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Food fortification: Now B12 too?
Fortification of the U.S. diet with several essential nutrients has occurred, both voluntarily and because it was mandated by the federal government. The usual vehicle is flour because of its widespread consumption, but salt (iodine) and the water supply (fluoride) have also been used.
At least two of the nutrients added to flour — iron and folic acid — are of more than a passing interest to hematologists and oncologists. Now, there is discussion about introducing vitamin B12 fortification. What are the reasons, and what, if any, are the risks?
Pros and cons
When a nutrient is added to the food supply, two issues dominate the discussion. First, what is the target group and purpose? And second, what are the possible side effects, and are there segments of the population that potentially could be harmed? In the case of iron, the target population was women, particularly the young and pregnant, as well as infants and young children.
The leading concern was that iron accumulation would be hastened in individuals carrying genes for hereditary iron overload who could phenotypically express hemochromatosis. A fine print theoretical possibility was that iron fortification might result in generation of free radicals that are implicated in a variety of degenerative diseases. Yet another concern was that the diagnosis of “silent” colonic cancers, which often first reveal their presence through symptoms of iron deficiency anemia due to occult bleeding, could be delayed by larger iron stores.
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With folic acid, the target group was pregnant women at risk for having a neural tube defect (NTD) pregnancy. The chief concern was that high folate intake might mask megaloblastic anemia in people with pernicious anemia, which could result in irreversible neurological damage. Interference with antifolate drugs such as methotrexate was another possible undesired consequence.
Now, 30 years after the second round of iron fortification and 12 years after folic acid fortification, we can take stock. Iron fortification has dramatically lowered the prevalence of iron deficiency and its associated anemia, and there is no clear evidence of adverse effects of the increased iron intake, although reports have appeared that show a higher HR for various cancers and for cardiovascular disease in those with higher levels of iron. Regarding folate, results are less cut and dried, although there has been a substantial reduction in the incidence of NTDs — about 20% to 30%.
It was widely expected that folic acid fortification would result in a lowering of homocysteine levels in the population, which it did. Because of the association of hyperhomocysteinemia with cardiovascular disease, some predicted that this would also result in a significant reduction in deaths from cardiac disease, but this has not been observed. However, some additional benefits appear to have been reaped. Most convincing has been an observed and significant reduction in fatal stroke in North America, coinciding with the implementation of folic acid fortification; that has not been the experience in the U.K., where fortification has not been introduced.
On the negative side of the balance sheet have been reports of an increased incidence of certain cancers, notably of the colon, following folic acid fortification in the USA and Canada. Another report from Norway found that co-administration of folic acid (0.8 mg) and vitamin B12 (0.4 mg) daily supplements for 7 years were associated with an overall increase of cancer mortality, due mainly to lung cancer. There is a plausible cause for concern regarding the safety of high folate as a possible risk factor for cancer, although this likely arises from nutritional supplements rather than through the food supply.
More recently, there have been studies pointing to a possible adverse effect of high folate levels in those with low B12 status. Although there has been no evidence of the classical masking of megaloblastosis in these individuals, there has been evidence of more marked interference in the metabolic pathways requiring B12, including higher homocysteine and methylmalonic levels when low B12 is associated with high folate. One study also reported lower hemoglobin values and more neurocognitive decline in the low B12 with high folate group.
Target groups
This brings us to the question of B12 fortification, which is now being contemplated at the CDC and elsewhere. Supporters of B12 fortification point to evidence that a subset of remaining NTDs may relate to B12 deficiency. Although this may be the case, there has been no demonstration of efficacy of B12 supplementation in either incidence or recurrence rates of NTDs, as was clearly the case with folate and NTDs that led to the folic acid fortification initiative.
A second target group is the elderly. In addition to autoimmune pernicious anemia, which has an estimated prevalence of 1% to 2% in the population older than age 65 years in the U.S., there is a larger segment of the growing elderly population with varying degrees of “subclinical B12 deficiency.” This somewhat nebulous entity associated with low normal B12 and raised homocysteine and methylmalonate has been attributed to food B12 malabsorption, caused by gastric atrophy and a variety of other conditions. It is uncertain whether any of these conditions progress to frank clinical B12 deficiency.
The problem with population-wide B12 fortification is that at the levels of B12 deemed practical, pernicious anemia sufferers and other malabsorbers of the soluble vitamin would not benefit, and it is questionable whether any useful purpose is served by providing B12 for the elderly with subclinical deficiency states. As for potential harmful effects, no safe upper limit for B12 is defined because there is little or no evidence of toxicity for the vitamin. However, new evidence is emerging that B12 can be degraded in the gastrointestinal tract with the generation of B12 analogues. The possibility that these analogues, if produced in sufficient amounts, could enter the body raises the concern that there could be interference with B12 metabolic pathways.
The bottom line is that the flimsy justification for B12 fortification, its dubious benefits and the possibility that it may have undesirable side effects all add up to a risk-benefit ratio that argues against further tinkering with the national food supply before gathering much more information.
Ralph Green, MD, PhD, FRCPath, is a professor in the departments of pathology and medicine at the University of California, Davis, and the associate editor of the red cell disorders section of HemOnc Today’s editorial board.
For more information:
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