History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors are low dietary folate intake; age >65 years; alcohol-use disorder; pregnancy or lactation; prematurity; intestinal malabsorption disorders; use of trimethoprim, methotrexate, anticonvulsants, sulfasalazine, or pyrimethamine; infantile intake of goats' milk; and congenital defects in folate absorption and metabolism.
Other diagnostic factors
common
prolonged diarrhoea
Chronic diarrhoeal states (such as tropical sprue and coeliac disease [non-tropical sprue]) and inflammatory bowel disease lead to poor absorption of folate.
loss of appetite and weight loss
Symptom of megaloblastic anaemia, the hallmark of folate deficiency. Weight loss is an objective vital sign in megaloblastic anaemia that results from both loss of appetite and increased energy demands of ineffective erythropoiesis.
fatigue
Symptom of megaloblastic anaemia, the hallmark of folate deficiency.
shortness of breath
Symptom of megaloblastic anaemia, the hallmark of folate deficiency.
dizziness
Symptom of megaloblastic anaemia, the hallmark of folate deficiency.
pallor
Megaloblastic anaemia, the hallmark of folate deficiency, can present as pallor.
headache
Symptom of megaloblastic anaemia, the hallmark of folate deficiency.
tachycardia
Can be a finding of anaemia.
tachypnoea
Can be a finding of anaemia.
heart murmur
Can be a finding of anaemia.
signs of heart failure
Can be a finding of anaemia. Signs include displaced apical impulse, gallop rhythm, and elevated jugular venous pressure.
signs of chronic alcohol misuse
Examination may reveal signs of underlying disease associated with folate deficiency.
signs of haemolytic anaemia
Examination may reveal signs of underlying disease (including pallor, jaundice, systolic flow murmur, hepatosplenomegaly) associated with folate deficiency, but related to increased cell turnover.
signs of exfoliative dermatitis
Examination may reveal signs of underlying disease, mainly exfoliation of skin, associated with folate deficiency.
uncommon
painful swallowing
Severe deficiency can cause inflammation of the oral mucosa, which results in painful swallowing.
petechiae
Advanced deficiency can cause thrombocytopenia, which can result in development of petechiae.
glossitis
Severe deficiency can cause glossitis; vitamin B12 (cobalamin) deficiency can also cause this problem.
angular stomatitis
Severe deficiency can cause angular stomatitis; other vitamin deficiency states can also produce the same picture.[Figure caption and citation for the preceding image starts]: Angular cheilitisFrom the collection of Dr Wanda C. Gonsalves; patient consent obtained [Citation ends].
neurological deficits in children
Neurological signs and symptoms are not typically seen in patients with folate deficiency. Exceptions are children with inborn errors of folate absorption and metabolism, or those who have experienced severe antenatal folate deficiency, who often have severe myelopathy and neurological dysfunction.
Manifestations in the central nervous system are likely to be explained by the involvement of folate in the synthesis of methionine and S-adenosylmethionine, which are essential for normal development of the central nervous system. Vitamin B12 (cobalamin) deficiency may present as megaloblastic anaemia with neurological findings.
Risk factors
strong
low dietary folate intake
Low dietary folate intake was the most common cause of folate deficiency until fortification of cereal-grain products with folic acid began in the late 1990s in the US (Food and Drug Administration, 1996), Canada, and parts of South America.
Countries with folic acid fortification have increased the folate levels in the general population, and reduced the incidence of neural tube defects (NTDs) and related neural malformations in neonates.[7][19][20] The increase in folate levels in the US general population has resulted in low dietary intake becoming an extremely rare cause of folate deficiency anaemia.[21]
In low- and middle-income countries, folate fortification has increased serum/plasma folate levels and, among women of reproductive age, reduced the prevalence of folate deficiency and pregnancies with NTDs.[22]
In countries without folic acid fortification, the potential persists for a significant percentage of the population to be folate deficient. In these countries, folate intake can be poor in the lower socio-economic groups, in vulnerable populations such as pregnant women, and in populations who rely on unfortified cereals (e.g., wheat and rice) with low consumption of green vegetables and legumes.[4][23]
The recommended intake of folate by adults is based on the amount required to normalise red blood cell folate, which in turn maintains normal levels of serum folate and plasma homocysteine. The recommended dietary allowance for folate increases from 150 micrograms/day at age 1 year, to 200-400 micrograms/day in adults.[24][25] US Department of Agriculture and US Department of Health and Human Services: dietary guidelines for Americans, 2020-2025 Opens in new window NIH: dietary supplement fact sheet - folate Opens in new window
age >65 years
Poor intake of foods rich in folate can lead to folate deficiency in older people. In the pre-fortification era in the US, older people formed 10.8% of the folate-deficient population.[3]
alcohol-use disorder
Most people consuming >80 g ethanol per day (about 1.5 litres of beer, 750 mL of wine, or 6 servings of distilled ethanol at 14 g/serving) have been found to be folate-deficient in the pre-fortification era.[26] [ Standard Drink Equivalents Opens in new window ]
Folate deficiency in people with alcohol-use disorder is rare in the US post-fortification.[27]
Folate deficiency in chronic alcohol-use disorder is caused by multiple mechanisms, including low intake, poor absorption, reduced enterohepatic circulation and storage in the liver, and increased urinary excretion.[9]
pregnant or lactating
Pregnant and lactating women have an increased folate demand, which can result in folate deficiency. In lactating women, breast milk concentrations of folate are maintained but at the expense of maternal folate status.[28]
Folate deficiency during pregnancy is strongly associated with fetal neural tube defects, 70% of which can be prevented by increased folic acid supplementation.[29][30][31]
Women who are planning to conceive or who are capable of becoming pregnant should receive pre-conception folic acid supplementation at a dose of 400-800 micrograms/day, with higher doses (up to 5 mg/day) recommended for certain risk groups.[32][33][34] The UK National Institute for Health and Care Excellence recommends 5 mg/day in certain risk groups.[35][36]
In the US, the recommended dietary allowance for folate during pregnancy and lactation varies from 400-800 micrograms/day depending upon factors such as diet, inclusion of food fortified with folic acid, socio-economic status, and individual medical history. US Department of Agriculture and US Department of Health and Human Services: dietary guidelines for Americans, 2020-2025 Opens in new window NIH: dietary supplement fact sheet - folate Opens in new window
prematurity
Red blood cell folate concentrations fall significantly in the first 2 to 3 months in preterm infants, whether breastfed or formula-fed.[37] Routine supplementation of folic acid for preterm infants is required.[38]
Folate levels are adequate in preterm infants fed modern formulas enriched with folic acid and in breastfed infants given folic acid supplements.[39]
intestinal malabsorptive disorders
Chronic diarrhoeal states (e.g., coeliac disease [non-tropical sprue], tropical sprue, and inflammatory bowel disease), other intestinal disorders (e.g., malignant infiltration, amyloidosis, Whipple's disease, and scleroderma), and extensive resection of the small intestine can lead to poor absorption of folate.[40]
In the post-fortification era in the US, folate deficiency was found in 3.6% of newly diagnosed cases of coeliac disease compared with 0.3% of age-matched controls.[41]
use of trimethoprim, methotrexate, sulfasalazine, pyrimethamine, or anticonvulsants (e.g., phenytoin, phenobarbital)
These drugs interfere with folate function or absorption by inhibiting enzymes in folate metabolism, and by other unknown mechanisms.[42]
infantile intake of goats' milk
Goats' milk is almost completely deficient in folate. Exclusive intake in infants can cause folate deficiency.
congenital defects in folate absorption and metabolism
Rare but potentially life-threatening. Defects include hereditary folate malabsorption, methylenetetrahydrofolate reductase deficiency, glutamate formiminotransferase deficiency, and functional methionine synthase deficiency.
Presentation is often during infancy, with varying combinations of megaloblastic anaemia, failure to thrive, chronic diarrhoea, neurological deficits, and developmental delay.[10]
weak
states of increased cell turnover
Increased desquamation of cells in exfoliative dermatitis, and increased cell turnover in chronic haemolytic anaemias, can cause folate deficiency.
intake of special diet
Patients with inborn errors of metabolism, such as phenylketonuria, who are on special diets that lack folate, may develop folate deficiency.
chronic dialysis
Folate is lost during dialysis, and folic acid supplements are generally used in chronic dialysis.
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