are you getting enough B12?

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http://www.veganhealth.org/b12/all

Vitamin B12: Are You Getting It?

by Jack Norris, RD

Introduction

For the last few months, I was feeling sluggish, had to lie down a couple of times a day, found it difficult to work evenings and to exercise for long periods. Under Klaper, MD's guidance, I was taking protein powder, creatine, testosterone, nystatin, etc., all to no avail. I was taking nutritional yeast every day, so I knew it wasn't B12 deficiency. Then, one day, I came across your B12 article [Vitamin B12: Are you Getting It?] by sheer accident. I wasn't going to read the whole thing, but I glanced through it and was struck by your insistence that none of the usual sources are adequate. I still didn't believe it, but I had some old B12 pills in the fridge, so I popped one. The effect was almost immediate and remarkable. I have been taking them almost every day, my stamina and energy level are up, and I feel middle-aged again instead of a tired old man.- Hershaft, PhD, President of FARM

Note: The links in this article are for the reader's convenience only. If you read the article from start to finish, all topics will be covered and there is no need to click on any links except those at the end of each page taking you to the next section.

Does Vitamin B12 Matter?

There are two types of B12 deficiency: mild and overt.

Overt B12 Deficiency:

B12 protects the nervous system. Without it, permanent damage can result (e.g., blindness, deafness, dementia). Fatigue, and tingling in the hands or feet, can be early signs of deficiency. B12 also keeps the digestive system healthy.

Mild B12 Deficiency:

By lowering homocysteine levels, B12 also reduces the risk of heart disease, stroke, and other diseases. Vegans and near-vegans who do not supplement with vitamin B12 have consistently shown elevated homocysteine levels. See the section Homocysteine, B12, Vegetarians, and Disease.

B12 is generally found in all animal foods (except honey). The overwhelming consensus in the mainstream nutrition community, as well as among vegan health professionals, is that plant foods do not provide vitamin B12. (Luckily, vitamin B12 is made by bacterial fermentation such that it does not need to be obtained from animal products.) Despite this, some vegan advocates still believe that "plant foods provide all the nutrients necessary for optimal health" and, therefore, do not address vitamin B12 when promoting the vegan diet. Other vegan advocates acknowledge the need for B12, but only as an afterthought.

The result is that many vegans do not eat B12 fortified foods or supplements. Many have developed overt B12 deficiency. In some cases, the symptoms have cleared up after taking B12 supplements, but not everyone has been so lucky.

Got Health?

While many current vegans report feeling better on a vegan diet, the most common complaint I hear from ex-vegans is that they didn't feel healthy. This seems reasonable: The people who feel good on the diet stick with it. The people who feel bad, don't. Could it be that some of the people who go back to eating animal products are feeling the effects of a reduced B12 status? Many vegans would not consider this a possibility, because humans need very little B12 and new vegans usually have a healthy store which can last months or years.

The fact that vegans tend to have lower B12 levels than lacto-ovo vegetarians or non-vegetarians is often countered with, "Few vegans have ever shown signs of B12 deficiency." However, most vegans appear to supplement their diet with B12 (often unknowingly through fortified foods), which could explain why most vegans never show overt B12 deficiency.

As for vegans whose diets are not supplemented, I disagree that they rarely show signs of B12 deficiency. As the reader will soon see, there have certainly been plenty of vegans who have suffered from B12 deficiency in the scientific literature. I meet vegans on a regular basis who report having been diagnosed with B12 deficiency or who came down with symptoms of B12 deficiency. It is time that there were no more. Vegans can ensure optimal B12 status, reducing their risk for many diseases, by following the recommendations.

This article is a thorough review of the scientific literature about vitamin B12 and the vegan diet, including every relevant study on vegans and vitamin B12 published since 1980. Vegan advocates who may otherwise not be interested in the details of vitamin B12 are encouraged to read the Recommendations and Can a Natural Diet Require Supplements?

B12-Related Laboratory Values

This article often refers to various laboratory values related to B12. A reference can be found in Appendix: B12-Related Laboratory Values.

Vitamin B12: A Pesky Molecule

B12 is a complicated vitamin with a unique absorption mechanism, wide array of deficiency symptoms, and a number of inactive analogues (molecules that appear to be active B12, but actually are not) that possibly interfere with its function.

Myth about How Often Someone Needs B12

Some vegan advocates have emphasized that humans need only small amounts of B12 and that it can be stored in the body for years. It is true that, at the time they become vegan, some people have enough B12 stored in their livers to prevent overt B12 deficiency for a number of years. But, these stores cannot prevent mild B12 deficiency (elevated homocysteine levels).

Additionally, to build up such stores, it takes many years of consuming B12 beyond one's daily needs without using supplements. Many people have not consumed B12 beyond their daily needs for many years and so cannot rely on B12 stores to prevent overt deficiency for a few years.

The body is constantly losing small amounts of B12 and the length of time that any given molecule of B12 will stay in the body will vary based on a number of variables. So, your body might store it for a long period of time, or it might not store it at all.

Of course, this is an easy problem to solve by simply eating B12-fortified foods or taking a supplement.

Small Amounts of Animal Products Do Not Cure B12 Deficiency

There is evidence that B12 function cannot be restored to optimal levels by adding small amounts of animal products into the diet:

van Dusseldorp et al.1 (1999, Netherlands) investigated whether moderate consumption of animal products is sufficient for achieving normal B12 function in 73 adolescents who had been strict macrobiotics (MAC) until 6 years old and then switched to a lacto-ovo-vegetarian (LOV) or non-vegetarian (NV) diet. 94 people who had never been macrobiotics or vegetarian were controls. Dairy supplied an average of ~ 1 µg B12/day for the MACs. They also ate fish, red meat, or chicken 2-3 times/week.

van Dusseldorp et al.1 (1999, Netherlands)

#

serum B12(pg/ml)

sMMA Range(µmol/l)

sMMA > .41 µmol/l

HCY > 12.8 µmol/l

MAC

Boys

37

288A

..29 (.09-.93)C

24%

8%

Girls

36

389B

..25 (.09-.70)D

17%

11%

Controls

Boys

39

653A

..15 (.06-.43)C

5%

5%

Girls

55

618B

..17 (.07-.40)D

A,B,C,D - Statistically significant difference between groups with same letters

Thus, moderate animal product consumption was not enough to restore normal B12 status for 21% of these children (based on MMA levels).

Notes for Small Amounts of Animal Products

1. van Dusseldorp M, Schneede J, Refsum H, Ueland PM, CM, de Boer E, van Staveren WA. Risk of persistent cobalamin deficiency in adolescents fed a macrobiotic diet in early life. J Clin Nutr. 1999 Apr;69(4):664-71.

Recommendations for Vegans and Near-Vegans

Step 1

If you have not had a regular source of B12 for some time, buy a bottle of 1,000 µg (or greater) B12 tablets. The following (and many others) are vegan:

Pangea VeganLife B12 Chewable Supplement 1,000 mcg tablets Freeda Vitamins 500 mcg lozenges

Place 2,000 µg under your tongue until the tablet(s) has dissolved, once a day, for 2 weeks. You can break the remaining tablets in half or quarters for Step #2. It's okay to take more than recommended. Then follow the advice under Step #2.

Step 2

If you have had a regular source of B12, skip Step 1. One of the following daily recommendations should maximize your B12 status:

1.5 - 2.5 µg, twice a day, from fortified foods or supplements1 10 - 100 µg, once a day, from a supplement1,2

Notes

In foods, B12 is measured in micrograms (aka "µg" or "mcg"). 1,000 µg = 1 mg. The DRI for vitamin B12 is 2.4 micrograms for adults. Fortified foods: Amounts listed on a nutrition label are based on 6 µg/day. For example, 25% of the Daily Value = .25 * 6 µg = 1.5 µg. Do not rely on any seaweed (e.g., algae, nori, spirulina), brewer's yeast, tempeh, or "living" vitamin supplement that uses plants as a source of B12. Do not rely solely on one type of fortified food such as Red Star Nutritional Yeast. Vegan infants: The Institute of Medicine recommends that infants of vegan mothers be supplemented with B12 from birth because their stores at birth and their mother's milk supply may be low.3 Exceptions: People with digestive or malabsorption diseases (such as pernicious anemia), chronic kidney failure, B12 metabolism defects, or cyanide metabolism defects should consult a bona fide health professional. Cigarette smokers should consider a non-cyanocobalamin source of B12. Click here for more information.

Click here for an explanation of how these recommendations were formulated.

Footnotes for Recommendations for Vegans and Near-Vegans

1. Lower limit based on minimum recommendations in What Every Vegan Should Know about Vitamin B12.2. In a single dose, B12 absorption drops to 1-1.5% for the amounts above 5 µg.3. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

Sources of B12 for Vegans

Fortified Foods

There are many vegan foods fortified with B12. They include non-dairy milks, meat substitutes, breakfast cereals, and one type of nutritional yeast.

The "Daily Value" for B12 found on food labels is based on 6 µg, which was the RDA in 1968. If a label says a food has, for example, 25% of the Daily Value of B12, it has 1.5 µg (25% of 6 µg = 1.5 µg).

Brewer's and Nutritional Yeasts

Brewer's and nutritional yeasts do not contain B12 unless they are fortified with it. At least two vegan B12-fortified yeasts are currently on the market: Red Star Vegetarian Support Formula and Twinlab Natural Nutritional Yeast (verified to be fortified with B12 via personal communication with Twinlab June 3, 2003). Unfortunately, there are some drawbacks to relying solely on B12-fortified nutritional yeast for B12:

Nutritional yeast often comes from bins in health food stores. If not careful, it would be easy for a store employee to order the wrong nutritional yeast out of the distributor catalogs which often list many yeasts. It would also be easy to accidentally put the wrong yeast into the Vegetarian Support Formula bin. B12 is light sensitive. Nutritional yeast is likely to be exposed to the light because it is often stored in clear bins or plastic bags. At least one vegan who thought he was getting B12 from nutritional yeast developed B12 deficiency symptoms that cleared up upon taking a B12 supplement.

If you are trying to use Red Star Vegetarian Support Formula for B12, make sure you are actually getting what you think. It is also best to keep it in the refrigerator or freezer, out of the light.

Please note: Red Star Vegetarian Support Formula nutritional yeast has many other nutrients and I eat it myself; but vegans shouldn't rely on it for their sole source of B12, in my opinion.

Cooking Foods

Cooking may destroy the B12 found naturally in animal foods. Cyanocobalamin, the form in fortified foods, may be more stable during cooking. For example, in an acid medium (pH 4-7), cyanocobalamin can withstand boiling at 120° C.1

Multivitamins

There are some concerns about vegans relying solely on multivitamins that contain only small amounts of B12 (less than about 10 µg):

Herbert et al.2 (1982, USA) reported that vitamins B1, B3, C, and E, and copper and iron can damage B12. They tested 15 multivitamin preparations used daily by approximately 100 million Americans for inactive B12 analogues and all preparations contained some (6-27% of total corrinoids). Vitamin C in doses of 500 mg or more taken with meals or within one hour after a meal, may diminish B12 availability or destroy the B12.3 Many multivitamins cannot be chewed, which is important for B12 absorption in some people.

That said, if a multivitamin is chewable and has 10 µg of B12 (as cyanocobalamin) or more, and taken daily, it is most likely adequate.

Supplements

Safety

In 1988, Herbert cautioned that large amounts of B12 may eventually be found to be harmful.4 In contrast, Hathcock & Troendle5 (1991) point out that there appears to be little or no question that B12 intakes of 500-1000 µg/day are safe. The Institute of Medicine has not set an Upper Tolerable Limit for a daily vitamin B12 intake.

The cobalt and the cyanide contribution of 1000 µg/day of cyanocobalamin are considered toxicologically insignificant.5 People with chronic kidney failure, cyanide metabolism defects, and probably smokers should take a different form of B12.

Chew or Dissolve Supplements Under the Tongue

Crane et al.6 (1994, USA) noted that tablets of one vitamin company dissolved slowly in water and acid. They then conducted a study to see if vegan patients who had not responded to oral B12 (described below) tablets swallowed whole could improve their B12 response by chewing the tablets. 7 people chewed the tablets of 100 µg (once a week for 6 weeks) and their average serum B12 levels went from 116 to 291. Of the 9 who didn't chew, theirs increased from 123 to only 139. (However, a 100 µg dose once a week is not a lot of B12. The more surprising result of this experiment was the large increase in the serum B12 of the 7 people who chewed the tablets, not the small increase of those who did not chew.)

7 of these 9 then chewed 500 µg/day for 10 days and their levels rose to normal with a final average of 524 ± 235. Three participants could not raise their levels orally and required B12 injections to maintain serum B12 above 300.

Oral B12 for People with Malabsorption

Some recent studies have shown that taking large amounts of sublingual B12 can normalize B12 status even in people with pernicious anemia. For more information, see Oral B12 for People with Malabsorption in Appendix: How Recommendations were Formulated.

Light

B12 supplements should not be left in the light as prolonged light damages cyanocobalamin.7,8

Origin of B12 in Supplements and Fortified Foods

Streptomyces griseus, a bacterium once thought to be a yeast, was the commercial source of vitamin B12 for many years.8,9 The bacteria Propionibacterium shermanii and Pseudomonas denitrificans have now replaced S. griseus.10 At least one company, Rhone Poulenc Biochimie of France, is using a genetically engineered microorganism to produce B12.11

Non-cyanocobalamin Supplements

In addition to cyanocobalamin, there are oral supplements available for methylcobalamin, adenosylcobalamin (known in the supplement industry as dibencozide and coenzyme B12), and to a lesser extent, hydroxocobalamin. See Appendix: Non-cyanocobalamin B12 Supplements. As mentioned above, these forms of B12 may be preferable for vegan smokers.

S-adenosylmethionine (aka SAM and SAMe) is another supplement that has received attention. It is found in the homocysteine-methionine pathway, and some people think it may be relevant to B12 status in people who have been B12 deficient. More information is in Appendix: SAMe.

Notes for Sources of B12 for Vegans

1. Personal communication, March 6-7, 2002 with Dr. Fumio Watanabe, Kochi Women's University, Department of Health Science, 5-15 Eikokuji-cho Kochi 780-8515 Japan.

2. Herbert V, Drivas G, Foscaldi R, Manusselis C, Colman N, Kanazawa S, Das K, Gelernt M, Herzlich B, Jennings J. Multivitamin/mineral food supplements containing vitamin B12 may also contain analogues of vitamin B12. N Engl J Med. 1982(July);307(4):255-6.

3. Groff J, Gropper S. Advanced Nutrition and Human Metabolism, 3rd ed. Wadsworth: 2000.

4. Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr. 1988;48:852-8.

5. Hathcock JN, Troendle GJ. Oral cobalamin for treatment of pernicious anemia? JAMA. 1991 Jan 2;265(1):96-7.

6. Crane MG, Sample C, Pathcett S, Register UD. "Vitamin B12 studies in total vegetarians (vegans). Journal of Nutritional Medicine. 1994;4:419-430.

7. Schneider Z, Stroinski A. Comprehensive B12. New York: Walter de Gruyter, 1987.

8. Linnell JC, s DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.

9. Vitamin B12. Code of Federal Regulations. U.S. Government Printing Office. Title 21, Volume 3. Revised. April 1, 2001. CITE: 21CFR184.1945 p. 550.

10. De Baets S, Vandedrinck S, Vandamme EJ. Vitamins and Related Biofactors, Microbial Production. In: Lederberg J, ed. Encyclopedia of Microbiology, Vol 4, 2nd Ed. New York: Academic Press; 2000:837-853.

11. Correspondence between Rhone Poulenc Biochimie and Red Star Yeast. May 1, 1997.

Special Concerns for Those Over 50

The Food and Nutrition Board says, "Since 10 - 30% of older people may malabsorb food-bound B12, it is advisable for those older than 50 to meet their RDA mainly by consuming foods fortified with B12 or a B12-containing supplement." This could be due to decreased digestive enzyme production and/or decreased stomach acid.1 Decreased stomach acid reduces enzyme action on protein-bound B12 and/or allows bacterial overgrowth in the stomach and small intestine. Some types of bacteria use B12 for themselves.2 Approximately 2% of older adults do not produce enough intrinsic factor to prevent pernicious anemia.1 In order to know whether someone suffers from such a problem, people should have their B12 status tested every 5 years starting after age 50. Because older adults (vegan or not) may not produce much intrinsic factor or

gastric acid, chewable tablets and sublingual supplements may be the best way for them to obtain B12. People over 50 years should consider occasionally taking a sublingual B12 supplement of 500-1,000 µg.

Notes for Special Concerns for Those Over 55

1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

2. Selhub J, Bagley LC, J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

Symptoms of Overt B12 Deficiency

Ways to Get B12 Deficiency

The two main ways people get vitamin B12 deficiency are inadequate dietary intake and inadequate absorption from loss of intrinsic factor or lack of stomach acid. Other, much less common ways are listed in Appendix: Ways to Get B12 Deficiency.

Elevated Homocysteine: No Symptoms

Please note that the symptoms listed below are found in overt vitamin B12 deficiency. You can be B12 deficient, increasing your risk of disease because of elevated homocysteine without suffering any noticeable symptoms.

Early, Noticeable Symptoms of Overt B12 Deficiency:1

unusual fatigue faulty digestion no appetite nausea loss of menstruation

Other symptoms of Overt B12 Deficiency:

numbness and tingling of the hands and feet1 nervousness1 diarrhea2 mild depression1 striking behavioral changes1 paranoia1 hyperactive reflexes1 fever3 frequent upper respiratory infections4 impotence5 impaired memory5 infertility6 sore tongue2 enlargement of the mucous membranes of the mouth, vagina, and stomach117 macrocytic anemia low platelet count3,7 and increased bleeding3 neutropenia3

Neurological Symptoms

Neurological symptoms, often referred to as subacute combined degeneration (SCD), are the biggest concern regarding B12 deficiency. The damage can be irreversible if not caught early enough. SCD affects peripheral nerves and the spinal cord, and is normally different in children than adults.8 .

Theories of How B12 Deficiency Causes Nerve Damage

There are 3 main theories as to how B12 deficiency causes nerve damage:

1. B12 deficiency produces a lack of methionine for conversion into S-adenosylmethionine (SAM).9 SAM is required for the production of phosphatidylcholine10 which is part of the myelin (the fatty material that insulates many nerves).10 (See Figure: Methionine-Homocysteine-Folate-B12 Cycle.)

2. The inability to convert methylmalonyl-CoA (a 3-carbon molecule) to succinyl-CoA (a 4-carbon molecule) results in an accumulation of propionyl-CoA (a 3-carbon molecule). Fatty acids are normally made by adding 2 carbons at a time to an even numbered carbon molecule. In an overabundance of 3 carbon molecules, large amounts of unusual 15-carbon and 17-carbon fatty acids may be produced and incorporated into nerve sheets, causing altered nerve function.11

3. Nerves are damaged by different hormone-like molecules (cytokines, tumor necrosis factor, and epidermal growth factor) which become unbalanced in the nerve tissue in B12 deficiency.8

When is it Time to Call a doctor?

There are some serious diseases that have similarities to B12 deficiency, including Guillian-Barre syndrome, Lyme neuropathy, heavy metal intoxication, and lupus myelopathy.12 Anyone who develops symptoms of nerve damage should see a doctor immediately for treatment.

Notes for Symptoms of B12 Deficiency

1. Crane MG, Sample C, Pathcett S, Register UD. "Vitamin B12 studies in total vegetarians (vegans). Journal of Nutritional Medicine 1994;4:419-430.

2. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell PD, Stabler SP, RH. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988 Jun 30;318(26):1720-8.

3. Sarode R, Garewal G, Marwaha N, Marwaha RK, Varma S, Ghosh K, Mohanty D, Das KC. Pancytopenia in nutritional megaloblastic anaemia. A study from north-west India. Trop Geogr Med. 1989 Oct;41(4):331-6.

4. Crane MG, Register UD, Lukens RH, R. Cobalamin (CBL) studies on two total vegetarian (vegan) families. Vegetarian Nutrition. 1998; 2(3):87-92.

5. Ho C, Kauwell GP, LB. Practitioners' guide to meeting the vitamin B-12 recommended dietary allowance for people aged 51 years and older. J Am Diet Assoc .1999 Jun;99(6):725-7.

6. Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr. 1991 Jan;150(3):205-8.

7. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.

8. Scalabrino G. Subacute combined degeneration one century later. The neurotrophic action of cobalamin (vitamin B12) revisited. J Neuropathol Exp Neurol. 2001 Feb;60(2):109-20.

9. Groff J, Gropper S. Advanced Nutrition and Human Metabolism, 3rd ed. Wadsworth: 2000.

10. Grattan- PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997 Jan;12(1):39-46.

11. von Schenck U, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child. 1997 Aug;77(2):137-9.

12. Licht DJ, Berry GT, DG, Younkin DP. Reversible subacute combined degeneration of the spinal cord in a 14-year-old due to a strict vegan diet. Clin Pediatr. (Phila). 2001 Jul;40(7):413-5.

B12 and Chronic Disease: Homocysteine

Summary: Vegetarians who do not supplement their diet with vitamin B12 tend to have elevated homocysteine levels. Elevated homocysteine is probably a cause of early mortality, heart disease, stroke and recurrent pregnancy loss. It also may be a partial cause of Alzheimer's disease, neural tube defects, and certain eye disorders. Vegetarians who eat B12-fortified foods or supplements in amounts of 3 to 100 µg per day will minimize any elevated homocysteine problems due to a low B12 intake. IntroductionMost vegans are probably aware of the need for vegans to ensure a reliable source of vitamin B12 to prevent nerve damage in cases of severe depletion. Recent research has uncovered another dangerous condition that can result from less severe B12 depletion: elevated homocysteine.

If homocysteine is a cause of the diseases with which it is associated, it is due to the body's prolonged exposure to homocysteine. People are now living longer, allowing homocysteine more time to do its damage. So, while it may seem unnatural to take a supplement, the need to do so may be at least partially caused by our increased longevity.

The most recent analysis of the Oxford Vegetarian Study was reported in 2002 in "Mortality in British Vegetarians."1 Overall mortality was the same between vegetarians and non-vegetarians. But vegetarians had 2.2 times the death rate from mental and neurological diseases as non-vegetarians. (The finding barely reached statistical significance.) An obvious guess as to why is that vegetarians probably had higher homocysteine and lower B12 levels leading to more neurological problems. If we fix this problem, we will, hopefully, begin to see better mortality rates than non-vegetarians with similiar lifestyles.

Introduction References

1. Appleby PN, Key TJ, Thorogood M, Burr ML, Mann J. Mortality in British vegetarians. Public Health Nutr. 2002 Feb;5(1):29-36. Abstract

Background on Homocysteine Methionine is an essential amino acid obtained from protein in the diet. Some methionine is turned into homocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12. If someone is B12-deficient, homocysteine levels will increase because this reaction cannot take place.

Homocysteine appears to be a nerve and vessel toxin, promoting mortality, cardiovascular disease (CVD), stroke, Alzheimer's Disease, birth defects, recurrent pregnancy loss, and eye disorders. These will each be discussed below.

Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l.1 Levels of homocysteine in typical Western populations are about 12 µmol/l.2 Although this is "normal," it is not necessarily healthy.

Keeping homocysteine at levels associated with lower rates of disease requires both adequate B12 and folate (also known as folic acid) status. Low vitamin B6 status can also cause elevated homocysteine in some people.

In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Since vegetarian diets are typically high in folate elevated homocysteine levels in vegetarians are normally due to a low B12 intake (click here for a list of plant sources of folate).

It is possible that free homocysteine is more harmful than protein-bound homocysteine.3 At this time, few studies on homocysteine and disease have distinguished between the two. Eventually, the research may focus on free homocysteine, although the treatment will probably be the same.

Background on Homocysteine References

1. Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50. 2. [No author.] Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8. 3. Chambers JC, Ueland PM, Obeid OA, Wrigley J, Refsum H, Kooner JS. Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine. Circulation. 2000 Nov 14;102(20):2479-83.

Homocysteine in Vegans and Lacto-Ovo-Vegetarians To date, there have been 14 studies looking at homocysteine levels in vegetarians. Vegetarians refers to vegans and lacto-ovo-vegetarians. Figure 1 shows the blood B12 levels of the participants of 13 of those studies (1 study did not report B12 levels12).

Figure 1: Serum B12 Levels in Homocysteine Studies on VegetariansA (pg/ml)

A - Most of these vegetarians did not supplement their diets with B1298 US - 1998 United States199 US - 1999 USA; averaged 5.6 µg B12/day299 AUS - 1999 Australia399 CH - 1999 Chile400 CH - 2000 Chile5 00 SLR - 2000 Slovak Republic6

01 IND - 2001 India701 GER - 2001 Germany802 TAI - 2002 Taiwan902 ITALY - 2002 Italy1002 GER - 2002 Germany1103 TAI - 2003 Taiwan1303 GER - 2003 Germany1403 GER B-Vit - 2003 Germany; took "B vitamins" (amounts not reported)14

Normal B12 levels are from 200 to 900 pg/ml. Figure 1 shows that vegans had the lowest B12 levels, followed by lacto-ovo-vegetarians, and then non-vegetarians. Please note that the US vegans had an average B12 intake, through fortified foods and supplements, of 5.6 µg/day. Some of the vegetarians in the GER 03 study were probably supplementing with B12, but amounts were not given. The vegetarians in the other studies did not supplement their diets with B12.Figure 2 shows the blood homocysteine levels in the vegetarians who did not eat B12 fortified foods or take supplements.

Figure 2: Homocysteine Levels in Vegetarians (Mostly or All) Not Supplementing with B12 (µmol/l)

98 US - 1998 United States199 AUS - 1999 Australia399 CH - 1999 Chile400 CH - 2000 Chile5 00 SLR - 2000 Slovak Republic6 01 IN - 2001 India7 01 GER - 2001 Germany8

02 TAI - 2002 Taiwan902 IT - 2002 Italy1002 GER - 2002 Germany1102 UK - 2002 United Kingdom1203 TAI - 2003 Taiwan1303 GER - 2003 Germany14

The results in Figure 2 are almost the exact opposite as those shown in Figure 1, with vegans having the highest homocysteine levels, lacto-ovo-vegetarians having the next highest, and non-vegetarians having the lowest. The consitency of this finding indicates that in vegetarians, B12 levels are inversely related to homocysteine levels.Figure 3 shows the homocysteine levels in vegetarians who either supplement with B12 or after a B12 injection (as indicated).

Figure 3: Homocysteine Levels in Vegetarians Receiving B12 (µmol/l)

98 USA - 500 µg/day for 2 months1; B12 levels increased to 553 pg/ml99 USA - averaged 5.6 µg B12/day200 CHILE - 1,000 µg intramuscular injection5 02 ITALY - B12 amount not reported10 03 GER - Germany; B12 amount not reported14

Neither the B12 levels nor the B12 intakes of the vegetarians in Italy were reported, and it is not clear why their homocysteine levels were so high. But the vegetarians in Chili, and the vegans in the USA, show very healthy homocysteine levels compared to those in Figure 2.Thus, vegans and vegetarians who supplement with B12 have homocysteine levels that are considered healthy, while vegans and vegetarians who do not supplement with B12 tend to have high homocysteine levels – higher than those in non-vegetarians. But, does this really matter?

Notes for Homocysteine in Vegans and Vegetarians

1. Crane MG, Register UD, Lukens RH, R Cobalamin (CBL) studies on two total vegetarian (vegan) families. Vegetarian Nutrition. 1998; 2(3):87-92.

2. Haddad EH, Berk LS, Kettering JD, Hubbard RW, s WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S.

3. Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, AK, FD. The effect of diet on plasma homocysteine concentrations in healthy male subjects. Eur J Clin Nutr. 1999 Nov;53(11):895-9.

4. Mezzano D, Munoz X, ez C, Cuevas A, Panes O, Aranda E, Guasch V, Strobel P, Munoz B, S, Pereira J, Leighton F. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost. 1999 Jun;81(6):913-7.

5. Mezzano D, Kosiel K, ez C, Cuevas A, Panes O, Aranda E, Strobel P, DD, Pereira J, Rozowski J, Leighton F. Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids. Thromb Res. 2000 Nov 1;100(3):153-60.

6. Krajcovicova-Kudlackova M, Blazicek P, Kopcova J, Bederova A, Babinska K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab. 2000;44(3):135-8.

7. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.

8. Herrmann W, Schorr H, Purschwitz K, Rassoul F, Richter V. Total homocysteine, vitamin b(12), and total antioxidant status in vegetarians. Clin Chem. 2001 Jun;47(6):1094-101.

9. Hung CJ, Huang PC, Lu SC, Li YH, Huang HB, Lin BF, Chang SJ, Chou HF. Plasma Homocysteine Levels in Taiwanese Vegetarians Are Higher than Those of Omnivores. J Nutr. 2002 Feb;132(2):152-158.

10. Bissoli L, Di Francesco V, Ballarin A, Mandragona R, Trespidi R, Brocco G, Caruso B, Bosello O, Zamboni M. Effect of vegetarian diet on homocysteine levels. Ann Nutr Metab. 2002;46(2):73-9.

11. Obeid R, Geisel J, Schorr H, Hubner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002 Nov;69(5-6):275-9.

12. Cappuccio FP, Bell R, IJ, Gilg J, Ueland PM, Refsum H, Sagnella GA, Jeffery S, Cook DG. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis. 2002 Sep;164(1):95-102.

13. Huang YC, Chang SJ, Chiu YT, Chang HH, Cheng CH. The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. Eur J Nutr. 2003 Apr;42(2):84-90.

14. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.

Homocysteine and Disease Elevated homocysteine levels are associated with many diseases. However, there is a question about whether elevated homocysteine causes, or is simply a result of, those diseases. Studies on homocysteine and disease can be divided into two types:

Cross-sectional – The homocysteine levels in people with diseases are measured and compared to those without diseases. Because the disease could cause elevated homocysteine levels, these studies only show an association; they do not give evidence of a cause. For this reason, such studies are not reviewed here in any depth. Prospective – Homocysteine levels are measured for a large population and that population is followed. The people who get diseases are compared to those who do not to see if there were originally differences in homocysteine levels. If the people with higher homocysteine levels get a fdisease at higher rates, it could be that homocysteine causes the disease.

Homocysteine and Mortality The table below shows the results of the 4 prospective studies1,2,3,4 of homocysteine and mortality. They included a total of 9,298 people. Unless otherwise noted, the findings were statistically significant (less than a 5% chance of being due to random chance).

Homocysteine and Increased Risk for MortalityA

Homocysteine level (µmol/l)

Increased mortality rate

1999, USA, Framingham Study11,933 people age 59-91 after 10-13 years follow-up

< 14.26B

controls

> 14.26B

1.54

Adjusted for: age, sex, diabetes, smoking, BP, cholesterol.

1999, Israel21,788 people age ≥ 50 after 9-11 years follow-up

≤ 8.52

controls

11.90-14.69

1.53

≥ 14.7

1.97

Adjusted for: age, BP, serum glucose, health status, serum creatinine. A SS association between plasma homocysteine and increased risk of mortality was found for all deaths, CVD, CHD, and all other causes, but not for cancer.

2000, Netherlands3811 people age 50-70 (at entry) after 5 years follow-up

< 14.0

controls

> 14.0

1.34NS

5 µmol/l increase

1.17NS

In subjects without Type II diabetes. Adjusted for cholesterol, BP, age, sex, smoking, and albumin. From data given, it appears that if subjects > 14 were compared to subjects with < 10, there would have been a SS difference.

2001, Norway44,766 people age 65-67 after a median of 4.1 years follow-up

5.1-8.9

controls

15.0-19.9

2.10

20.0-137

1.64

5 µmol/l increase

1.49

For those with no history of heart attack, stroke, angina, diabetes, or high BP treatment; and adjusted for total cholesterol, blood pressure, smoking, body mass index, physical activity, age, and gender.

A - For example, "1.54" means that group of people had a 54% higher rate of death than the control groupB - Average and median for the group were not reportedBP – Blood pressure NS - Not statistically significant

All of the studies adjusted their results for the blood pressure of the participants. The USA, Norway, and Netherlands studies also adjusted for cholesterol levels. These studies show a considerable risk in mortality associated with high homocysteine levels. If you average the two studies that calculated a risk of death per 5 µmol/l, you get an increased risk of early death of 33% per 5 µmol/l increase in homocysteine. Using this figure, lowering homocysteine from about 15 to about 8 µmol/l would be associated with a 46% lower risk of early death.

Notes for Homocysteine and Mortality

1. Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D'Agostino RB, Wolf PA, Jacques PF, PW. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999 May 24;159(10):1077-80.

2. Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999 Sep 7;131(5):321-30.

3. Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation. 2000 Apr 4;101(13):1506-11.

4. Vollset SE, Refsum H, Tverdal A, Nygard O, Nordrehaug JE, Tell GS, Ueland PM. Plasma total homocysteine and cardiovascular and non cardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001 Jul;74(1):130-6.

Homocysteine and Cardiovascular Disease Cardiovascular disease (CVD) includes ischemic heart disease (IHD) (heart attack), coronary artery disease (CAD; plaque obstruction of the coronary arteries to the heart), and stroke. In October and November of 2002, two meta-analyses of prospective studies examining homocysteine and CVD were published. The Homocysteine Studies Collaboration (HSC) included 11 prospective studies of IHD and 8 of stroke.1 It compiled data from 9,025 people. HSC's analysis was geared mainly towards how much disease could be reduced through lowering homocysteine levels by 25% (about 3 µmol/l). After adjusting for age, sex, smoking, systolic blood pressure, and total cholesterol levels, a 25% lower homocysteine level reduced the risk of IHD by 11%, and the risk of stroke by 19%.The second meta-analysis was Homocysteine and cardiovascular disease: evidence on causality from a

meta-analysis.2 In 16 prospective studies of IHD, a 5 µmol/l increase in homocysteine increased risk 23%. In 8 prospective studies on stroke, a 5 µmol/l increase in homocysteine increased risk 42%. The results were adjusted for age, sex, smoking, cholesterol, and blood pressure (except for one study which adjusted only for age and sex).To get a ballpark idea of what lowering risks might mean for the typical person, the Table below shows reduced risks based on data provided by the American Heart Association.3 Particularly for stroke, the decreased rates are tangible. The greater effect of elevated homocysteine on stroke compared to heart disease could explain why vegetarians have not been shown to have lower rates of death from stroke, while they do have lower rates of death from heart disease.4

Heart Attack and Stroke Rates Among Americans andPotential Reductions by Reducing Risk3

Chances of Heart Attack Between the Ages of 35 and 74 years old

Average Risk:

Reducing Risk By:

1 out of

11% (1 out of)

23% (1 out of)

Women

Black

3.6

4

4.6

Non-black

6.5

7.3

8.4

Men

Black

2.3

2.5

2.9

Non-black

2.2

2.5

2.9

Chances of StokeBetween the Ages of 45 and 74 years old

Average Risk:

Reducing Risk By:

1 out of

19% (1 out of)

42% (1 out of)

Women

Black

4.5

5.6

7.8

White

12.7

15.7

21.9

Men

Black

4.8

6

8.4

White

5.8

7.1

10

Thus, both meta-analyses found that even after adjusting for blood pressure and cholesterol levels, homocysteine either causes IHD and stroke, or is strongly paired with an unknown factor that causes IHD and stroke. A few caveats should be made about these studies:

They do not prove causality. However, they do show that homocysteine either promotes these diseases or is strongly associated with another factor that promotes these diseases. Elevated homocysteine might cause an increase in blood pressure. One study found that after folate (5 mg) and vitamin B6 (250 mg/d) therapy for 2 years, blood pressure went down in a group of 130 relatively healthy people, 65% of whom had elevated homocysteine at the beginning of the study.5 If elevated homocysteine raises blood pressure, then adjusting disease risk for blood pressure will dilute the true effect of elevated homocysteine. People with high homocysteine at the beginning of these studies might have changed their diets or supplementation behaviors after the initial measurement of homocysteine. This would dilute the true effect of elevated homocysteine.

So, while it is true that the above studies do not prove that homocysteine causes the diseases with which it is associated, it is also likely that the true effect of elevated homocysteine levels is masked.

Notes for Homocysteine & Cardiovascular Disease

1. No author listed. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002 Oct 23-30;288(16):2015-22.

2. Wald DS, Law M, JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.

3. Raw data (first and recurrent cases per 1,000 people per decade) used to make calculations was provided by Haase, Biostatistics Consultant, Science and Medicine, National Center, American Heart Association, 7272 Greenville, Dallas, TX 75231-4596. December 2, 2002. Data for heart disease is from the Atherosclerosis Risk in Communities (ARIC) study of the National Heart, Lung, and Blood Institute (NHLBI), 1987-94. Data for stroke is from ARIC for ages 45-54 and 55-64; Cardiovascular Health Study (CHS) for 65-74.

4. Key TJ, Fraser GE, Thorogood M, Appleby PN, Beral V, Reeves G, Burr ML, Chang-Claude J, Frentzel-Beyme R, Kuzma JW, Mann J, McPherson K. Mortality in vegetarians and nonvegetarians: detailed findings from a collaborative analysis of 5 prospective studies. Am J Clin Nutr. 1999 Sep;70(3 Suppl):516S-524S.

5. A.J.M. van Dijk, Jan A. Rauwerda, Mieke Steyn, Jos W.R. Twisk, and Coen D.A. Stehouwer. Long-Term Homocysteine-Lowering Treatment With Folic Acid Plus Pyridoxine Is Associated With Decreased Blood Pressure but Not With Improved Brachial Artery Endothelium-Dependent Vasodilation or Carotid Artery Stiffness: A 2-Year, Randomized, Placebo-Controlled Trial. Arterioscler Thromb Vasc Biol. 2001 21: 2072-2079.

Treatment of High Homocysteine with Folate, B12, & B6 in Non-vegetarians The British Medical Journal published an analysis of 12 studies on the effectiveness of reducing homocysteine levels with folic acid and vitamin B12 and/or B6 supplements for 3-12 weeks.1 They concluded that folic acid in the range of 500-5,000 µg/day reduced homocysteine by 25%, and that B12 supplements (average intake of 500 µg/day) reduced it a further 7%. Vitamin B6 supplements (average of 16.5 mg/day) did not reduce homocysteine further. 500 µg B12/day is probably more than necessary. In one study reported in the BMJ, only 100 µg B12/day (combined with folate and B6) was successful in reducing homocysteine from 7.2 to 5.8 µmol/l.1 In another, only 20 µg B12/day (combined with folate and B6) resulted in reducing homocysteine from 11.9 to 7.8 µmol/l.1 Smaller amounts of B12 were not tested.

Notes for Treatment of High Homocysteine with Folate, B12, & B6 in Non-vegetarians

1. No author. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998 Mar 21;316(7135):894-8.

Reversing Carotid Artery Plaque Progression through Homocysteine Treatment Hackam et al.1 (2000, Canada) treated 100 patients with rapidly progressing atherosclerosis who had not responded well to a program of diet, exercise, smoking cessation, or drug treatment for high cholesterol and triglycerides. The treatment consisted of 2.5 mg folic acid, 25 mg vitamin B6, and 250 µg B12/day for about 2 years. The results were:

Results of Hackam et al.

In those with HCY:

HCY ≤ 14

HCY > 14

Number

50

51

HCY range (µmol/l)

4.7-13.9

14.3-69.4

Duration of vitamin therapy (yrs)

1.9 ± .9

1.8 ± .7

Carotid artery plaque progression before vitamin therapy (cm2/year)

..13 ± .24A

..21 ± .41B

Carotid artery plaque progression after vitamin therapy (cm2/year)

-.024 ± .29A,C

-.049 ± .24B,C

A, B - Statistically significant difference between groups with same letters.C - Not a statistically significant difference between groups with same letters.HCY - Homocysteine

Vitamin therapy actually reversed the amount of plaque in some of the patients, including some with a homocysteine level below 14 µmol/l. It should be noted that:

The vitamin therapy might have worked in ways other than by lowering homocysteine. (Post-treatment homocysteine levels were not measured.) There was no control group, so the results might not have been due to the vitamin therapy.

Thus, more studies are needed before lowering homocysteine can be said to reverse atherosclerosis.

Notes for Reversing Heart Disease through Homocysteine Treatment

1. Hackam DG, JC, Spence JD. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. Am J Hypertens. 2000 Jan;13(1 Pt 1):105-10.

But Aren't Vegans Protected From CVD? Studies show that vegans have lower cholesterol levels1 and blood pressure2 than non-vegetarians. These, and possibly other factors in the vegan diet, have led some to believe that vegans are protected against these diseases so much that they do not need to care about homocysteine. However, as noted, the above studies on homocysteine and mortality and CVD were adjusted for differences in cholesterol levels and blood pressure. Therefore, vegans should not consider themselves completely protected.

Unless there is a study that follows vegans with elevated homocysteine for many years, we will not know the effects with certainty. Because of the enormous cost, such a study will probably not be conducted. Since B12 succeeds in normalizing most vegans' homocysteine levels without any adverse effects, there is a simple solution and no reason to take any risk.

Notes for But Aren't Vegans Protected From CVD?

1. Appleby PN, Thorogood M, Mann JI, Key TJ. The Oxford Vegetarian Study: an overview. Am J Clin Nutr. 1999 Sep;70(3 Suppl):525S-531S.

2. Appleby PN, Davey GK, Key TJ. Hypertension and blood pressure among meat eaters, fish eaters, vegetarians and vegans in EPIC-Oxford. Public Health Nutrition. 2002;5:645-654.

B12, Homocysteine, & Alzheimer's Disease Approximately 6-8% of all people older than 65 have Alzheimer's Disease (AD).1 At least two recent literature reviews1,2 and a letter to the editor3 note people with AD have elevated homocysteine, elevated methylmalonic acid (a metabolite indicating low B12 status), reduced B12, or reduced folate levels; although the data is somewhat mixed.3 In some cases, B12-deficient dementia (which is a concern in itself) may be misdiagnosed as AD.4 There have been 2 prospective studies:

Seshadri et al.5 (2002, USA) conducted an 8-year prospective study of 1092 elderly people in which a 5 µmol/l increase in homocysteine increased the risk of AD by 40%. Wang et al.6 (2001, Sweden) studied 370 non-demented people for over 3 years. They found that having both a B12 level ≤ 203 pg/ml and a folate level ≤ 10 nmol/L increased risk for AD 2.3 times compared to those with folate and B12 above those levels (after adjusting for age, sex, and education). Homocysteine levels were not measured.

Thus, there is some preliminary evidence that elevated homocysteine can cause AD, although the question is far from resolved.

Notes for B12, Homocysteine, & Alzheimer's Disease

1. Nourhashemi F, Gillette-Guyonnet S, Andrieu S, Ghisolfi A, Ousset PJ, Grandjean H, Grand A, Pous J, Vellas B, Albarede JL Alzheimer disease: protective factors. Am J Clin Nutr. 2000 Feb;71(2):643S-649S.

2. Selhub J, Bagley LC, J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

3. McCaddon A, Davies G, Hudson P. Nutritionally independent B12 deficiency and Alzheimer disease. Arch Neurol. 2000 Apr;57(4):607-8.

4. Rieder CR, Fricke D. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001 Nov 13;57(9):1742-3.

5. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83.

6. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001 May 8;56(9):1188-94.

B12, Folate, Homocysteine, & Birth Defects Folic acid intake in the weeks before and after conception has been shown to decrease the number of neural tube defects (NTD), such as spina bifida, in at least four studies.1 The basis for this is not yet completely clear. It could be that when homocysteine cannot be converted back into methionine, there is not enough methionine available for normal closure of the neural tube. Some evidence for this is a case-control study in which women with the lowest methionine intakes had a higher rate of having a baby with a NTD.2 While the focus has been primarily on folate, there has been increasing interest in B12's part, which would be important to vegans:

Kirke et al.3 (1993, Ireland) studied folate and B12 in 328 pregnant women. There was a statistically significant difference between B12 levels of women who had an infant with a NTD 243 pg/ml) and those who did not (296 pg/ml). Afman et al.4 (2001, The Netherlands) found that low levels of a particular measure of B12 activity increased the risk of having a baby with a NTD by 5 times. Wald et al.5 (1996, UK) studied 135 women, 27 of whom had a baby with a NTD. The women who had children with NTDs had B12 levels an average of 38 pg/ml lower in the first trimester than controls. However, after adjusting for folate levels, there was no independent association for B12 and NTDs.

Ensuring adequate B12 and folic acid intakes in the weeks before and after conception may reduce the chances of NTDs.

Notes for B12, Folate, Homocysteine, & Birth Defects

1. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001 May;85 Suppl 2:S109-13.

2. Shaw GM, Velie EM, Schaffer DM. Is dietary intake of methionine associated with a reduction in risk for neural tube defect-affected pregnancies? Teratology. 1997 Nov;56(5):295-9.

3. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993 Nov;86(11):703-8.

4. Afman LA, Van Der Put NM, CM, Trijbels JM, Blom HJ. Reduced vitamin B12 binding by transcobalamin II increases the risk of neural tube defects. QJM. 2001 Mar;94(3):159-66.

5. Wald NJ, Hackshaw AD, Stone R, Sourial NA. Blood folic acid and vitamin B12 in relation to neural tube defects. Br J Obstet Gynaecol. 1996 Apr;103(4):319-24.

Homocysteine and Recurrent Early Pregnancy Loss A number of retrospective, case-control studies have been performed looking at elevated homocysteine levels and recurrent first trimester pregnancy loss. Nelen et al.1 (2000) conducted a meta-analysis of the studies performed from 1992 to 1999. They found that women with elevated homocysteine levels (> 10-18.3 µmol/l) had a statistically significant, 170% greater chance of two or more pregnancy losses in the first trimester. They were not able to determine whether elevated homocysteine is a marker or a cause of the pregnancy loss.

Notes for Homocysteine and Recurrent Early Pregnancy Loss

1. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril. 2000 Dec;74(6):1196-9.

Homocysteine and Eye Disorders

Though more work needs to be done before anything can be said definitively, two eye diseases have been associated with elevated homocysteine levels in at least one study:

Nonarteritic anterior ischemic optic neuropathy (NAION)1 Retinal venous occlusive diseases (RVOD)1,2,3

Notes for Homocysteine and Eye Disorders

1. Pianka P, Almog Y, Man O, Goldstein M, Sela BA, Loewenstein A. Hyperhomocystinemia in patients with nonarteritic anterior ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Ophthalmology. 2000 Aug;107(8):1588-92.

2. Brown BA, Marx JL, Ward TP, Hollifield RD, Dick JS, Brozetti JJ, RS, Thach AB. Homocysteine: a risk factor for retinal venous occlusive disease. Ophthalmology. 2002 Feb;109(2):287-90.

3. Weger M, Stanger O, Deutschmann H, Temmel W, Renner W, Schmut O, Quehenberger F, Semmelrock J, Haas A. Hyperhomocyst(e)inemia, but not methylenetetrahydrofolate reductase C677T mutation, as a risk factor in branch retinal vein occlusion. Ophthalmology. 2002 Jun;109(6):1105-9.

One Week of Vegan Diet (with B12) and Other Lifestyle Changes Lower Homocysteine

DeRose et al.1 (2000, USA) placed 40 people with various diseases (heart disease, diabetes, hypertension, and high cholesterol) on a vegan-diet-based lifestyle program for 1 week. The program included:

No B vitamin supplements. However, the subjects had an average intake of .4 µg of B12/day. Personal communication with the author verified that this was from fortified foods. Moderate physical exercise. Stress management and spirituality enhancement sessions. No caffeine, alcohol, or tobacco.

Homocysteine levels fell 13%, from 8.66 ± 2.7 to 7.53 ± 2.12 µmol/l. The researchers estimated that the subjects' folate intakes had gone from 301 µg for men and 226 µg for women (based on typical U.S. intakes) to 480 µg. The researchers did not think this could explain the entire homocysteine reduction. Other diet and lifestyle changes would probably explain the remaining reduction.

Please note that this study was not conducted on vegans and was only one week in duration. B12 intakes that low (.4 µg) or lower cannot be expected to keep homocysteine levels in check for long periods of time.

Notes for One Week of Vegan Diet (with B12) and Other Lifestyle Changes Lower Homocysteine

1. DeRose DJ, -Marcel ZL, Jamison JM, Muscat JE, Braman MA, McLane GD, Mullen J. Vegan diet-based lifestyle program rapidly lowers homocysteine levels. Prev Med. 2000 Mar;30(3):225-33.

What Level of B12 Should You Aim For?

Although homocysteine is not the only issue of concern in formulating recommendations for B12 levels, it is a fairly good proxy for other issues. Selhub et al.1 analyzed data from 8,083 people, including whites, blacks, and Hispanics. They found that elevated homocysteine levels (> 11.4 µmol/l for men, > 10.4 µmol/l for women) were associated with B12 levels less than 338 pg/ml. A level of 430 pg/ml provides a safety factor for homocysteine and other potential problems.In any given dose (at least six hours from ingestion of another dose of B12), the first 2 µg of B12 result in an absorption rate of 50%, or 1 µg. A dose of 5 µg will result in an additional .5 µg absorbed for a total of 1.5 µg. Any amount above 5 µg is absorbed at a rate of 1%.2 B12 levels of 350 to 430 pg/ml require 1 to 2.5 µg of B12 to be absorbed per day. This can be accomplished by following the recommendations listed here.

Notes for What Level of B12 Should You Aim For?

1. Selhub J, Bagley LC, J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

2. See the section How Recommendations were Formulated of Vitamin B12: Are You Getting It?

Should Vegans Get their Homocysteine or B12 Levels Checked?

Click here to see the Appendix: Should I Get My B12 Status Tested?

Homocysteine is Elevated in People with Kidney Disease

Homocysteine levels are often highly elevated in those with kidney disease. See Appendix: Homocysteine and Kidney Disease for more information.

B12 and Chronic Disease: Cancer

Summary: There is some evidence that a low B12 intake could play a role in the development of cancer.

To be confident of a link between a nutrient deficiency and cancer, numerous prospective studies should be conducted showing such an association. As of May of 2002, there was only one prospective study performed with the purpose of examining the relation between B12 and cancer (discussed below), and it was not performed on people with especially low B12 levels. Thus, there is not a lot of evidence one way or the other at this time. On the other hand, there is some evidence that low B12 intakes increase DNA damage which could then lead to cancer.

B12 and DNA Damage

It is thought that since B12 is needed for proper DNA production, a lack of B12 could have an effect on cancer through the incorporation of uracil into DNA. This can cause chromosome breakage resulting in a cancerous cell.1 The same can be said of folate.1

Fenech2 studied folate and B12 levels and intake in respect to DNA damage in white blood cells (lymphocytes) which has been shown to be a good marker for future cancer. They found that serum B12 > 405 pg/ml and a supplemental intake of 7 µg of B12/day was optimal for reducing DNA damage. The subjects were not vegetarian.

Notes for B12 and DNA Damage

1. Ames BN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutat Res. 2001 Apr 18;475(1-2):7-20.

2. Fenech M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat Res. 1999 Jul 16;428(1-2):299-304.

B12 and Breast Cancer

In the only prospective study looking at B12, folate, B6 and breast cancer, Wu et al.1 (1999, USA) found no association between serum folate or B6. There was a small increased risk for the postmenopausal women in the lower one-fifth of B12 levels (averaging 280 pg/ml) in one of the two groups studied. In the other group, where lower levels of B12 were not associated with increased risk, the women in the lowest one-fifth of serum B12 levels averaged 312 pg/ml, which are higher than average B12 levels in vegans who do not supplement (which tend to be around 200 pg/ml).

Notes for B12 and Breast Cancer

1. Wu K, Helzlsouer KJ, Comstock GW, Hoffman SC, Nadeau MR, Selhub J. A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev. 1999 Mar;8(3):209-17.

B12 and Chronic Disease: Depression

Summary: There is evidence that depression is often related to B12 deficiency. Some evidence suggests B12 deficiency can be confined to the brain. In such cases, massive doses of methylcobalamin might be necessary to replete B12 stores in the brain.

I have not had a chance to research this subject in detail. However, Syd Baumel, a vegan activist and science writer from Winnipeg, Canada, has done so. Click here to open, in a new window, Syd's article, A Shot in Time Saves Mind: Vitamin B12 and Depression."

Vitamin B12 Analogues

Vitamin B12 is a coenzyme: it is needed for enzymes to do their job of changing one molecule into another. As vitamins go, B12 is large. One part of its structure is known as the corrin nucleus, which holds an atom of cobalt. The corrin resembles the heme of hemoglobin which holds an atom of iron. Any molecule that contains a corrin nucleus is considered a corrinoid. The corrin plus other atoms make up the cobalamin part of B12. There are many different cobalamins and they are named after their attachments. For example, methylcobalamin is cobalamin with a methyl group (one carbon and three hydrogens) attached. Only two cobalamins are active as coenzymes in the human body: adenosylcobalamin and methylcobalamin. The body has the ability to convert at least some other cobalamins into one of these active forms. Cyanocobalamin (a cyanide molecule attached to a cobalamin) is the form most often found in

supplements and fortified foods because it is the most stable form of B12. The cyanide in cyanocobalamin is in amounts small enough not to be harmful for everyone except possibly those with cyanide metabolism defects (see the Safety section of Sources of B12 for Vegans and the Cyanide Metabolism Defects section of People Who Should Not Take the Cyanocobalamin Form of B12 for more information). Most people readily convert cyanocobalamin into one of the B12 coenzymes.1 Hydroxocobalamin is also common in foods and the body; it can be converted into a B12 coenzyme. All corrinoids (including all cobalamins) are considered B12 analogues. Many corrinoids, and possibly even some cobalamins, are not useable by human B12 enzymes. These are considered inactive B12 analogues.

About 1/3 of the corrinoids in the typical person are inactive analogues, while the rest are active B12.2 In this article, unless otherwise noted, "B12" refers only to active B12 analogues.

B12 in Animal Foods

In animal foods, B12 is protein-bound and partially light-protected.4

It is mostly in the form of adenosylcobalamin and hydroxocobalamin. In cow's milk it is mainly adenosylcobalamin, but in dried milk it is mostly hydroxocobalamin with a trace of cyanocobalamin. Egg yolks and sardines contain a substantial proportion of methylcobalamin.4

Inactive Analogues: Worse than Useless

Carmel et al.3 (1988, USA) examined the medical records of 364 patients with low B12 levels. Both R-protein and human intrinsic factor were used to measure their B12 levels. Because active B12 analogues would be detected using either method, any difference between the two methods would indicate inactive B12 analogues. Results were:

Patients with primarily neurological problems had significantly higher inactive B12 analogue levels (as shown by a difference between assays), than did patients with primarily blood problems. 33 of the 76 patients with neurological symptoms had a normal serum B12 when measured with R-protein. But when measured with intrinsic factor, many of these patients had much lower serum B12 levels. The R-protein assay was a reliable indicator of B12 deficiency in patients whose symptoms were primarily blood-related.

This study indicates that one of the following is probably true:

1. Some B12 analogue may be harmful to the nervous system.2. Some B12 analogue may have B12 activity in bone marrow (which produces blood cells) but not in the nervous tissue.

Notes for The B12 Molecule

1. Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr. 1988;48:852-8.

2. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S.

3. Carmel R, Karnaze DS, Weiner JM. Neurologic abnormalities in cobalamin deficiency are associated with higher cobalamin ‘analogue' values than are hematologic abnormalities. J Lab Clin Med. 1988 Jan;111(1):57-62.

4. Linnell JC, s DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.

Digestion, Absorption, and Transport of B12

Digestion & Absorption of Protein-Bound B12 Microorganisms, primarily bacteria, are the only organisms known to manufacture B12. These bacteria are thought to live in water, soil, and the digestive tracts of animals. In animals, B12 is normally attached to a protein either for transport or storage. When humans eat animal foods, the B12 is protein-bound. When the protein-B12 complex reaches the stomach, the stomach secretes acids and enzymes that detach the B12 from the protein. Then, in a process unique to B12, another protein, R-protein (aka cobalophilin, haptocorrin, and transcobalamin I1) picks up the B12 and transports it through the stomach and into the small intestine. R-protein is found in many fluids in the human body including saliva and stomach secretions. In addition to B12, R-protein can pick up any corrinoid.2 The stomach cells also produce a protein called intrinsic factor (IF),

which travels to the small intestine. When the corrinoid-R-protein complex gets to the small intestine, the corrinoid is liberated from the R-protein by enzymes made by the pancreas.3 Of the liberated corrinoids, only the cobalamins attach to intrinsic factor. Intrinsic factor then carries the cobalamins to the last section of the small intestine, the ileum. The cells lining the ileum contain receptors for the cobalamin-IF complex. The cobalamin-IF complex protects the cobalamin against bacterial and digestive enzyme degradation.4 The IF-receptor also ensures that cobalamins will be given priority for absorption over non-cobalamin corrinoids. In addition to the IF mechanism, passive diffusion normally accounts for 1-3% of B12 absorbed when obtained through normal food sources.3 Some inactive B12 analogues are most likely absorbed through passive diffusion. Digestion & Absorption of Unbound

B12 In supplements, B12 is not bound to protein, and therefore does not need digestive enzymes or stomach acid to be detached from a protein. Stomach acid is needed to dissolve some B12 tablets, especially if not chewed. When taken in large enough doses, unbound B12 can overcome intrinsic factor defects because so much can be absorbed through passive diffusion. There is some preliminary evidence that unbound B12, especially when combined with an absorption enhancer, can be directly absorbed through the membranes under the tongue at higher rates than through passive diffusion in the digestive tract. Enterohepatic Circulation Various studies have indicated that .1-.2% of the body's B12 pool is lost per day; the .2% loss occurs in those with pernicious anemia5 (see below for an explanation of pernicious anemia). The average nonvegetarian stores

2,000-3,000 µg B12,5 while losing only about 3 µg/day.6 About 60% of the total amount of B12 in the body is stored in the liver and 30% is stored in the muscles.4 The body has a special circuit between the digestive tract and the liver. Bile, which is made in the liver and needed to digest fat, is secreted into the beginning of the small intestine. It is then reabsorbed at the end of the small intestine (the ileum) and taken back to the liver where it is used again. This circuit is called enterohepatic circulation. People normally secrete 1.4 µg/day of B12 into their small intestines via their bile.5 Consequently, healthy people can reabsorb about .7µg B12/day from their bile.5 It is thought that in states of low B12 intake, absorption increases which can delay overt B12 deficiency, sometimes for 20-30 years.7 For vegans who do not supplement, slight

differences in enterohepatic circulation may determine how long one can go before developing B12 deficiency symptoms.8 One study has looked at changes in serum B12 (sB12) levels in new vegans. Crane et al.9 (1994, USA) had 13 students change from a lacto-ovo vegetarian to a vegan diet:

All 4 with sB12 in the 600-900 range fell to below 500 pg/ml in 2 months. 10 students followed the diet for 5 months and their average sB12 went from 417 ± 187 to 276 ± 122 pg/ml. After 5 months, 2 went from normal to below normal.

Transport in the Blood After B12 is absorbed into the intestinal cells, it attaches to transcobalamin II (TC2). Transcobalamin II is made in the intestinal cells7 where it picks up B12 and transports it to all body tissues through the blood and cerebrospinal fluid.1 Cyanocobalamin appears in the blood no longer than 5 hours after ingestion of B12.10 Once the B12-TC2 complex arrives at the cell where it is needed, B12 is released from TC2 in the form of hydroxocobalamin. It is then turned into methylcobalamin or adenosylcobalamin3 and used for their respective enzymes. Transcobalamin II also transports B12 to the liver for storage on transcobalamin III.

If the circulating B12 exceeds the binding capacity of the blood, the excess is excreted in the urine. This normally happens only after a B12 injection.5

Pernicious Anemia Without intrinsic factor, very little B12 is absorbed. People with intrinsic factor defects who do not get treatment eventually develop a very serious, pernicious (deadly) anemia. More recently, pernicious anemia (PA) has become the term referring to people with intrinsic factor defects. PA requires medical treatment. Most doctors will prescribe B12 injections, although there is evidence that oral B12 is adequate (see Oral B12 for People with Malabsorption in How Recommendations were Formulated. Studies on people with PA have provided a great deal of insight into the role of B12 and amounts needed by humans.

Notes for Digestion, Absorption, and Transport of B12

1. Scalabrino G. Subacute combined degeneration one century later. The neurotrophic action of cobalamin (vitamin B12) revisited. J Neuropathol Exp Neurol. 2001 Feb;60(2):109-20.

2. Herbert V, Drivas G, Manusselis C, Mackler B, Eng J, Schwartz E. Are colon bacteria a major source of cobalamin analogues in human tissues? 24-hr human stool contains only about 5 µg of cobalamin but about 100 µg of apparent analogue (and 200 µg of folate). Trans Assoc Am Physiol. 1984;97:161-71.

3. Groff J, Gropper S. Advanced Nutrition and Human Metabolism, 3rd ed. Wadsworth: 2000.

4. Messina M, Messina V. The Dietitian's Guide to Vegetarian Diets. Gaithersburg, MD: Aspen Publishers, Inc., 1996.

5. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

6. von Schenck U, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child. 1997 Aug;77(2):137-9.

7. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S.

8. son MS. Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000;44(5-6):229-34. And personal communication with author Jan 31, 2002.

9. Crane MG, Sample C, Pathcett S, Register UD. "Vitamin B12 studies in total vegetarians (vegans). Journal of Nutritional Medicine. 1994;4:419-430.

10. Linnell JC, s DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21. Review.

Coenzyme Functions of Vitamin B12In the cells of mammals,1 B12 performs two different functions according to its form:2, 6

Methylcobalamin - used by the enzyme methionine synthase to turn homocysteine (HCY) into methionine. 5'-deoxyadenosylcobalamin - used by 1) the enzyme methylmalonyl-CoA mutase in converting methylmalonyl-CoA to succinyl-CoA, and 2) by the enzyme leucine aminomutase which converts B-leucine into L-leucine and vice-versa.

Homocysteine Clearance

Methionine is an essential amino acid provided by the diet. Some methionine is turned into homocysteine. Homocysteine appears to be a nerve and vessel toxin, promoting cardiovascular disease (CVD) at elevated levels. HCY is thought to cause CVD by way of oxidative and vessel wall damage.3 The body normally turns HCY into other molecules, one of which is back into methionine. If this pathway is blocked, HCY levels increase. Methylcobalamin (B12) is needed by methylmalonyl-CoA mutase to convert HCY into methionine. Thus, if someone is B12 deficient, HCY levels will increase.

Anemia, DNA, and Folate

Traditionally, B12 deficiency, normally resulting from the inablity to absorb B12, was diagnosed by finding abnormally large red blood cells. This sort of anemia has two names:

Macrocytic anemia - when the average volume of the red blood cells, known as the Mean Corpuscular Volume (MCV), is larger than normal Megaloblastic anemia - when abnormally large red blood cells are observed under a microscope

The vitamin folate (aka folic acid) affects the anemia symptoms of B12 deficiency. Folate is needed to turn uracil into thymidine, an essential building block of DNA.4 DNA is needed for new red blood cell production and division. B12 is involved in this process because in creating methylcobalamin (used in the HCY to methionine reaction), B12 produces a form of folate needed to make DNA. If there is no B12 available, this form of folate can become depleted (known as the methyl-folate trap) and DNA production slows.5 See Methionine-Homocysteine-Folate-B12 Cycle for an illustration of this pathway.

Only RNA is needed to produce the hemoglobin found in the red blood cells. Unlike DNA, RNA does not require thymidine. Therefore, if there is not adequate folate, the new red blood cells (which start out as large cells called reticulocytes) divide slowly, as they are dependent on DNA for division. At the same time, their hemoglobin is only dependent on RNA and it is produced at a normal rate. This causes large red blood cells known as macrocytes.4,6 If enough of these macrocytes accumulate, the result is macrocytic anemia.

If there are large amounts of incoming folate from the diet, the body does not need to rely on regeneration of folate from the B12 cycle. Instead, it can use the extra dietary folate to produce DNA, thus preventing macrocytic anemia (see Methionine-Homocysteine-Folate-B12 Cycle, bottom right-hand portion). This is why high intakes of folate are said to "mask" a B12 deficiency.

To add insult to injury, an iron deficiency (which results in small red blood cells from inadequate hemoglobin synthesis) can counteract the macrocytic cells, making it appear as though the blood cells are normal in the face of multiple nutritional deficiencies.7

Intestinal cells are also rapidly dying and being replaced using DNA. A B12 deficiency can make itself worse because it can prevent the production of the intestinal cells needed to absorb B12.

Lack of Anemia Does Not Mean B12 Status is Healthy

Traditionally, the existence of macrocytic anemia was relied on to indicate a B12 deficiency. However, neurological disorders due to B12 deficiency commonly occur in the absence of a macrocytic anemia.

Lindenbaum et al.8 (1988, USA) examined 141 cases of neurological problems due to B12 deficiency. 40 (28%) had no macrocytic anemia (iron deficiency may have contributed to a lack in 6 patients, and folate therapy could account for 2 others). These 40 had very high serum MMA levels (range: .76-187 µmol/l, 78% > 2 µmol/l) and homocysteine levels (23-289 µmol/l, 45% > 100 µmol/l). Characteristic features of patients with B12 deficiency but without macrocytic anemia included: sensory loss, inability to move muscles smoothly (ataxia), dementia, and psychiatric disorders. They also had borderline (and sometimes normal) B12 levels (see table below). One patient died during the first week of treatment, but the other 39 benefited from B12 therapy. Some patients had residual abnormalities after years of treatment.

Table: B12 Levels in Neurological Patients Without Macrocytic Anemia (pg/ml)

Number of patients

serum B12

2

> 200

16

100-200

22

< 100

Methylmalonic Acid (MMA)

The second coenzyme form of B12, adenosylcobalamin, takes part in the conversion of methylmalonyl-CoA to succinyl-CoA. When B12 is not available, methylmalonyl-CoA levels increase. Methylmalonyl-CoA is then converted to methylmalonic acid (MMA) which then accumulates in the blood and urine. Since B12 is the only coenzyme required in this pathway, MMA levels are the best indicators of a B12 deficiency.

High MMA levels can also (but rarely) be caused by genetic defects, kidney failure, low blood volume, gut bacteria changes, pregnancy, and thyroid disease.9,10

A normal serum MMA level is .07 to .27 µmol/l. Above, under Lack of Anemia Does Not Mean B12 Status is Healthy, we saw that patients with serum MMA levels in the range of .76 to 187 µmol/l had neurological problems. What about the range between .27 and .76 µmol/l?

In a study of non-vegetarian, older adults with slightly elevated methylmalonic acid (MMA) levels (.29-3.6 µmol/l), higher sMMA levels did not predict neurological problems.10 However, these individuals were not compared to people with normal sMMA levels. Because there was no control group, we cannot say that people with slightly elevated sMMA are not at risk for neurological problems. We can only suggest that increasing sMMA from .29 to 3.6 may not do any further, measurable neurological harm.

In another study,11 older adults with slightly elevated MMA levels (.27 - 2.00 µmol/l) were treated with cyanocobalamin injections: MMA levels decreased 66% and homocysteine levels decreased 23%. Patients with MMA in the range of .60-2.00 µmol/l had neurological improvements after B12 therapy.

These studies indicate:

Slightly increasing sMMA levels from .29 to .60 µmol/l may not increase one's risk for neurological problems. People with MMA levels above .27 µmol/l may have elevated homocysteine which can benefit from B12 therapy. People with sMMA levels above .60 µmol/l may have neurological problems that can benefit from B12 therapy.

Notes for Coenzyme Functions of Vitamin B12

1. Scalabrino G. Subacute combined degeneration one century later. The neurotrophic action of cobalamin (vitamin B12) revisited. J Neuropathol Exp Neurol. 2001 Feb;60(2):109-20.

2. Seetharam B, Li N. Transcobalamin II and its cell surface receptor. Vitam Horm. 2000;59:337-66.

3. Hackam DG, JC, Spence JD. What level of plasma homocyst(e)ine should be treated? Effects of vitamin therapy on progression of carotid atherosclerosis in patients with homocyst(e)ine levels above and below 14 micromol/L. Am J Hypertens. 2000 Jan;13(1 Pt 1):105-10.

4. Guyton AC, Hall JE. Textbook of Medical Physiology, 9th ed. Philadelphia, PA: W.B. Saunders, Co: 1996. p. 845-7.

5. Murray RK, Granner DK, Mayes PA, Rodwell VW. Harper's Biochemistry, 24th ed. Appleton & Lange, 1996.

6. Groff J, Gropper S. Advanced Nutrition and Human Metabolism, 3rd ed. Wadsworth: 2000.

7. Herbert V. The 1986 Herman Award Lecture. Nutrition science as a continually unfolding story: the folate and vitamin B-12 paradigm. Am J Clin Nutr. 1987;46:387-402.

8. Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell PD, Stabler SP, RH. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988 Jun 30;318(26):1720-8.

9. Minet JC, Bisse E, Aebischer CP, Beil A, Wieland H, Lutschg J. Assessment of vitamin B-12, folate, and vitamin B-6 status and relation to sulfur amino acid metabolism in neonates. Am J Clin Nutr. 2000 Sep;72(3):751-7.

10. Hvas AM, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med. 2001 Jun 25;161(12):1534-41.

11. Hvas AM, Ellegaard J, Nexo E. Vitamin B12 treatment normalizes metabolic markers but has limited clinical effect: a randomized placebo-controlled study. Clin Chem. 2001 Aug;47(8):1396-404.

Blood B12 Level: Not a Reliable Measure of B12 Adequacy

A serum B12 (sB12) level below the normal range indicates that B12 levels are becoming depleted. However, as described below, a sB12 level in the normal range does not ensure that B12 levels are healthy. Unfortunately, medical practitioners still use serum B12 to evaluate function, even of vegans.

Seaweeds Can Falsely Inflate sB12 Levels

Methods for determining sB12 levels rarely, if ever, distinguish between B12 and all inactive B12 analogues. Seaweeds contain a variety of inactive B12 analogues. Someone who is eating large amounts of seaweed may have serum B12 levels well above normal, but much of it could be inactive B12 analogues that may actually be interfering with B12 function (see the section Inactive Analogues: Worse than Useless in Vitamin B12 Analogues).

Transcobalamin II

Transcobalamin II (TC2) transports B12 to tissues. In non-vegetarians TC2 normally contains about 20% of B12 in the blood.1 TC1 and TC3 are the proteins that normally store the other 80% of the B12 in the blood.1 If TC2 lacks B12, the vitamin will not be delivered to tissues, regardless of whether the total sB12 is low, normal, or high.2 When absorption of B12 via the intestines slows, B12-TC2 levels fall rapidly.1 There is evidence that TC2 is depleted of B12 within days after absorption stops.1

What this means is that a malabsorption disease can result in tissues not receiving B12 even though serum B12 appears normal. And, even at a normal serum B12 level, when intake of B12 is low or none, the tissues might not be receiving nearly as much B12 as they would otherwise be receiving when intake is normal.

In 2003, Herrmann et al. published a study looking at vegan and vegetarians' TC2 levels.3 Some vegans and vegetarians were taking B vitamins, though amounts of B12 were not reported. Results were:

Results of Herrmann et al.

NV

LOV

Vegan

B Vit

No B Vit

B Vit

No B Vit

Number

79

13

53

17

12

Serum B12 (pg/ml

387

409

242

259

170

B12-TC2 (pg/ml)

73

35

31

19

5.4

Homocysteine (umol/l)

8.8

9.6

10.9

11.1

14.3

MMA (umol/l)

0.16

0.23

0.37

0.71

0.78

B12-TC2 - B12 on Transcobalamin IILOV - Lacto-ovo-vegetariansMMA - Methyl malonic acidNV - Non-vegetarians

From the table, you can see that vegans' B12-TC2 levels were quite low, while homocysteine levels, especially for the vegans not taking any B vitamins, were much higher than for the non-vegetarians. Statistical analysis by the authors showed that B12-TC2 levels were the best predictors of homocysteine levels.

Table: B12-Related Laboratory Values shows normal values. Homocysteine, B12, Vegetarians, and Disease discusses the repercussions of elevated homocysteine levels.

B12-Deficient Nerve Damage with Normal sB12 and No Macrocytosis

Some people with normal B12 levels and without macrocytic anemia suffer from B12-deficient nerve damage, elevated homocysteine, and elevated MMA acid levels. See Lack of Anemia Does Not Mean B12 Status is Healthy under Coenzyme Functions of Vitamin B12 for more details.

Notes for Blood B12 Level: Not a Reliable Measure of B12 Adequacy

1. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S.

2. Herbert V. The 1986 Herman Award Lecture. Nutrition science as a continually unfolding story: the folate and vitamin B-12 paradigm. Am J Clin Nutr. 1987;46:387-402.

3. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.

B12 Status: Vegans Infants & Toddlers

Summary: Infants breast-fed by vegan mothers who supplement their diets with B12, or infants who receive B12 through fortified foods or supplements, develop normally. Infants breast-fed by vegan mothers who do not supplement with B12 and do not receive B12 fortified foods or supplements often develop severe B12 deficiency and nerve-related disorders.

Pregnancy

During pregnancy, B12 is actively transported by the placenta to the fetus, which can reduce the mother's stores of B12 if she has none in her diet.1

Infancy: A Critical Time

Weaning may be a critical time to ensure that vegan infants have plenty of B12, as low B12 levels at weaning were correlated to retarded growth in one study of vegan, macrobiotic children.2

In contrast to the adult's normal storage of 2-3,000 µg B12, newborn infants (of mothers with normal B12 stores) have body stores of only 25 µg. B12 stores in infants at birth are normally adequate to last the first several weeks of life,1 after which they must get it from breast milk or other sources. Studies have shown that colostrum and/or milk during the first week of life contains larger amounts of B12 (as much as 2421 pg/ml) than later milk.3 The B12 in mother's milk is more related to current B12 intake than to mother's B12 stores.4 Serum B12 levels of healthy, nonvegetarian infants decrease progressively until 6 months,5 after which they start to increase again.

If the mother is B12 deficient during pregnancy, the baby may have low B12 levels and some have developed clinical signs of deficiency as young as 2 weeks of age.6 At birth, these newborns typically have higher B12 levels than their mothers and usually show no deficiency symptoms.5

Minet et al.7 (2000, Switzerland) found that among apparently healthy infants, low serum B12 (and serum folate) was correlated with increased homocysteine levels; many infants in the lower range of normal serum B12 had elevated homocysteine levels. Breast-fed infants had significantly lower B12 levels and significantly higher homocysteine levels than infants using a formula fortified with B12. This does not mean that mothers should choose formula over breast milk, as there are many advantages to breast-feeding. Rather, it indicates that even among the non-vegetarian population, B12 can be a problem in infants, and breastfeeding mothers should consider a B12 supplement for themselves and/or their infants.

In rare cases, some infants cannot convert cyanocobalamin to an active form of vitamin B12 and thus cannot rely on cyanocobalamin supplements.47 These infants require medical treatment.

Notes for Pregnancy and Infancy: A Critical Time

1. Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr. 1991 Jan;150(3):205-8.

2. Schneede J, Dagnelie PC, van Staveren WA, Vollset SE, Refsum H, Ueland PM. Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets. Pediatr Res. 1994 Aug;36(2):194-201.

3. Specker BL, Black A, L, Morrow F. Vitamin B-12: low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am J Clin Nutr. 1990 Dec;52(6):1073-6.

4. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

5. Messina M, Messina V. The Dietitian's Guide to Vegetarian Diets. Gaithersburg, MD: Aspen Publishers, Inc., 1996.

6. Drogari E, Liakopoulou-Tsitsipi T, Xypolyta-Zachariadi A, Papadellis F, Kattamis C. Transient methylmalonic aciduria in four breast fed neonates of strict vegetarian mothers in Greece. Journal of Inherited Metabolic Disease. 1996 19S:A84. (Abstract)

7. Minet JC, Bisse E, Aebischer CP, Beil A, Wieland H, Lutschg J. Assessment of vitamin B-12, folate, and vitamin B-6 status and relation to sulfur amino acid metabolism in neonates. Am J Clin Nutr. 2000 Sep;72(3):751-7.

Infants of Vegan Mothers Who Do Not Use B12 Supplements

Since 1980, and excluding the Black Hebrews described below, there have been at least 30 reports of very serious B12 deficiency in vegan mothers' infants whose main or only food was breast milk. This happened only when the mother did not supplement her own or the baby's diet with B12. In many cases, the mother belongs to a subculture which does not believe in supplementation. Lack of B12 in the mother's diet during pregnancy has been shown to cause a severe lack of myelin in nerve tissue.1

Appendix: Vegan Infants & Toddlers with Serious B12 Deficiency lists the cases since 1981 in which infants of vegan mothers have suffered from B12 deficiency. In all cases, the infants are healthy until about 1-12 months of age after which they fail to thrive and show developmental regression. They are lethargic, lose their ability to use their muscles adequately, and sometimes cannot sense properly. They normally have macrocytic anemia, which is unusual in childhood and normally due to nutritional deficiency rather than to congenital disease.2

Notes for Infants of Vegan Mothers Who Do Not Use B12 Supplements

1. Lovblad K, Ramelli G, Remonda L, Nirkko AC, Ozdoba C, Schroth G. Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Pediatr Radiol. 1997 Feb;27(2):155-8.

2. JR, Goldenring J, Lubin B. Nutritional vitamin B12 deficiency in infants. Am J Dis Child. 1981(Jun);135:566-7.

Black Hebrews

Zmora et al.1 (1979, Israel) reported severe nutritional deficiencies in 4 infants from a vegan religious community, the Black Hebrews. The Black Hebrews originated in the USA. The infants received breast milk until the age of 3 months; thereafter, breast milk was supplemented with, or replaced by, extremely low caloric preparations. All of the infants had profound protein-calorie malnutrition, severe rickets, osteoporosis, and B12 and other deficiencies. One infant died, while 3 others recovered after treatment.

After discharge of the infants from the hospital, the community responded well to a modification of the infants' diet which did not violate their vegetarian philosophy. However, they refused to give their infants B12 on a regular basis.

Shinwell & Gorodischer2 (1982, Israel) also reported on a Black Hebrew religious community. Infants were breast-fed for 3 months and then fed mainly a dilute, homemade soymilk from 3 months to 1 year. 25 infants showed evidence of protein-calorie malnutrition, iron and B12-deficient anemia, rickets, zinc deficiency, and multiple recurrent infections. 3 of the infants were dead on arrival to a hospital. 5 more died within a few hours of admission despite treatment. Serum B12 levels were low in 9 of 15 cases (undetectable in 3).

Shinwell & Gorodischer said, "In spite of tactful but perseverant contact with the community health leaders during this time, no change in feeding habits of infants was achieved."

The reason the Black Hebrew leaders gave for withholding vitamin supplements:

If the organism of the cow subsists by eating plant foods only, why should the human organism need artificial vitamins, animal foods, and drugs?

Notes for Black Hebrews

1. Zmora E, Gorodischer R, Bar-Ziv J. Multiple nutritional deficiencies in infants from a strict vegetarian community. Am J Dis Child. 1979 Feb;133(2):141-4.

2. Shinwell ED, Gorodischer R. Totally vegetarian diets and infant nutrition. Pediatrics. 1982 Oct;70(4):582-6.

Correction of B12 Deficiency in Infants

Although B12 supplementation has been shown to result in rapid lab value improvements in these infants, concern has been raised about their long-term development.

von Schenck1 (1997) reviewed 25 reports of infant B12 deficiency which had appeared in the scientific literature. Among the 25 cases, vegan mothers were associated with 13. (9 of which occurred since 1980 and are included in Appendix: Vegan Infants & Toddlers with Serious B12 Deficiency. Of the 7 vegans that were followed, 5 had abnormal neurological development at their final follow-up (26 months, 26 months, 2 years, 5 years, and 12 years after diagnosis). 2 were normal at their respective final follow-up (13 months and 2 years).

von Schenck says, "Efforts should be directed therefore to preventing deficiency in pregnant and breast-feeding women on vegan diets and their infantsÂ…. If dietary changes are not acceptable to parents, vitamin B12 supplements are essential."

Grattan- et al.2 (1997, Australia) reports the cases of 3 infants of vegan mothers who developed muscle twitching and/or seizure-like symptoms upon treatment with B12 in doses of 500 µg or more. Other infants have developed tremors at doses of 300 µg. Grattan- et al. state that in the cases of dietary deficiency in infants, it seems unnecessary to give such high doses of B12.

Interestingly, Goraya3 (1998, India) reported that in India, many infants have "infantile tremor syndrome." This occurs in exclusively breast-fed infants from low socioeconomic conditions. Documented B12 deficiency, megaloblastic anemia, and response to B12 therapy was observed in some but not all patients.

Notes for Correction of B12 Deficiency in Infants

1. von Schenck U, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child. 1997 Aug;77(2):137-9.

2. Grattan- PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997 Jan;12(1):39-46.

3. Goraya J. letter about Persistence of neurological damage induced by dietary vitamin B-12 deficiency. Arch Dis Child. 1998;78(4):398-9.

Vegan Infants Taking B12 Supplements

In stark contrast, 1 (1988, UK) studied the growth and development of 37 vegan children. All were breast-fed for their first 6 months and in most cases well into their second year. The majority of these children grew and developed normally. They tended to be smaller in stature and lighter in weight than the general population. Energy, calcium, and vitamin D intakes were usually below the recommended amounts. Their diets were generally adequate with a few children having low intakes of riboflavin and B12. Most parents knew to supplement the diet with B12.

concludes that provided sufficient care is taken, a vegan diet can support normal growth and development. In another paper,2 points out that many potential hazards of vegan diets can be avoided by the use of soymilks fortified with calcium and B12 in the post-weaning period.

Fulton et al.3 (1980, USA) studied 48 preschool children between 2-5 years old, who had followed a vegan diet since birth. They lived at The Farm, a vegan commune in Tennessee, where soymilk was fortified with B12 at a rate of 6.25 µg per 8 oz of milk. They also supplemented with nutritional yeast containing 2.0 µg B12 per tablespoon, which they used as a flavoring agent in many foods. B12 status was not assessed, but there were no cases of overt B12 deficiency reported.

Notes for Vegan Infants Taking B12 Supplements

1. TA. Growth and development of British vegan children. Am J Clin Nutr. 1988 Sep;48(3 Suppl):822-5.

2. TA. Vegetarian diets and children. Pediatr Clin North Am. 1995 Aug;42(4):955-65.

3. Fulton JR, Hutton CW, Stitt KR. Preschool vegetarian children. Dietary and anthropometric data. J Am Diet Assoc. 1980 Apr;76(4):360-5.

B12 Status: Vegan Children & Teenagers

Vegan Children & Teenagers Supplementing with B12

& Purves (1981, UK) assessed the nutritional status of 23 vegan children (1-5 yrs old), contacted through The Vegan Society (UK). All the children had been breast-fed for at least the first 6 months of life and in most cases well into the second year. The majority of children were growing normally but tended to be shorter and lighter than the standards. Energy, calcium, and vitamin D intakes were usually below those recommended. Their diets were generally adequate with a few children having low intakes of vitamin B2 and B12. All parents were aware of the need for B12 supplementation and provided it through yeast extract, soymilk, TVP, or B12 syrup. B12 intake was 2.7 ± 0.63 (range: .3 - 15.2 µg/day). The parents were very receptive to advice.

concluded that, provided sufficient care is taken, a vegan diet can meet the nutritional requirements of the preschool child.

Reference: TA, Purves R. An anthropometric and dietary assessment of the nutritional status of vegan preschool children. J Hum Nutr. 1981 Oct;35(5):349-57.

Vegan Children & Teenagers Not Supplementing with B12

There have been no studies of vegan children or teenagers not supplementing with B12 who were not on a macrobiotic diets or Genmai-Saishoku diet. However, there have been 4 case studies of vegan or vegetarian children and teenagers who developed serious B12 deficiency. They are listed in B12 Status: Individual Cases.

B12 Status: Vegan Adults

Summary: VEgan adults who do not supplement with vitamin B12 tend have lower serum B12 levels than non-vegetarians. They sometimes have higher Mean Corpuscular Volume and MMA levels. They sometimes have overt B12 deficiency symptoms. These charactiristics increase the longer one is on a vegan diet. Vegans who supplement their diets with vitamin B12 tend to have serum B12 levels in the normal range, but could stand to increase them to 350 - 405 pg/ml to ensure healthy homocysteine levels and reduce DNA damage.

Individual cases of overt B12 deficiency are listed in B12 Status: Individual Cases. Additional studies of vegan B12 status are located in Homocysteine, B12, Vegetarians, and Disease.

Studies on Adult Vegans Not Supplementing with B12

Australians have a lifestyle similar to North Americans, but with limited B12 fortified foods. Hokin & (1999) examined Australian Seventht-day Adventist ministers, aged 22-80, who did not take B12 supplements. The results in the table below showed vegans to have significantly lower B12 levels.

Results of Hokin &

#

B12 (range)

Malabsorption / IF deficiency

NV

53

394A ± 196 (181-973)

NR

LOV

234

NRB

20% / 10%

Vegans

11

224A ± 100 (99-420)

NR

Total

298

A – Statistically significant difference between groups with same lettersB - Not significantly different from the NVNR - Not reportedNV – Non-vegetarians

Reference: Hokin BD, T. Cyanocobalamin (vitamin B-12) status in Seventh-day Adventist ministers in Australia. Am J Clin Nutr. 1999 Sep;70(3 Suppl):576S-578S.

Crane et al. (1998, USA) studied 2 families (9 people) who were vegan for over 1 year and who did not regularly take B12 supplements or fortified foods:

They ate food from their gardens or local grocery stores. Serum B12 (sB12) was below 200 pg/ml in 8 members; average sB12 was 190 ± 65 pg/ml. The only family member over 200 pg/ml, with a B12 level of 331 pg/ml, was also the only one with signs of deficiency (mild numbness in one hand and easy fatigue). These cleared up after starting oral B12, so her high levels might be attributable to inactive B12 analogues. 8 had high urinary MMA. Homocysteine levels were in the normal range, but dropped after B12 therapy. The subjects were given 500 µg B12/day, which they chewed before swallowing. After 2 months:

Average red blood cell count increased. Average total cholesterol decreased by 10.3% and LDL cholesterol decreased by 19.6%. (Note: This is the only study that observed a cholesterol reduction in vegans because of B12 supplementation.) Serum MMA levels dropped dramatically (from .65 ± .61 to .13 ± .06 µmol/l). Average sB12 rose to 553 ± 113 pg/ml.

Crane et al. write:

The laboratory evidence in these two families is too strong to believe that they had an adequate amount of [b12]. It is remarkable that they had been on a total vegetarian diet for so long, yet with little or no clinical symptoms or signs of an insufficiency of cobalamin. In this study none of the family members were aware of symptoms of easy fatigability, tingling in the extremities, or frequent upper respiratory infections.

Reference: Crane MG, Register UD, Lukens RH, R. Cobalamin (CBL) studies on two total vegetarian (vegan) families. Vegetarian Nutrition. 1998; 2(3):87-92.

Crane et al. (1994, USA) measured the sB12 of healthy adult vegans (1-28 years on the diet) who had not used B12 supplements or fortified foods in the previous year or more. Results were:

Results of Crane et al.

#

sB12 < 200 pg/ml

sB12 < 100 pg/ml

sB12 range

no FF or SUP for 1 yr

76

47 (62%)

19%

41-615

fortified soymilk for 1 yr

20A

304-540

A - 8 were childrenFF - Fortified foodssB12 - Serum B12SUP - supplements

Participants with low B12 levels were given oral B12. The B12 levels of some of these participants did not increase, which led to the study about chewing B12 tablets mentioned under Chew or Dissolve Supplements Under the Tongue in Sources of B12 for Vegans.

Crane et al. also examined urinary MMA levels in 29 vegan adults who had not used B12 supplements or fortified foods in the previous year:

11 had B12 levels < 200 pg/ml. Their average MCV (95.9 ± 5.5 fl) was significantly higher than those with higher B12 levels. 7 of these 11 had high MMA. None with normal B12 levels had elevated MMA. One vegan of 5 years had no symptoms of B12 deficiency despite a sB12 of 90 pg/ml. However, after 1 month of oral B12, he noticed that his chronic indigestion after meals had disappeared.

Reference: Crane MG, Sample C, Pathcett S, Register UD. "Vitamin B12 studies in total vegetarians (vegans). Journal of Nutritional Medicine. 1994;4:419-430.

Tungtrongchitr et al. (1993, Thailand) studied 132 Thai adult vegetarians (64 males, 68 females) and 47 healthy nonvegetarians. The vegetarians apparently ate no animal products. Serum B12 levels were:

Results of Tungtrongchitr et al.

Serum B12

Serum B12 range

Male NV

490

176-825

Female NV

500

270-1400

Male Veg

117

31-730

Female Veg

153

22-460

NV – Non-vegetarians

There were some blood cell differences between vegetarians and non-vegetarians. Serum B12 decreased as years as a vegetarian increased. Groups practicing vegetarianism for ≥ 6 years resulted in particularly low average sB12 levels (83-135 pg/ml).

Reference: Tungtrongchitr R, Pongpaew P, Prayurahong B, Changbumrung S, Vudhivai N, Migasena P, Schelp FP. Vitamin B12, folic acid and haematological status of 132 Thai vegetarians. Int J Vitam Nutr Res. 1993;63(3):201-7.

Bar-Sella et al. (1990, Israel) compared 36 vegans (5-35 years on diet) to 36 non-vegetarians. None of the vegans used supplements. Vegans had significantly lower levels of B12 (164 vs. 400 pg/ml). No non-vegetarian was deficient in B12, but 2 were borderline. No subjects had blood abnormalities. 4 vegans had a history of muscle pain, abnormal sensations in the legs, and difficulty concentrating. Their serum B12 levels were:

B12 Levels in 4 Vegans with History of Nerve-related Problems

Subject

1

2

3

4

Age

56

64

40

57

Serum B12 (pg/ml)

65

84

89

90

3 of the 4 were followed and showed substantial clinical improvement after B12 injections which increased their B12 levels to over 200 pg/ml.

Reference: Bar-Sella P, Rakover Y, Ratner D. Vitamin B12 and folate levels in long-term vegans. Isr J Med Sci. 1990;26:309-312.

Areekul et al. (1988, Thailand) found a significant difference between B12 levels (62 ± 78 pg/ml) in 29 apparently healthy vegetarians and 60 omnivores (629 ±160 pg/ml). 8 vegetarians had undetectable B12 levels, while only 2 had levels over 200 pg/ml. The researchers did not state whether any of the vegetarians were taking B12 supplements, but they appeared not to be doing so.

Reference: Areekul S, Churdchu K, Pungpapong V. Serum folate, vitamin B12 and vitamin B12 binding protein in vegetarians. J Med Assoc Thai. 1988 May;71(5):253-7.

Vegans Taking B12 Supplements

Haddad et al. (1999, USA) compared vegans to non-vegetarians. Results were:

Results of Haddad et al.

#

yrs on diet

# taking B12 SUPA,B

B12 (pg/ml)

# withB12 < 203

sMMA> .38 µmol/l

Had 1 Indicator ofB12 deficiency

Vegans

25

4.2 (1-25)

9

421 ± 169

3

5

10

NV

20

423 ± 134

0

0

A - Per correspondence with authorB - Some vegans ate B12 fortified foodsSUP - Supplements

There were no differences in homocysteine between the groups. There was a significant association between B12 supplementation and sB12 but no relation with sMMA. In private correspondence, Haddad suggested this was because some vegans did not regularly take the supplements and some had only recently begun. Blood will reflect recent higher B12 intake while MMA levels take longer to change.

Reference: Haddad EH, Berk LS, Kettering JD, Hubbard RW, s WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S.

Harman & Parnell (1998, New Zealand) compared 24 adult vegetarian Seventh-day Adventists (SDA) (including some vegans; number not specified) to 23 non-vegetarian SDAs. Some vegetarians were taking B12 supplements and injections. Results were:

Results of Harman & Parnell

sB12 (pg/ml)

Male Vegetarians

220 ± 103

Female Vegetarians

282 ± 132

Male NV

331 ± 142

Female NV

331 ± 167

NV – Non-vegetarian

B12 levels did not differ significantly between groups.

Reference: Harman SK, Parnell WR. The nutritional health of New Zealand vegetarian and non-vegetarian Seventh-day Adventists: selected vitamin, mineral and lipid levels. NZ Med J. 1998 Mar 27;111(1062):91-4.

et al. (1994, New Zealand) looked at 18 vegetarians. B12 levels were:

B12 levels in et al.

#

Years on diet

sB12

Vegan

5

6.6 (1-12)

277

LOV

13

> 5

229

Other findings were as follows:

6 had B12 levels below the reference range: 82, 86, 182, 190, 197 (vegan or LOV wasn't specified). None had macrocytosis. The woman with the lowest value was found to have an intrinsic factor deficiency. 7 vegetarians took B12 supplements and only one had low B12 levels, but their levels were not significantly different than those who did not take supplements. The vegans actually had a higher average sB12 than the LOV.

Reference: D, Ball MJ, Mann J. Nutrient intake and haematological status of vegetarians and age-sex matched omnivores. European Journal of Clinical Nutrition. 1994;48:538-546.

et al. (1978, UK) compared adult vegan (no animal products ≥ 1 year; average 8 yrs) members of The Vegan Society (UK) to age and sex matched non-vegetarians. 18 of the vegans were taking B12 supplements or eating fortified foods. Results were:

et al. (1978, UK)

Serum B12 (pg/ml)

22 Vegans

289 R 120-675

22 NV

371 R 250-775

NV - Non-vegetarian

5 vegans were not taking B12 supplements or fortified foods:

et al. (1978, UK)

Years as vegan

2

4

6

6

13

Serum B12

200

225

230

180

120

The results indicate that supplementing vegans had higher sB12 levels than non-supplementing.

Reference: TA, Ellis FR, Dickerson JW. Studies of vegans: the fatty acid composition of plasma choline phosphoglycerides, erythrocytes, adipose tissue, and breast milk, and some indicators of susceptibility to ischemic heart disease in vegans and omnivore controls. Am J Clin Nutr. 1978 May;31(5):805-13.

B12 Status: Elderly Vegetarians

Summary: Elderly lacto-ovo-vegetarians and vegans often have very low serum B12 levels. They should make sure they are getting a reliable source of B12. In fact, all people over age 50 should get some B12 by way of fortified foods or supplements due to lower stomach acid decreasing absorption of food-bound B12.

Studies of the B12 Status of Elderly Vegetarians

Brants et al. (1990, Netherlands) and Lowik et al. (1990, Netherlands) compared the B12 status of elderly (65-97 yrs) lacto-ovo-vegetarians to non-vegetarians. Results were:

Results of Brants et al.

#

Serum B12 (pg/ml)

B12 < 186.3 pg/ml

NV males

54

NR

4%

NV females

54

NR

6%

LOV males

17

317 ± 277

35%

LOV females

23

247 ± 96

13%

LOV - Lacto-ovo-vegetariansNR - Not reportedNV – Non-vegetarians

They concluded that a lacto-ovo or lacto-vegetarian diet can be adequate in old age, with positive impacts on heart disease risks, provided that it is carefully planned, especially with respect to iron, zinc, and B12.

References

Brants HA, Lowik MR, Westenbrink S, Hulshof KF, Kistemaker C. Adequacy of a vegetarian diet at old age (Dutch Nutrition Surveillance System). J Am Coll Nutr. 1990 Aug;9(4):292-302.

Lowik MR, Schrijver J, Odink J, van den Berg H, Wedel M. Long-term effects of a vegetarian diet on the nutritional status of elderly people Dutch Nutrition Surveillance System). J Am Coll Nutr. 1990 Dec;9(6):600-9.

Woo et al. (1998, Hong Kong) compared 106 elderly Chinese LOV and vegan women to 229 non-vegetarians:

All were older than 65 yrs (avg. 81); all were apparently healthy. Vegetarians had been on the diet > 10 yrs. Low B12 (< 203 pg/ml) occurred in 53.8% of the vegetarians (data not given for non-vegetarians). 16 vegetarians had B12-deficient anemia compared to 1 non-vegetarian. Vegetarians had a lower prevalence of a history of smoking and heart disease.

Reference: Woo J, Kwok T, Ho SC, Sham A, Lau E. Nutritional status of elderly Chinese vegetarians. Age Ageing. 1998 Jul;27(4):455-61.

B12 Status: Raw Foodist Vegans

Summary: Raw foodist vegans' B12 status appears to be no different than other vegans. There is some evidence that some probiotics (supplements of intestinal bacteria) could improve B12 status to a small degree.

Letter from a Raw Foodist Vegan

April 24, 2003

Someone gave me a hard copy of your Vitamin B12: Are You Getting It? (06 2000). I wish I had had all this information when I developed a severe B12 deficiency (macrocytic anemia & peripheral neuropathy) about 8 1/2 years ago due to a dietary deficiency of this vitamin. This was the hospital consultant's diagnosis. I had been a raw food vegan for many years before I developed the B12 deficiency symptoms.

- A.K., London, UK

Hallelujah Acres Diet

son,1 (2000, USA) studied people following the Hallelujah Acres diet, a vegan diet consisting mostly of raw foods with small amounts of cooked whole grains and root vegetables.

Subjects in the study did not take B12 supplements. Some ate small amounts of nutritional yeast resulting in an average intake of 5 ± 11 µg B12/month, with a median intake of .7 µg/month. Results are in the table:

Results of son1

Number

Total

49

sB12 < 347 pg/ml

44

sB12 < 200 pg/ml

6

sB12 < 160 pg/ml

0

uMMA ≥ 4 µg/mg creatinine

23

sB12 - Serum B12

19 subjects had normal sB12 levels with elevated uMMA levels. Subjects with elevated (and one with borderline) uMMA were divided into four groups to receive different treatment:

1. Sublingual B12: 500 µg Twinlab sublingual B12 3x/wk. 2. Nutritional yeast: 5 µg B12/day via 1 tablespoon of Red Star Vegetarian Support Formula nutritional yeast. 3. Probiotic Formula intestinal bacteria: 2 capsules/day which contain 5 bacteria species:

Lactobacillus plantarum Lactobaccillus salivarius Lactobacillus acidolphilus Bifidobacterium bifidus Bacillus subtilis

4. Flora Food intestinal bacteria: 2 capsules/day which contain 2 bacteria species:

Lactobacillus plantarum variant OM Lactobacillus salivarius

The results after 3 months were:

Results of treatment in son1

Sublingual B12

Nutritional yeast

Probiotic Formula

Flora Food

Total number

8

8

4

4

uMMA ≥ 4.1 µg/mg creatinine after 3 months

1 (uMMA = 4.1)

5 (all improved)

4(3 improved)

4(1 improved)

uMMA - Urinary Methylmalonic Acid

son suggests that the small improvement from taking intestinal bacteria could be from:

The bacteria producing B12 while still in the supplement. The bacteria taking up residence in the digestive system and producing B12.

In either case, these probiotics were not enough to normalize B12 status and are not recommended for vegans to rely on in improving their B12 status.

Living Food Eaters in Finland

Rauma et al.2 (1995, Finland) examined the B12 status in long-term adherents of a strict, uncooked (raw) vegan diet called the "living food diet." They assumed their large intake of bacterially fermented foods (about 2 kg/day in this study) would provide plenty of B12 as well as modify their intestinal bacteria to provide more B12.

In Part 1 of the study, food consumption data were collected and blood samples were taken from 9 vegan "living food eaters" (LFE) (1 male, 8 females), 2 years apart. Six of the 9 vegans showed slow, consistent deterioration of B12 status over this period, indicating that the supply of B12 from the "living food diet" was inadequate to maintain the sB12.

In Part 2, sB12 of LFE were compared to nonvegetarians. Blood values (MCV, hemoglobin) of LFE did not differ significantly from the nonvegetarians' nor did they correlate with B12 levels. In the vegan group, B12 analogue intake (through nori and chlorella) correlated with sB12. Results were:

Results of Rauma et al., Part 22

#

sB12 (pg/ml)

< 203 pg/ml

LFE

21

261A R: 47-551

6

consuming seaweed

16

298 R: 101-551

not consuming seaweed

5

142 R: 47-340

NV

21

420A R: 177-651

1

A – Statistically significant difference between groups with same lettersLFE - Living Foods EatersNV - Non-vegetarians R - Range

The Finnish eaters of the living food diet participating in this study started to supplement their diet after finding out their low vitamin B12 status.

Natural Hygiene Society Conference

Dong & 3 (1982, USA) examined 83 subjects from an American Natural Hygiene Society conference. They tended to follow natural hygiene diets consisting of whole raw fruits, vegetables, nuts, and seeds, with a minimal intake of grains and legumes. They considered this to be a natural primate diet and believed their bodies received B12 through small intestinal bacteria which live only in the intestines of those who follow whole raw food diets. The table below shows the results among subjects who did not supplement with B12.

Results of Dong & 3

#

sB12 < 200 pg/ml

sB12 < 100 pg/ml

Vegans

13

92%

53%

LV

28

64%

LOV

15

47%

13%

SV

10

20%

LOV - Lacto-ovo-vegetariansLV - Lacto-vegetariansSV - Semi-vegetarians

Macrocytic anemia among the vegetarians was minimal. One 63-year-old vegan with a B12 level of 117 pg/ml had a nerve-related disorder. For males who did not take B12 supplements, there was a correlation between length of time as a vegetarian and lower B12 levels. Among subjects who had taken B12 or multivitamins, all had B12 levels above 200 pg/ml. Dong & concluded that there is no indication that natural hygiene vegetarian diets contribute to higher B12 levels than other vegetarian diets.

Notes for Raw Foodist Vegans and B12

1. son MS. Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000;44(5-6):229-34. And personal communication with author Jan 31, 2002.

2. Rauma AL, Torronen R, Hanninen O, Mykkanen H. Vitamin B-12 status of long-term adherents of a strict uncooked vegan diet ("living food diet") is compromised. J Nutr. 1995 Oct;125(10):2511-5.

3. Dong A, SC. Serum vitamin B12 and blood cell values in vegetarians. Ann Nutr Metab. 1982;26(4):209-16.

B12 Status: Macrobiotics

Summary: Many macrobiotics who do not supplement their diets with B12 are found to be deficient. There is growth retardation in some macrobiotic children due to low B12 intake.

The Macrobiotic Diet

A macrobiotic diet typically consists of 50-60% whole cereal grains, 5% soups, 20-25% vegetables, and 5-10% beans and sea vegetables. Occasionally, small quantities of other foods, such as seafood, are included. Meat is avoided and little or no dairy or eggs are eaten. Vitamin supplements generally are not taken.1 Infants are normally breast-fed until whole foods are added (i.e., infants are not fed formula).

Notes for The Macrobiotic Diet

1. DR, Specker BL, Ho ML, Norman EJ. Vitamin B-12 status in a macrobiotic community. Am J Clin Nutr. 1991 Feb;53(2):524-9.

Macrobiotic Adults

et al. (1991, New England USA) studied 110 macrobiotic adults and 42 macrobiotic children:

The group's average B12 level was 202 pg/ml. 51% of adults had serum B12 < 200 pg/ml. 30% of adults sampled had high uMMA. Serum B12 negatively associated with time on the diet and urinary MMA.

Several had low serum B12 after a short time as a MAC (they may have had poor status before beginning the diet).

Reference: DR, Specker BL, Ho ML, Norman EJ. Vitamin B-12 status in a macrobiotic community. Am J Clin Nutr. 1991 Feb;53(2):524-9.

Macrobiotic Children

Dagnelie & van Staveren (1994, Netherlands) found that growth in macrobiotic infants and children was retarded between ages of 6 - 18 months, and did not catch up (by age 10) unless animal products were added to the diet.

Reference: Dagnelie PC, van Dusseldorp M, van Staveren WA, Hautvast JG. Effects of macrobiotic diets on linear growth in infants and children until 10 years of age. Eur J Clin Nutr. 1994 Feb;48 Suppl 1:S103-11; discussion S111-2.

et al. (1991, New England USA) studied 110 macrobiotic adults and 42 macrobiotic children:

The group's average B12 level was 202 pg/ml. 55% of the children had high urinay MMA. Children were short in stature. Decreased stature was related to high uMMA.

Reference: DR, Specker BL, Ho ML, Norman EJ. Vitamin B-12 status in a macrobiotic community. Am J Clin Nutr. 1991 Feb;53(2):524-9.

Dwyer et al. (1982, Boston, MA) studied 39 vegetarian and semi-vegetarian children. Average age was 4.0 years old (range: 0.8 – 8.4 years). 27 were macrobiotic, and 9 of those were vegan. 2 of the vegans used supplements. The average B12 level was 489 pg/ml (range: 100 – 700 pg/ml). All the children appeared to be normal.

Reference: Dwyer JT, Dietz WH Jr, s EM, Suskind RM. Nutritional status of vegetarian children. Am J Clin Nutr. 1982 Feb;35(2):204-16.

Macrobiotic Infants

Schneede et al. (1994, Netherlands) compared macrobiotic infants to non-vegetarian infants:

Diet Group

Number

Serum B12 (pg/ml)

Macrobiotic

41

191 (Range: 79-459)

Non-vegetarian

50

538 (Range: 261-1108)

Homocysteine and serum MMA levels were above normal in the macrobiotic infants, and were inversely related to B12 levels.

Reference: Schneede J, Dagnelie PC, van Staveren WA, Vollset SE, Refsum H, Ueland PM. Methylmalonic acid and homocysteine in plasma as indicators of functional cobalamin deficiency in infants on macrobiotic diets. Pediatr Res. 1994 Aug;36(2):194-201.

Dagnelie et al. (1989, Netherlands) compared macrobiotic infants to non-vegetarian infants:

Diet group

Number

Serum B12 (pg/ml)

Macrobiotic

50

201

Non-vegetarian

57

545

50% of macrobiotics had B12 levels < 188 pg/ml, and 10% had levels < 107 pg/ml. The authors stated, "Our findings indicate that the plasma B12 concentration in macrobiotic infants is sufficiently low to have physiological consequences raising concerns about neurological development."

Reference: Dagnelie PC, van Staveren WA, Vergote FJ, Dingjan PG, van den Berg H, Hautvast JG. Increased risk of vitamin B-12 and iron deficiency in infants on macrobiotic diets. Am J Clin Nutr. 1989 Oct;50(4):818-24.

Specker et al. (1988, USA) studied 17 vegan, macrobiotic mothers. 56% had B12 levels less than 200 pg/ml. They were compared to 6 non-vegetarian mothers whose B12 levels were not reported. The infants of the vegan mothers had higher urinary MMA levels, which dropped after 7 – 10 days of B12 therapy.

Reference: Specker BL, D, Norman EJ, Greene H, KC. Increased urinary methylmalonic acid excretion in breast-fed infants of vegetarian mothers and identification of an acceptable dietary source of vitamin B-12. Am J Clin Nutr. 1988 Jan;47(1):89-92.

Macrobiotic Breast Milk

Specker et al. (1990, USA) compared the B12 levels of breast milk in 13, mostly vegan macrobiotics who did not take supplements (312 ± 127 pg/ml) to 6 non-vegetarians, 5 of whom took supplements (510 ± 101 pg/ml). B12 in breast milk decreased as time on the macrobiotic diet increased. Infant urinary MMA levels were inversely related to milk B12 levels for those below 489 pg/ml.

Reference: Specker BL, Black A, L, Morrow F. Vitamin B-12: low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am J Clin Nutr. 1990 Dec;52(6):1073-6.

B12 Status: Lacto-Ovo Vegetarians

In general, lacto-ovo vegetarians (LOV) whose diets are not supplemented with B12 have lower serum B12 levels and higher homocysteine levels than non-vegetarians. Though B12 is less of a concern for LOV than vegans, if B12 supplements or fortified foods are available, they should be used regularly to ensure optimal B12 status.

B12 Status: Individual Cases

This list does not include infants and toddlers. They are listed in Appendix: Vegan Infants & Toddlers with Serious B12 Deficiency.

57 Year Old Vegan Develops Irreversible Subacute Sclerotic Combined Degeneration of the Spinal Cord

Brocadello et al. (2007, Italy) reported a 57-year-old man hospitalized due to weakness, inability to walk, difficulty in handling utensils, constipation, and urinary retention, among other things. His measurements were:

serum B12 - 30 pg/mlMCV - 115 flHcy - 15.4 µmol/LuMMA - 1.3 µmol/L

It's somewhat surprising that his homocysteine and urinary MMA levels weren't higher than that. The authors also mention that his diet was low in protein and calories. Upon treatment, his blood values returned to normal, but after one year he still had not regained the ability to walk.

Brocadello F, Levedianos G, Piccione F, Manara R, Pesenti FF. Irreversible subacute sclerotic combined degeneration of the spinal cord in a vegan subject. Nutrition. 2007 Jul-Aug;23(7-8):622-4.

15 Year Old Vegan Not Supplementing with B12 Develops Lameness

Chiron et al. (2001, France) reported a 15-year-old boy hospitalized because of lameness and jaundice. He had B12-deficiency anemia as well as rickets. A diet supplemented with calcium, vitamin D, and B12, and orthopedic treatment stabilized the bone lesions. The anemia was cured by a B12 injection(s). The authors state, "The adolescent and his brother were victims of a diet imposed by a cult and a lack of care due to their parents refusing that a vegan diet was the cause of the deficient pathology." The article is in French and no further information was given in the abstract.

Reference: Chiron R, Dabadie A, Gandemer-Delignieres V, Balencon M, Legall E, Roussey M. [Anemia and limping in a vegetarian adolescent] Arch Pediatr. 2001 Jan;8(1):62-5. French. (Abstract)

10 Year Old Develops Serious Neurological Problems

Cornejo et al. (2001, Spain) reported a 10 year old boy with serious neurological problems. They said the boy was as "a member of a religious community who were strict vegetarians." The article is in Spanish and no further information was given in the abstract.

Reference: Cornejo W, F, Toro ME, Cabrera D. [subacute combined degeneration. A description of the case of a strictly vegetarian child] Rev Neurol. 2001 Dec 16;33(12):1154-7. Spanish. (Abstract)

14 Year Old Vegan Develops Fatigue, Aching, Stumbling, and Heart Murmur

Licht et al. (2001, USA) reported a 14 year old boy with a serum B12 of 281 pg/ml. This is not particularly low. However, he had developed fatigue, daytime sleeping, an aching calf, stumbling, and a heart murmur. He was small for his age and withdrawn. His mean corpuscular volume was 108 fl, serum MMA was 2.5 µmol/l, and homocysteine was 64.4 µmol/l. He did not have anemia. His mother considered him a "picky eater." He was treated with a number of 1,000 µg intramuscular injections of B12.Treatment resulted in normal gait, but after 18 months he still had nerve problems.

Reference: Licht DJ, Berry GT, DG, Younkin DP. Reversible subacute combined degeneration of the spinal cord in a 14-year-old due to a strict vegan diet. Clin Pediatr (Phila). 2001 Jul;40(7):413-5.

33 Year Old Vegan Not Supplementing with B12 Develops Nerve Problems and Vision Damage

Milea et al. (2000, France) reported a male vegan of 13 years who appeared to have a poor diet given deficiencies of vitamins A, B1, B12 (154 pg/ml), C, D, E, and folate, and zinc and selenium. He had been vegan for "improved health," and did not smoke or drink alcohol. He was found to have severe optic nerve disease, sensory nerve problems, reduced hemoglobin, and a 110 fl. MCV. He had no signs of malabsorption. After a multivitamin and B12 injections of 1000 µg/day for 1 week, his hemoglobin and sensory nerve problems disappeared, but his vision didn't recover. The authors concluded that "The optic neuropathy in our patient was apparently related to deficiencies of B12 and B1, but other associated deficiencies may have had a role."

Reference: Milea D, Cassoux N, LeHoang P. Blindness in a strict vegan. N Engl J Med. 2000 Mar 23;342(12):897-8.

36 Year Old Vegan Not Supplementing with B12 Develops Poor Vision

Li & McKay (2000, UK) reported a woman who was vegan for many years. She had megaloblastic anemia due to folate deficiency 6 years earlier. Her B12 levels and absorption were normal at that time. During her current visit to the clinic, she reported decreased vision during the previous week. Again, she had signs of megaloblastic anemia, but this time with low B12 level (130 pg/ml) and low folate. She was treated with oral folate and iron, and a B12 injection. Her vision returned to normal within days. Again, there were no features of malabsorption and Li & McKay concluded that her vitamin deficiencies were of dietary origin.

Reference: Li K, McKay G. Images in clinical medicine. Ischemic retinopathy caused by severe megaloblastic anemia. N Engl J Med. 2000 Mar 23;342(12):860.

80 Year Old Vegan Not Supplementing with B12 Develops Nerve DamageBernstein (2000, USA) describes a man in his eighties who had been in excellent health, and was a runner. He had been vegan for 38 years and attributed his ability to outperform younger people to his diet. In the span of a few weeks, mental disturbances began to set in. He cried, was confused, got lost, was incontinent, lost control of his bowels, and lost motor skills to the point where he could barely stand with help. He was diagnosed with "senile dementia." A blood test showed slightly large red blood cells. Further blood tests revealed that his B12 level was undetectable. He was given an injection of 1000 µg of B12. The next morning he could sit without help. His bladder control returned within 48 hours. By the end of the week, he could play simple card games, read get-well cards, and talk on the phone. He still cried easily and his attention span was too short to go

back to work. Bernstein concludes, "[A] diet free of animal protein can be healthful and safe, but it should be supplemented periodically with vitamin B12." Reference: Bernstein, L. Dementia without a cause. Discover. February 2000:31.

50 Year Old Vegetarian Develops Neurological Problems from Short-term Nitrous Oxide Anesthesia

Rosener & Dichgans (1996, Geremany) reported a 50-year-old vegetarian woman eating mostly apples, nuts, and raw vegetables who underwent nitrous oxide anesthesia for a hip fracture after injuring herself ice-skating. She was ventilated with nitrous oxide for 2 hours. Four weeks later, she developed rapidly increasing sensory impairment of the legs. Six weeks later, she could not walk. She was diagnosed with neurological degeneration secondary to B12 deficiency. After 5 months of treatment with cyanocobalamin injections, she could walk on crutches. At one year later, she had continued to improve. Vegetarians should make sure their B12 status is healthy before undergoing nitrous oxide anesthesia.

Reference: Rosener M, Dichgans J. Severe combined degeneration of the spinal cord after nitrous oxide anesthesia in a vegetarian. J Neurol Neurosurg Psychiatry. 1996(Mar);60(3):354.

14 Year Old Vegetarian Not Supplementing with B12 Develops Nerve Problems

Ashkenazi et al. (1987, Israel) reported a 14-year-old girl who had been vegetarian (and apparently vegan) for 8 years after witnessing the slaughter of a cow. She had been healthy previously and seemed well nourished. She had neurological problems including an unstable walk, unsteady standing with eyes closed, some impaired sensations, mildly reduced muscle strength, and reduced ankle-jerk reflex. Her serum B12 was 50 pg/ml. Absorption was normal. She had not been taking B12 supplements as her parents were unaware of the need and her doctor was unaware of her diet. Injections and supplements were given, and the girl followed advice to begin eating fish and dairy products. (This was, of course, unnecessary). A rapid improvement was noted with a complete neurological recovery after 4 months.

Reference: Ashkenazi S, Weitz R, Varsano I, Mimouni M. Vitamin B12 deficiency due to a strictly vegetarian diet in adolescence. Clinical Pediatrics. 1987;26(Dec):662-663.

Rastafarian Community

et al. (1982, Jamaica) reported 10 Rastafarian men (age 18-49) with B12 deficiency. They had been vegan 2-20 years. 8 had neurological symptoms. B12 malabsorption was ruled out in all cases. 8 had moderate to severe macrocytic anemia. 6 were jaundiced, 3 had a swollen tongue, 2 had anorexia, 1 had vomiting, 1 had abdominal pain, and there were other symptoms. Their serum B12 range was 10-130 pg/ml, with only 2 over 75 pg/ml. Their blood completely responded to cyanocobalamin injections. Of 3 who had subacute neurological degeneration, one recovered completely. Another improved considerably but had residual motor defects after several months of treatment. The third patient died of a heart attack 11 days after admission. stated, "Our patients were not very cooperative in taking oral vitamin B12 or attending the clinic for vitamin B12 injectionsÂ…."

Reference: M, Lofters WS, Gibbs WN. Rastafarianism and the vegans syndrome. BMJ (Clin Res Ed). 1982 Dec 4;285(6355):1617-8.

56 Year Old Vegan Not Supplementing with B12 Develops Extremely Low B12 Levels

(1981, UK) reported a male vegetarian of 40 years. He had been vegan for the previous 4 years since developing angina. He had been treated for the previous 8 years with phenobarbital for epileptic seizures. He was admitted for an aortic valve replacement and found to have low hemoglobin, a 98 fl. MCV, and 50 pg/ml B12 level. Folate was normal. A deoxyuridine suppression test showed B12 deficiency. He was treated with 5 µg B12/day, orally, for one month. His serum B12 levels rose to 205 pg/ml and his hemoglobin returned to normal.

Reference: MF. Vitamin B12 deficiency due to a low-cholesterol diet in a vegetarian. Ann Intern Med. 1981 Jan;94(1):57-8.

57 Year Old Vegan Not Supplementing with B12 Develops Nerve Problems

Carmel (1978, USA) reported on a man admitted to the hospital in 1976 with trouble walking. He had been in good health until 1972 when he retired because of fatigue. He had been almost vegan, eating small amounts of dairy, for 25 years. He had siblings who ate a similar diet, but who took B12 and did not develop problems. In 1974, a chiropractic nutritionist told him his problems were not related to a B12 deficiency. He then replaced the dairy in his diet with a raw egg yolk every other day. He improved for a short time but then got worse. Two weeks before admission, he began taking 100 µg B12/day. Upon admission, he had decreased sensation in the hands and below the knees, with slight megaloblastic anemia. His B12 level was 146 pg/ml. He was injected with 1000 µg/day of B12 for 3 weeks which caused rapid improvement. He then received B12 injections once a month for 6 months (by which time his only neurological problem was in his feet) and then he

started 100 µg/day orally. He also started eating fish, dairy products, and eggs. His B12 level stabilized at about 300 pg/ml. He had slightly depressed intrinsic factor secretion and reduced stomach acid, which was apparently not due to the B12 deficiency as it did not improve with treatment. His problems were probably due to a combination of low B12 intake and decreased absorption.

Reference: Carmel R. Nutritional vitamin-B12 deficiency. Possible contributory role of subtle vitamin-B12 malabsorption. Ann Intern Med. 1978 May;88(5):647-9.

B12 Status: Immerman - The Exception

The lone peer-reviewed article that downplayed, rather than emphasized, the need for vegans to supplement their diets with B12 was by Immerman1 (1981). Immerman reviewed 13 case studies in which a vegan was found to have B12 deficiency. He lists a number of criteria which he claims must be used to determine a true B12 dietary deficiency versus a different problem such as:

Malabsorption via:

Inadequate protein, calories, or folate Radiation, drugs and toxins (neomycin, colchicine, para-amino salicylic acid, alcohol) Pancreatic tumor Failure of the small intestine to contract and move food associated with bacterial overgrowth Oral contraceptives

Increased excretion due to liver or kidney disease Tobacco smoking Vitamin B6 or iron deficiency

None of the case studies listed by Immerman met all of his criteria. He was particularly critical of the idea that a dietary B12 deficiency exists if B12 symptoms improve upon B12 injections rather than oral tablets. However, because the authors of earlier case studies were interested in helping the patients rather than proving whether vegans should take B12, they used injections, the common method of clearing up B12 deficiency quickly. The injections helped their patients.

Immerman says that low B12 levels should not be used to determine a B12 deficiency. By this criterion, he says "t would be necessary to characterize not only most Western vegetarians but also much of the population of India and other Eastern countries as deficient; this is clearly unacceptable." In recent years, numerous studies (presented here) show that much of the world's vegetarian population who do not supplement with B12 could improve their B12 status resulting in health benefits.

Immerman says that cooking destroys significant amounts of B12 and that consuming primarily raw foods could increase one's intake of B12. Future studies have shown that vegan raw foodists do not appear to have an advantage over other vegetarians.

Immerman states, "[M]any studies have found apparently adequate B12 status in individuals consuming [a vegetarian or vegan] diet, although the investigations in some of these studies have been incomplete. It must be concluded, therefore, that pure dietary B12 deficiency in all classes of vegetarians is the exception rather than the rule."

Immerman was writing in 1981, before the great majority of the studies included in this article were published and before much was known about homocysteine. While it is true that the worst cases of B12 deficiency listed by Immerman and here were sometimes aggravated by other health problems, it seems likely that had these vegans been taking oral B12, the problems never would have become so severe, and in many cases, never would have occurred at all. In many of the cases, B12 deficiency was immediately cleared up through oral B12.

In the end, even Immerman suggests that vegetarians have their B12 levels checked every 4-5 years. It would be more prudent, and easier, to take B12 supplements or eat fortified foods. Why wait 4-5 years for a doctor to tell you what you should have been doing all along?

Analysis of Immerman's Paper

A more rigorous analysis of Immerman's paper appears online in the article Comparative Anatomy and Physiology Brought Up to Date, by Tom Billings at BeyondVeg.com.

Notes for Immerman: The Exception

1. Immerman AM. Vitamin B12 status on a vegetarian diet: A critical review. World Rev Nutr Diet. 1981;37:38-54.

Measuring B12: Why the Confusion?

Summary: Inactive B12 analogues in plant foods compromise the accuracy of traditional methods used to determine the vitamin B12 amounts and activity of a food. Bacterial contamination of a food can create the false impression that all such foods contain B12 analogues. The only reliable way to determine if a food is a source of active B12 is to test various batches of that food to see if it reduces methyl malonic acid (MMA) levels in humans.

B12 Amounts Versus B12 ActivityIt is important to distinguish between the amounts of B12 in a food, and the B12 activity of a food. There are a number of ways that have traditionally been used to measure B12 amounts:

Microbiological Assay R-protein Assay Intrinsic Factor Assay Paper Chromatography

There are also a number of ways to measure B12 activity:

Macrocytic Anemia Improvements Homocysteine Reduction Methyl Malonic Acid (MMA) Reduction

Methods for Measuring Amounts of B12

Microbiological Assay

Microbiological assays use a process in which B12 is measured by "feeding" a food to certain B12-dependent bacteria and measuring how well they grow. Various test organisms for measuring B12 have been used:

Test Organisms for B12 Microbiological Assays

Organism

Organism

Notes

Escherichia coli mutant 113-31

bacteria

Not recommended because it responds to so many inactive B12 analogues.1

Lactobacillus leichmannii 3261

bacteria

May utilize some inactive B12 corrinoids.1

Lactobacillus delbrueckii ATCC 7830152

bacteria

New name for Lactobacillus leichmannii2

Euglena gracilis Z-alga1

protozoa

May utilize some inactive B12 corrinoids.1

Ochromonas malhamensis1

protozoa

Most specific for cobalamins.1

Arthrobacter Lochhead 38

bacteria

A 1959 study showed it to be similar to O. malhamensis.3

Some or all of these bacteria thrive on various inactive B12 analogues, making them unreliable for measuring the B12 content of plants, which often contain a variety of inactive B12 analogues. Despite this, many laboratories, especially those of private companies who want to market their product as containing B12, still use the less reliable of these methods when measuring the B12 content of plant foods and seaweeds.

Notes for Microbiological Assay

1. Schneider Z, Stroinski A. Comprehensive B12. New York: Walter de Gruyter, 1987.

2. Watanabe F, Takenaka S, Kittaka-Katsura H, Ebara S, Miyamoto E. Characterization and bioavailability of vitamin B-12-compounds from edible algae. Journal Of Nutritional Science And Vitaminology. 2002(Oct);48(5): 325-331.3.

3. Goldberg MK, Hutner SH, Ford JE. Nutrition of a cobalamin-requiring soil bacterium. Can J Microbiol. 1959;3:329-334.

R-protein AssayThe R-protein assay measures the B12 analogue content of a food by seeing how much will bind to R-protein, which is a B12 transport protein found in the mouth and other places. R-protein is known to bind to inactive B12 analogues.Intrinsic Factor Assay The Instrinsic Factor (IF) assay measures the B12 analogue content of a food by seeing how much will bind to IF, which is a B12 transport protein secreted by the stomach. For a few years, it was thought that IF only binded to active B12 analogues. In fact, the difference in amounts between an R-protein and an IF assay was thought to tell how much inactive B12 analogue a food contained.

Intrinsic Factor Assay Shown to be Unreliable in Humans

Dagnelie et al.1 (1991, Netherlands) quickly changed the thought that intrinsic factor assays can predict the contribution of foods to B12 status. Macrobiotic toddlers (14-26 months old) with B12 deficient anemia (serum B12 < 184) were given foods that had been found to have some B12 analogue using IF assays. According to Dagnelie, as little as 0.1 µg/day of B12 can lead to a full therapeutic response in 1 month.1 4-6 months after eating these foods their serum B12 levels had increased, but the anemia was worse in the vegan children:

Results of Dagnelie et al.1

subject

µg/day of B12 analogue given

B12 analoguesource

anemia(MCV)

vegans

1

2.7

spirulina, nori

worse

2

2.1

spirulina, nori

worse

3

1.5

nori

worse

4

0.3

nori

worse

5

0.1

sourdough bread, kombu, barley malt syrup

worse

non-vegans

6

1.5 / 0.5

algae / fish & milk

better

7

0.3

fish

better

8

0.2

fish

better

9

0.2

fish, milk

better

10

0.15

fish, nori

worse

11

0.2

supplement, fish, nori

worse

MCV - Mean Corpuscular Volume

A likely explanation for the poor response is that nori, spirulina, and kombu either contained no active B12 or they contained enough inactive B12 analogue that it overcame the active B12, producing an overall negative effect. Dagnelie et al. say, "It seems unjustified to advocate algae and other plant foods as a safe source of vitamin B12 because its bioavailability is questionable." It should be noted that, based on a more recent study, intakes as high as .3 µg/day for infants 6-16 months old are probably not enough to prevent B12 deficiency (based on MMA levels).2 Thus, some of the patients in Dagnelie et al.'s study above may have needed more B12 for a positive response. Degnalie et al's study showed that it is important to measure a food's B12 activity in humans rather than to rely only on measurements of B12 amounts using assays. You simply do not know for sure until you test the food. To make things more

complicated, batches of some foods may have B12 from bacterial contamination, while other batches of the same food do not. Tempeh is an example.

Notes for Intrinsic Factor Assay Shown to be Unreliable in Humans

1. Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991;53:695-7.

2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

Ochromonas malhamensis Fares Better than an Intrinsic Factor AssayBaker et al.151 compared Ochromonas malhamensis to an IF assay and found that IF gave a 44% higher reading than Ochromonas malhamensis. The authors suggest that O. malhamensis may be the most effective of the various assays at measuring metabolically active B12. Unfortunately, only one study on B12 in plant foods has used O. malhamensis . Still, it is not know whether O. malhamensis growth is an accurate measurement of B12 activity in humans.

Notes for Ochromonas malhamensis Fares Better than an Intrinsic Factor Assay

1. Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991;53:695-7.

2. Baker H, O, Khalil F, DeAngelis B, Hutner SH. Determination of metabolically active B12 and inactive B12 analog titers in human blood using several microbial reagents and a radiodilution assay. J Am Coll Nutr. 1986;5(5):467-75.

Paper Chromatography For simplicity, paper chromatography is the term used here to refer to an array of methods that when combined can provide a fairly precise determination of the exact structure of a molecule. These methods are more reliable than those mentioned above, but are difficult to perform. Furthermore, they cannot tell the actual B12 activity of a given plant food as a whole; they can only look at the parts.

Methods for Measuring B12 Activity of a Food

Macrocytic Anemia ImprovementsB12-deficiency can cause macrocytic anemia (large red blood cells). However, folate deficiency can do the same. If someone with macrocytic anemia is known to have adequate folate status, and is fed a food thought to have B12, and their anemia improves, it is a fairly safe bet that the food has some B12-activity for red blood cells. Unfortunately, it is not know for sure if B12 that is active for blood cells is always active for nerve cells. See the section Inactive Analogues: Worse than Useless in Vitamin B12 Analogues.

Homocysteine Reduction B12-deficiency can cause elevated homocysteine levels in the blood. However, folate and vitamin B6 deficiency can do the same. Reducing homocysteine levels might give a good idea as to the B12 activity of a food, but because folate and B6 can confound the results, it is not the safest test for determing B12 activity.Methyl Malonic Acid (MMA) Reduction: The Gold Standard Because the biochemical pathway that reduces MMA levels in the blood uses only vitamin B12, lowering MMA levels is a test that is specific for B12 activity. Although it is not known for sure, it likely that this biochemical pathway is an integral part of B12's nerve tissue function(s). Thus, if a food lowers MMA levels, it can be assumed to provide full B12 activity.

Bacterial Contamination Because some bacteria produce B12 and might live in the growing medium or contaminate some foods (e.g., see section on tempeh) it is not enough simply to test a food one time to see if it reduces MMA levels. Numerous batches of the food from various regions, using various preparation methods, should be tested to make sure the B12 is consistently found in the food.

B12 in Tempeh, Seaweeds, Organic Produce, and Other Plant Foods

Summary: The only plant foods which have been tested for B12 activity using the gold standard of lowering MMA levels in humans are dried and raw nori from Japan. Dried nori made MMA status worse, indicating that it can reduce B12 status and can possibly harm people who are B12-deficient. Raw nori kept MMA levels about the same, indicating that it didn't harm B12 status, but it did not help either.

No food in Europe or the U.S. has been tested for lowering MMA levels. Thus, the discussion about whether Western vegans can get B12 from plant foods can, and probably should, end here (until proper research is conducted). Because so many plant foods have failed other tests that do not measure up to the MMA lowering test, and because there are so many false rumors being passed around, the studies of B12 in plant foods are examined in detail below.Of all the foods studied below, only tempeh in Indonesia or Thailand, dulse, Chlorella, raw nori, and coccolithophorid algae warrant much further attention for providing B12. Unless these foods are shown consistently to correct B12 deficiency, vegans should not rely on them as a B12 source.Skip to next section.

Contents of B12 in Tempeh, Seaweeds, Organic Produce, and Other Plant Foods

Introduction Plant Foods with Practically No Detectable B12 Analogue Tempeh

Seaweeds

Various Seaweeds: Dulse Warrants Further Study Aphanizomenon Flos-aquae Chlorella Spirulina Nori Coccolithophorid Algae A Case of False Reporting on Seaweed and Fermented Foods' Benefit Genmai-Saishoku Paradox?

Soil and Organic Produce as a B12 Source for Vegans

B12 Analogue in Soil Plants Fertilized with Human Manure Organic Produce as a B12 Source for Vegans

Soybean Plants Absorb B12 Plants Absorb B12 Analogue when Fertilized with Cow Dung Conclusion about Organic Produce as a B12 Source for Vegans

IntroductionIt would be great to find a reliable plant source of B12 for vegans. One might get the opposite impression given my level of critique of some of these studies. My skepticism is only due to the potential harm from relying on a food that contains inactive B12 analogues which can make a B12 deficiency even worse. There has been a long history of misconceptions about which, if any, plant foods are sources of B12. Much of this stems from the methods of measuring B12 analogues. Other confusion stems from bacterial contamination that occurs in some foods but not others. Please see Measuring B12 in Plant Foods: Why the Confusion? for an explanation of the methods for for measuring B12 analogues in plant foods. Unlike animals, most, if not all, plants have no B12 requirement for any function, and therefore have no active mechanisms to produce or store

B12. Many seaweeds have been shown to have B12 analogues. (Note: Most seaweeds are algae, which are technically not plants.) It is not clear whether the algae make the B12 analogues or whether they absorb the B12 analogues from their environment.1 During the 1970s, two enzymes in plants (potatoes and bean seedlings) were found to respond to the addition of adenosylcobalamin2,3 (a co-enzyme form of B12). One explanation is that adenosylcobalamin provides some factor that is usable by these enzymes, but that adenosylcobalamin is not required by these plants for growth. Thus far, these plants have not been shown to counteract B12 deficiency symptoms (though I am not aware of any well-designed attempts as it is assumed that they do not contain B12). It is probably safe to assume that many vegans who have developed severe B12 deficiency ate potatoes and beans. There are some rumors, though no evidence of which I am

aware, that if you let organic produce, such as carrots, sit at room temperature for a few hours, bacteria on the surface of the carrots will produce B12. For this to happen, specific species of bacteria would be required, as would cobalt. Until there is research showing that such a method can lower MMA levels, such produce should not be considered to provide B12.

Notes for Introduction

1. Watanabe F, Katsura H, Takenaka S, Fujita T, Abe K, Tamura Y, Nakatsuka T, Nakano Y. Pseudovitamin B(12) is the predominant cobamide of an algal health food, spirulina tablets. J Agric Food Chem. 1999 Nov;47(11):4736-41.

2. Poston JM. Coenzyme B12-dependent enzymes in potatoes: leucine 2,3-aminomutase and methylmalonyl-coa mutase. Phytochemistry. 1978;17:401-402.

3. Poston JM. Leucine 2,3-aminomutase: a cobalamin-dependent enzyme present in bean seedlings. Science. 1977;195:301-302.

Plant Foods with Practically No Detectable B12 Analogue Various studies have tested the foods in the table below for B12 analogues and found none. To my knowledge, other than in Mozafar's studies (below) in which B12 and cow dung were carefully added to the soil of potted plants, no published study has shown any B12 analogues in any of these foods.

Foods with No Detectable B12 Analogue

amesake rice1

barley miso1

miso2

natto2

rice miso1

shoyu1

tamari1

umeboshi prunes1

various fruits, vegetables, nuts,seeds, & grains2

The following table shows the B12 analogue content of various plant foods:

B12 Analogue Content (µg/30 g) of Various Foods

Country

Netherlands1

Thailand2,3

Assay

IF

IF or R-proteinA

fermented soybean

0.15

barley malt syrupsourdough bread parsleyshiitake mushrooms

..006-0.1Only info given

dried fermented soybean

0.01

tofu

ND

0.02

soybean paste

0.03

soy sauce

..01B

A - Used an assay method by Lau et al.57 (1965) which uses R-protein or IFB - µg/30 mlIF - Intrinsic Factory Assay ND - None Detected

As you can see, there are very small amounts, if any. Since the amounts are so small, any inactive analogues should not significantly interfere with an individual's active B12 from other sources, and if the analogue is active B12, it will not provide much. Thus, these foods should neither add to, nor detract from, a vegan's B12 status.

Notes for Plant Foods with Practically No Detectable B12 Analogue

1. van den Berg H, Dagnelie PC, van Staveren WA. Vitamin B12 and Seaweed. Lancet Jan 30, 1988.

2. Areekul S, Churdchu K, Pungpapong V. Serum folate, vitamin B12 and vitamin B12 binding protein in vegetarians. J Med Assoc Thai 1988 May;71(5):253-7.

3.Areekul S, Pattanamatum S, Cheeramakara C, Churdchue K, Nitayapabskoon S, Chongsanguan M. The source and content of vitamin B12 in the tempehs. J Med Assoc Thai 1990 Mar;73(3):152-6.

Tempeh For a long time, tempeh has been said to contain B12. Table A.3 shows the results of measuring B12 analogue in various tempehs.

B12 Analogue Content (µg/30 g) of Tempehs

Country

Netherlands1

USA2

Indonesia3,4

Assay

IF

IF

IF or R-proteinA

tempeh

ND

..02C

..054-1.2B

A - Used an assay method by Lau et al.57 (1965) which uses R-protein or IFB - 10 commercial tempeh samples purchased from various markets in Jakarta, IndonesiaC - Cooked for 60 minutesIF - Intrinsic FactoryND - None Detected

The studies in the USA and in The Netherlands showed little to no B12 analogue.In contrast, Areekul et al.4 (1990, Indonesia/Thailand) found more significant amounts of B12 analogue. Tempeh production requires molds belonging to the genus Rhizopus. These were found not to produce B12 analogues in Areekul et al's study. Rather, a bacterium, identified as Klebsiella pneumoniae, was isolated from the commercial tempeh starter and determined to be the B12 analogue source. This confirmed Albert et al.'s5 (1980) finding that the Klebsiella genera could produce B12 analogues. In Albert's study, the analogue was thought to be active B12. Whether the analogues found by Areekul et al. were the same as in Albert's study is not known. Given that K. pneumoniae is not required for tempeh production, we can conclude that the B12 analogue found in the tempeh's in Indonesia were due to bacterial contamination (though

apparently common there). Tempeh in Europe and the U.S. cannot be relied on as a source of B12. Until tempeh in Indonesia are shown to reduce MMA levels, it should not be relied upon there, either.

Notes for Tempeh

1. van den Berg H, Dagnelie PC, van Staveren WA. Vitamin B12 and Seaweed. Lancet Jan 30, 1988.

2. Specker BL, D, Norman EJ, Greene H, KC. Increased urinary methylmalonic acid excretion in breast-fed infants of vegetarian mothers and identification of an acceptable dietary source of vitamin B-12. Am J Clin Nutr 1988 Jan;47(1):89-92.

3. Areekul S, Churdchu K, Pungpapong V. Serum folate, vitamin B12 and vitamin B12 binding protein in vegetarians. J Med Assoc Thai 1988 May;71(5):253-7.

4. Areekul S, Pattanamatum S, Cheeramakara C, Churdchue K, Nitayapabskoon S, Chongsanguan M. The source and content of vitamin B12 in the tempehs. J Med Assoc Thai 1990 Mar;73(3):152-6.

5. Albert MJ, Mathan VI, Baker SJ. Vitamin B12 synthesis by human small intestinal bacteria. Nature 1980;283(Feb 21):781-2.

Seaweeds

Various Seaweeds: Dulse Warrants Further StudyThe following tables show the B12 analogue content of arame, dulse, hijiki, kelp, kombu, and wakame per 30 g of seaweed. Please note that 30 g is a lot of seaweed. A serving size would be closer to 3 grams. Seaweeds also tend to be very high in iodine, which can cause problems at high intakes. So, consuming mass quantities of seaweed is unadvisable.

B12 Analogue Content (µg/30 g) of Various Seaweeds

Country

Netherlands1

USA2

Assay

IF

L. leich.

IF

arame

0.042

dulse (Palmaria palmata)

3.9

3

hijiki

< .006

< .006

kelp

1.2

0.12

kombu

0.84

0.018

..57-1.3A

wakame

1.4

0.009

1.29B

IF - Intrinsic Factory AssayA - Range of 5 samples of 3 different brands, with 3 samples cooked for 60 minutesB - Cooked for 60 minutes

The only seaweed in this list that warrants further study is dulse (also spelled "dulce"), which contains .3 to .39 µg of B12 analogue per 3 g serving. Unless dulse is eventually shown to lower MMA levels, it should not be considered a source of active B12.

Notes for Various Seaweeds

1. van den Berg H, Dagnelie PC, van Staveren WA. Vitamin B12 and Seaweed. Lancet Jan 30, 1988.

2. Specker BL, D, Norman EJ, Greene H, KC. Increased urinary methylmalonic acid excretion in breast-fed infants of vegetarian mothers and identification of an acceptable dietary source of vitamin B-12. Am J Clin Nutr 1988 Jan;47(1):89-92.

Aphanizomenon Flos-aquae Cell Tech and some other companies market algae from Klamanth Lake in Oregon. Cell Tech markets a species, Aphanizomenon flos-aquae, they call Super Blue Green Algae (SBGA). On April 16, 2003, Cell Tech's site stated:

"Is the vitamin B12 in SBGA bioavailable and bioactive? "Yes. The Super Blue Green Algae (SBGA) strain, Aphanizomenon flos-aquae, has been tested by Lancaster Labs for B12 analog levels using microbiological testing methods that are comparable to methods 952.20 and 960.46 of the Association of Analytical Chemists (AOAC). "Unlike other plant foods such as Spirulina, which contain corrinoids with virtually no vitamin B12 activity, Aphanizomenon flos-aquae is a reliable source for vegetarians seeking to supplement their diets with a bioactive form of this important nutrient."

However, test methods 952.20 and 960.46 use Lactobacillus leichmannii,1 which can measure non-B12 corrinoids.2 See the table Test Organisms for B12 Microbiological Assays in Measuring B12: Why the Confusion? Thus, it can only be concluded that Cell Tech's SBGA contains B12 analogues whose activity is yet to be determined.

Notes for Aphanizomenon Flos-aquae

1. Helrich K, ed. Official Methods of Analysis, Volume 2: Food Composition; Additives; Natural Contaminants, 15th Edition. Arlington, VA: Association of Official Analytical Chemists, Inc; 1990.

2. Schneider Z, Stroinski A. Comprehensive B12. New York: Walter de Gruyter, 1987.

Chlorella

Pratt & 1 (1968, USA) studied numerous batches of chlorella and occasionally found amounts of B12 analogue that were in the range of error for the test method. In other words, they were not able to detect practical amounts. They noted that their extraction processes might not have been adequate though they used many different methods. They also noted that their synthetic medium on which the chlorella was grown might have interfered with B12 analogue synthesis.

Kittaka-Katsura et al.2 (2002, Japan) measured B12 analogue levels in Chlorella using both a Lactobacillus leichmannii ATCC 7830 and an intrinsic factor assay. Both methods showed about the same amount of B12 analogue, listed in the table below:

Chen and Jiang3 (2008, Taiwan) used capillary electrophoresis to detect cyanocobalamin and hydroxocobalamin in chlorella. Capillary electrophoresis is relatively new method that should be able to detect the exact structure of a cobalamin analogue. They found considerable amounts of cyanocobalamin in two samples of Chlorella, with negligible amounts of B12 analogues.

B12 Analogue Content (µg/30 g) of Chlorella

Country

USA1

Japan2

Taiwan3

Assay

E. gracilis & O. malhamensis

L. leich.

IF

Capillary Electrophoresis

Chlorella vulgaris

ND

Chlorella pyrenoidosa

ND

Chlorella sp.

60.4 - 85.7

60.1 - 63.5

3.9

11.4

IF - Intrinsic Factor

Until chlorella is tested on humans to determined whether it lowers MMA levels, it should not be considered to be a reliable source of vitamin B12, especially since the study by Pratt & 1 showed no vitamin B12.

Notes for Chlorella

1. Pratt R, E. Deficiency of vitamin B12 in Chlorella. J Pharm Sci. 1968 Jun;57(6):1040-1.

2. Kittaka-Katsura H, Fujita T, Watanabe F, Nakano Y. Purification and characterization of a corrinoid compound from Chlorella tablets as an algal health food. J Agric Food Chem. 2002 Aug 14;50(17):4994-7. (Abstract)

3. Chen JH, Jiang SJ. Determination of cobalamin in nutritive supplements and chlorella foods by capillary electrophoresis-inductively coupled plasma mass spectrometry. J Agric Food Chem. 2008 Feb 27;56(4):1210-5. Epub 2008 Feb 2.

SpirulinaThe following table shows the B12 analogue content (µg/30 g) of various spirulina batches:

B12 Analogue Content (µg/30 g) of Spirulina

Country

Netherlands1

USA2

Japan3

Assay

IF

L. leich.

IF

L. leich.

L. leich.

IF

PC

spirulina

14.5

67

36.7

193.1

73

2.5

0.44

spirulina

6

35.3

38

1.9

0.32

spirulina

1.67

8.7

44

5.2

0.88

IF - Intrinsic Factory AssayPC - Paper Chromotography Assay

The wide range of B12 analogues from one measurement method to another indicates that spirulina has a wide variety of different analogues, many of which are inactive. Some may interfere with B12 activity in humans.

Notes for Spirulina

1. van den Berg H, Dagnelie PC, van Staveren WA. Vitamin B12 and Seaweed. Lancet. Jan 30, 1988.

2. Herbert V, Drivas G. Spirulina and Vitamin B12. JAMA. 1982;248(23):3096-7.

3. Watanabe F, Katsura H, Takenaka S, Fujita T, Abe K, Tamura Y, Nakatsuka T, Nakano Y. Pseudovitamin B(12) is the predominant cobamide of an algal health food, spirulina tablets. J Agric Food Chem. 1999 Nov;47(11):4736-41.

NoriThe table below shows the B12 analogue content of various nori types and batches:

B12 Analogue Content (µg/30 g) of Nori

Country

Netherlands1

Japan2

Japan3

Assay

IF

L. leich.

L. leich.

IF

E. Coli 215

IF

PC

nori (P. umbilica)

3.6

nori (P. tenera)

5.4-12.9A

nori (purple, Porphyra sp)

9.7

7.5

nori (green, Enteromorpha sp)

19.1

21

nori (P. tenera)

20.1

20.1

dried nori (P. tenera)

4.3

< 4.3

1.5

raw nori (P. tenera)

3.8

~ 3.8

2.7

A - Range of 3 different samplesIF - Intrinsic Factory AssayPC - Paper Chromotography Assay

Various batches of nori were found to contain significant amounts of B12 analogue. One study verified the molecular weight through paper chromotagraphy, indicating that there is a good chance that some of this B12 is active. Yamada et al.4 (1996, Japan) determined that nori contains what they considered to be active B12 analogues using various assays and methods (results not reported here). However, in light of Dagnelie's results, Yamada et al.3(1999, Japan), decided to test the nori to see if it could reduce methylmalonic acid (MMA) levels, the gold standard for determining the B12 activity of a food: Raw nori was purchased within 48 hours of harvesting. Dried nori was purchased from a store. Inactive vs. active B12 was determined by IF assay and confirmed by paper chromatography. 10 people (all nonvegetarian) were then studied. The results were:

Yamada et al.'s3 Study of Nori's Impact on urine MMA Levels

N

B12 found tobe analogue

amount

duration

uMMA

dried nori

6

65%

40 g (20 sheets)A

6-9 days

increased 77% SS

raw nori

4

27%

320 g/day A

3-6 days

increased 5% NS

A - Equivalent amountsNS - Not statistically significantSS - Statistically significantN - Number of people tested

The results indicate that B12 in raw nori can be changed into harmful inactive B12 analogues by drying, and that dried nori decreases B12 status. Yamada et al. said that although dried nori cannot be used as a B12 source, in small amounts it is not harmful. However, they believe that raw nori is an excellent source of genuine B12.I disagree with their conclusion that raw nori is an excellent source of active B12. While eating raw nori, the subjects'uMMA levels increased 5%. While this was not enough of an increase to be statistically significant, it indicates that the raw nori did not improve B12 status (which would have required MMA levels to drop, rather than increase). This study showed that this batch of raw nori did not have enough inactive B12 versus active B12 analogue to be considerably detrimental, but it did not prove any benefit. The study by Yamada et al. was further confounded by adding valine (an amino

acid that can be converted into MMA when B12 is deficient) to the subjects' diet in order to increase MMA levels so that a difference could be seen. The valine did not appear to do this when given without the nori, and no control groups were included, making the results even more difficult to interpret. Another study (Watanabe et al., 2000) was conducted measuring the B12 analogue content of purple nori (results not reported here).5 The researchers did not test the nori to see if it could lower MMA levels.

Notes for Nori

1. van den Berg H, Dagnelie PC, van Staveren WA. Vitamin B12 and Seaweed. Lancet. Jan 30, 1988.

2. Watanabe F, Takenaka S, Katsura H, Masumder SA, Abe K, Tamura Y, Nakano Y. Dried green and purple lavers (Nori) contain substantial amounts of biologically active vitamin B(12) but less of dietary iodine relative to other edible seaweeds. J Agric Food Chem. 1999 Jun;47(6):2341-3.

3. Yamada K, Yamada Y, Fukuda M, Yamada S. Bioavailability of dried asakusanori (porphyra tenera) as a source of Cobalamin (Vitamin B12). Int J Vitam Nutr Res. 1999 Nov;69(6):412-8.

4. Yamada S, Shibata Y, Takayama M, Narita Y, Sugawara K, Fukuda M. Content and characteristics of vitamin B12 in some seaweeds. J Nutr Sci Vitaminol (Tokyo). 1996 Dec;42(6):497-505. (Abstract)

5. Watanabe F, Takenaka S, Katsura H, Miyamoto E, Abe K, Tamura Y, Nakatsuka T, Nakano Y. Characterization of a vitamin B12 compound in the edible purple laver, Porphyra yezoensis. Biosci Biotechnol Biochem. 2000 Dec;64(12):2712-5. (Abstract)

Coccolithophorid Algae Coccolithophorid algae (Pleurochrysis carterae) is being used in Japan as a calcium supplement. Miyamoto et al.1 (2001, Japan) analyzed it for B12 analogue content:

B12 Analogue Content (µg/30 g) of Coccolithophorid Algae

Country

Japan1

Assay

IF

L. delbrueckii

coccolithophorid algae (Pleurochrysis carterae)

37.6

37.6A

A - Study said the amount was "identical" to that found with IF; the number was not actually givenA - Equivalent amountsIF - Intrinsic Factor

They tried to verify whether it is an active form of B12 through liquid chromatography, and thought that is was. B12 analogue remained stable for 6 months of storage. They later followed up with a second study on coccolithophorid algae,2 but still did not test it to see if it can lower MMA levels in humans.This algae deserves further attention to see if it can lower MMA levels.

Notes for Coccolithophorid Algae

1. Miyamoto E, Watanabe F, Ebara S, Takenaka S, Takenaka H, Yamaguchi Y, Tanaka N, Inui H, Nakano Y. Characterization of a vitamin B12 compound from unicellular coccolithophorid alga (Pleurochrysis carterae). J Agric Food Chem. 2001 Jul;49(7):3486-9.

2. Miyamoto E, Watanabe F, Takenaka H, Nakano Y. Uptake and physiological function of vitamin B12 in a photosynthetic unicellular coccolithophorid alga, Pleurochrysis carterae. Biosci Biotechnol Biochem. 2002 Jan;66(1):195-8. (Abstract)

A Case of False Reporting on Seaweed and Fermented Foods' Benefit Specker et al.1 (1988, USA) reported a macrobiotic mother of an infant with a uMMA of 146 µg/mg who modified her diet by increasing her consumption of seaweeds and fermented foods. The infant's uMMA dropped to 27 µg/mg in 2 months and to 13 µg/mg in 4 months. It was later discovered that this mother had also eaten fish and clam broth which were probably responsible for the improvement rather than the seaweeds and fermented foods.2 Specker et al. stated, "The vegetarian community we worked with believed fermented foods in their diet contained adequate amounts of vitamin B12." However, on analysis, the fermented foods were shown not to have B12.1

Notes for A Case of False Reporting

1. Specker BL, D, Norman EJ, Greene H, KC. Increased urinary methylmalonic acid excretion in breast-fed infants of vegetarian mothers and identification of an acceptable dietary source of vitamin B-12. Am J Clin Nutr. 1988 Jan;47(1):89-92.

2. Dagnelie PC, van Staveren WA, van den Berg H. Vitamin B-12 from algae appears not to be bioavailable. Am J Clin Nutr. 1991;53:695-7.

Genmai-Saishoku Paradox? Suzuki1 (1995, Japan) studied 6 vegan children eating a genmai-saishoku (GS) diet, which is based on high intakes of brown rice and contains plenty of sea vegetables, including 2-4 g of nori per day ("dried laver"); as well as hijiki, wakame, and kombu. The foods are organically grown and many are high in cobalt (buckwheat, adzuki beans, kidney beans, shiitake, hijiki). Serum B12 levels of the children are shown:

Results of Suzuki.1

age (yrs)

years vegan

serum B12

7.1

4.4

520

7.7

4.4

720

8.6A

8.6

480

8.8A

8.8

300

12.7

10

320

14.6

10

320

average

443 (± 164)

A - Exclusively breast-fed until 6 months old. Mothers had been vegan for 9.6 and 6.5 yrs prior to conception. Both mothers consumed 2 g of nori per day.

None of the many measurements between the vegans and 4 nonvegan controls were significantly different, including serum B12, MCV, and iron indicators. MMA and homocysteine levels were not measured. Some suggestions as to how the vegans got their B12 are:

From nori or the other seaweeds. The nori was most likely dried. Small amounts of B12 from B12 uptake or contamination of plants grown in manure. B12 from their mother's stores.

These results are both interesting and perplexing. The serum B12 levels are easy to explain as possibly being inactive B12 analogues. But it is particularly impressive that the eight-year-olds were doing well given that their mothers had been vegan for some time, supposedly without B12-fortified foods or supplements. Unfortunately, many vegan children have not had the same positive results and until more is known about the GS children's diets, this study should be considered an unsolved mystery. If these children were my own, I would make sure they started to get at least a modest B12 supplement to ensure their continue good health.

Notes for Genmai-Saishoku Paradox?

1. Suzuki H. Serum vitamin B12 levels in young vegans who eat brown rice. J Nutr Sci Vitaminol 1995;41:587-594.

Soil and Organic Produce as a B12 Source for Vegans It is common in vegan circles to hear that if your produce has soil on it and you do not wash the produce before eating it, bacteria that lives in the soil and on the produce will provide B12. It is also claimed that in today's world, our food supply is very sanitized whereas in the past, vegan humans would have received plenty of B12 from the unsanitized produce. What is the evidence for these claims?

B12 Analogue in Soil There is a one paragraph report often cited in vegan literature for showing that B12 is found in the soil. Robbins et al.1 (1950, New York Botanical Gardens) used Euglena gracilis var. bacillari as a microbiological assay for vitamin B12 "or its physiological equivalent." A considerable proportion of bacteria and actinomycetes (molds) in the soil were found to synthesize B12 analogues. B12 analogues were also found in the roots of plants (.0002-.01 µg B12/g of fresh material). Some stems had some B12 analogue, but leaves and fruit generally did not. B12 analogue was also found in pond water and pond mud. There was no indication in the report as to how many different soils were tested, but the impression was that it was all in one local area. There is no way to know whether these molecules were active or inactive B12 analogues.

Notes for B12 Analogue in Soil

1. Robbins WJ, Hervey A, Stebbins ME. Studies on Euglena and vitamin B12. Science 1950(Oct 20):455.

Plants Fertilized with Human Manure Herbert1 (1988) reports that in 1959, some Iranian vegans were found to be growing plants in night soil (human manure). The vegetables were eaten without being carefully washed and the amount of B12 was enough to prevent deficiency. However, for this information, Herbert cites Halstead et al. (1959),2 who do not mention these Iranians in their paper. Strauss, science reporter with the Globe and Mail newspaper in Toronto, tried to track down this story. He spoke with Halstead's son, who said his father never performed such a study.3 Thus, at this time, this anecdote should be considered unsubstantiated.

Notes for Plants Fertilized with Human Manure

1. Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr. 1988;48:852-8.

2. Halsted JA, Carroll J, Rubert S. Serum and tissue concentration of vitamin B12 in certain pathologic states. N Engl J Med. 1959;260:575-80.

3. Personal communication with Strauss via e-mail. July 16, 2001.

Organic Produce as a B12 Source for Vegans

Soybean Plants Absorb B12

Mozafar & Oertli1 (1992, Switzerland) added cyanocobalamin to the soil of soybean plants in amounts ranging from 10 to 3200 µmol/l. Using an intrinsic factor assay, 12-34% of the B12 was absorbed by the plants. 66-87% of the absorbed vitamin remained in the roots and the rest was transported to the various other parts, mainly the leaves. Mozafar points out that the concentrations of B12 in the soil used in this study were many times higher than the reported vitamin concentration in soil solution (.003 µmol/l) measured by Robbins83 (mentioned above in section 15.1).

Notes for Soybean Plants Absorb B12

1. Mozafar A, Oertli JJ. Uptake of microbially-produced vitamin (B12) by soybean roots. Plant and Soil. 1992;139:23-30.

Plants Absorb B12 Analogue when Fertilized with Cow Dung In light of the above results, Mozafar71 (1994, Switzerland) then studied how the B12 levels in plants are affected by adding cow dung to the soil. An assay using pig intrinsic factor was used to measure the B12 analogue. The study looked at the B12 analouge content of both organically fertilized soil and plants. Two samples were taken from soil that had been treated with organic fertilizer every 5 years over the previous 16 years. The B12 analogue in these samples were compared to soil that had only synthetic fertilizer applied. Results were:

B12 Analogue in Soil1

Sample 1(µg/kg)

Sample 2(µg/kg)

synthetically fertilized soil

9

5

organically fertilized soilA

14

10

A - Treated with organic fertilizer once every 5 years

Soybean, barley, and spinach plants were then grown in pots of 2.5 kg of soil. 10 g dry cow manure was added to each pot. Plant parts were thoroughly washed to remove any soil before B12 was measured. Results were:

B12 Analogue (ng/g) in Plants1

nothing addedto soil

"organic"(10 g dry cow manure added)

soybeans

1.6

2.9

barley kernels

2.6A

9.1A

spinach

6.9B

17.8B

A,B - Statistically significant difference between groups with same letters

Further analysis showed that most or all of the B12 analogue in the plants was unbound. Mozafar concluded that plant uptake of B12 from the soil, especially from soil fertilized with manure, could provide some B12 for humans eating the plants, and may be why some vegans, who do not supplement with B12, do not develop B12 deficiency. Does this mean that organic foods are a good source of B12? No. These studies show that when B12 analogues are placed in the soil, plants can absorb them.

Notes for Plants Absorb B12 Analogue when Fertilized with Cow Dung

1. Mozafar A. Enrichment of some B-vitamins in plants with application of organic fertilizers. Plant & Soil. 1994;167:305-311.

Conclusion about Organic Produce as a B12 Source for Vegans Unless uncleaned, organic produce is shown to lower MMA levels, it is unjustified to claim that B12 can be obtained in such a manner, or to claim with certainty that humans have ever relied on it as a source of B12. Only until organic foods are chosen randomly from markets and grocery stores throughout the country (or world) and are consistently shown to decrease MMA levels will someone not be taking a considerable risk in relying on organic foods for B12. This article documents many vegans suffering from B12 deficiency, and it is safe to assume that many of them consumed significant amounts of organic foods.Additional note: The vegan movement is typically not aiming for a world where there are enough cows to produce a significant amount of manure for fertilizer.

Are Intestinal Bacteria a Reliable Source of B12?

Summary: Given that many otherwise healthy vegans develop B12 deficiency when not supplementing their diets with B12, intestinal bacteria cannot be relied upon to prevent B12 deficiency in vegans.Are raw foodists or people who eat fermented foods exceptions? No. See the section B12 Status: Raw Foodist Vegans.

Bacteria in the Large Intestine It has long been assumed that B12 is produced by bacteria in the large intestine (aka the colon), but since B12 is produced below the ileum (where B12 is absorbed), it is not available for absorption. This theory is reinforced by the fact that many species of totally or primarily vegetarian animals eat their feces. It is surmised that eating feces allows them to obtain B12 on their diets of plant foods. Although I believe this to be true, it has not been verified beyond a reasonable doubt.The best evidence I have found for this theory is reported by Herbert.1 He reports a study in the 1950s in England where vegan volunteers with B12 deficiency (as shown by megaloblastic anemia) were fed B12 extractions made from their own stools and it cured their deficiency. He said it proves that the colon bacteria of vegans produce enough B12 to cure a deficiency, but that the B12 produced by the

bacteria in the colon is excreted rather than absorbed. This appears to be convincing evidence. However, the study Herbert cites as the source, "Callender ST, Spray GH. Latent pernicious anemia. Br J Haematol. 1962;8:230-40," does not mention this experiment.There is another study by Callender and Spray that sounds like it could be the one Herbert is describing, "Preparation of hematopoietically active extracts from faeces. Lancet 1951(June 30):1391-2." This study was not performed on vegans, but rather on people with pernicious anemia who cannot properly absorb B12. Because these people were ingesting B12, the B12 in their stool could have been from the B12 they were eating.On the other hand, according to Lactobacillus lactis Dorner and Lactobacillus leichmannii assays, there were substantial amounts of B12 analogue found in the feces (e.g., 5 µg per 10 ml (2 teaspoons)). This seems like too much to have

been provided by only the diet and enterohepatic circulation. Apparently, some of this B12 analogue was active, and there was enough to counteract any inactive B12 analogue in their stools. Thus, this study provides good evidence that there is active B12 produced by bacteria in the colon of at least some humans. A variable to consider is that there are over 400-500 species of bacteria in the average human's colon and these bacteria have not all been delineated. It is plausible that some humans have B12-producing bacteria in significant amounts while other humans do not. Some bacteria in the digestive tract absorb B12 for their own use, further complicating this situation.

Notes for Bacteria in the Large Intestine

1. Herbert V. Vitamin B-12: plant sources, requirements, and assay. Am J Clin Nutr 1988;48:852-8.

Bacteria in the Small Intestine B12 deficiency has been found with relatively high frequency among vegetarian Indian immigrants in England, while it is supposedly uncommon among native Indians with identical dietary patterns.1,2 Healthy Indian subjects have a more extensive amount of bacteria in their small intestine than people in the West.1 Albert et al.1 (1980) measured B12 production of bacteria in the small intestines of people in India using a Euglena gracilis Z assay. Results were confirmed by an Ochromonas malhamensis assay, which is thought to be specific for active B12. They determined that some active B12 was produced by members of the bacteria genera Klebsiella and Pseudomonas. Further confirmation using chromatography and bioautography showed a molecule with similar properties to cyanocobalamin. Albert et al. speculated that when Indians migrate to the

West, their digestive tracts become like those characteristic of people in Western countries: with little or no bacteria in their upper small intestines. An article in Nutrition Reviews3 (1980) suggested some alternative causes of Indian immigrants to Britain having more B12 deficiency than Indian natives:

In India, water is contaminated with various bacteria, including those from human and animal feces. The practice of defecating in open fields and lack of proper sewage. The mode of toilet hygiene where water is used instead of toilet paper.

It should also be noted that there are few vegans in India and there is also evidence that B12 deficiency is not so uncommon there (see Table below),2 especially in lower economic, lacto-ovo vegetarians.4

B12 Status of a Group of Indians age 27-552

Number

Average serum B12

serum B12 < 203

MMA > .26 µmol/l

HCY > 15 µmol/l

NVALOVB

3627

216

46%

70%

81%C

A - Tended to eat only small amounts of animal productsB - 1 person was veganC - A low folate status could have contributed to the high HCY levels5LOV - lacto-ovo-vegetarianHCY - homocysteineMMA - methyl malonic acidND - None DetectedNV - non-vegetarian.

Notes for Bacteria in the Small Intestine

1. Albert MJ, Mathan VI, Baker SJ. Vitamin B12 synthesis by human small intestinal bacteria. Nature. 1980;283(Feb 21):781-2.

2. Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.

3. No author. Contribution of the microflora of the small intestine to the vitamin B12 nutriture of man. Nutrition Reviews. 1980 Aug;38(8):274-5.

4. Sarode R, Garewal G, Marwaha N, Marwaha RK, Varma S, Ghosh K, Mohanty D, Das KC. Pancytopenia in nutritional megaloblastic anaemia. A study from north-west India. Trop Geogr Med. 1989 Oct;41(4):331-6.

5. Antony AC. Prevalence of cobalamin (vitamin B-12) and folate deficiency in India--audi alteram partem. Am J Clin Nutr. 2001 Aug;74(2):157-9.

B12 and Non-Human Animals

Some have suggested that vegans do not need to fortify their diets with B12, because other herbivorous animals do not do so. For this reason, I have included the following short discussion on the subject. Summary: There are many ways that mostly, or completely, herbivorous animals can potentially obtain B12 which are not available to vegans living in Western society.Ruminants Cows are ruminants (as are bison, buffalo, goats, antelopes, sheep, deer, and giraffes).1 Ruminants have a four-chambered stomach and a rich supply of bacteria in their rumen (the first chamber that their food enters).1 Some of these bacteria produce B12 in amounts normally sufficient to meet their needs.2 Primates Non-human primates typically eat small amounts of eggs, insects, and small vertebrates and/or soil.3,4 Gorillas, possibly the closest to vegan of all the species

closely related to humans, eat insects,3,4 and sometimes feces.5Other Herbivores Horses, elephants, zebras, rabbits, hares, and many rodents have large cecums in their digestive tracts, located between the small and large intestine,1 where bacterial fermentation takes place. Some sources say that all non-ruminant herbivores require some B12 fortification of their feeds,2 but at least one source says that bacteria in a horse's digestive tract are able to produce enough B12 to prevent a dietary need.6Many wild herbivores, such as elephants,7 inadvertently ingest soil on a regular basis. Hares, rabbits, and some rodents eat their fecal pellets, which provide an opportunity to obtain vitamins produced by bacteria in their digestive tracts.1Cobalt is Necessary for Bacterial Production of B12 The availability of B12 for animals

who rely on bacterial synthesis of B12 (rather than getting it from animal foods) is dependent on cobalt levels in the soil. Citing an article from the ls of the New York Academy of Science (1964;112:735-55), Crane et al.8 point out that some soils in Australia, New Zealand, Britain, Canada, Ireland, Germany, Holland, Kenya, Poland, South Africa, Sweden, Russia, and the USA have insufficient cobalt for adequate B12 formation. They state, "This is a major concern of ours because vegans commonly seem to hold to the concept that all essential nutrients will be supported in foods from non-animal sources. They fail to realize that plants can grow readily in soil that is too low in cobalt for bacterial action to supply animals with sufficient B12."

Notes for B12 and Non-Human Animals

1. Hickman CP. LS. Larson A. Integrated Principles of Zoology, 9th Edition. St. Louis, MO: Mosby-Year Book, Inc.; 1993.

2. Subcommittee on Vitamin Tolerance, Committee on Animal Nutrition, Board on Agriculture, National Research Council. Vitamin Tolerance of Animals. Washington, DC: National Academy Press; 1987.

3. Billings, Tom. Comparative Anatomy and Physiology Brought Up to Date. Part 2: Looking at Ape Diets--Myths, Realities, and Rationalizations. Accessed March 7, 2002.

4. Billings, Tom. Humanity's Evolutionary Prehistoric Diet and Ape Diets--continued, Part E: Correcting the vegetarian myths about ape diets. Accessed March 7, 2002.

5. Woodland Park Zoo, Seattle, WA. Frequently Asked Questions About the Gorillas. Accessed March 7, 2002.

6. Vita-Flex Nutrition. Horse nutrition fact sheet. Accessed March 7, 2002.

7. University of Michigan. Animal Diversity website. Accessed March 7, 2002.

8. Crane MG, Sample C, Pathcett S, Register UD. "Vitamin B12 studies in total vegetarians (vegans). Journal of Nutritional Medicine. 1994;4:419-430.

Conclusion: Can a Natural Diet Require Supplements?

Some vegans wrote me after reading earlier versions of Vitamin B12: Are You Getting It?, saying that by implying vegans need to take a supplement, I am portraying the vegan diet as unnatural. One person said, "All the vegans I know are healthy and they neither take vitamin B12 supplements nor eat foods fortified with vitamin B12."

It is true that many vegans do not supplement with B12 and remain apparently healthy for many years. These vegans normally have no idea what their homocysteine levels are, nor what chronic diseases such elevated levels might be causing. They also do not know if they are suffering from unnoticeable nerve damage. You are taking a big chance by assuming you have transcended a need for a typical B12 intake.

As people live longer, homocysteine has more years to cause damage to the body. Because of this, the human need for B12 has increased over time. The longer a vegan does not supplement with B12, the lower their active B12 levels will drop, increasing their homocysteine levels.

In Western society today, it is easy to ensure an adequate B12 intake. Vegans who supplement with B12 can have superior B12 status to non-vegetarians who do not supplement. In fact, the Food and Nutrition Board says that all people (not just vegans) over age 50 should "meet their RDA mainly by consuming foods fortified with B12 or a B12-containing supplement."

I would encourage vegan advocates to make achieving superior B12 status for all vegans one of our goals. As such, all new vegans should be told to ensure an adequate supply of B12 by the people or organizations who encourage them to change their diet. Is the vegan diet natural? Whether any prehistoric humans were vegan cannot be concluded from the research presented here. But in the interest of disclosure, and because knowledge and truth can only help the vegan cause, I recommend an article that examines the subject of the naturalness of a vegan diet: Comparative Anatomy and Physiology Brought Up to Date: Are Humans Natural Frugivores/Vegetarians, or Omnivores/Faunivores? by Tom Billings. After an extensive review of the research, Billings concludes that humans are not naturally vegetarians or vegans. Despite this, he says:

I am both pro-vegetarian and pro-[eating raw foods as a large portion of the diet]. Readers should be aware that I am a long-time vegetarian (since 1970), a former long-time (8+ years) fruitarian (also a former vegan),... However, I am definitely not a promoter of, or a "missionary" for, any specific diet. In reality, I am tired of seeing raw and [vegan/vegetarian] diets promoted in negative ways by extremists whose hostile and dishonest behavior is a betrayal of the positive moral principles that are supposedly at the heart of veg*ism.

He continues:

You really don't need the naturalness claim to be a veg*n! That is, moral/spiritual reasons alone are adequate to justify following a veg*n diet (assuming the diet works for you, of course). Further, if the motivation for your diet is moral and/or spiritual, then you will want the basis of your diet to be honest as well as compassionate. In that case, ditching the false myths of naturalness presents no problems; indeed, ditching false myths means that you are ditching a burden.

Readers may also be interested in the article Humans are Omnivores, adapted from a talk by McArdle, PhD (originally published in the May/June 1991 edition of the Vegetarian Journal).Whose Diet is Really Natural? The suffering endured by the majority of animals raised in contemporary animal agriculture far outweighs any desire of mine to eat the same as my prehistoric ancestors. But, even if the animals' suffering were of no consequence, these assumptions are dubious:

There is one prehistoric or natural diet. This diet can reasonably be approximated today. This diet is optimal for human health in today's world.

Today's commercial plant foods and meats are different than the foods available in prehistoric times. We eat hybrids of plants and we feed foods to animals that they would not normally eat. We keep them confined so that they do not exercise. We cook animal products to make them palatable and to kill pathogens. We cook vegetable foods that would otherwise be inedible. The U.S. food supply is routinely fortified with a host of vitamins and minerals (such as vitamin D in milk), and most people who turn to what they consider to be a more natural diet as adults have often benefited from this supplementation.The Medical Community: Future of Research on VegansSome vegans dislike the medical community. By refusing to accept the scientific evidence in favor of the need to supplement with B12, the vegans who dislike the medical community are providing a steady flow of vegans with poor health for the medical community to study. If you do

not like the medical community, the best thing you can do is ensure that you do not develop B12 deficiency and will never be used by them to say that a vegan diet is unhealthy. I tend not to believe that medicine is one big conspiracy against veganism, and am glad that research has been done on vegans who do not supplement with B12. But enough is enough. I am tired of seeing study after study looking at vegans who do not supplement with B12. It is the vegan community's responsibility to stop this flow of research subjects. When a researcher decides to do a study looking at the various health problems of vegans who do not supplement their diets with B12, it would be best if they simply could not find any.Encourage New Vegans to Concern Themselves with B12 SupplementsAll vegan advocates should be made aware of the symptoms of B12 deficiency (with the realization that

elevated homocysteine levels occur long before these symptoms are noticeable). As pointed out earlier (in the section Transcobalamin II under Blood B12 Level: Not a Reliable Measure of B12 Adequacy), adequate transport of B12 to the tissues may considerably slow after B12 intake significantly decreases. Some people who try a vegan diet may already have low B12 levels or hampered absorption mechanisms. Some of these factors could cause a new vegan to feel badly and go back to eating animal products. Therefore, it is prudent for new vegans to follow the Recommendations. This will prevent any potential lapse in adequate B12 delivery to tissues.Daily or Weekly Supplementation? Throughout human history, people have ingested B12 on a daily basis, and most often throughout the day. This has given people a steady supply of B12 to their

tissues (above that which is reabsorbed through the enterohepatic circulation). While there is no research on whether a vegan is better off taking B12 on a daily vs. weekly basis, I would err on the side of caution and supplement daily. The End If you found the information in this article important for the spread of veganism, please consider a donation to Vegan Outreach. Thank you. Acknowledgements

Matt Ball and Anne Green for supporting this work through Vegan Outreach. Ornelas, head of Viva!USA, for proofreading and support. Tom Billings for research assistance. Mark McEahern for generous website assistance. Strauss for research and sharing correspondence. Greger, Panos, and Walsh for various contributions.

Thanks!

First Appendix

Appendix: Vegan Infants & Toddlers with Serious B12 Deficiency

Unless otherwise noted, all infants were healthy until about 6-12 m after which they failed to thrive and showed developmental regression. All became lethargic and lost their ability to use their muscles adequately. Some could not sense properly and most had macrocytic anemia. "Additional Symptoms" only lists symptoms in addition to those just described.

Normal serum B12 (sB12) for newborns: 160-1300 pg/ml

2007, France, Two Infants, 11 and 13 months oldserum B12: deficientInfants were breast fed by strict vegetarians.Results/Notes: Outcome not clear from abstract (article is in French).

Reference: Mathey C, Di Marco JN, Poujol A, Cournelle MA, Brevaut V, Livet MO, Chabrol B, Michel G. [Failure to thrive and psychomotor regression revealing vitamin B12 deficiency in 3 infants] Arch Pediatr. 2007 May;14(5):467-71. Epub 2007 Apr 6. French.

2005, France, Girl, 9.5 months oldserum B12: deficientInfant was exclusively breast fed by a vegan mother who was also B12 deficient.Results/Notes: No outcome details given in abstract (article is in French).

Reference: Wagnon J, Cagnard B, Bridoux-Henno L, Tourtelier Y, Grall JY, Dabadie A. [breastfeeding and vegan diet] J Gynecol Obstet Biol Reprod (Paris). 2005 Oct;34(6):610-2. French.

2005, Italy, Boy, 10 months oldserum B12: 30 pg/mluMMA: 851 (normal is < 2)Infant was breast fed by a mother who had been vegan for ten years.Additional symptoms: Labored breathing, brain atrophy.Treatment: 1000 mcg/day B12, 7.5 mg/day folate, 50 mg/day iron, and put on a mechanical ventilator.Results/Notes: Marked improvement 11 days afer admission. At age 4, important improvements achieved but still having psychomotor delay and involuntary movements when agitated.

Reference: Codazzi D, Sala F, Parini R, Langer M. Coma and respiratory failure in a child with severe vitamin B(12) deficiency. Pediatr Crit Care Med. 2005 Jul;6(4):483-5.

2003, USA (Georgia), 2 Infants

When this story broke in 2003, there were some counter-articles making their way around the web, one saying that these infants were suffering from a genetic B12 metabolism defect rather than from a lack of intake. For that reason, some points are clarified on these two infants.

Case 1 Mother: Vegan with supplements. Took supplements, but B12 content unkown. Infant:

Breast-fed for first 8 months (possibly with other foods) Apparently vegan from 8 - 15 months, with no B12 intake. At 15 months:

Failure to thrive, developmental delay Serum B12: 100 pg/ml (normal: 210-911) Urine Methyl Malonic Acid (MMA): marked elevation Treatment:

First 3 days: Extra food via tube; 2,000 ug and 3,000 ug injections of B12. At some later point, she was prescribed daily B12 sublingual supplements.

At 32 months: Was making progress but had some developmental delays.

This infant was apparently vegan from 8 - 15 months, possibly with no B12 intake at all (the report is not clear as to whether the baby received breast milk during this period). MMA is the most precise marker of B12 function, and this infant's markedly elevated MMA shows she was suffering either from a lack of intake, lack of absorption, or inability to utilize B12. She received two B12 injections at 15 months, followed by daily B12 supplements.

Improvement from a B12 injection can generally last 3 to 6 months. This infant was apparently still making progress 17 months after her B12 injections, indicating that she did not have a B12 utilization problem. While it is possible that this infant doesn't absorb B12 efficiently and must rely on higher-than-normal doses, her problems were most likely due to a low or absent B12 intake between her 8th and 15th month.

Case 2 Mother: Plant-based with small amounts of animal products; "intermittent" B12 supplements of 250 mcg Infant:

Exclusively breast-fed for 9 months At 9 months:

Growth and development appeared delayed. Treatment: Breast-milk supplemented with fruit and dried cereals.

At 11 months:

Poor speech and growth development. Treatment: Soy and diary formula tried, but not tolerated; thus started on Mulitagrain Milk (B12 content, if any, not given), chicken, and an unknown vitamin supplement

At 30 months:

Serum B12: 100 pg/ml (normal: 210-911) Urine MMA: Moderate elevation Plasma homocysteine: 12.4 umol/l (normal 3.3-8.3) MCV (mean corpuscular volume): 103.2 fl (normal: 77 - 86) Normal serum folate Treatment:

1,000 mcg B12 injection 2 weeks later: 1,000 mcg sublingual B12 daily Speech, language, and occupational therapies

At 36 months: Slight speech and fine motor skill delays, but normal gross motor skills

This infant had 2 indicators of poor B12 activity: somewhat elevated MMA, and a high homocysteine and MCV with normal folate. Once vitamin B12 was injected, his development improved. His progress was measured again only 6 months after the injection, so it is possible that he was suffering from an inability to absorb or utilize B12.

Since there is no indication that he ever received an adequate amount of B12 on a regular basis, lack of B12 in the diet is the most likely explanation.

Reference: No authors listed. From the Centers for Disease Control and Prevention. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin--Georgia, 2001. JAMA. 2003 Feb 26;289(8):979-80.

2001, Czech Republic, Girl, 13 months old, Serum B12: lowAdditional Symptoms: Brain atrophy. Treatment: B12 supplements. Results/Notes: English abstract says she was fed only "vegetables" after 9 months of age, but Marek Vorsilka informs me that the original paper in Czech says she was fed a range of plant foods including fruit, potatoes, millet, corn gruel, lentlis, beans, rice, carrot, soya milk, sunflower, flaxseed and sesame seeds. . Elevated MMA. Condition improved after treatment.

Reference: Smolka V, Bekarek V, Hlidkova E, Bucil J, Mayerova D, Skopkova Z, Adam T, Hruba E, Kozich V, Buriankova L, Saligova J, Buncova M, Zeman J. [Metabolic complications and neurologic manifestations of vitamin B12 deficiency in children of vegetarian mothers] Cas Lek Cesk. 2001 Nov 22;140(23):732-5. In Czech. (Abstract)

2001, Czech Republic, Boy, 8 months old, Serum B12: lowTreatment: B12 supplements.Results/Notes: Fed breast milk and fruit juice only after 6 m. Elevated MMA & HCY. Mother's B12 was low. Improved after treatment but still had problems including language delay.

Reference: Smolka V, Bekarek V, Hlidkova E, Bucil J, Mayerova D, Skopkova Z, Adam T, Hruba E, Kozich V, Buriankova L, Saligova J, Buncova M, Zeman J. [Metabolic complications and neurologic manifestations of vitamin B12 deficiency in children of vegetarian mothers] Cas Lek Cesk. 2001 Nov 22;140(23):732-5. In Czech. (Abstract)

2001, Hungary, 9 months old, Serum B12: Not reported.Additional Symptoms: Repetitive vomiting, trouble swallowing, tremors. Treatment: B12 injections. Results/Notes: Improved dramatically in days. Blood was normal after 6 weeks. Article in Hungarian. Only the abstract was available.

Reference: Fogarasi A, Neuwirth M, Bekesi A, Bocskai E. [No title given.] Orv Hetil. 2001 Nov 18;142(46):2581-5. Hungarian. (Abstract)

2000, Italy, Boy, 22 months old, Serum B12: 75 pg/mlAdditional Symptoms: pH 6.95 (severe acidosis)Treatment: Intravenous hydroxocobalamin 1,000 µg/d, biotin, carnitine, and high-caloric, low protein formula. Results/Notes: Mother's B12 level was 162 pg/ml. Made complete recovery in 3 months. Lack of elevated HCY led researchers to determine the boy had a mild case of genetic methylmalonyl-CoA mutase deficiency which was exacerbated by a low B12 intake.

Reference: Ciani F, Poggi GM, Pasquini E, Donati MA, Zammarchi E. Prolonged exclusive breast-feeding from vegan mother causing an acute onset of isolated methylmalonic aciduria due to a mild mutase deficiency. Clin Nutr. 2000 Apr;19(2):137-9.

1999, Australia, 2 NewbornsIn screening 137,120 newborns for inborn error of metabolism, they found 2 B12 deficient babies of vegan mothers. No further information was given. "B12-deficient" was not defined.

Reference: Wiley V, Carpenter K, Wilcken B. Newborn screening with tandem mass spectrometry: 12 months' experience in NSW Australia. Acta Paediatr. Suppl 1999 Dec;88(432):48-51

1999, France, Boy, 10 months old, Serum B12: Not reportedAdditional Symptoms: Regurgitation, edema. Treatment: 300 µg/day of B12 Results/Notes: Suffered muscle tremors during 1st 4 days of treatment. Normal after 2 months. Mother had a sB12 of 109 pg/ml with normal intrinsic factor function.

Reference: Renault F, Verstichel P, Ploussard JP, Costil J. Neuropathy in two cobalamin-deficient breast-fed infants of vegetarian mothers. Muscle Nerve. 1999 Feb;22(2):252-4.

1999, France, Boy, 12 months old, Serum B12: Not ReportedAdditional Symptoms: Low level of red and white blood cells, and platelets. Treatment: 1,000 µg/day B12 Results/Notes: Had increased homocysteine and MMA in urine. Suffered muscle tremors during 1st 3 days of treatment. Normal after 3 weeks.

Reference: Renault F, Verstichel P, Ploussard JP, Costil J. Neuropathy in two cobalamin-deficient breast-fed infants of vegetarian mothers. Muscle Nerve. 1999 Feb;22(2):252-4.

1999, Australia, Boy, 18 months old, Serum B12: 202 pg/mlAdditional Symptoms: Stopped developing at 1 year. Treatment: 500 µg B12/day injections. Results/Notes: Mother's diet showed a B12 intake of .3 µg/day and sB12 of 202. She also had B12 malabsorption thought to be due to a temporary small intestine problem caused by B12 deficiency. After treatment, child's twitching developed into episodes more like seizures as his neurological status gradually improved.

Reference: Grattan- PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997 Jan;12(1):39-46.

1999, Australia, Girl, 12 months old, Serum B12: 50 pg/mlAdditional Symptoms: Irritable, lethargic, and constipated. Treatment: 1500 µg B12 injections. Results/Notes: After 2nd injection, she developed tremors which eventually went away and she returned to normal.

Reference: Grattan- PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997 Jan;12(1):39-46.

1999, Australia, Boy, 10 months old, Serum B12: 47 pg/mlAdditional Symptoms: Intermittent tremors that had started at 4 months. Treatment: 1000 µg B12/day injections for 6 d. Results/Notes: Developed tremors (after treatment) which lasted for 6 weeks. By 23 months, motor skills were normal, but intellectual development appeared to be slow for his age.

Reference: Grattan- PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin deficiency: developmental regression and involuntary movements. Mov Disord. 1997 Jan;12(1):39-46.

1997, Germany, boy, 14 months old, serum B12: Not reportedAdditional Symptoms: Severe nerve problems. Comatose at hospital admission. Severe brain atrophy. Treatment: One 250 µg B12 injection. 25 µg oral B12/day plus supplemented soy formula. Results/Notes: uMMA was initially very high. Mother had been vegan for 6 years, and vegetarian for 8 years prior to that. She ate a high proportion of raw foods. The infant had been exclusively breast-fed for 9 months and then ate small amounts of fruit.Regained consciousness in hours. By day 3 was able to walk, eat, drink, and was discharged. Parents agreed to give soy formula and oral B12. Cranial MRI 10 weeks later showed all structural brain abnormalities had disappeared, but he continued to show nerve damage. At 2 years, still showed psychomotor retardation, was agitated, and had poor concentration. Could not speak any words.3-year-old sister had B12 level

of 139 pg/ml. Mother had B12 level of 149 pg/ml which became normal after oral supplementation.

Reference: von Schenck U, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child. 1997 Aug;77(2):137-9.

1997, Switzerland, Girl, 14 months old, Serum B12: 124 pg/mlAdditional Symptoms: Severe brain atrophy. Treatment: Multivitamin, iron, folic acid, trace elements, *1 ng B12 every other day. Results/Notes: Responded well and at 20 months could sit alone, crawl, walk with help, and speak simple words.*The "1 ng" was probably a typographical error and was actually "1 mg" (1,000 µg).

Reference: Lovblad K, Ramelli G, Remonda L, Nirkko AC, Ozdoba C, Schroth G. Retardation of myelination due to dietary vitamin B12 deficiency: cranial MRI findings. Pediatr Radiol. 1997 Feb;27(2):155-8.

1996, Greece, 3 Boys and 1 Girl, 2 - 5 weeks old, Serum B12: Very low.Additional Symptoms: Low hemoglobin, no megaloblastic anemia. Vomiting in 3 out of 4. Elevated urinary MMA (exact number not reported). Treatment: "Appropriate treatment." Results/Notes: Mothers also had elevated urinary MMA. All children doing very well after 4 - 5.5 years.

Reference: Drogari E, Liakopoulou-Tsitsipi T, Xypolyta-Zachariadi A, Papadellis F, Kattamis C. Transient methylmalonic aciduria in four breast fed neonates of strict vegetarian mothers in Greece. Journal of inherited metabolic disease. 1996 19S:A84. (Only an abstract.)

1993, France, 15 months old, Serum B12: Very lowAdditional Symptoms: Severe megaloblastic anemia. No growth. Lack of muscle tone and psychomotor development. Treatment: Injections and possibly a blood transfusion.Results/Notes: Very low levels of B12 in milk of mother who had been vegan for 10 years. At 4 years old, patient's growth and psychomotor development were normal.

Reference: Monfort-Gouraud M, Bongiorno A, Le Gall MA, Badoual J. Severe megaloblastic anemia in child breast fed by a vegetarian mother. Ann Pediatr (Paris). 1993 Jan;40(1):28-31. [Article in French.] (Abstract)

1991, Switzerland, Girl, 9 months old, Serum B12: 28 pg/mlAdditional Symptoms: Optic nerve atrophy. Treatment: 1000 µg injection for 4 days. 1000 µg orally on 5th day. Results/Notes: Urinary MMA and plasma homocysteine were initially very high.All muscle problems vanished after 10 days. Girl was discharged and parents were given an oral vitamin B complex including B12. Parents agreed to add eggs and dairy to her diet. By 15th month, her physical measurements and lab values were normal.

Reference: Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr. 1991 Jan;150(3):205-8.

1992, Australia, 3 InfantsResults/Notes: Reviewed the cases of B12 deficiency seen during the previous 10 y at Prince of Wales Children's Hospital to obtain long-term follow-up. 3 of the 6 patients were infants of vegetarian mothers. 1 had borderline intellectual development at age 5.

Reference: Graham SM, Arvela OM, Wise GA. Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants. J Pediatr. 1992 Nov;121(5 Pt 1):710-4.

1992, Canada, Girl, 2.5 months old, Serum B12: 104 pg/mlAdditional Symptoms: Had no symptoms. Treatment: Oral B12. Results/Notes: Urinary MMA started at 537 µmol/mmol Cr, but dropped to 10.9 after 2 weeks. Mother's B12 level was 81 pg/ml.

Reference: Michaud JL, Lemieux B, Ogier H, Lambert MA. Nutritional vitamin B12 deficiency: two cases detected by routine newborn urinary screening. Eur J Pediatr. 1992 Mar;151(3):218-20.

1990, Israel, 14 months old, Serum B12: Not reproted.Additional Symptoms: Severe nerve damage. Treatment: B12 therapy. Results/Notes: Partially corrected.

Reference: Bar-Sella P, Rakover Y, Ratner D. Vitamin B12 and folate levels in long-term vegans. Isr J Med Sci. 1990;26:309-312.

1989, France, Girl, 6 months old, Serum B12: 45 pg/mlAdditional Symptoms: Hemoglobin 1.9 g/dl. Treatment: B12 injection(s). Results/Notes: Parents' B12 levels: 110 and 105 pg/ml.B12 in mother's milk: 12 pg/ml.Treatment was successful.

Reference: Cheron G, Girot R, Zittoun J, Mouy R, Schmitz J, Rey J. Severe megaloblastic anemia in 6-month-old girl breast-fed by a vegetarian mother. Arch Fr Pediatr. 1989 Mar;46(3):205-7. [Article in French.] (Abstract)

1987, Germany, Boy, 18 months old, Serum B12: 63 pg/mlAdditional Symptoms: Progressive nerve disorder since 6 months of age. Treatment: 1000 µg B12/day. Results/Notes: Serum MMA and urinary MMA were not elevated. At 5 weeks, anemia was gone and nerve problems dramatically improved. At 26 months, was functioning at a 12-month-old level with exaggerated reflexes. Continued to make psychomotor progress. Authors thought the normal MMA levels were possibly due to the small amounts of animal products prior to hospital admission.

Reference: Stollhoff K, Schulte FJ. Vitamin B12 and brain development. Eur J Pediatr. 1987 Mar;146(2):201-5.

1986, Switzerland, Boy, 11 months old, Serum B12: Not reported.Treatment: Admitted to hospital and given three 500 µg B12 injections in 6 days. Results/Notes: Full recovery. Discharged with an oral vitamin supplement containing 6 µg B12/day and oral iron. Mother did not follow the advice to give iron. Child was readmitted 2 months later showing iron deficiency. He was put on an iron supplement and blood values returned to normal in 1 month. No relapse of B12 deficiency was noted after oral supplementation.The infant was a twin. The other twin was not reported to have problems.

Reference: Gambon RC, Lentze MJ, Rossi E. Megaloblastic anaemia in one of monozygous twins breast-fed by their vegetarian mother. Eur J Pediatr. 1986 Dec;145(6):570-1.

1986, USA, Boy, Serum B12: Not reported.Additional Symptoms: Swelling of hands, feet, and abdomen. Treatment: Blood transfusion, 1000 µg B12 injections for 5 days.Child & Mother:

1 month of 50 µg B12/day4 months of multivitamins

Results/Notes: Improved in 48 hours. Discharged on 4th day. Was doing much better after 6 months.The parents had been vegan for 6 years. 2 weeks prior to admission, a naturopath suggested they take him to a hospital. The parents refused, but the mother agreed to begin taking a multivitamin.

Reference: Sklar R. Nutritional vitamin B12 deficiency in a breast-fed infant of a vegan-diet mother. Clin Pediatr (Phila). 1986 Apr;25(4):219-21.

1985, Norway, Girl, 2 years old, Serum B12: 54 pg/mlTreatment: B12 injections, vitamin D, calcium, and iron. Results/Notes: Also suffered from rickets. The girl ate small amounts of milk, eggs, and cod liver oil. Her symptoms of rickets and B12 deficiency resolved after 2 weeks.Mother was pregnant and her serum B12 was 149 pg/ml. She was given B12 injections and a multivitamin and she and the baby have both done well.

Reference: Hellebostad M, Markestad T, Seeger Halvorsen K. Vitamin D deficiency rickets and vitamin B12 deficiency in vegetarian children. Acta Paediatr Scand. 1985 Mar;74(2):191-5.

1983, Dominica, Boy, 12 months old, Serum B12: Not reported.Additional Symptoms: Vomiting. Treatment: Oral B12 for 42 days. Results/Notes: Full recovery.

Reference: Close, GC. Rastafarianism and the vegans syndrome. British Medical Journal. 1983;286(Feb 5):473.

1981, USA, Boy, 6 months old, Serum B12: Not reportedAdditional Symptoms: Heart failure. Treatment: B12 injections. Results/Notes: Mother's B12 was 278 pg/ml. By day 28, all blood values were normal. Infant was then given 50 µg B12 twice per week.

Reference: JR, Goldenring J, Lubin B. Nutritional vitamin B12 deficiency in infants. Am J Dis Child. 1981(Jun);135:566-7.

Appendix: People Who Should Not Take the Cyanocobalamin Form of B12

Chronic Kidney Failure

People with chronic kidney failure do not detoxify cyanide as well as people with healthy kidneys. It is thought that this may lead to nerve problems, especially in smokers.1 For this reason it is better for kidney patients to take a form of B12 other than cyanocobalamin. Koyama et al.1 suggest that patients on hemodialysis receive 500 µg of methylcobalamin intravenously after each dialysis. Vegans with kidney disease, whether or not they are on dialysis, should take a non-cyanocobalamin form of B12. These patients should talk to their health professionals about how much should be taken. 1,000 µg (1 mg) of methylcobalamin or adenosylcobalamin per day might be adequate.

Notes for Chronic Kidney Failure

1. Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N. Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant. 1997 Aug;12(8):1622-8.

Cyanide Metabolism Defects

Cobalamin has a strong attraction to cyanide. While being a natural chemical produced in the body, cyanide is toxic, and the body turns it into thiocyanate in order to excrete it. If this pathway is defective or overwhelmed through ingestion of too much cyanide (such as in smokers, or people in Nigeria who eat large amounts of cassava which is high in cyanide), the body may detoxify the cyanide by attaching it to cobalamin and then excreting the cyanocobalamin. Leber's optic atrophy, tobacco-alcohol amblyopia, and other eye diseases can sometimes respond to high doses of hydroxocobalamin which serve to detoxify the cyanide. In these cases, there may be too much cyanide in the tissues (preventing conversion of cyanocobalamin to methylcobalamin or adenosylcobalamin) for cyanocobalamin supplements to be effective in maintaining B12 status.1 In such cases, a different form of B12 should be given (speak to your health

professional).2

Notes for Cyanide Metabolism Defects

1. Linnell JC, s DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.

2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

Appendix: Smokers and Cyanocobalamin

In one study, smokers were found to excrete 35% more B12 than nonsmokers.1 In another study, smokers' serum B12 did not differ from nonsmokers', and the Institute of Medicine concluded that "The effect of smoking on the B12 requirement thus appears to be negligible."1

Hydroxocobalamin injections decreased blood cyanide levels by 59% in smokers (1.5-3 packs/day); cyanide was eliminated in the urine as cyanocobalamin.2 This indicates that cyanocobalamin may be actively excreted rather than used in people with elevated cyanide levels. Thus, I am concerned that vegan smokers may not receive much benefit from cyanocobalamin supplementation. Most smokers have an intake of hydroxocobalamin, and other non-cyanocobalamin forms of B12, through animal foods, which can counteract their bodies excretion of cyanocobalamin. Unless vegans take a non-cyanocobalamin supplement, they do not have a non-cyanocobalamin source of B12.

In contrast, I know two vegan smokers whose B12 source has only been cyanocobalamin, and who have not developed overt B12 deficiency in over ten years on the diet. There are probably others. Unfortunately, I could find no studies looking at cyanocobalamin supplementation in smokers, much less in vegan smokers.

To be cautious, I am suggesting that vegan smokers supplement with a non-cyanocobalamin form of B12. The amounts will have to be somewhat arbitrary because of the lack of information on the absorption rates and detoxification action of the various forms of B12 in smokers. I have not seen evidence of oral adenosylcobalamin's effectiveness in counteracting B12 deficiency. son had success with oral methylcobalamin. I would, therefore, tentatively recommend 500 µg/day, sublingually, of methylcobalamin for vegan smokers. Most tablets are 1,000 µg, so they will need to be broken in half to get 500 µg. At that rate, a month's supply of methylcobalamin should cost about $4.

It could be that the recommendations for vegan smokers need not be any different than those for nonsmokers. At this time, I do not feel that there is enough evidence one way or the other.

There is no evidence that cyanocobalamin is harmful to vegan smokers; including a modest source of cyanocobalamin (e.g., 3-5 µg/day), in addition to methylcobalamin, could serve as insurance.

Notes for Smokers and Cyanocobalamin

1. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

2. Forsyth JC, Mueller PD, Becker CE, Osterloh J, Benowitz NL, Rumack BH, Hall AH. Hydroxocobalamin as a cyanide antidote: safety, efficacy and pharmacokinetics in heavily smoking normal volunteers. J Toxicol Clin Toxicol. 1993;31(2):277-94.

Appendix: Non-cyanocobalamin B12 Supplements

Introduction

The typical non-cyanocobalamin forms of vitamin B12 in supplemental forms are methylcobalamin and adenosylcobalamin (also known as 5'-deoxyadenosylcobalamin, dibencozide, coenzyme B12, cobamamide, and cobinamide). Calling adenosylcobalamin "co-enzyme B12" is somewhat misleading because methylcobalam is also a co-enzyme from of B12. Hydroxocobalamin is the form typically used in B12 injections.

Some researchers question whether these non-cyanocobalamin supplements are stable in their oral form. For this reason, much larger amounts are typically used with hope that at least some are absorbed intact. One study suggests that once absorbed, methylcobalamin may be retained in the body better than cyanocobalamin.30

Notes for Introduction

1. Okuda K, Yashima K, Kitazaki T, Takara I. Intestinal absorption and concurrent chemical changes of methylcobalamin. J Lab Clin Med. 1973 Apr;81(4):557-67.

Methylcobalamin in a Small Sample of Vegans

son1 (2000, USA) studied 3 vegans with elevated uMMA levels who were treated with 1/2 to 1 sublingual methylcobalamin tablet (from Enzymatic Therapy, Green Bay, WI), 2 times/day for 3 weeks. Correspondence with the author (March 21, 2002) verified that these tablets contain 1,000 µg methylcobalamin each.

Two of the subjects' urinay MMA normalized while the remaining subject's stayed slightly elevated at 4.1 µg/mg creatinine (normal is < 4.0 µg/mg creatinine). Thus, at a rate of 1-2,000 µg/day, methylcobalamin appears to be absorbed at a high enough rate to improve B12 status in some vegans. Additionally, this indicates that the methylcobalamin was able to improve the MMA pathway which requires adenosylcobalamin (in other words, methylcobalamin was apparently converted into adenosylcobalamin in these people).

Notes for Methylcobalamin in a Small Sample of Vegans

1. son MS. Metabolic vitamin B12 status on a mostly raw vegan diet with follow-up using tablets, nutritional yeast, or probiotic supplements. Ann Nutr Metab. 2000;44(5-6):229-34.

Therapeutic Use of Coenzyme Forms of B12

The coenzyme forms of B12 appear to be more effective in treating certain conditions than is cyanocobalamin (though they are often injected rather than taken orally). 1 (1997) reviewed the research on supplementing with the coenzyme forms of B12 (methylcobalamin and adenosylcobalamin). Results of studies performed on humans are listed here:

Conditions Reported to Improve by Coenzyme Forms of B12

Therapeutic dose recommended by 1

Conditions reported to improve from treatment1,A

Methylcobalamin

1500-6000 µg/day

Diabetic neuropathyInfertilityHyperhomocysteinemia in diabetesSleep disordersBBell's Palsy

Adenosylcobalamin, aka: 5'-deoxyadenosylcobalamin, dibencozide, coenzyme B12, cobamamide, and cobinamide

1000-6000 µg/day

Neurological problems secondary to anorexiaHepatitis AViral hepatitisB

A – In many cases, treatment was not compared to cyanocobalaminB - More effective than cyanocobalamin

Notes for Therapeutic Use of Coenzyme Forms of B12

1. G. The co-enzyme forms of vitamin B12: Toward an understanding of their therapeutic potential. Alt Med Rev. 1997;2(5):459-471.

Hydroxocobalamin

Hydroxocobalamin is the form of B12 typically found in food. There are not many oral forms for people to take; it is normally injected. One study suggests that after injections, hydroxocobalamin is retained in the body better than cyanocobalamin.1

Notes for Hydroxocobalamin

1. Tudhope GR, Swan HT, Spray GH. Patient variation in pernicious anaemia, as shown in a clinical trial of cyanocobalamin, hydroxocobalamin and cyanocobalamin-zinc tannate. Br J Haematol. 1967 Mar;13(2):216-28.

Vegan Sources of Methylcobalamin

Enzymatic Therapy Wonder Laboratories Please note that their statement "The liver does not convert the cyanocobalamin form of vitamin B-12 into adequate amounts of methylcobalamin," implies that all vegans need a source of methylcobalamin. In fact, most vegans can rely solely on cyanocobalamin. Their Supplement Facts label (to show it is vegan) is below:

Appendix: SAMe

Figure 3 shows that S-adenosylmethionine (SAM, aka SAMe) is in the homocysteine-methionine pathway. SAM has been used in the treatment of liver disease, neurological disorders, rheumatoid arthritis,1 and fibromyalgia.2,3 Houston et al.4 noted that SAM is depleted in B12 deficiency. Loehrer et al.1 reported that SAM levels are low in a significant proportion of coronary artery disease patients. suggests that SAM is involved in converting cyanocobalamin to methylcobalamin.

Loehrer et al.1 showed that 400 mg of SAM (in the form of S-adenosylcobalamin bis(sulfate)-p-toluenesulfonate) taken orally after an overnight fast (with the fast continuing for 6 more hours), caused serum SAM levels to increase substantially, indicating that SAM is absorbed when taken orally. It was well tolerated by all 14 volunteers.

Not enough research has been done to determine whether vegans who have depleted their stores of B12 can benefit from supplementing with SAM in addition to B12. Looking at the biochemical pathways, it would appear that if homocysteine levels are high (which would be expected in B12 deficiency) and folate is adequate, supplementing with B12 would be enough to replenish SAM stores. However, if supplementing with B12 does not resolve symptoms, someone might consider discussing SAM supplementation with their physician.

Notes for SAMe

1. Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.

2. sen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol. 1991;20(4):294-302.

3. Leventhal LJ. Management of fibromyalgia. Ann Intern Med. 1999 Dec 7;131(11):850-8.

4. Houston DK, MA, Nozza RJ, Gunter EW, Shea KJ, Cutler GM, Edmonds JT. Age-related hearing loss, vitamin B-12, and folate in elderly women. Am J Clin Nutr. 1999 Mar;69(3):564-71.

5. G. The co-enzyme forms of vitamin B12: Toward an understanding of their therapeutic potential. Alt Med Rev. 1997;2(5):459-471.

Appendix: How Recommendations were Formulated

Step 1

Step 1 states:

If you have not had a regular source of B12 for some time, buy a bottle of sublingual B12. Place 2,000 µg under your tongue until the tablet(s) has dissolved, once a day, for 2 weeks. Then follow the advice under Step #2. (Note: you can break the remaining tablets in half or quarters for Step #2. It's okay to take more than recommended.)

These recommendations about how to replenish one's B12 stores are based on the success that people with B12 malabsorption problems have had with oral B12 supplements (as described next).

Oral B12 for People with Malabsorption

Intramuscular injections (IMI) of B12 are the typical way to treat B12 deficiency. The injections can be painful and expensive. Norberg1 (1999, Sweden) points out that investigations in the 1950s and 60s showed that oral B12 is absorbed by an alternative pathway not dependent on intrinsic factor or an intact ileum. Approximately 1% of an oral dose in the range of 200-2000 µg/day was absorbed by the alternative pathway in those investigations. Based on this research, oral treatment, rather than IMI, has been in use for the majority of B12 deficiency cases in Sweden since the early 70s.

In a literature review encouraging the use of oral B12 therapy over injections for patients with pernicious anemia, Lederle2 (1991, USA) reported that Swedish investigators recommend 2000 µg of oral B12 twice a day or injections to replenish B12 stores. After initial therapy, doses of 1000 µg/day appear to be enough. 58

Kuzminski et al.3 (1998, USA) studied 33 newly diagnosed B12-deficient patients (almost all had malabsorption) who received cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90; or 2000 µg orally on a daily basis for 120 days (4 months). Results were:

Results of Kuzminski et al.

serum B12 (pg/ml)

serum MMA (µmol/l)

HCY (µmol/l)

Pretreatment

oral

93

3.85

37.2

injection

95

3.63

40

After 4 months

oral 2000 µg/day

1005A

..169B

10.6

injection

325A

..265B

12.2

A,B - Statistically significant difference between groups with same letters

Kuzminski et al. conclude that 2000 µg/day of oral cyanocobalamin was as effective as 1000 µg injected intramuscularly each month, and may be superior.

Delpre & Stark4 (1999, Israel) studied patients with B12 deficiency to see if B12 can be absorbed by holding a tablet under the tongue, known as sublingual. The theory behind sublingual is that the mucous membranes under the tongue are efficient at absorbing certain molecules, particularly if combined with something fat soluble such as a cyclodextrin. 5 patients had pernicious anemia, 7 were vegetarians, and 2 had Crohn's disease (which can prevent the absorption of B12 in the ileum). The patients held two 1000 µg B12 tablets (equaling 2,000 µg/day), made by Solgar, under their tongues for 30 minutes until completely dissolved. This was done for 7 to 12 days. Average serum B12 levels went from 127.9 ± 42.6 to 515.7 ± 235. All patients' serum B12 normalized. There were no side effects and all patients preferred this to injections. Unfortunately, Delpre & Stark did not include a control group who chewed the B12 tablets, so there

is no way to know if taking the tablets sublingually was more effective than chewing and swallowing them. On the basis of Kuzminski et al. above, swallowing seems to be as effective if done for 3 months.

Please note that the large doses mentioned in this section are for people with B12 malabsorption (or vegans who have neglected their B12 intake for a few months). People without malabsorption problems or current B12 deficiency do not need such large doses; hence Step 2 of the recommendations.

Notes for Oral B12 for People with Malabsorption

1. Norberg B. Turn of tide for oral vitamin B12 treatment. J Intern Med. 1999 Sep;246(3):237-8.

2. Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best kept secret? JAMA. 1991 Jan 2;265(1):94-5.

3. Kuzminski AM, Del Giacco EJ, RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998 Aug 15;92(4):1191-8.

4. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation. Lancet. 1999 Aug 28;354(9180):740-1.

Step 2

Step 2 states:

One of the following daily recommendations should maximize your B12 status:

From fortified foods

3-5 µg

From 1 daily supplement

10-100 µg

From 2 daily supplements spaced at least 6 hours apart

5 µg

Absorption Rates of B12

et al.1 (2001, Boston, MA) measured B12 absorption rates from milk and bread fortified with .1 µg B12, in healthy people who were over age 60 and had normal stomach acid (results are in the table below). Absorption rates of different doses of cyanocobalamin have also been measured and appear in the table below.

B12 Absorption Rates

Food / Oral Dose

% absorbed

µg absorbed (avg)C

fortified milk1

65%A

fortified bread1

55%

mutton1

65%

chicken1

60%

trout1

39%

eggs1

24-36%

liver2

11%

..1 µg 3

77%

0.08

..25 µg3

75%

0.19

..5 µg3,4

71-90%

..35-.45 (.4)

..6 µg3

63%

0.38

1 µg2,3,4,5

50-80%

..5-.8 (.6)

2 µg3,4,5

40-50%

..8-1 (.9)

5 µg2,3,4,5,6

20-55%

1-2.8 (1.7)

103,5

15-16%

1.5-1.6

25 µg2

5%

1.25

50 µg4,5

3%

1.5 (1.5)

1,000 µg2,4

1-1.5%B

10-15 (12.5)

A - Number represents only the fortified portion of B12 in the milkB - Even without intrinsic factorC - Average of all measurements (i.e., not the mid-range)

A 5 µg supplemental dose of cyanocobalamin appears to saturate the intrinsic factor absorption mechanism. Thus, B12 absorption drops to 1-1.5% for any additional B12 ingested above 5 µg.

The second of two doses given 4-6 hours apart is absorbed as well as the first.2 Absorption of non-protein-bound B12 does not appear to decrease with age.2

There appears to be no published research comparing sublingual B12 absorption rates to oral (swallowing). It is possible that B12 is better absorbed when taken sublingually, but until research is published, we should not assume this. Thus, the recommendations given in this article are based on absorption rates of B12 that is swallowed.

Notes for Absorption Rates of B12

1. RM, Baik H, Kehayias JJ. Older men and women efficiently absorb vitamin B-12 from milk and fortified bread. J Nutr. 2001 Feb;131(2):291-3.

2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

3. Mollin DL. Radioactive vitamin B12 in the study of blood diseases. Brit Med Bull. 1959;15(1):8-13.

4. Estren S, Brody EA, Wasserman LR. The metabolism of vitamin B12 in pernicious and other megaloblastic anemias. Adv Intern Med. 1959;9:11.

5. Chanarin I. The Megaloblastic Anemias 3rd Ed. Oxford, UK: Blackwell Scientific Publications; 1990.

6. Heyssel RM, Bozian RC, Darby WJ, Bell MC. Vitamin B12 turnover in man. The assimilation of vitamin B12 from natural foodstuff by man and estimates of minimal daily dietary requirements. Am J Clin Nutr. 1966 Mar;18(3):176-84.

What Is a Healthy B12 Level?

Assuming that absorption is good, meeting the RDA of 2.4 µg for adults should keep macrocytic anemia from occurring. In 4 Indian vegetarians with B12-deficient anemia, .10 - .25 µg of B12 (through the diet) was not enough to correct anemia, while .3-.65 was enough.1 Not all patients, however, require so little. Studies have shown that 1.5 µg/day of injected B12 covers the needs of almost all patients with pernicious anemia.2 In fact, the RDA for B12 intake for adults is based on this number.2 However, I'm not convinced that meeting the RDA for B12 is enough to keep everyone's homocysteine (HCY) and methylmalonic acid levels in check, and to minimize DNA damage and nerve problems. Consider these findings:

German vegans who were getting some (the exact amount was not quantified) vitamin B12 through supplements, had an average serum B12 level of 259 pg/ml. These levels were not enough to keep their homocysteine levels low. Their homocysteine levels were 11.1 µmol/l, with below 8 being ideal.6 On the other hand, U.S. vegans who supplemented with B12 had an average serum B12 level of 421 pg/ml and average homocysteine levels of 7.9 µmol/l.7 Selhub et al.3 analyzed data from 8083 people, including whites, blacks, and Hispanics, and found that elevated homocysteine levels (> 11.4 for men, > 10.4 µmol/l for women) were associated with serum B12 levels less than 338 pg/ml. Fenech4 studied folate and B12 levels and intake in respect to DNA damage in white blood cells (lymphocytes) which, according to Fenech, has been shown to be a good marker for future cancer. They found that serum B12 > 405 pg/ml and a supplemental intake of 7 µg of B12/day were optimal for reducing DNA damage. Fenech says that folate and B12 intakes 3.5 times higher than the U.S. RDA minimize DNA damage. However, Fenech did not measure B12 intake from food, so not enough information was provided to determine the amount of B12 absorbed. It can be assumed that about 1.5 µg was absorbed from the 7 µg supplement; thus, more than 1.5 µg must have been absorbed per day (given that the subjects also had a normal dietary intake of B12) in order to minimize DNA damage. Lindenbaum et al.5 studied MMA and HCY levels in 548 elderly people from the Framingham Heart Study (Table L.2.2). The authors chose a serum B12 level of 350 pg/ml as the lower limit for suspecting a B12 deficiency because so many subjects with levels below this limit had elevated levels of sMMA:

Results of Lindenbaum et al.

Number

Number with MMA> .376 µmol/l

Number withMMA > .376 µmol/l & HCY > 21.3 µmol/l

% taking B12 SUPB(reporting)

serum B12 < 350

222

62 (28%)

21 (9%)

12% (160)

serum B12 > 350

326

20 (6%)A

4 (1%)

40% (241)

A - At least 10 subjects had elevated MMA due to poor kidney function, putting the number closer to 10 (3%)B - Median amount of B12 in supplements was 6 µgSUP - supplement

Based on the above research, serum B12 levels of 338 - 405 pg/ml seem necessary to limit damage.

Notes for What Is a Healthy B12 Level?

1. Baker SJ, Mathan VI. Evidence regarding the minimal daily requirement of dietary vitamin B12. Am J Clin Nutr. 1981 Nov;34(11):2423-33.

2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

3. Selhub J, Bagley LC, J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

4. Fenech M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat Res. 1999 Jul 16;428(1-2):299-304.

5. Lindenbaum J, Rosenberg IH, PW, Stabler SP, RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994 Jul;60(1):2-11.

6. Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.

7. Haddad EH, Berk LS, Kettering JD, Hubbard RW, s WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S.

B12 Intake Needed to Achieve a Healthy Level

Tucker et al.1 (2000, USA) examined the B12 status of 2999 subjects in the Framingham Offspring Study. Serum B12 was associated with B12 intake. Based on Figure 1 in Tucker et al.,1 2 µg from foods (at a 50% absorption rate) should keep one's serum B12 levels at about 350 pg/ml. An intake of about 5 µg from foods (at a 50% absorption rate) keeps serum B12 levels at about 430 pg/ml, a level at which people rarely, if ever, have B12-related problems (and which covers Fenech's findings on DNA damage above). This translates into 2.5 µg/day being absorbed.

Based on rates listed in the table above, B12 Absorption Rates, the table below lists the amounts of B12 needed from fortified foods and supplements to match the intakes extrapolated from Tucker et al.1

B12 Intake Needed to Achieve a Given Serum B12 Level

Serum B12 target

~ 350 pg/ml

~ 430 pg/ml

OtherB

Intake/day per Tucker et al.1

2 µg

5 µg

Absorbed per day at a 50% rate

1 µg

2.5 µg

Amount needed to equal above amounts absorbed:

Fortified foods throughout the day

2 µg

5 µg

3 µg

1 daily SUP

2-5 µgE

100 µg

10 µg

1 SUP, 2x dailyA

2 µg

4-5 µgE

1 weekly cyanocobalamin supplementC,D

700 µg

1700 µg

2000 µg

A - Spaced 6 hours apartB - Minimum recommended amounts by vegan health professionals in What Every Vegan Should Know about Vitamin B12C - Chewed or sublingualD - Based on 1% absorption rateE - Absorption rates in doses of between 2 and 5 µg are not known

Absorption Rate Calculation Example: Amount Needed to Absorb 2.5 µg

At a 5 µg dose, about 1.5 µg is absorbed.About 1% is absorbed of anything above 5 µg.By adding 1.5 µg absorbed from the first 5 µg of a cyanocobalamin supplement, plus .1 µg for each additional 10 µg increment (.01 * 10 µg), we can compile enough B12 to equal 2.5 µg absorbed:2.5 µg needed - 1.5 µg (from the first 5 µg of a given dose) = 1.0 µg remaining to be absorbed1.0 µg remaining / .1 µg (amount absorbed from an additional 10 µg dose) = 10 (doses of 10 µg needed)10 remaining doses * 10 µg = 100 µg100 µg + (the first) 5 µg = 105 µg totalBecause 100 µg translates into 2.4 µg absorbed, which is almost the same as 2.5 µg, 105 µg can be rounded down to 100 µg.

Notes for B12 Intake Needed to Achieve a Healthy Level

1. Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, PW, Selhub J. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000 Feb;71(2):514-22.

Minimum Recommendations

In What Every Vegan Should Know about Vitamin B12, minimum recommendations are given for vegans:

3 µg from fortified foods1 daily 10 µg supplement1 weekly 2000 µg supplement

As can be seen from the table above, B12 Intake Needed to Achieve a Given Serum B12 Level, these recommendations should put B12 levels between 350 and 430 pg/ml. Thus, for consistency with other vegan health professionals, I have used them as minimum amounts.

Step 2: Conclusion

Taking a weekly supplement, to keep B12 levels up and homocysteine levels down, has not been tested. For this reason, I am more in favor of the fortified foods and daily supplement options.

Some people may wonder what levels are ideal, rather than minimal (assuming one does not suffer from intrinsic-factor-related problems). Thus I have suggested a range above which should provide no further benefit and below which there is evidence of at least modest adverse effects. My final recommendations to keep B12 levels between 350-430 pg/ml are:

From fortified foods

3-5 µg

From 1 daily supplement

10-100 µg

From 2 daily supplements spaced at least 6 hours apart

5 µg

Appendix: Homocysteine and Kidney Disease

Homocysteine can be greatly elevated for people on dialysis or with a kidney transplant (typical average amounts range from 20-60 µmol/l).1 Thus far, there have been no studies examining whether reducing homocysteine in these patients can reduce cardiovascular problems. Shemin et al.1 report that, for this reason, the American Heart Association and the American Society of Nephrology consider screening and treatment of elevated HCY to be inappropriate. However, if I had kidney disease, the mere lack of direct evidence would not be comforting.

Unfortunately, to date, very high doses of folic acid (1,000-60,000 µg/day), B6 (50-110 mg/day), and B12 (12-1,000 µg/day) have not succeeded in normalizing homocysteine levels to 12 µmol/l in kidney disease patients. However, they have often succeeded in reducing homocysteine to 16-20 µmol/l which could be worthwhile. Note: vitamin B6 is sometimes toxic at very high doses for long periods of time.

Because people with kidney disease can have impaired cyanide metabolism or clearance, a non-cyanocobalamin form of B12 is preferable. Anyone with kidney disease who is concerned about homocysteine can suggest the review by Shemin et al.1 to their dietitian and/or doctor.

Notes for Appendix: Homocysteine and Kidney Disease

1. Shemin D, Bostom AG, Selhub J. Treatment of hyperhomocysteinemia in end-stage renal disease. Am J Kidney Dis. 2001 Oct;38(4 Suppl 1):S91-4.

Appendix: Ways to Get B12 Deficiency

(Reference: Herbert1 where not otherwise noted.)

Inadequate dietary intake. Inadequate absorption:

Pernicious anemia - Problems with intrinsic factor.

Loss of intrinsic factor: Genetically predetermined and age-dependent (sometimes as early as 45 yrs). The most common cause of B12 deficiency in non-edlerly, nonvegetarians. Autoimmunity to intrinsic factor: Circulating antibodies to intrinsic factor indicate eventual pernicious anemia if not treated. A chronic B12 deficiency damages immune function and the antibodies may disappear as B12 deficiency progresses.

Food-cobalamin malabsorption - Loss of gastric acid and/or protein digesting enzymes which break the protein-B12 bonds in food. This can be caused by stomach surgery, atrophy or inflammation of the stomach, medications that suppress acid secretion, or a stomach infection by H. pylori or anaerobic bacteria (which can be due to low stomach acid).2 Pancreatic disease reduces free calcium in the ileum (calcium is needed for B12 absorption). Can be improved with calcium and/or bicarbonate. Unhealthy ileum. Drugs decreasing absorption include cimetidine, metformin (ties up free calcium in intestines), potassium chloride, and cholestyramine.3 Infection by tapeworms,4Diphyllobothrium latum,5 or Giardia lamblia.3

Defects in B12 enzymes, transport proteins, or storage proteins.

Defects in B12 enzymes that result in high MMA levels are rare. One researcher reported that they occur in 1 out of 28,000 people.6 Ciani et al.6 provide an informative diagram showing which enzymes are involved in the various B12 metabolic pathway defects.

Increased requirement during pregnancy or hyperthyroidism. Increased excretion caused by alcoholism. Nitrous oxide anesthesia in people with low serum B12 (nitrous oxide can change the cobalt atom of B12).4 Hypothyroidism (possibly autoimmune).7 AIDS can cause B12 deficiency as shown through macrocytic anemia and neurological problems without elevated homocysteine levels.

Notes for Appendix: Ways to Get B12 Deficiency

1. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S.

2. Ho C, Kauwell GP, LB. Practitioners' guide to meeting the vitamin B-12 recommended dietary allowance for people aged 51 years and older. J Am Diet Assoc. 1999 Jun;99(6):725-7.

3. Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, PW, Selhub J. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000 Feb;71(2):514-22.

4. Groff J, Gropper S. Advanced Nutrition and Human Metabolism, 3rd ed. Wadsworth: 2000.

5. Halsted JA, Carroll J, Rubert S. Serum and tissue concentration of vitamin B12 in certain pathologic states. N Engl J Med. 1959;260:575-80.

6. Ciani F, Poggi GM, Pasquini E, Donati MA, Zammarchi E. Prolonged exclusive breast-feeding from vegan mother causing an acute onset of isolated methylmalonic aciduria due to a mild mutase deficiency. Clin Nutr. 2000 Apr;19(2):137-9.

7. PR Jr, Roloff JS. Vitamin B12 deficiency in an infant strictly breast-fed by a mother with latent pernicious anemia. J Pediatr. 1982 Jun;100(6):917-9.

Appendix: Elevated Serum B12 and Increased Risk of Disease

Summary: Two studies have shown an increased risk coronary heart disease (CHD) or mortality in subjects with elevated serum B12. Pancharuniti et al. found a increased risk of CHD that barely reach statistical significance. Zeitlin et al. found (what equaled) an increased risk of death of 7% for every 100 pg/ml increase in serum B12. Both of these findings were probably due to B12 being a marker for foods associated with heart disease and not that B12 itself was damaging. As reported throughout this article, most studies have shown B12 levels on the higher end of normal to be healthy.

Pancharuniti et al. (1996) performed a retrospective study in which serum B12 levels did not differ significantly between those with CAD and matched controls. However after controlling for homocysteine levels and other CAD risk factors, there was a barely significant association between serum B12 and increased risk of CHD (rr = 1.5; CI: 1.0, 1.8). The authors thought this could be due to the fact that B12 is found in foods that increase one's risk of heart disease such as red meats.

Reference: Pancharuniti N, CA, Sauberlich HE, Perkins LL, Go RC, Alvarez JO, Macaluso M, Acton RT, Copeland RB, Cousins AL, et al. Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Am J Clin Nutr. 1994 Apr;59(4):940-8. Erratum in: Am J Clin Nutr. 1996 Apr;63(4):609.

Zeitlin et al. (1997) followed 488 people aged 75-85 for an average of 6 years. Average B12 levels were 515 pg/ml. In measuring death, stroke, heart attack, coronary heart disease, and cardiovascular disease events, there was no significant difference in serum B12 between those who did (569 ± 479 pg/ml) and did not (491 ± 267 pg/ml) have an event. However, each increase of 1 pg/ml in serum B12 was associated with a .07% increase in risk of death (P = .041). This means that someone with a 100 pg/ml higher serum B12 had a 7% higher risk of death. Zeitlin et al. suggest that the higher risk of death could be because B12 is a marker for animal product intake, and not from B12 itself. But, they also speculate that high B12 stores could cause liver damage, contributing to death. This is purely conjecture as there are no reports of liver toxicity due to high B12 stores.

Reference: Zeitlin A, Frishman WH, Chang CJ. The association of vitamin b 12 and folate blood levels with mortality and cardiovascular morbidity incidence in the old old: the Bronx aging study. American Journal of Therapeutics. 1997 Jul-Aug;4(7-8):275-81.

Appendix: Conditions That Increase B12 Levels

Some diseases can cause serum B12 levels to increase higher than normal in some people. These include kidney, liver, cancer, and duodenal ulcers,1 diabetes, obesity,2 and cyanide metabolism defects.3 B12 deficiency can be hidden by alcoholism because excess B12 is released into the blood from the damaged liver.4

Notes for Conditions That Increase B12 Levels

1. Halsted JA, Carroll J, Rubert S. Serum and tissue concentration of vitamin B12 in certain pathologic states. N Engl J Med. 1959;260:575-80.

2. Fischbach F. A Manual of Laboratory & Diagnostic Tests, 6th Ed. Philadelphia, PA: Lippincott & Wilkins; 2000.

3. Linnell JC, s DM. Cobalamin metabolism and its clinical aspects. Clin Sci (Lond). 1984 Feb;66(2):113-21.

4. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S-1222S.

Appendix: Should I Get My B12 Status Tested?

Serum B12 Levels

Vegans do not need to get their homocysteine or B12 levels checked merely because they are vegan. Rather, being vegan means that you should get a regular, reliable source of vitamin B12 from fortified foods and/or supplements. (Though if you've gone a month or so without a reliable source of B12, you should replenish your stores as described in Step 1 of the Recommendations.)

About 2% of people do not absorb B12 well. While this has nothing to do with being vegan, it is nice to know if you are such a person. You will not be able to tell unless you first have a reliable source of B12 for at least a few weeks before your B12 level is checked. Additionally, there are specific tests that directly measure B12 absorption.

If you get your B12 level checked, please note that eating seaweeds can falsely inflate B12 levels. Methods for determining B12 levels do not distinguish between B12 and some inactive B12 analogues. Many seaweeds contain a variety of inactive B12 analogues. Someone who is eating large amounts of seaweed may have serum B12 levels well above normal, but much of it could be inactive B12 analogues.

Homocysteine: Most Important Metabolite of B12 Status

Blood homocysteine level is not a direct measure of vitamin B12 status because it is also affected by intake of, or metabolic problems with, folate and vitamin B6. However, homocysteine is the only known product of early B12 depletion that is thought to cause harm. For that reason, it is probably the most important marker of B12 status.

Some doctors recommend that all adults over age 45 have their homocysteine levels checked in order to catch a genetic predisposition to high homocysteine, which can often be successfully treated. It is best to ensure a reliable source of B12 and folic acid for a few weeks prior to the test. Otherwise, a high homocysteine will not tell you whether you have a genetic predisposition, or if it was simply from a lack of B12 or folic acid in your diet. On the other hand, high homocysteine after a period of adequate B12 and folic acid intake shows that something else is a problem.

Methylmalonic Acid: Most Specific Test for B12 Status

Methylmalonic Acid (MMA) builds up in the system when B12 status is poor. It is the most specific test for measuring B12 status because B12 is the only necessary co-enzyme needed to keep levels low. MMA can be measured in both the urine and the blood. If you want a snapshot of what your B12 status is at a given moment, then MMA is the test. The laboratory will tell you normal values for the specific test they are using. General parameters for MMA levels are listed here.

Just like for homocysteine, getting your MMA level tested when not having a reliable source of vitamin B12 is probably a waste of time as there is a good chance it will be high, and it will only tell you what you already know: Everyone needs a reliable source of vitamin B12. In fact, I would see no reason to have MMA levels tested unless your serum B12 levels are normal, but you are still having symptoms of B12 deficiency. In this case, high MMA levels could indicate that you might have a B12 metabolism problem that can then be treated in some way. Of course, this should be done under the guidance of a physician.

Homocysteine and MMA Tests are Only Short-Term

Some people might think that instead of worrying about getting a reliable supply of B12, they will just have their MMA or homocysteine levels tested and if they are fine, then there's no reason to get a reliable supply of B12 for the time being. The problem with this is that you never know when you will hit the point in which MMA or homocysteine levels start to rise. They may stay low for years, months, or only days after they are tested and found to be healthy. At this time, there is no test that can tell you how long your B12 status will be adequate if you are not getting a reliable source of B12.

Recommendations on Getting B12 Status Tested

As mentioned above, for a variety of reasons, it is prudent for people to routinely have their homocysteine levels tested every 5 years after age 45. But unless you suspect a B12 absorption or metabolic problem, there is no reason to get MMA or B12 levels tested if you follow the recommendations here.

Table: B12-Related Laboratory Values

Serum B12 (sB12) is measured in both pmol/l and pg/ml. All sB12 values in this article are in pg/ml (using a conversion factor of 1 pg/ml = 1.35 * pmol/l1).

U.S. Recommended Dietary Allowances for vitamin B122

Age

Micrograms (µg, mcg)

0 - 5 months

0.4

6 - 11 months

0.5

1 - 3 years

0.9

4 - 8 years

1.2

9 - 13 years

1.8

14 years and older*

2.4

Pregnancy

2.6

Lactation

2.8

*The Food and Nutrition Board says, "Since 10 - 30% of older people may malabsorb food-bound B12, it is advisable for those older than 50 to meet their RDA mainly by consuming foods fortified with B12 or a B12-containing supplement."

Average daily dietary intake of B12 for adults in the USA2

men

5 µg

women

3.5 µg

Normal serum B12

range, newborns3

160 - 1300 pg/ml

range, adultsA

200 - 900 pg/ml

average

450 pg/ml

Breast MilkB,4

180 - 300 pg/ml

Normal MCV Range5

80-96 fl

Methylmalonic Acid (MMA)

normal serum MMA (sMMA)

..07 - .27 µmol/l6,7

serum MMA cutoff in diagnosing B12 deficiency

..376 µmol/l7

normal urine MMA (uMMA)

..58 - 3.56 µmol/mmol Cr8

Normal Serum Homocysteine (HCY)

2.2 - 13.2 µmol/l9

Pre-treatment ranges in infants and children who have serious neurological problems due to genetic defects in B12 metabolism10

serum MMA

65-246 µmol/l

urine MMA

820 - 11,292 µmol/mmol Cr

serum HCY

trace - 89 µmol/l

A - sB12 does not change more than 7% from week to week under normalconditions (i.e. consistent intake, no disease).11B - Numbers vary widely depending on measurement methods anddifferences in maternal stores and intake.

Notes for Appendix of B12 Values

1. Tucker KL, Rich S, Rosenberg I, Jacques P, Dallal G, PW, Selhub J. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000 Feb;71(2):514-22.

2. Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 2000.

3. Fischbach F. A Manual of Laboratory & Diagnostic Tests, 6th Ed. Philadelphia, PA: Lippincott & Wilkins; 2000.

4. Kuhne T, Bubl R, Baumgartner R. Maternal vegan diet causing a serious infantile Neurological disorder due to vitamin B12 deficiency. Eur J Pediatr. 1991 Jan;150(3):205-8.

5. Stedman's Medical Dictionary, 26th ed. Baltimore: & Wilkins, 1995.

6. Kuzminski AM, Del Giacco EJ, RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998 Aug 15;92(4):1191-8.

7. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum H, Sandberg S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem. 1999 Feb;45(2):189-98.

8. Rasmussen K, Moelby L, Jensen MK. Studies on methylmalonic acid in humans. II. Relationship between concentrations in serum and urinary excretion, and the correlation between serum cobalamin and accumulation of methylmalonic acid. Clin Chem. 1989 Dec;35(12):2277-80.

9. Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.

10. Biancheri R, Cerone R, Schiaffino MC, Caruso U, Veneselli E, Perrone MV, Rossi A, Gatti R. Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics. 2001 Feb;32(1):14-22.

11. Halsted JA, Carroll J, Rubert S. Serum and tissue concentration of vitamin B12 in certain pathologic states. N Engl J Med. 1959;260:575-80.

Table: Plant Sources of Folate

Plant Sources of Folate

Food

amount

µg

cooked lentils

1/2 Cup

179

cooked black beans

1/2 Cup

128

romaine lettuce

1 1/2 Cup

114

orange juice

1 Cup

109

cooked spinach

1/2 Cup

103

canned refried beans

1/2 Cup

106

cooked garbanzo beans(aka chickpeas)

1/2 Cup

80

cooked navy beans

1/2 Cup

82

cooked broccoli

1 Cup

78

sunflower seeds

1/4 Cup

76

cooked pinto beans

1/2 Cup

72

cooked kidney beans

1/2 Cup

63

RDA for folate is 400 µg for people over age 13.

Reference: Wardlaw GM. Perspectives in Nutrition, 4th Ed. Boston, MA: McGraw-Hill; 1999.

Figure: Methionine-Homocysteine-Folate-B12 Cycle

References for Methionine-Homocysteine-Folate-B12 Cycle

1. Groff J, Gropper S. Advanced Nutrition and Human Metabolism, 3rd ed. Wadsworth: 2000.

2. Herrmann W, Schorr H, Purschwitz K, Rassoul F, Richter V. Total homocysteine, vitamin b(12), and total antioxidant status in vegetarians. Clin Chem. 2001 Jun;47(6):1094-101.

3. DeRose DJ, -Marcel ZL, Jamison JM, Muscat JE, Braman MA, McLane GD, Mullen J. Vegan diet-based lifestyle program rapidly lowers homocysteine levels. Prev Med. 2000 Mar;30(3):225-33.

4. Krajcovicova-Kudlackova M, Blazicek P, Kopcova J, Bederova A, Babinska K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab. 2000;44(3):135-8.

5. Selhub J, Bagley LC, J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S.

6. Refsum H. Folate, vitamin B12 and homocysteine in relation to birth defects and pregnancy outcome. Br J Nutr. 2001 May;85 Suppl 2:S109-13.

7. Kirke PN, Molloy AM, Daly LE, Burke H, Weir DG, JM. Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Q J Med. 1993 Nov;86(11):703-8.

8. Fenech M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat Res. 1999 Jul 16;428(1-2):299-304.

9. Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.

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