Following the FDA’s mandated folate-fortification of foods in the USA in 1998, the Choosing Wisely Campaign recommended in 2017 that laboratories discontinue the measurement of blood folate levels. The Campaign instead suggested that clinicians should supplement folate in patients with suspected macrocytic anemia, without prior evaluation of their folate status. However, the proposition to supplement folate without first testing may be challenged by recent reports associating high blood folate with the risk of certain cancers . Other established reports demonstrate the relationship between high folate level and vitamin B-12 deficiency masking . Is Medicine latently swinging from combating folate deficiency towards susceptibility to folate toxicity, thereby, compromising patient safety?
Folate deficiency has garnered more attention partly due to the multitude of anemia and pregnancy-related conditions associated with it. Generally, pregnant women have higher folate requirement (800 micrograms daily limit) compared with the general population (400 micrograms daily limit). Expectant mothers with insufficient intake of folate risk neonatal conditions such as anencephaly, spina bifida and encephalopathy to their unborn child. The biochemical mechanism of folate metabolism elucidates the clinical manifestations of these conditions. Folate is required by cells for the synthesis of nucleic acids in cells and erythropoiesis. The conversion of deoxy uridine monophosphate to deoxy cytosine thymidine monophosphate is catalyzed by thymidylate synthase which requires tetrahydrofolate- essentially folate, as a cofactor . Biological cell division is dependent on DNA replication and this necessitates the synthesis of thymidine, the key base that distinguishes DNA from RNA. Therefore, the absence or diminished presence of folate decelerates the cell cycle process, including restricted erythropoiesis, being the principal etiology of the symptoms of folate deficiency anemia. Folate fortification of food has been shown to drastically reduce the incidence of folate deficiency-related diseases. But misguided supplementation without prescription, in addition to prescribed supplementation by clinicians, without prior folate testing may be creating a lurking medical problem of folate toxicity.
An article by MD Anderson Cancer Center as well as other sources reported the link between elevated red blood folate and the risk of developing colorectal and other types of cancers [3, 5]. The study team enrolled a 781-patient pool from a clinical trial which was comparing the efficacy of folate versus aspirin in the prevention of precancerous colorectal polyps. The report suggested that individuals with high folate levels were more likely to have a shutdown of two important tumor suppressor genes . This extreme down regulation of the tumor suppressor genes is blamed on increased DNA methylation. Most active genes normally undergo alternating cycles of DNA methylation and demethylation as a means of epigenetic gene regulation process. DNA methylation inhibits transcription of the gene, while demethylation promotes activation of the gene and a consequential protein synthesis. The researchers focused on the Era and SFRP1 genes, known to be normally expressed in healthy individuals but methylated and silenced in breast, prostate and lung cancer patients. They found a strong association between RBC folate and the methylation of both genes. Folate was previously reported as cancer-preventing when ingested in the right amounts, but it’s cancer-promoting characteristics are just beginning to now baffle
scientists. More concerning is the fact that folate is available over-the-counter in most pharmacy shops and can be self-administered unrestrictedly. A recent study reported that of 593 patients presenting with anemia, 5% had elevated folate values, suggesting that we may be on the brink of a silent folate toxicity epidemic .
In addition to its link with malignancy, another important apprehension for elevated blood folate is its relationship with vitamin B12 deficiency masking. In macrocytic anemia, the red blood cells are larger in size than normal with an MCV of >100 fL compared with normal and reduced size in normocytic and microcytic anemia respectively. Megaloblastic macrocytic anemia is caused by deficiency of either vitamin B12 or folate or both. The physiological function of folate and vitamin B12 are connected in the sense that methyl folate is required for the activation of vitamin B12 to convert homocysteine to methionine, relieving the cardio-destructive effect of homocysteine. In the disproportionate overabundance of folate and simultaneously reduced vitamin B12 levels, the effects of vitamin B12 deficiency are delayed until neurological damage sets in. More so, in cases of non-megaloblastic macrocytic anemia in which macrocytosis is caused by factors other than vitamin B12 or folate deficiency, folate prescription could exacerbate folate toxicity.
In the wake of unquantifiable abuse of over-the-counter folate supplements, against the backdrop of folate fortification of food, as well the reported risks highlighted here, there may be the need for a critical review of test-utilization campaigns against folate testing.
1. Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. Jama 2009;302(19):2119-26
2. Ankar A, Kumar A. Vitamin B12 Deficiency. StatPearls. Treasure Island (FL), 2021.
3. Mishanina TV, Koehn EM, Kohen A. Mechanisms and inhibition of uracil methylating enzymes. Bioorg Chem 2012;43:37-43
4. Kristin Wallace PD, Maria V. Grau, M.D., Jiang Gui, Ph.D., Elizabeth Barry, Ph.D., and John Baron, M.D. High Red Blood Folate Levels Linked to Silenced Tumor-Suppressors. 2010.
5. Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Njølstad I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009 Nov 18;302(19):2119-26.
6. Bremansu Osa-Andrews, Melissa Sanchez, Ibrahim A Hashim, The Continued Need for the Routine Assessment of Folate Status, Laboratory Medicine, 2023.Imac148.