Approach
Folate deficiency in the classic form presents as anaemia with decreased reticulocyte numbers and oval macrocytosis (mean corpuscular volume [MCV] >100 femtolitres). Severe folate deficiency can present as pancytopenia (anaemia, neutropenia, and thrombocytopenia).
Neurological signs and symptoms are not typically seen in patients with folate deficiency.
Alternative explanations, such as co-existing vitamin B12 (cobalamin) deficiency, thiamine deficiency, or alcohol-use disorder, should be considered in cases of macrocytic anaemia with neurological signs and symptoms.
Risk groups
Certain patient groups are at increased risk for developing folate deficiency. The following groups should be considered when taking a medical history:
Low socio-economic groups with poor nutrition
Older people with poor dietary intake
People who misuse alcohol (producing a sharp decline in serum folate within a few days)
Pregnant and lactating women and preterm infants (increased demand)
People with chronic haemolytic anaemia or chronic exfoliative dermatitis (increased cell turnover increases folate requirement)
People taking drugs that interfere with folate absorption and metabolism, including sulfasalazine, trimethoprim, pyrimethamine, methotrexate, and anticonvulsants (e.g., phenytoin, phenobarbital)
People with hereditary folate malabsorption and inborn errors of folate metabolism, often manifesting in early life
People with chronic diarrhoeal states and other intestinal disorders (can cause poor absorption of folate)
Chronic dialysis patients (folate is water soluble and lost in the dialysis fluid)
Infants who are fed goats' milk exclusively, and children with inborn errors of metabolism given a synthetic diet.
Symptoms and signs
Megaloblastic anaemia is the hallmark of folate deficiency.
Severe folate deficiency presents as symptomatic macrocytic anaemia and pancytopenia; non-severe folate deficiency includes signs of macrocytosis without anaemia.
Symptomatic inquiry should cover symptoms associated with anaemia, including fatigue, palpitations, shortness of breath, dizziness, headaches, jaundice, loss of appetite, and weight loss. Patients may complain of painful swallowing, inflammation of the tongue (glossitis), and discomfort at the corners of the mouth (angular stomatitis) in severe folate deficiency.[Figure caption and citation for the preceding image starts]: Angular cheilitisFrom the collection of Dr Wanda C. Gonsalves; patient consent obtained [Citation ends].
Symptoms of underlying disease should also be elucidated, such as chronic diarrhoea and weight loss, or failure to thrive in intestinal disorders.
A complete physical examination should be performed, to look for signs of anaemia (pallor, tachycardia, tachypnoea, heart murmurs, signs of heart failure, jaundice) and underlying disease (e.g., signs of chronic alcohol misuse, haemolytic anaemia, exfoliative dermatitis). Petechiae may be present in those with thrombocytopenia.
Neurological dysfunction, although rarely reported, is not typically present. The exceptions are children with inborn errors of folate absorption and metabolism, who often have severe myelopathy and neurological dysfunction.
Initial tests
All patients with suspected folate deficiency should have a full blood count with peripheral blood smear and reticulocyte count.
Haematological findings
In the classic case of severe folate deficiency, the patient presents with severe anaemia, oval macrocytosis (MCV >100 femtolitres), and elevated mean corpuscular haemoglobin. Corrected reticulocyte counts are decreased. As anaemia advances, poikilocytes and teardrop cells appear. In extremely severe anaemia, receding macrocytosis has been reported, a probable effect of poikilocytosis and red blood cell (RBC) fragmentation.[40]
Classic findings may not always be present, or may be altered:
In early folate deficiency states, the haemoglobin and MCV are normal. As the deficiency progresses, there is an increase in MCV, followed by reduced haemoglobin.
Macrocytosis can be masked by co-existing iron deficiency or thalassaemia. Iron studies may not reveal deficiency initially; the true iron status becomes evident several days after initiating folic acid therapy.
Transfusion of infants with pancytopenia can lead to neutropenia and thrombocytopenia as the only haematological features.
The presence of hypersegmented neutrophils is a characteristic feature of folate deficiency. It is defined as the presence of 5 lobes in >5% of neutrophils, or the presence of one or more neutrophils with 6 or more lobes. Hypersegmentation often precedes anaemia, but is not found in sub-clinical vitamin deficiencies. It can also be present in patients receiving medications that inhibit DNA synthesis (e.g., 5-fluorouracil, hydroxyurea) and, rarely, in patients with myelofibrosis, chronic myelogenous leukemia, or a benign hereditary condition.[Figure caption and citation for the preceding image starts]: Megaloblastic macrocytic anaemia: A. Peripheral blood smear of a patient with megaloblastic anaemia. B. Peripheral blood smear of healthy individualPhotomicrograph from Mark J. Koury, MD; used with permission [Citation ends].
Neutropenia and thrombocytopenia are present in advanced folate deficiency.
Confirmatory tests
As the initial screen, measuring serum folate level is recommended in suspected folate deficiency.
Serum folate depends on intake, and falls rapidly into the deficient range during deprivation.[1][54] Approximately 5% of patients who have folate deficiency will have normal serum folate levels.[55][56] The RBC folate level decreases more slowly during the 3- to 4-month turnover period of RBCs. Although RBC folate may be a better indicator of tissue folate levels, the assay is complex and more expensive than serum folate assessment. RBC folate level can be low in vitamin B12 deficiency.
Serum folate <7 nanomol/L (<3 nanograms/mL) indicates folate deficiency and often leads to morphological features (megaloblastic changes in bone marrow and macrocytic anaemia).[55] A folate level between 7 nanomol/L and 11 nanomol/L (3 nanograms/mL and 5 nanograms/mL) can cause metabolic changes (elevated plasma homocysteine), and therefore is suspicious for folate deficiency.
When serum folate levels are normal or borderline, in the presence of a strong clinical suspicion, RBC folate (lower limit of normal: <317 nanomol/L [<140 nanograms/mL]) and plasma homocysteine levels (>15 micromol/L; may be indicative of folate deficiency) can be obtained to aid diagnosis.[55][57]
False-negative serum folate test results can be found after recent folate intake. False-positive low serum folate test results may be found in patients with anorexia, alcohol consumption, normal pregnancy, and in patients on anticonvulsant medications.[57]
Contributory tests
Further testing should include bilirubin, liver function tests, lactate dehydrogenase (LDH), haptoglobin, and serum iron studies.
Biochemical tests
The laboratory signs of ineffective erythropoiesis and haemolysis co-exist with macrocytosis and anaemia; these include elevated LDH, increased unconjugated bilirubin, and low haptoglobin. Serum iron, ferritin, and transferrin receptor levels are elevated.[40]
Bone marrow aspirate and biopsy
Examination of bone marrow shows megaloblastic erythropoiesis. The morphological hallmark of megaloblastic anaemia are erythroblasts that are larger than expected based on cytoplasmic appearance, with large, uncondensed nuclei. Late-stage erythroblasts may have lobulated nuclei. Giant band cells and metamyelocytes are seen.[Figure caption and citation for the preceding image starts]: Megaloblastic marrow cellsPhotomicrograph from Mark J. Koury, MD; used with permission [Citation ends].
Bone marrow examination is not necessary to confirm the diagnosis of folate deficiency, although it can be used to exclude important causes of macrocytic anaemia and pancytopenia, such as myelodysplasia or aplastic anaemia.
Differential diagnosis
Underlying vitamin B12 deficiency should be ruled out before implementing therapy with folic acid, because such therapy may mask neurological complications of untreated vitamin B12 deficiency. However, it is important to note that vitamin B12 deficiency and folate deficiency can co-exist in certain patients.
Vitamin B12 deficiency can cause megaloblastic anaemia with similar symptoms and signs as those of folate deficiency.[8] Neurological signs are, however, absent in folate deficiency (with the exception of children with inborn errors of folate absorption and metabolism, or those who have experienced severe antenatal folate deficiency).
Plasma or serum methylmalonic acid levels rise in vitamin B12 deficiency but are normal in folate deficiency. Homocysteine levels rise in both vitamin B12 deficiency and folate deficiency.[58][59] Levels of methylmalonic acid and homocysteine can be affected by renal function.
Evaluating underlying aetiology
Once folate deficiency is diagnosed, recognition of the underlying precipitating cause is important to prevent ongoing folate deficiency states.
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