize after 8 weeks of therapy. Body stores can be replenished with additional treatment for 1 month. Patients with ongoing folate loss (e.g., malabsorptive disorders) and those with a continued state of increased demand (e.g., pregnancy) usually need continued supplementation.These people are at high risk for folate deficiency and it is advisable to monitor such patients periodically for both folate and vitamin B12 deficiencies.

Dietary modification : Patients consuming a folate-poor diet should include foods rich in folate. Alternatives include consuming foods fortified with folic acid or supplementing folate through multivitamin intake.

Diagnosis

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

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.

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

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.

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.

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.

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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