Intended for healthcare professionals

Rapid response to:


Folic acid fortification remains an urgent health priority

BMJ 2004; 329 doi: (Published 09 December 2004) Cite this as: BMJ 2004;329:1376

Rapid Response:

Folic acid does not cause pernicious anemia

Dr. Kapil importantly notes the effectiveness of folic acid fortification of grains to improve public health. It is unfortunate that nutrition guidelines include a "tolerable upper intake level" of 1000 micrograms a day of synthetic folic acid. The tolerable upper level is not needed and often leads to inferences that are simply wrong--not based on the actual data.

Dr. Kapil's letter says that folic acid causes pernicious anemia. This is, of course, simply wrong. Unfortunatley this mistaken inference often raises its head in discussions of mandatory folic acid fortification of flour. Pernicious anemia is caused by the absence of intrinsic factor that leads to impaired absorption of vitamin B12. This impaired absorption can lead to very low serum levels and tissue levels of vitamin B12. It is this severe depletion of vitamin B12 that causes clinically symptomatic pernicious anemia. Since pernicious anemia can be and usually is a progressive disease, if a patient is not treated with sufficient vitamin B12, the patient will become get sicker. If a patient is not treated with vitamin B12 and is treated with folic acid, penicillin or other drugs that are not vitamin B12, the patient will become sicker. The patient not treated with vitamin B12 becomes sicker because severe vitamin B12 deficiency is toxic, not because they take other medicine, including folic acid. Unfortunately, studies conducted in the early 1950s continue to be misunderstood.

At a time when patients with pernicious anemia were treated successfully with injectable liver extract, about 500 patients in 3 studies were deliberately removed from effective threapy (injections of liver extract) and placed on an inappropriate and ineffective therapy for pernicious anemia--folic acid in very high doses--up to 50,000 micrograms a day. Although not known at the time that folic acid would be ineffective therapy, we now know that folic acid is ineffective therapy for vitamin B12 deficiency caused by pernicious anemia. The findings from these 500 patients were that about 25% remained well, about 25% had the onset of anemia, about 25% had the onset of anemia and neuropathy and about 25% had the onset of only neuropathy. Perhaps the 25% who remained well had folate deficiency responsible for the orignial symptoms and signs that led to an inappropriate diagnosis of pernicious anemia. Those who developed anemia and or neuropathy had the usual clinical presentations of clinical disease from pernicious anemia that is undiagnosed and untreated with vitamin B12. Given what we know about pernicious anemia, the most reasonable interpretation of the data in these old studies is that folic acid is not an effective therapy for pernicious anemia, that untreated, clinically symptomatic pernicious anemia requires vitamin B12 therapy and the disease will progress if not treated and will reappear if effective therapy with vitamin B12 is discontinued. An additional inference is that folic acid in very substantial doses--50,000 micrograms a day for weeks, is safe, as these patients did not develop disease other than that that could be reasonable attributed to severe vitamin B12 deficiency that would occur if one removed effective vitamin B12 therapy from patients diagnosed with the anemia and or neuropathy of pernicious anemia.

It is time to remove from nutritional guidelines any tolerable upper intake level for folic acid. The existing science does not provide a rational base for the need for a tolerable upper intake level. As long as this misunderstanding provided the fodder to warn medical students and physicians that it is important to determine whether a patient with a macrocytic anemia was caused by folate deficiency and or B12 deficiency and then treat with the appropriate drugs, there was perhaps no pressing reason to correct the mistaken inferences handed down in textbooks for generations. Times have changed. We know know that folate deficiency is widespread, is present in all countries and causes, in addition to folate deficiency anemia, also spina bifida and anencephaly. Folate deficiency is the main reason for increases in homocysteine concentrations and is likely the cause of substantial mortality and morbidity from cardiovascular disease in every country. The evidence linking folate deficiency to causing mutation and cancer has grown in the last few years. When mandatory folic acid fortification is discussed, those opposed to it erroneously put in the discussion that folic acid is harmful to people with vitamin B12 deficiency, for which the data simply does not exist to support this contention. Unfortunately such arguments have either limited the amout of folic acid that was added to flour--the United States and Canada--or have been the major reason fortification has not been required- -the United Kingdom, Europe, New Zealand, and Australia. We now know that limiting the folic acid concentration is responsible for children being born unnecessarily with severe birth defects and that having no fortification is responsible for children also being born unnecessarily with severe birth defects and for adults to unnecessarily have folate deficiency anemia and unnecessarily high homocyteines causes about as many unnecessary deaths a year as occur from vehicular crashes.

It is time to let the idea of masking and that folic acid causes pernicious anemia to be discarded so that we can speed up the rate at which we implement the mandatory folic acid fortification programs that will rid the world of folate deficiency diseases.

Competing interests: Please see commentary

Competing interests: No competing interests

13 December 2004
Godfrey P. Oakley, Jr.
Research Professor of Epidemiology, Rollins School of Public Health of Emory University
1558 Clifton Road NE Altanta GA 30345