Vitamin B12 Helps Build Blood and Bone

Vitamin B12—How Much Is Enough?
Elderly people with a B12 deficiency may need
more than 200 times the RDA to get enough
By Hyla Cass, M.D.

ouldn’t it be nice if scientists decided that we all ought to be eating 200 times as much chocolate as we do? Or if the government admitted that we’ve been paying 200 times as much in taxes as we should? (The refund would help pay for all that chocolate. And by the way, doesn’t a tax refund make you feel great? Until you realize that it was your money to begin with.) It’s not often that we’re told that something we’ve been doing is off by a factor of 200. It gets your attention, doesn’t it?

Of course, how easily you’ll be able to handle a 200-fold change in something will depend on what that something is: whereas 200 times a large number is a huge number, 200 times a tiny number is still a small number. This article is about a tiny number—2.4 mcg (micrograms) per day—which is the FDA’s Recommended Dietary Allowance (RDA) for vitamin B12. That’s by far the smallest amount for any vitamin, because B12 is by far the most biologically active of all the vitamins.

Vitamin B12 is unique in other ways too: it has the largest and most complex molecular structure of any vitamin, and it’s the only vitamin to contain a metal ion (cobalt—which is why cobalt is an essential trace element). It was the last vitamin to be discovered (in 1948), but the possibility of other vitamins yet to be discovered cannot be ruled out. (For more on this odd vitamin, including why it should always be taken together with folic acid, see the first sidebar.)

Vitamin B12 from What?

Believe it or not, the richest sources of vitamin B12 are sewage, manure, soil, and mud, which harbor anaerobic bacteria that contain abundant amounts of this vitamin. Fortunately, we can turn elsewhere (whew!) for our dietary B12. The best food sources (in descending order of B12 concentration) are steamed clams, liver, braised beef, steamed mussels, steamed crab, and 100% fortified breakfast cereals. Lesser but still significant amounts are found in a variety of fish, meat, poultry, eggs, and dairy products. (It’s worth noting that the cooking method can make a big difference: fried clams and broiled beef, for example, contain minimal B12 compared with the other versions mentioned.)

But what is this odd vitamin, exactly? Vitamin B12 is the name given to any of several closely related compounds derived from cobalamin, a very complex molecule with a cobalt ion, Co+, at its center (the name cobalamin comes from the words cobalt and vitamin). It is a dark red crystalline solid. There are six chemical groups attached to the cobalt ion, of which five are fixed and the sixth is variable; it’s the nature of the sixth group that distinguishes the various cobalamin derivatives and gives them their names.

The form of B12 used in almost all vitamin supplements is cyanocobalamin, so called because the sixth group is a cyano group, –CN (yes, it’s the same one found in cyanide compounds, but in vitamin B12 it’s not poisonous). Although cyanocobalamin is considered to be the definitive form of vitamin B12 (the terms are synonymous), it is not, paradoxically, the form that is biologically active in our bodies. There cyanocobalamin is readily converted to two other forms, methylcobalamin and 5’-deoxyadenosylcobalamin, which have different physiological functions: one helps keeps a molecular monster in check, and the other helps produce energy and build blood.

Methylcobalamin acts an enzyme cofactor in the chemical conversion of homocysteine to methionine, a vital process that’s carried out by the B-vitamin folic acid. Homocysteine is a natural amino acid found in our bodies and is essential for good health. As long as its levels remain within normal limits, it’s innocuous. As we age, however, there is a tendency for homocysteine levels to increase to dangerous levels, leading to a variety of bodily harm that would do a horror filmmaker proud.

Adequate amounts of dietary folic acid are vital to keep homocysteine levels in check—but so are adequate amounts of vitamin B12, because folic acid without B12 is impotent. The functions of these two B-vitamins are so closely tied, in fact, that they should always be taken together, because too much of one can mask a deficiency in the other.

5’-Deoxyadenosylcobalamin acts as an enzyme cofactor in the chemical conversion of methylmalonyl-coenzyme A to succinyl-coenzyme A. This reaction plays an important role in cellular energy metabolism, and succinyl-coenzyme A is also required for the synthesis of hemoglobin, the oxygen-carrying molecule in our red blood cells. A telltale sign of vitamin B12 deficiency is elevated levels of methylmalonic acid in the blood, indicating that succinyl-coenzyme A (and, therefore, hemoglobin) is not being produced in adequate amounts.

Good Diet May Not Prevent B12 Deficiency

Except among vegetarians, dietary deficiency of vitamin B12 is rare in American adults, because the RDA of 2.4 mcg/day is easy to obtain through foods of animal origin. That fact, however, obscures a much more important one: physiological B12 deficiency—inadequate B12 in the circulation—is easy to come by as we grow older, regardless of our diet. That’s because B12 from food can become increasingly difficult for the body to absorb—most of it is eliminated as waste. As far back as 1986, Linus Pauling recommended that all adults take 100–200 mcg/day of B12, along with what came to be called “megadoses” of most other vitamins.1

The common symptoms of vitamin B12 deficiency are anemia, neuropathy (any disorder of the nervous system), and neuropsychiatric disorders, including cognitive decline or dementia;* there may also be glossitis (inflammation of the tongue). Anemia is any condition in which there is a deficiency of hemoglobin or red blood cells; there are dozens of causes. Its characteristic symptoms are pallor of the skin and mucous membranes, shortness of breath, heart palpitations, lethargy, and fatigue.


*For more on how vitamin B12 and folic acid may help prevent dementia, see “Fight Alzheimer’s and Heart Disease with B-Vitamins” (December 2001), “Folic Acid to the Rescue!” (September 2002), and “Add Brain Assault to Homocysteine’s Rap Sheet” (February 2006).


Although there are numerous causes of physiological B12 deficiency (including celiac disease, Crohn’s disease, tropical sprue, pancreatic insufficiency, alcoholism, AIDS, and chronic use of antacids), two conditions stand out as the most important: pernicious anemia and food-bound vitamin B12 malabsorption.2

Pernicious anemia

Low levels of vitamin B12 are associated with pernicious anemia, a formerly fatal disease that is now treated with the vitamin. Thus it might appear that a dietary deficiency of B12 causes pernicious anemia—but diet has nothing to do with it. Pernicious anemia is a chronic, progressive, autoimmune disease that arises spontaneously in older adults. It causes a physiological B12 deficiency even if dietary intake is adequate by normal standards. This condition—the B12 deficiency and the anemia it causes—represents the end stage of the disease. The deficiency and anemia can take years to develop, because B12 is stored in the liver, and the average healthy adult liver holds enough of it to last for up to five years.*


*Pernicious anemia acquired its sinister name before the advent of vitamin B12 therapy. Now that it’s treatable in this way, the anemia is no longer considered “pernicious,” but the name has stuck. That may be appropriate, however, because of another, decidedly pernicious, factor: the underlying autoimmune disease causes neurological damage leading to mental illness, which often appears years before the symptoms of anemia do. Also, pernicious anemia is associated with a higher risk for bone fracture (see the sidebar below).


Folic Acid and Vitamin B12 Help Prevent Hip Fractures

In last month’s issue of Life Enhancement, we saw that vitamin K, the coagulation vitamin, is associated with increased bone mineral density and a markedly reduced incidence of bone fractures, both vertebral and nonvertebral, in postmenopausal women. (See “Vitamin K Helps Prevent Bone Fractures,” October 2006.) Thus, vitamin K evidently goes beyond mere blood clotting—it’s more versatile than had been thought.

More versatile too are folic acid (aka folate) and vitamin B12, the dynamic duo whose important roles in a variety of health arenas—especially vascular and neurological—are already well known. We have now learned that these two B-vitamins can also help protect bones—at least the hip bones of elderly stroke patients.

Stroke greatly increases the risk of hip fracture because of the tendency of hemiplegic patients (those with paralysis of one side of the body) to fall down and to develop osteoporosis through inactivity. Even after accounting for these and other factors, however, there is an increased risk for hip fracture, and scientists believe that it may be due to an elevated blood level of the amino acid homocysteine, which is characteristic of stroke patients.

Because folate, with vitamin B12 as an essential cofactor, is the premier homocysteine fighter, a team of Japanese researchers investigated the possible role of these vitamins in preventing hip fractures in poststroke hemiplegic patients.1 They recruited 628 patients aged 65 or older (both sexes) and gave them 5 mg of folate and 1500 mcg (1.5 mg) of B12 (in the form of methylcobalamin), or a double placebo, daily for 2 years. At baseline, all the patients had elevated homocysteine levels and reduced levels of folate and B12.

During the 2-year period, homocysteine levels declined by 38% in the treatment group while increasing by 31% in the placebo group. Interestingly, bone mineral density (BMD) declined in both groups by the same amount (3%), suggesting that BMD is not affected by homocysteine levels. The two groups did not differ significantly in the number of falls per patient, but there was a major difference in the number of hip fractures: 6 in the treatment group vs. 27 in the placebo group. For all fractures (hip and other), these figures were 8 and 32, respectively. Because BMD had not changed between the groups, these results suggest that the differences were due to bone quality, not bone quantity.

Thus it appears that folate and vitamin B12 dramatically reduced the risk for fracture in these patients, perhaps by improving bone quality. The study had significant limitations, however, and whether or not the observed effect is related to homocysteine levels is still open to question.2 It could be the independent result of increased vitamin B12 levels, which are known to be linked to bone health; for example, patients with B12 deficiency, as in pernicious anemia, have a higher risk for bone fractures.

References

  1. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke. JAMA 2005; 293:1082-8.
  2. van Meurs JBJ, Uitterlinden AG. Homocysteine and fracture prevention. JAMA 2005;293:1121-2.

In pernicious anemia, the patient’s own antibodies gradually destroy glands in the stomach lining that produce the acid and digestive enzymes required for releasing B12 from the proteins to which the vitamin is chemically bound in our food. And unless the B12 is freed from such “bondage,” it’s useless. The destruction of these glands also leads to decreased secretion of a protein called intrinsic factor, which is required for the next step in the process: absorption of the B12 by facilitating its active transport through the walls of the gut. If the vitamin cannot be absorbed, it will remain in the gastrointestinal (GI) tract and be eliminated as waste.

As the degenerative processes of pernicious anemia unfold in our GI tract, absorption of vitamin B12 declines—and so, therefore, does our production of hemoglobin (see the first sidebar). The result is anemia. Because the vitamin is so poorly absorbed, therapy with an oral B12 supplement must entail very large dosages in order for adequate amounts to get through to the circulation (the maximum absorbable amount in the presence of intrinsic factor is about 3 mcg per meal).

Even in the absence of intrinsic factor, about 1% of a given amount of oral B12 is absorbed by passive diffusion (as opposed to active transport) through the gut, so it would take 100 times the normal amount of B12 to get this amount through that way. (To bypass the GI tract, the vitamin can also be given by intramuscular injection, and it can be taken transmucosally in the form of liposomes.)

Food-bound vitamin B12 malabsorption

Here the disorder is different, but the result is similar. Food-bound vitamin B12 malabsorption is thought to result mainly from atrophic gastritis, a chronic inflammation of the stomach lining that leads to the gradual loss (atrophy) of glands that produce digestive acid and enzymes. (Gastritis is strongly associated with infection by Helicobacter pylori, the bacterium that also causes peptic ulcers and stomach cancer.)

In this disorder, however, production of intrinsic factor is not impaired, so free (non-food-bound) vitamin B12, if it were present, could be absorbed. This is a key fact, because one can easily obtain free B12 in the form of supplements. Thus, people with food-bound vitamin B12 malabsorption don’t need increased amounts of B12—they just need their B12 in the form of a supplement rather than from food.2

How Much B12 Do We Need?

An important question is how much oral B12 should be prescribed for patients with a confirmed deficiency of this vitamin. A research group from the Netherlands, England, and Norway has addressed this question by seeking to determine the lowest dose of B12 required to normalize certain biological markers for B12 deficiency.3 The primary marker they chose was methylmalonic acid (MMA), whose blood levels increase when B12 levels decrease (see the first sidebar). The specific objective was to determine the lowest dose of B12 that would produce 80–90% of the estimated maximal reduction in MMA levels, which would indicate a satisfactory return to healthy B12 levels.

The researchers recruited 120 healthy, elderly Dutch adults (average age 80) who had mild B12 deficiency, as evidenced by B12 levels within a certain below-normal range and MMA levels above a certain value. Over a 16-week period, the volunteers were given vitamin B12 (cyanocobalamin) in a range of doses: 2.5, 100, 250, 500, and 1000 mcg daily. The 2.5-mcg dose represented the Dutch RDA, and the 1000-mcg (1-mg) dose represented the amount used for intramuscular injections (typically monthly) for B12-deficient patients. No adverse events were reported with any dosage.

A Lot!

The patients’ blood was tested at the outset and again at 8 weeks and 16 weeks; the results seen during the first 8 weeks remained stable for the next 8 weeks. The principal result was that the 500-mcg dose was the lowest dose required for the purpose described above; there was little additional benefit in using more than that. The authors summarized their work as follows:3

The results of this trial indicate that the lowest dose of oral cyanocobalamin required to normalize biochemical markers of mild vitamin B12 deficiency in older people with a mild vitamin B12 deficiency is more than 200 times greater than the recommended dietary allowance for vitamin B12 of approximately 3 mcg/day. Clinical trials are currently assessing the effects of high doses of oral cobalamin on markers of cognitive function and depression. If such trials can demonstrate that the reported associations of vitamin B12 deficiency with cognitive impairment or depression are causal and reversible by treatment, the relevance of correction of vitamin B12 deficiency in older people could be substantial. However, the present trial demonstrates that much higher doses of cyanocobalamin are required to normalize vitamin B12 deficiency than were previously believed.

Think Big

As far as scientists know, the FDA’s RDA value of 2.4 mcg/day for vitamin B12 is appropriate—assuming your digestive tract is in perfect working order. But what if it’s not? You are getting older, aren’t you? The problem is that there may be a yawning gulf between ingesting 2.4 mcg and actually getting 2.4 mcg into your circulation, where it’s needed.

Thus, the older you get, the more likely it is that you will need to take far more B12 than the RDA to obtain this vitamin’s benefits. If you actually have a B12 deficiency (only a lab test can tell for sure), you may need to ingest at least 200 times the RDA: about 500 mcg or more. That’s 0.5 mg—still a very small amount, but getting up there. Now, about the RDA for chocolate . . .

References

  1. Pauling L. How to Live Longer and Feel Better. W. H. Freeman, New York, 1986.
  2. Higdon J. Vitamin B12. Linus Pauling Institute, Corvallis, OR, 2003.
  3. Eussen SJPM, de Groot LCPGM, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, van Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med 2005;165:1167-72.


Dr. Hyla Cass is a nationally recognized expert in integrative medicine, an assistant clinical professor of psychiatry at the UCLA School of Medicine, and the author or coauthor of several popular books, including Natural Highs: Supplements, Nutrition, and Mind-Body Techniques to Help You Feel Good All the Time and 8 Weeks to Vibrant Health: A Woman’s Take-Charge Program to Correct Imbalances, Reclaim Energy, and Restore Well-Being.

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