From the Guidelines
The best test to screen for folate deficiency in macrocytic anemia is a serum folate level, which directly measures the amount of folate in the bloodstream, with a normal level typically being above 10 nmol/L 1. When evaluating a patient with macrocytic anemia, ordering both serum folate and vitamin B12 levels is recommended since these deficiencies can present similarly with elevated mean corpuscular volume (MCV).
- A normal serum folate level is typically above 10 nmol/L, as indicated by the espen micronutrient guideline 1.
- Red blood cell (RBC) folate can also be measured and may better reflect tissue stores since it indicates folate status over the previous 3 months, whereas serum folate reflects more recent intake.
- However, serum folate is more commonly used as the initial screening test due to its availability and cost-effectiveness.
- It's essential to collect the sample before folate supplementation begins, as even a single dose can normalize serum levels. Additional testing should include a complete blood count with peripheral smear, which may show hypersegmented neutrophils in folate deficiency.
- Homocysteine levels are often elevated in both folate and B12 deficiency, while methylmalonic acid is elevated only in B12 deficiency, helping to distinguish between these two causes of macrocytic anemia 1. The microbiological assay (MBA) using Lactobacillus rhamnosus is viewed as the gold standard technique for folate status assessment, as it can respond to all active monoglutamate forms of folate 1.
- The development of methods using Liquid chromatography-mass spectrometry (LC-MS) has enabled quantification of different folate forms with good sensitivity and precision, but requires expensive instrumentation and experienced staff 1.
- Plasma homocysteine can be measured by immuno- and enzymatic assays, but the use of LC-MS/MS provides high selectivity, specificity, and simultaneously measures other molecules to help interpretation 1.
From the Research
Screening for Folate Deficiency in Macrocytic Anemia
To determine the best test for screening folate deficiency in macrocytic anemia, several studies have been considered. The key findings are summarized below:
- Serum Folate Assay: A study from 2 found that the serum folate assay is a valuable routine test in patients with macrocytic anemia and low serum vitamin B12. It indicated that a low folate level makes the diagnosis of pernicious anemia unlikely and is a strong indication for full investigation of small intestinal function.
- Clinical Utility of Folate Levels: However, a study from 3 questioned the clinical utility of folate levels in evaluating macrocytosis or anemia, suggesting that empirical supplementation with folic acid could be used in place of testing for deficiency due to the low frequency of low folate levels and the limited impact on clinician behavior.
- Investigation of Macrocytic Anemia: Another study from 4 recommended serum vitamin B12 determination as the best test for unmasking vitamin B12 deficiency and suggested ordering serum and red cell folate determinations in conjunction with this test when investigating macrocytic anemia.
- Combined Deficiencies: A case report from 5 highlighted the importance of considering combined vitamin B12 and folate deficiency in the diagnosis of macrocytic anemia, as these deficiencies can masquerade as other conditions like thrombotic thrombocytopenic purpura.
- Differential Diagnosis: A practical approach to the differential diagnosis and evaluation of macrocytic anemia, as outlined in a study from 6, includes a carefully obtained history, examination, peripheral blood smear, reticulocyte count, and specific tests like serum vitamin B12 and folate levels based on initial findings.
Key Tests for Screening
Based on the evidence, the following tests are considered useful for screening folate deficiency in macrocytic anemia:
- Serum folate assay
- Serum vitamin B12 determination
- Red cell folate determinations
- Peripheral blood smear
- Reticulocyte count
These tests, combined with a thorough clinical evaluation, can help in identifying folate deficiency as a cause of macrocytic anemia and guide appropriate management.