14.7: Folate

Late in the 1920s, a puzzling epidemic occurred in Bombay, India that resulted in the death of many young women. The disease matched nothing in the textbooks. It had its own striking pattern, tragically occurring in pregnancy. It was an anemia, reminiscent of the pernicious anemia caused by vitamin B₁₂ deficiency, yet different. It was described as “pregnancy anemia.”

Anemia represents a less-than-normal number of red blood cells, or a less-than-normal amount of hemoglobin in the red blood cells (hemoglobin is the red, iron-containing protein that carries oxygen). The common result is a reduced capacity of the blood to carry oxygen.

Anemia is often a sign of a nutritional deficiency, so it’s important to know that there are different kinds of anemia, differing in cause and character. Otherwise, one can easily draw false conclusions from simple tests for anemia.

It’s true that iron deficiency is the most common cause of anemia in this country, but it’s not the only cause. Even when a test shows too little iron-containing hemoglobin, it doesn’t necessarily indicate a deficiency of iron. Instead, there can be defects which keep the iron from being used, defects of the cells which make the hemoglobin protein, or deficiencies of other nutrients needed in the making of red blood cells or hemoglobin.

Figure 14-4: Folate deficiency results in anemia. Developing red blood cells can’t divide, leaving large immature cells (megaloblasts) and enlarged red blood cells (macrocytes).

The young women in India with pregnancy anemia weren’t well fed (their diets were mainly based on polished rice and bread), but their diets weren’t deficient in any of the nutrients then linked to anemia. With no other treatment at hand, and aware that extracts of the “vitamin B complex” held substances that were still mysterious, the sick women were given extracts of yeast and liver. Dramatically, they began to get well.

To test for whether a vitamin was involved, monkeys were fed similar diets. They developed similar anemias, and were cured by yeast extracts. But a decade passed before researchers understood what was happening in even a general way.

Finally in 1941, researchers succeeded in making an impure extract of the missing vitamin from spinach leaves—giving it its first name, folic acid (from the Latin folium, meaning leaf). Its identity and structure were determined in 1946.

Folate Chemistry

Folate is found in many different forms. Folic acid is one form that’s rarely found in food; it’s chemically manufactured and used in vitamin pills and to fortify foods because it’s so stable and easily absorbed. The vitamin value of various forms of folate are standardized as dietary folate equivalents.

The most dramatic functions of folate didn’t become clear until the chemistry of heredity began to be understood. Folate is a part of coenzymes essential to the making of nucleic acids. We saw in Chapter 7 that the blueprint of life is found in the nucleic acids of DNA, and that protein synthesis is dependent on the nucleic acids of RNA.

Understanding that the folate coenzymes are necessary in this most fundamental body chemistry helps us to see why folate has a role to play in virtually every living cell.

The connection between folate and growth also becomes obvious. Cells can’t reproduce and grow normally when their ability to make DNA and RNA is impaired. This leads to an understanding of why folate deficiency results in an anemia in which blood cells can’t reproduce themselves properly.

Moreover, it isn’t only through DNA and RNA that folate is important. The body needs folate coenzymes to make and use a number of amino acids.

As with some other B-vitamins, alcohol both hinders absorption of folate from the intestine and interferes with its use in metabolism. Again, as is true with some other B-vitamins, normal folate function can be upset by various drugs.

The drug—methotrexate—is a powerful drug used against the rapid cell division of cancer, precisely because it’s so effective in interfering with folate’s function in cell division. Methotrexate is a kind of chemical gamble. The cancer cells grow rapidly, in a disordered way. The gamble is that depriving the body of folate activity will kill the rapidly dividing cancer cells before it kills too many of the slower dividing normal cells.

After as many cancer cells as possible have been injured or killed, “rescue” doses of folate are given, hoping to save as many of the normal cells as possible. The heroic nature of this therapy is eloquent testimony to the urgency of folate needs.

Folate Intake

Folate is a difficult chemical to assay—it’s hard to measure. This isn’t only because of the various forms of folate itself, but because folate is usually bound to other substances that can affect both its chemical assay and its absorption from the intestine. This makes folate requirements and the folate content of food hard to measure.

Figure 14-5: Folate requirements go up when pregnant or nursing.

As a rule of thumb, and as a matter of good sense, the less science is able to determine vitamin needs accurately, the more generous are the safety margins of the recommended intake. For folate, the margins are kept wide. But folate deficiency has been fairly common during pregnancy for women who have poor diets.

Pregnancy increases a woman’s folate RDA, as does lactation (breastfeeding) (see Fig. 14-5). It’s easy to see why pregnancy makes special demands for folate. A pregnant woman is supporting spectacular cell division, and a blood supply for two. The resulting increase of need is striking.

This brings us back to the 1920s mystery of the deadly “pregnancy anemia” among the young women of Bombay. Their diet of mainly polished rice and bread was markedly deficient in folate. Already deficient, the increased demands of pregnancy produced the fatal anemia.

A folate deficiency in the first month of pregnancy—before a woman may know she’s pregnant—increases the risk of neural tube defects in the fetus. (The neural tube is an embryonic structure that develops into the brain and spinal cord). In 1998, folate was included in the group of nutrients (iron, thiamin, riboflavin, niacin) added by law since 1943 to enrich staple grains like white flour. Folate deficiency and related birth defects are now less common in the U.S.

Because folate is usually bound to other substances in food, the amount absorbed can be uncertain. Adequate folate is so important in early pregnancy that women of childbearing age are advised to get their RDA of 400 µg of folate in synthetic form (folic acid), as in fortified foods (such as fortified breakfast cereals) and vitamin pills. Many breakfast cereals are fortified with 100% DV of folate (400 µg), as are one-a-day type of multivitamins. Here, the recommendation is for the “synthetic” over the “natural” (as in food) form of folate.