Vitamin B12 deficiency easy to avoid
Vitamin B12 (cobalamin) is an important water-soluble vitamin. In contrast to other water-soluble vitamins it is not excreted quickly in the urine, but rather accumulates and is stored in the liver, kidney and other body tissues. As a result, a vitamin B12 deficiency may not manifest itself until after 5 or 6 years of a diet supplying inadequate amounts. Vitamin B12 functions as a methyl donor and works with folic acid in the synthesis of DNA and red blood cells and is vitally important in maintaining the health of the insulation sheath (myelin sheath) that surrounds nerve cells. The classical vitamin B12 deficiency disease is pernicious anaemia, a serious disease characterized by large, immature red blood cells. It is now clear though, that a vitamin B12 deficiency can have serious consequences long before anaemia is evident. The normal blood level of vitamin B12 ranges between 200 and 600 picogram/milliliter (148-443 picomol/liter). Although deficiency is far more common than excess when it comes to vitamin B12 status cases have been reported where blood levels exceeded 3000 picograms/milliliter. Such high levels may be caused by bacterial overgrowth as outlined in the article Vitamin B-12 Overload
A deficiency often manifests itself first in the development of neurological dysfunction that is almost indistinguishable from senile dementia and Alzheimer's disease. There is little question that many patients exhibiting symptoms of Alzheimer's actually suffer from a vitamin B12 deficiency. Their symptoms are totally reversible through effective supplementation. A low level of vitamin B12 has also been associated with asthma, depression, AIDS, multiple sclerosis, tinnitus, diabetic neuropathy and low sperm counts. Clearly, it is very important to maintain adequate body stores of this crucial vitamin.
The amount of vitamin B12 actually needed by the body is very small, probably only about 2 micrograms or 2 millionth of a gram/day. Unfortunately, vitamin B12 is not absorbed very well so much larger amounts need to be supplied through the diet or supplementation. The richest dietary sources of vitamin B12 are liver, especially lamb's liver, and kidneys. Eggs, cheese and some species of fish also supply small amounts, but vegetables and fruits are very poor sources. Several surveys have shown that most strict, long-term vegetarians are vitamin B12 deficient. Many elderly people are also deficient because their production of the intrinsic factor needed to absorb the vitamin from the small intestine decline rapidly with age.
Fortunately, oral supplementation with vitamin B12 is safe, efficient and inexpensive. Most multi-vitamin pills contain 100-200 microgram of the cyanocobalamin form of B-12. This must be converted to methylcobalamin or adenosylcobalamin before it can be used by the body. The actual absorption of B12 is also a problem with supplements. Swallowing 500 micrograms of cyanocobalamin can result in absorption of as little as 1.8 microgram so most multivitamins do not provide an adequate daily intake. The best approach is to dissolve a sublingual tablet of methylcobalamin (1000 micrograms) under the tongue every day. That will be sufficient to maintain adequate body stores. However, if a deficiency is actually present then 2000 microgram/day for one month is recommended followed by 1000 microgram/day. Some physicians still maintain that monthly injections of vitamin B12 is required to maintain adequate levels in the elderly and in patients with a diagnosed deficiency. There is however, no scientific evidence supporting the notion that injections are more effective than sublingual supplementation.
KINGSTON, CANADA. Many older people suffer from a deficiency of vitamin B12 (cobalamin). A low intake of animal protein, the use of medications to reduce stomach acid, a Helicobacter pylori infection, an inflammation of the stomach lining, and problems with the pancreas can all contribute to the development of a deficiency. Medical researchers at Queen's University now report that daily supplementation with a multivitamin containing 2.6 – 37.5 micrograms of vitamin B12 is enough to prevent a cobalamin deficiency in most older healthy people. Their study involved 242 active, relatively healthy men and women aged 65 years or older. Sixty-six (27.3 per cent) of the volunteers had been taking a daily multivitamin containing 2.6 – 37.5 micrograms of vitamin-B12 for at least six months.
All volunteers had blood samples drawn for the measurement of cobalamin level as well as the levels of the related metabolites methylmalonic acid (MMA), homocysteine (HCYS) and methylcitric acid (MCTR). Thirty- seven (15.3 per cent) of the 242 participants were deficient in cobalamin (level below 165 pmol/L). Of these 37 only 2 were taking multivitamins. An elevated level of MMA was found in 53 participants of whom 46 (87 per cent) were not taking multivitamins. An elevated level of homocysteine was found in 17 participants of whom 16 were not supplementing. The researchers conclude that oral supplementation with 25 micrograms/day or higher may be sufficient to prevent vitamin B12 deficiency in a large proportion of older people. They caution though that their findings cannot be extrapolated to frail or sick old people who may require larger doses to avoid deficiency.
Garcia, Angela, et al. Is low-dose oral cobalamin enough to normalize cobalamin function in older people? Journal of the American Geriatrics Society, Vol. 50, August 2002, pp. 1401-04
Vitamin B12 deficiency and ulcer drugs
DENVER, COLORADO. Researchers at the University of Colorado School of Pharmacy warn that prolonged use of acid-suppressing drugs such as cimetidine (Tagamet), ranitidine (Zantac) and omeprazole (Losec) can lead to a serious vitamin-B12 deficiency. They cite the case of a 78-year-old non-vegetarian, white woman with GERD (gastroesophageal reflux disease) who had been taking cimetidine or ranitidine for 4.5 years. She was started on cimetidine (300 mg four times daily) in February 1990, which was changed to ranitidine (150 mg twice daily) in April 1993. Her vitamin B12 level was normal (413 pg/mL) in August 1992, but by June 1994 it had decreased to 256 pg/mL and her homocysteine level had increased dramatically to 27.3 micromol/L. Note: A homocysteine level above 10 micromol/L vastly increases the risk of atherosclerosis and stroke with a 5 micromol/L increase corresponding to a 70 per cent increase in the risk of heart disease and a 50 per cent increase in stroke risk.
The patient was started on 1000 micrograms/day of sublingual vitamin B12 supplementation and by November 1994 her level was back up to 517 pg/mL and her homocysteine level was down to 20.3 micromol/L. Further improvements were observed in March 1998 when her vitamin B12 level was up to 629 pg/mL and homocysteine was down to 13.9 micromol/L. The researchers point out that other studies have shown that omeprazole also lowers vitamin B12 levels and conclude that older people on long-term acid-suppressing drugs should be monitored for vitamin B12 deficiency and supplement if necessary.
Ruscin, J. Mark, et al. Vitamin B12 deficiency associated with histamine2-receptor antagonists and a proton-pump inhibitor. Annals of Pharmacotherapy, Vol. 36, May 2002, pp. 812-16
Diabetes drug linked to vitamin B12 deficiency
A Wisconsin doctor reports a case of a 63-year-old man who developed a severe vitamin-B12 deficiency after having taken metformin (Glucophage) for five years. Replacing the metformin with sulfonylurea and taking 1000 mg of cyanocobalamin (vitamin B12) for two months reversed the deficiency. Dr. Mary Ann Gilligan estimates that 10 to 30 per cent of patients on metformin develop a vitamin B12 deficiency and points out there is some evidence that calcium supplementation will prevent it.
Archives of Internal Medicine, Vol. 162, February 25, 2002, pp. 484-85
Helicobacter pylori and vitamin B12 deficiency
ANKARA, TURKEY. It is estimated that more than 50 per cent of adults in developed countries are infected with the Helicobacter pylori bacterium. H pylori has been implicated in stomach ulcers, indigestion (dyspepsia), gastritis (inflammation of the stomach lining), stomach cancer, and MALT lymphoma. About 10-15 per cent of adults over 60 years of age are affected by a vitamin B12 (cobalamin) deficiency. Researchers at the Turkish Military Medical Academy now provide convincing evidence that the two are linked. A detailed study of 138 patients with vitamin B12 deficiency and anaemia discovered that 77 (58 per cent) of the patients had a H pylori infection. Eradication of this infection successfully cured the anaemia and reversed the vitamin B12 deficiency in 31 (40 per cent) of the 77 infected patients. The researchers conclude that a H pylori infection can cause a vitamin B12 deficiency and that this deficiency, in many cases, can be totally eliminated by eradicating the infection. EDITOR'S NOTE: Memory loss, fatigue, and mental confusion are often the first indicators of a vitamin B12 deficiency.
Kaptan, Kursad, et al. Helicobacter pylori - Is it a novel causative agent in vitamin B12 deficiency? Archives of Internal Medicine, Vol. 160, May 8, 2000, pp. 1349-53
Stopeck, Alison. Links between Helicobacter pylori infection, cobalamin deficiency, and pernicious anaemia. Archives of Internal Medicine, Vol. 160, May 8, 2000, pp. 1229-30 (editorial)
Vegetarians are vitamin B12 deficient
SYDNEY, AUSTRALIA. It is generally assumed that vitamin B12 deficiencies are rare among people consuming a varied diet. However, there is some question whether vegetarians get enough B12 as it is not present in plants. Researchers at the Sydney Adventist Hospital have just completed a study aimed at resolving this question. Their study involved 245 Adventist ministers who were either lactoovovegetarians or vegans. The average age of the ministers was 46 years (range 22 to 80 years) and most of them had been vegetarians for over 20 years. The study participants filled out a diet questionnaire and had a fasting blood sample drawn for a 20-test biochemical profile including vitamin B12 concentrations. The mean vitamin B12 level was 199 pmol/L and 73 per cent of the ministers had a level below the recommended lower limit of 221 pmol/L. Vitamin B12 concentrations were also measured in a control group of 53 ministers who consumed fish, poultry or red meat on a regular basis. In this group 40 per cent had vitamin B12 concentrations below the recommended lower limit; this indicates that vitamin B12 deficiency is widespread even among non-vegetarians.
Additional tests showed that the vitamin B12 deficiencies observed among lactoovovegetarians were due to dietary deficiencies rather than to malabsorption. The researchers conclude that as many as 73 per cent of Australian vegetarians are vitamin B12 deficient and recommend that they increase their intake either from vitamin B12-containing foods (animal products), from supplements or from vitamin B12- fortified foods.
Hokin, Bevan D. and Butler, Terry. Cyanocobalamin (vitamin B-12) status in Seventh-day Adventist ministers in Australia. American Journal of Clinical Nutrition, Vol. 70, September 1999, pp. 576S- 78S
Vitamin B12 deficiency and breast cancer
BALTIMORE, MARYLAND. Researchers at the Johns Hopkins University report that women with breast cancer tend to have lower vitamin B12 levels in their blood serum than do women without breast cancer. The researchers determined vitamin B12 concentrations in blood samples obtained in 1974 and in 1989 and compared the levels found in 195 women who later developed breast cancer with the levels found in 195 women free of cancer. They found that postmenopausal women with the lowest serum levels of vitamin B12 had a 2.5-4.0 times greater likelihood of being in the breast cancer group than did women with the highest levels. The researchers found no correlation between breast cancer risk and serum levels of folic acid, vitamin B6, and homocysteine.
In a subsequent review of the findings Dr. Sang-Woon Choi, MD of Tufts University points out that serum levels of folate are a poor indicator of levels in tissues and that it may well be that there is a correlation between folate levels in breast tissue and breast cancer risk. Dr. Choi speculates that a vitamin B12 deficiency may lead to breast cancer because it could result in less folate being available to ensure proper DNA replication and repair.
Wu, K., et al. A prospective study of folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer. Cancer Epidemiol. Biomarkers Prev., Vol. 8, March 1999, pp. 209-17
Choi, Sang-Woon. Vitamin B12 deficiency: a new risk factor for breast cancer? Nutrition Reviews, Vol. 57, August 1999, pp. 250-60
Vitamin B12 deficiency linked to neuropsychiatric abnormalities
KINGSTON, CANADA. Dr. Dianne Delva, MD, Assistant Professor of Family Medicine at Kingston University, reviews the evidence for and against routine supplementation with vitamin B12 (cobalamin) in the elderly. Several studies have shown that anywhere from 5 to 15 per cent of elderly people suffer from a vitamin B12 deficiency. Although the only formally recognized disorder linked to a cobalamin deficiency is megaloblastic anaemia, it is now becoming clear that many neurological and psychiatric symptoms may also be caused by a vitamin B12 deficiency. Ataxia (shaky movements and unsteady gait), muscle weakness, spasticity, incontinence, hypotension, vision problems, dementia, psychoses, and mood disturbances are but a few of the disorders which have recently been linked to possible vitamin B12 deficiencies. Dr. Delva points out that these disorders may occur at vitamin B12 levels just slightly lower than normal and considerably above the levels normally associated with anaemia. She also cautions that the blood level of cobalamin is an unreliable indicator of deficiency and that tissue levels of the vitamin may be quite low even though the blood levels are normal. The best test of cobalamin deficiency involves measuring the blood levels of homocysteine and methylmalonic acid. If the level of these two precursors to the metabolic reactions controlled by cobalamin are high then the vitamin B12 level is low. Vitamin B12 deficiencies may be treated by injections of the vitamin or by oral supplementation. Oral supplementation is just as effective as injections in most people and a lot less expensive. An oral dose of 100-250 micrograms/day is usually adequate although patients with absorption difficulties may need 1000 micrograms/day. Cobalamin has no known toxic effects.
Delva, M. Dianne. Vitamin B12 replacement - To B12 or not to B12? Canadian Family Physician, Vol. 43, May 1997, pp. 917-22
Vitamin B-12 deficiency common in older people
MOLNLYCKE, SWEDEN. Swedish researchers have discovered that many older people are deficient in vitamin B-12. Their study involved 368 men and women aged 75 years or older. Analysis of blood serum showed that 11 per cent of the participants were deficient in cobalamin (vitamin B-12). The researchers point out that a vitamin B-12 deficiency has been linked to neuropsychiatric disorders such as memory loss and dementia. The researchers discovered several cases of gastritis (inflammation of the lining of the stomach) and two cases of celiac disease among patients with low serum values of cobalamin. They conclude that routine screening for a vitamin B-12 deficiency is justified in the case of older people.
In a separate letter to the Journal of the American Geriatrics Society doctors from the Union Memorial Hospital in Baltimore report on a case of vitamin B-12 deficiency. The patient, an 85-year-old man, had developed progressive memory loss and lethargy over a two-year period. Although his serum level of vitamin B-12 was within the currently accepted range, the doctors decided to proceed with vitamin B-12 therapy. The patient received an intramuscular injection of 1000 micrograms of vitamin B-12 for three consecutive days, then 1000 micrograms weekly for a month, and then one injection every month. By the fifth injection his mental status had vastly improved and his lethargy had completely vanished. The doctors conclude that the levels of serum vitamin B-12 concentrations currently considered normal in the United States may be too low and should be reassessed. The lower limit of 200 pg/mL is based on the level that causes abnormalities in the blood (pernicious anaemia). In contrast the lower limit in Japan and some European countries is 500-550 pg/mL and is based on the level that causes mental manifestations such as dementia and memory loss. The doctors suggest that a trial of vitamin B-12 therapy is warranted in patients with borderline cobalamin serum levels as it is effective and inexpensive.
Eggersten, Robert, et al. Prevalence and diagnosis of cobalamin deficiency in older people. Journal of the American Geriatrics Society, Vol. 44, No. 10, October 1996, pp. 1273-74
Goodman, Mark, et al. Are U.S. lower normal B-12 limits too low? Journal of the American Geriatrics Society, Vol. 44, No. 10, October 1996, pp. 1274-75
Vitamin B-12 deficiency common after stomach surgery
PHILADELPHIA, PENNSYLVANIA. It is becoming increasingly clear that a vitamin B-12 deficiency can have serious consequences, particularly in elderly people. A vitamin B-12 deficiency can be misdiagnosed as Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), spinal cord compression, or alcoholic or diabetic peripheral neuropathy. A vitamin B-12 deficiency is also associated with elevated homocysteine levels that in turn have been linked to a significantly increased risk for atherosclerosis and heart disease. The elderly are at special risk for being deficient in vitamin B-12 and, as researchers at the Philadelphia Veterans Affairs Medical Centre report, so are people who have had stomach surgery for peptic ulcers and similar conditions. The study involved 61 patients with a mean age of 63 years who had undergone gastric surgery as far back as 30 years ago and 107 controls. The researchers found that 31 per cent of the surgery group had a vitamin B-12 deficiency as compared to 2 per cent among the controls. The presence of a deficiency was established through measurements of the levels of vitamin B-12, total homocysteine, and methylmalonic acid in the blood. The deficiencies were corrected by daily injections of 1000 micrograms of vitamin B-12 for five days followed by monthly injections. Folic acid supplementation (1 mg/day) was also used. The researchers recommend that physicians ensure that those of their patients who had gastric surgery, no matter how long ago, be checked periodically for a vitamin B-12 deficiency. If one is found, the patients should be given lifelong vitamin B-12 therapy (periodic intramuscular injections).
Sumner, Anne E., et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin B-12 deficiency after gastric surgery. Annals of Internal Medicine, Vol. 124, No. 5, March 1, 1996, pp. 469-76
Vitamin B12 deficiency common among elderly people
NEW YORK, NY. Researchers at Columbia University have confirmed that elderly people often suffer from a lack of vitamin B12 (cobalamin). The deficiency is usually only discovered when patients develop megaloblastic anaemia. However, before this stage is reached, cobalamin-deficient individuals may develop neuropsychiatric damage and show signs of disorientation and confusion. The researchers evaluated 548 men and women aged 67 to 96 years and compared their cobalamin and folate status to that of 117 healthy, younger control subjects. They found that 40.5 per cent of the elderly people suffered from a vitamin B12 deficiency versus only 17.9 per cent in the younger group. There was no significant difference in folate status between the two groups. The researchers also found that people who took oral supplements containing vitamin B12 and folate (6 micrograms and 400 micrograms per day respectively) were much less likely to suffer from a deficiency than were people who did not supplement. They point out that as people age they become less and less able to absorb vitamin B12 from food and therefore are likely to develop a deficiency. As gastric atrophy progresses vitamin B12 status can only be maintained by taking high oral doses of cobalamin (500-1000 micrograms daily) or by routine intramuscular injections providing 1 mg per month. The researchers also point out that a vitamin B12 deficiency leads to an accumulation of homocysteine in the blood. An increased serum concentration of homocysteine and its derivatives is now recognized as a major risk factor in heart disease and stroke.
Lindenbaum, John, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. American Journal of Clinical Nutrition, Vol. 60, July 1994, pp. 2-11
Allen, Lindsay H. and Casterline, Jennifer. Vitamin B-12 deficiency in elderly individuals: diagnosis and requirements. American Journal of Clinical Nutrition, Vol. 60, July 1994, pp. 12-14
Vitamin B deficiencies are common in elderly people
LEUVEN, BELGIUM. An international team of researchers have confirmed that elderly people often suffer from a deficiency of vitamins B-6, B-12 and folic acid. Their investigation involved 99 healthy young people (aged 19-55), 64 healthy elderly subjects (aged 65-88), and 286 elderly hospitalized patients (aged 61-97). The researchers measured the blood concentrations of the vitamins in all subjects as well as the concentration of certain metabolic products that tend to build up if a vitamin deficiency is present. They found that 9% of the healthy elderly subjects had a low vitamin B-6 level as compared to more than 51% for the hospitalized patients. Corresponding numbers for vitamin B-12 and folic acid were 6% and 5%, and 5% and 19% respectively. Of perhaps greater significance was the finding that in 63% of the healthy elderly subjects and in 83% of the elderly patients the researchers observed an increased serum concentration of one or more of the metabolic products that indicate a deficiency in vitamin B-6, B-12 or folate. Thus an elevated level of the metabolite (methylmalonic acid), which indicates a B-12 deficiency, was found in 23% of the healthy elderly people and in 39% of the elderly hospitalized patients. Recent experiments have shown that weekly injections of vitamin B-12, B-6, and folate are highly effective in normalizing the elevated metabolite concentrations in elderly people.
Joosten, Etienne, et al. Metabolic evidence that deficiencies of vitamin B-12 (cobalamin), folate, and vitamin B-6 occur commonly in elderly people. American Journal of Clinical Nutrition, Vol. 58, No. 3, September 1993, pp. 468-76
Vitamin B12 Supplementation
B12 deficiency requires high supplement doses
WAGENINGEN, THE NETHERLANDS. Vitamin B12 deficiency is fairly common among older people and can cause anemia, pain and depression. Supplementation with cobalamin may reverse the deficiency, however, the ideal dose when given orally is yet to be determined. A team from the University of Wageningen undertook a study in which 120 participants were given either 2.5, 100, 250, 500 or 1,000ug (micrograms) of cyanocobalamin in capsules per day. These doses cover the full range from recommended dietary allowance in the Netherlands to the normal dose used in injections for B12 deficiency. The participants were aged 70 to 94, with an average age of 80. They were all mildly deficient in vitamin B12, with serum concentrations of 100 to 300 picomoles per liter. Their levels of methylmalonic acid (MMA, a marker for vitamin B12 deficiency) were above 0.26umol per liter, showing a deficiency. All of the participants received each of the experimental doses for 16 weeks, in a random order. Compliance with the medication was very high, at 98 per cent. Overall, levels of MMA and serum vitamin B12 improved with increasing doses of cobalamin. Elevated MMA was significantly reduced after 8 weeks, and remained so after 16 weeks. The percentages of participants whose MMA reduced to below 0.26umol per liter when taking 2.5, 100, 250, 500 or 1,000ug cobalamin were 21, 38, 52, 62 and 76 per cent respectively.
The researchers explain that a major knowledge gap existed over the lowest oral cobalamin dose required to normalize elevated MMA. They state that in this study, a daily dose of 647-1032ug was the lowest dose to give 80-90 per cent of the maximum reduction in MMA. These doses led to an average reduction in MMA of 33 per cent. However, they add that diagnosing vitamin B12 deficiency is complicated due to the limitations of current techniques. The authors conclude that the lowest dose needed to normalize vitamin B12 deficiency is more than 200 times higher than the recommended dietary allowance. They add that the relevance of treating vitamin B12 deficiency in older people could be substantial, were further trials able to show benefits to cognitive functioning and depression.
Eussen, S. J. P. M., et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency. Archives of Internal Medicine, Vol. 165, May 2005, pp.1167-1172
Effectiveness of vitamin B12 supplementation
DENVER, COLORADO. It is estimated that about 16% of older adults are vitamin B12 (cobalamin) deficient. This deficiency is mostly related to an inability to absorb cobalamin bound to food. Several experiments have shown that this problem does not affect people's ability to absorb free or synthetic cobalamin. A lack of vitamin-B12 can lead to megaloblastic anemia and, if untreated, to irreversible neurological damage that may mimic Alzheimer's disease.
There is ample evidence that injections of cobalamin can quickly correct a deficiency as can oral supplementation with 1-2 mg/day. It is not clear, however, whether smaller amounts, such as the 25 mcg or so found in multivitamins, are sufficient to correct a deficiency.
A team of researchers from the universities of Washington and Colorado has just released a study designed to determine just how much oral cobalamin supplementation is required to reverse a deficiency. The study involved 23 older patients who had been diagnosed as being vitamin B12 deficient (serum cobalamin level less than 221 pmol/L and serum methylmalonic acid [MMA] level greater than 271 nmol/l). All participants received 25 mcg/day of cobalamin during the first 6 weeks, 100 mcg/day during the next 6 weeks, and 1000 mcg/day during the final 6 weeks of the study. Two participants achieved normal MMA levels with the 25 mcg/day dose, an additional 5 with the 100 mcg/day dose, but it took 1000 mcg/day (1 mg/day) before an additional 12 regained normal MMA levels. Thus 19 out of 23 patients (83%) normalized their MMA level and eliminated their vitamin B12 deficiency at a daily intake of 1000 mcg/day. The 1000 mcg/day dose was also effective in lowering homocysteine level in 75% of the patients, but folic acid supplementation was required in 4 of the patients in order to bring homocysteine concentrations down to an acceptable level.
The researchers conclude that most cobalamin-deficient older people require more than 100 mcg/day of oral cobalamin to correct their deficiency.
Rajan, S, et al. Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults. Journal of the American Geriatrics Society, Vol. 50, November 2002, pp. 1789-95
Supplement recommendations for chronic fatigue syndrome
BERKELEY, CALIFORNIA. Dr. Melvyn Werbach, MD of the UCLA School of Medicine has just published a thorough review of nutritional deficiencies involved in chronic fatigue syndrome (CFS). These include deficiencies in vitamin C, coenzyme Q10, magnesium, zinc, sodium, l-tryptophan, l-carnitine, essential fatty acids, and various B vitamins. He points out that there is some evidence that the deficiencies are caused by the disease itself rather than by an inadequate diet. He suggests that the deficiencies not only contribute to the symptoms of CFS but also impair the healing process. Although the results of supplementation trials involving CFS patients have been inconclusive so far Dr. Werbach nevertheless recommends that CFS patients be given large doses of certain supplements for at least a trial period to see if their symptoms improve. His recommendations are:
- Folic acid: 1-10 mg/day for 3 months
- Vitamin B12: 6-70 mg (intramuscular injection) per week for 3 weeks
- Vitamin C: 10-15 grams/day
- Magnesium: 600 mg/day + 2400 mg/day of malic acid for 8 weeks
- Zinc: 135 mg/day for 15 days
- 5-hydroxytryptophan: 100 mg three times daily for 3 months (if fibromyalgia is present)
- L-carnitine: 1-2 grams three times daily for 3 months
- Coenzyme Q10: 100 mg/day for 3 months
- Essential fatty acids: 280 mg GLA and 135 mg EPA daily for 3 months
The supplements should be administered with medical supervision and accompanied by a high-potency vitamin/mineral supplement for the duration of the trial. [95 references]
Werbach, Melvyn R. Nutritional strategies for treating chronic fatigue syndrome. Alternative Medicine Review, Vol. 5, No. 2 April 2000, pp. 93-108
Vitamin B-12 - Is oral supplementation effective?
CAMBRIDGE, UNITED KINGDOM. It is common medical dogma that patients suffering from pernicious anaemia are unable to absorb sufficient vitamin B-12 from their diet and therefore require intramuscular injections of the vitamin on a regular basis. Recent research is questioning this assumption. In a commentary in The Lancet Dr. M. Elia of the Dunn Clinical Nutrition Centre persuasively outlines the reasons why oral supplementation is at least as effective as intramuscular injections. Dr. Elia points out that vitamin B-12 is absorbed from the intestine via two different routes. One involves intrinsic factor and is estimated to lead to absorption of about 60 per cent of the amount of vitamin B-12 ingested in the diet. The other does not need intrinsic factor (which is absent in pernicious anaemia patients) and only leads to absorption of about 1 per cent of the ingested amount. The body needs about 1-2.5 micrograms/day so oral supplementation with 100-200 micrograms/day should be adequate. However, Dr. Elia suggests a daily intake of 1000 micrograms/day is needed to ensure successful long-term results in patients with pernicious anaemia. A recent study showed that oral supplementation with 2000 micrograms/day was three times as effective as intramuscular injections in increasing vitamin B-12 levels in pernicious anaemia patients. Dr. Elia also questions whether the current RDA (Recommended Dietary Allowance) of 1-2.5 micrograms/day is adequate for older people. He points out that mild vitamin B-12 deficiency, which can lead to abnormalities in cognitive function and increased risk of cardiovascular disease, affects 12-15 per cent of all elderly people in the United States where the average daily vitamin B-12 intake is about six micrograms - well above the RDA.
Elia, M. Oral or parenteral therapy for B12 deficiency. The Lancet, Vol. 352, November 28, 1998, pp. 1721-22 (commentary)
Oral vitamin B12 and pernicious anaemia
MINNEAPOLIS, MINNESOTA. Pernicious anaemia can be treated with intramuscular injections of cobalamin (vitamin B12). These injections can be painful and expensive, but are still widely used despite the fact that research done 30 years ago clearly established that oral doses of one mg/day of vitamin B12 are effective in treating pernicious anaemia and other cobalamin deficiency disorders. The problem, according to Dr. Frank Lederle, MD of the Minneapolis Veterans Affairs Medical Center, is that physicians are unaware that oral cobalamin works. Dr. Lederle performed a survey among Minneapolis internists in 1989 and again in 1996. In 1989 none of the 245 respondents used oral cobalamin in the treatment of pernicious anaemia. In 1991 a review of the use of oral cobalamin was published in the Journal of the American Medical Association. A subsequent survey in 1996 showed that 19 per cent of the 223 internists responding were now using oral cobalamin. However, even in 1996, 71 per cent of the internists still held the incorrect view that sufficient quantities of cobalamin cannot be absorbed from oral supplements (91 per cent of the internists held this view in 1989). Dr. Lederle concludes that the majority of Minneapolis interns are still unaware of the oral treatment option.
Lederle, Frank A. Oral cobalamin for pernicious anemia: back from the verge of extinction. Journal of the American Geriatrics Society, Vol. 46, September 1998, pp. 1125-27
Oral administration of vitamin B-12 is effective
BRUSSELS, BELGIUM. Older people are often found to have a vitamin B-12 deficiency even though they do not suffer from pernicious anaemia. The body's ability to absorb vitamin B-12 from food decreases markedly with age probably because of a lack of stomach acid. The conventional way of correcting a vitamin B-12 deficiency has been through intramuscular injection of the vitamin. Now researchers at the Universities of Brussels and Antwerp report that oral administration of free vitamin B- 12 is effective in normalizing low vitamin B-12 levels. Their experiment involved 94 patients without pernicious anaemia with a mean age of 84 years who through repeated tests had been found to have an average vitamin B-12 level (in serum) of 146.5 ng/L. The patients were treated for one month with 100 micrograms/day of vitamin B-12 taken as an oral solution of the vitamin in water (10 ml of a solution containing 1 mg vitamin B-12 in 100 ml water). After 10 days 69 per cent of the patients had normal vitamin B-12 levels (271.5 ng/L average) and after 30 days 88 per cent had achieved normal levels (371.2 ng/L average). The researchers conclude that older patients with a vitamin B-12 deficiency unrelated to pernicious anaemia can be successfully treated with orally administered vitamin B-12.
Verhaeverbeke, I., et al. Normalization of low vitamin B-12 serum levels in older people by oral treatment. Journal of the American Geriatrics Society, Vol. 45, No. 1, January 1997, p. 124 (letter to the editor)
Vitamin E protects vitamin B-12
LITTLE ROCK, ARKANSAS. Adenosylcobalamin is an important coenzyme, which is involved in the metabolism of branched-chain amino acids, cholesterol, methionine, and odd-chain fatty acids. It is synthesized in the cell nucleus from vitamin B-12 (cyanocobalamin). Now researchers at the University of Arkansas have found that the synthesis of adenosylcobalamin is impaired if the cell membranes have been subjected to peroxidative (free radical) attack. They also found, through experiments with cell cultures, that vitamin E effectively prevents the peroxidation and thereby allows the enzyme synthesis to proceed unhindered.
Turley, Charles P. and Brewster, Marge A. Alpha-tocopherol protects against a reduction in adenosylcobalamin in oxidatively stressed human cells. Journal of Nutrition, Vol. 123, July 1993, pp. 1305-12
Effects of vitamin B12 on cognitive function in older people
WAGENINGEN, NETHERLANDS. Deficiency of vitamin B12 is common among older people. As this vitamin is crucial for brain and nervous system functioning, researchers have proposed that supplementation may have beneficial effects on cognitive function in this group. However, randomized trial results have so far been inconclusive. Researchers from Wageningen University carried out a large study with a long duration and rigorous cognitive tests. They investigated the effects of daily oral supplementation with vitamin B12 at a high dose (1,000ug) on adults aged 70 years or above with a mild deficiency. High-dose vitamin B12 supplements are considered to be safe and no upper safety level has been set in the US or Europe. Among the group of 195 participants, some were given 400ug folic acid alongside the vitamin B12, and others a placebo. Compliance was very high, with a mean of 99 per cent. After 24 weeks, vitamin B12 status and cognitive function were assessed. Vitamin B12 supplementation reversed deficiency, and those taking folic acid showed raised folic acid levels in their red blood cells. Both supplementation groups had lower homocysteine levels, which is beneficial in terms of heart disease risk. Homocysteine was lowered to a greater extent in the combined supplement group, as expected based on knowledge of how the two nutrients interact.
However, neither supplement was linked to better results than placebo on tests of cognitive performance which covered attention, construction, sensomotor speed, memory, and executive function. Participants in all three groups showed improved memory, but the researchers concluded that the supplementation regimes used in this study did not lead to improved cognitive function. This may be because a longer course of vitamin B12 is necessary to repair any existing cognitive damage. Despite the results, the authors write, these findings cannot exclude beneficial effects on cognitive function from longer-term vitamin B12 supplementation. Individuals who have had mild cognitive impairment for less than six months may also be more likely to respond to treatment with vitamin B12.
Eussen, S. J. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. The American Journal of Clinical Nutrition, Vol. 84, August 2006, pp. 361-70
Antibiotic combats Alzheimer's disease
BOSTON, MASSACHUSETTS. Two years ago researchers at the Massachusetts General Hospital reported that the antibiotic clioquinol inhibited and even reduced the build-up of amyloid plaques in the brain of mice engineered to developed Alzheimer-like deposits. Now researchers at the Harvard Medical School and the University of Melbourne are about to release the results of a phase II trial involving the use of clioquinol in human Alzheimer's patients. So far the findings are extremely promising. Clioquinol treatment slowed down the disease and significantly reduced the accumulation of beta-amyloid plaques, a cardinal feature of Alzheimer's.
Dr. Ashley Bush of the Harvard Medical School believes that Alzheimer's disease begins when iron, copper and zinc accumulates in the brain and turns beta-amyloid into a rogue enzyme that catalyses the production of hydrogen peroxide which then attacks and destroys brain cells. In the process beta-amyloid forms into the long chain of insoluble plaque so characteristic of Alzheimer's. Dr. Bush believes that clioquinol works by removing (chelating?) the metals from the brain. This, in turn, stops the formation of hydrogen peroxide and thus the destruction of brain cells and also prevents the beta-amyloid particles from clumping together. There is some concern that clioquinol depletes vitamin-B12 in the body so vitamin B12 supplementation is a must when taking clioquinol.
Helmuth, Laura. An antibiotic to treat Alzheimer's? Science, Vol. 290, November 17, 2000, pp. 1273- 74
Westphal, Sylvia Pagan. You must remember this… New Scientist, August 3, 2002, p. 14
Vitamin B12 deficiency and Alzheimer's disease
SACRAMENTO, CALIFORNIA. Vitamin B12 deficiency is associated with the development of megaloblastic anemia, mental dysfunction, and dementia resembling Alzheimer's disease. Vitamin-B12 (cobalamin) is a very important cofactor in several biochemical reactions including the conversion of homocysteine to methionine and the synthesis of SAMe (S-adenosylmethionine). These reactions are believed to be crucial in maintaining neurological health.
Researchers at the University of Milan now report that a vitamin B12 deficiency is associated with higher levels of the inflammatory cytokine, tumour necrosis factor-alpha (TNF-alpha) and reduced levels of epidermal growth factor (EGF). It is believed that high levels of TNF-alpha speed up the progression of Alzheimer's disease thus explaining the association between low vitamin B12 levels and Alzheimer's. The researchers point out that the increase in TNF-alpha and the decrease in EGF can both be reversed by vitamin B12 supplementation. TNF-alpha is also implicated in the progression of HIV to AIDS and vitamin B12 has been found to slow this progression. Editor's Note: Vitamin B12 deficiency is widespread among older people. Taking a 1 mg sublingual B12 tablet daily could prevent a lot of future health problems.
Miller, Joshua W. Vitamin B12 deficiency, tumor necrosis factor-alpha and epidermal growth factor: a novel function of vitamin B12? Nutrition Reviews, Vol. 60, May 2002, pp. 142-51
Vitamin deficiency implicated in Alzheimer's disease
STOCKHOLM, SWEDEN. Some studies have found a correlation between low vitamin B12 levels and the development of Alzheimer's disease (AD) and dementia; other studies have found no such correlation. Researchers at the Karolinska Institute now provide convincing evidence that a deficiency of either vitamin B12 or folic acid (folate) is associated with an increased risk of AD and dementia.
Their study involved 370 non-demented people aged 75 years and older who were not supplementing with vitamin B12 or folate. The participants were tested at baseline to determine mental status and had blood samples drawn for analysis of vitamin-B12 and folate levels. Only subjects who showed no signs of dementia was included in the follow-up group. Three years later 77 of the participants had developed dementia; of these 59 were diagnosed with AD. Compared with participants with normal levels of vitamin B12 and folate the participants with low levels of at least one of the vitamins had a 2.3 times higher risk of AD and a 1.7 times risk of any kind of dementia. These risk estimates were obtained after adjusting for other risk factors such as age, sex, and educational attainment.
The researchers speculate that homocysteine, a known neurotoxin, may be involved in the development of AD and that vitamin B12 and folic acid help prevent this effect by reducing homocysteine levels in the body.
Wang, H-X, et al. Vitamin B12 and folate in relation to the development of Alzheimer's disease. Neurology, Vol. 56, No. 9, May 8, 2001, pp. 1188-94
Vitamin B12 deficiency implicated in Alzheimer's disease
CLWYD, NORTH WALES. Suspicion has been growing that a lack of vitamin B12 is somehow implicated in the development of Alzheimer's disease. Now researchers in the United Kingdom have confirmed this suspicion. They evaluated members of a family with a genetic predisposition towards Alzheimer's disease. They found that four out of six (67 per cent) of family members with confirmed Alzheimer's disease had abnormally low vitamin B12 levels in their blood. This compares to only one out of 12 (8 per cent) among the family members who were at equal genetic risk for developing Alzheimer's disease but did not. The researchers speculate that a vitamin B12 deficiency could result in impaired methylation reactions in the central nervous system - a characteristic feature in Alzheimer's disease. They also consider the possibility that the genetic predisposition to Alzheimer's disease may actually be related to a genetic impairment in the ability to absorb vitamin B12. Vitamin B12 deficiency in itself often causes disorientation and confusion and thus mimics some of the prominent symptoms of Alzheimer's disease.
McCaddon, A. and Kelly, C.L. Familial Alzheimer's disease and vitamin B12 deficiency. Age and Ageing, Vol. 23, July 1994, pp. 334-37
Grain fortification with vitamin B12?
DUBLIN, IRELAND. Since 1998 it has been mandatory to fortify grain-based foods with folic acid in the United States. Recent reports indicate that this measure has resulted in a 19 per cent decrease in the incidence of neural tube defects. A similar fortification program is being considered in the UK. Irish researchers now suggest that the fortification protocol should include not only folic acid, but also vitamin B12. They point out that folic acid supplementation also lowers the level of homocysteine, a potent risk factor for heart and vascular disease. However, a recent trial carried out by the Dublin researchers clearly showed that as blood levels of folic acid increased through supplementation, blood levels of vitamin-B12 became the limiting factor. In other words, additional folic acid as well as additional vitamin B12 is required in order to attain the maximum reduction in homocysteine levels. Four to five hundred micrograms per day of folic acid were found to increase folic acid levels by 80 to 180 per cent and lower homocysteine levels by about 30 per cent in both men and women. Both folate and homocysteine levels tended to revert to their pre-supplementation levels after 10 weeks of no supplementation; this shows that continuous supplementation is necessary in order to keep homocysteine levels under control.
Quinlivan, E.P., et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. The Lancet, Vol. 359, January 19, 2002, pp. 227-28 (research letter)
B vitamins and atherosclerosis
TAIPEI, TAIWAN. High blood levels of the amino acid homocysteine have been associated with an increased risk of atherosclerosis. Homocysteine is formed in the body from methionine (an amino acid found in proteins) in a process that can be blocked by folic acid and vitamins B6 and B12. High homocysteine levels can induce endothelial dysfunction (a narrowing of the arteries), which in turn is believed to be a precursor of atherosclerosis. Researchers at the National Taiwan University Hospital now report that homocysteine-induced endothelial dysfunction can be avoided or very significantly ameliorated by supplementing with folic acid and vitamins B6 and B12.
The study involved two men and fourteen women between the ages of 41 and 55 years. At the start of the study all participants had their blood levels of homocysteine and their blood flow through the brachial artery measured after a 10-14 hour overnight fast. They were then given an oral methionine-loading test to simulate the intake of a high protein meal. Four hours later their average homocysteine level had increased from 7 micromol/L to 22.7 micromol/L and the blood flow (flow-mediated vasodilatation) had decreased by 40 per cent. The experiment was repeated, but this time 5 mg of folic acid was given together with the methionine; the results were similar to those obtained in the first experiment indicating that folic acid does not act immediately as an "antidote" to a high intake of methionine. The participants were then given 5 mg of folic acid, 100 mg of vitamin B6, and 0.5 mg of vitamin B12 daily for five weeks. At the end of the five weeks their average homocysteine level had decreased to 5.2 micromol/L. The methionine-loading test was repeated. Four hours later the average homocysteine level among the participants had increased to 17 micromol/L, but there was no statistically significant difference in blood flow before and after the methionine-loading test. The researchers conclude that short-term (five weeks) administration of folic acid and vitamins B6 and B12 will reduce post-methionine load homocysteine levels and eliminate or ameliorate endothelial dysfunction (an early manifestation of atherosclerosis).
Chao, Chia-Lun, et al. Effect of short-term vitamin (folic acid, vitamins B6 and B12) administration on endothelial dysfunction induced by post-methionine load hyperhomocysteinemia. American Journal of Cardiology, Vol. 84, December 1, 1999, pp. 1359-61
A daily vitamin pill helps combat atherosclerosis
CLEVELAND, OHIO. A high blood level of the amino acid homocysteine has been linked to an increased risk of atherosclerosis and thrombosis. It is known that oral supplementation with folic acid will lower homocysteine levels to acceptable norms, but it is not clear just how much folic acid is required to achieve this effect. Now researchers at the Cleveland Clinic Foundation report that the amount of folic acid (400 micrograms) found in most multivitamin preparations is sufficient to lower homocysteine levels in heart disease patients. Their experiment involved 95 patients who had either had a heart attack or suffered from advanced atherosclerosis. The patients were divided into four groups with one group receiving 400 micrograms/day (0.4 mg/day) of folic acid, one group receiving 1 mg/day, one group receiving 5 mg/day, and the fourth group receiving a placebo. All patients receiving folic acid also received 12.5 mg of vitamin B6 per day and 500 micrograms of vitamin B12. After 90 days the plasma homocysteine levels had dropped from 13.8 to 9.6 micromol/L in the 400 micrograms/day folic acid group, from 13.0 to 9.8 micromol/L in the 1 mg/day group, and from 14.8 to 9.7 micromol/L in the 5 mg/day group. Also after 90 days the plasma levels of folic acid had risen from 28 nanomol/L in the placebo group to 63 nmol/L in the 400 micrograms/day supplement group, to 80 nmol/L in the 1 mg/day group, and to 162 nmol/L in the 5 mg/day group. Vitamin B6 levels rose from 75 nmol/L to about 250 nmol/L in the supplemented groups and vitamin B12 levels rose from about 300 picomol/L to 525 picomol/L. The researchers conclude that a daily dose of 400 micrograms of folic acid combined with vitamins B6 and B12 will normalize homocysteine levels in heart disease patients.
Lobo, Arlene, et al. Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12. American Journal of Cardiology, Vol. 83, March 15, 1999, pp. 821- 25
Vitamin B-12 increases efficiency of folic acid
BONN, GERMANY. There is increasing evidence that high blood levels of the amino acid homocysteine increases the risk of vascular disease, coronary heart disease, neural tube defects, and Alzheimer's disease. Folic acid supplementation is known to lower homocysteine levels and laws have recently been passed in the United States mandating folic acid fortification of bread and cereal. Now researchers at the University of Bonn report that folic acid's homocysteine lowering capacity can be markedly increased by also supplementing with vitamin B-12 (cobalamin). Their study involved 150 young, healthy women (average age of 24 years) who after a four-week washout period were randomized into three groups. Group 1 received a daily supplement of 400 micrograms of folic acid, group 2 received 400 micrograms/day of folic acid and 6 micrograms/day of vitamin B-12, and group 3 received 400 micrograms/day of folic acid and 400 micrograms/day of vitamin B-12. After four weeks the average concentration of plasma homocysteine had dropped by 11 per cent in group 1, 15 per cent in group 2, and 18 per cent in group 3. The researchers noted that study participants with high initial homocysteine concentrations benefited more from supplementation than did women with lower initial homocysteine levels. It was also noted that vitamin B-12 levels increased significantly over the four-week period in the women whose supplements included vitamin B-12. This provides further proof that oral vitamin B-12 is indeed adequately absorbed. The researchers conclude that the benefits of folate supplementation can be markedly enhanced by the addition of vitamin B-12. They point out that vitamin B-12 deficiency is widespread especially among the elderly. The addition of vitamin B-12 to folic acid supplements also prevents the possibility that supplementation with just folic acid could mask pernicious anaemia resulting from a vitamin B-12 deficiency which in turn may lead to irreversible nerve damage.
Bronstrup, Anja, et al. Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy, young women. American Journal of Clinical Nutrition, Vol. 68, November 1998, pp. 1104-10
Major new risk factor for heart disease discovered
VANCOUVER, CANADA. It is becoming increasingly evident that an elevated blood level of homocysteine is a potent risk factor for cardiovascular disease. Recent studies also suggest that high homocysteine levels may be associated with kidney disease, psoriasis, breast cancer, and acute lymphoblastic leukemia. Extensive past research has shown a close link between the development of neural-tube defects in babies and the mother's homocysteine level prior to and during pregnancy. Researchers at the University of British Columbia have just released a major report that summarizes the current knowledge about homocysteine and its effect on health. Homocysteine is formed in human tissues during the metabolism of methionine, a sulfur-containing essential amino acid. A normal, desirable level is 10 micromol/L or less. A level of 12 micromol/L is considered borderline and levels of 15 micromol/L or above are considered to be indicative of increased risk for cardiovascular disease. Several factors (age, smoking, vitamin deficiencies, and genetic abnormalities) have been linked to increased homocysteine levels. Medications that interact with folate such as methotrexate, carbamazepine, phenytoin, and colestipol/niacin combinations have also been linked to increased homocysteine levels. The researchers reviewed 23 studies dealing with the association between atherosclerosis and homocysteine levels and found that patients with vascular diseases had an average level of homocysteine that was 26 per cent higher than the level in healthy subjects. One study found that a homocysteine level of 4 micromol/L above normal corresponds to a 41 per cent increase in the risk of developing vascular disease. Another study estimates that the lives of 56,000 Americans could be saved every year if average homocysteine levels were lowered by 5 micromol/L. The researchers conclude that abnormally high homocysteine levels are a potent risk factor for cardiovascular and several other diseases. They point out that elevated homocysteine levels can, in most cases, be safely and effectively lowered by supplementation with as little as 400 micrograms per day of folic acid. Other researchers have found that a combination of folic acid (0.4-10 mg/day), vitamin B-12 (50-1000 micrograms/day), and vitamin B-6 (10-300 mg/day) is highly effective in lowering homocysteine levels. (153 references). Medical doctors at the University of Wisconsin echo the findings of the Canadian researchers in a separate report and describe a case of a 57-year-old man who lowered his homocysteine level from 29 micromol/L to 2 micromol/L by supplementing with 800 micrograms/day of folic acid for two months.
Moghadasian, Mohammed H., et al. Homocysteine and coronary artery disease. Archives of Internal Medicine, Vol. 157, November 10, 1997, pp. 2299-2308
Fallest-Strobl, Patricia C., et al. Homocysteine: A new risk factor for atherosclerosis. American Family Physician, Vol. 56, October 15, 1997, pp. 1607-12
Vitamins may help prevent strokes in lupus patients
BALTIMORE, MARYLAND. Systemic lupus erythematosus (SLE) patients have an increased risk of suffering strokes, heart attacks, and other arterial thrombotic events such as gangrene of the fingers. It is believed that this higher risk is at least partially related to a greater propensity among SLE patients to develop premature atherosclerosis. High concentrations of homocysteine (a sulphur-containing amino acid) have previously been linked to an increased risk of stroke and coronary artery disease. Now researchers at the Johns Hopkins Medical Institutions report that many SLE patients have high homocysteine levels and that these higher levels correspond to a significantly increased risk for stroke and other thrombotic events. The study involved 337 SLE patients who were followed for an average of 4.8 years. The average age of the patients was 35 years and 93 per cent of them were women. The researchers found that 15 per cent of the patients had raised homocysteine levels (greater than 14.1 micromol/liter). They also noted a strong inverse correlation between homocysteine levels and the levels of folic acid and vitamin B-6 in the blood. After adjusting for other relevant risk factors the researchers conclude that SLE patients with elevated homocysteine levels have a 2.4 times higher risk of having a stroke and a 3.5 times higher risk of having an arterial thrombotic event. The researchers suggest that supplementation with folic acid and vitamin B-6 may help prevent thrombotic events in SLE patients. Other studies have found a clear inverse correlation between homocysteine levels and vitamin B-12 levels. This correlation was not observed in the present study - most likely because the patients were relatively young and therefore less likely to be deficient in vitamin B-12.
Petri, Michelle, et al. Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. The Lancet, Vol. 348, October 26, 1996, pp. 1120-24
Folic acid helps prevent coronary heart disease
SEATTLE, WASHINGTON. A high level of homocysteine in the blood has been clearly implicated in heart disease, stroke and peripheral vascular disease. Homocysteine is an amino acid that is not found in protein as such, but is involved in the metabolism of other amino acids (methionine and cysteine). The average blood level of total homocysteine in male adults is about 10 micromol/L. Now researchers at the University of Washington confirm that people with a higher than normal level of homocysteine have a greater risk of developing vascular disease. The researchers evaluated 17 studies dealing with the link between homocysteine levels and the risk of coronary artery disease (CAD). They found that men with a level of 15 micromol/L had a 60 per cent greater risk of developing CAD while the increased risk for women was 80 per cent. The risk for cerebrovascular disease (stroke) was found to be almost twice as high in men and women with elevated (15 micromol/L) homocysteine levels. The risk of developing peripheral vascular disease (e.g. intermittent claudication) was found to be almost seven times higher among people with elevated homocysteine levels. The researchers conclude that a high homocysteine level is an independent risk factor for vascular disease and that a 5 micromol/L elevation results in the same increase in CAD risk as a cholesterol increase of 0.5 mmol/L (20 mg/dL).
The researchers also evaluated 12 studies concerning the connection between dietary intake of folic acid and homocysteine level. They found that folic acid is very effective in lowering homocysteine levels. An intake of 400 micrograms per day (the level found in most supplements) lowers the homocysteine level by about 6 micromol/L. The researchers conclude that over 44,000 lives could be saved every year if just half the population of the United States were to supplement with 400 micrograms per day of folic acid. Unfortunately, recent surveys have shown that 88 per cent of American adults have a daily intake of folic acid below 400 micrograms. The researchers warn that an increased intake of folic acid may mask a vitamin B-12 deficiency and recommend that 1 mg of vitamin B-12 be added to all supplements containing 400 micrograms of folic acid. They also recommend that consideration be given to fortifying grain products with 350 micrograms of folic acid per 100 grams of grains. This strategy would have the added advantage of making it easier to prevent neural tube defects in newborn babies.
Boushey, Carol J., et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Journal of the American Medical Association, Vol. 274, No. 13, October 4, 1995, pp. 1049- 57
Elevated Blood Levels of Vitamin B12
by Georges Mouton, MD
This article was first published in International Health News Issue 164, February 2006
|Physicians sometimes encounter cases where a patient’s blood level of vitamin B12 (cobalamin) is substantially higher than the normal upper limit. These cases are often assumed to be due to excessive supplementation, consumption of cobalamin-fortified energy drinks or from intramuscular injections or oral supplements prescribed by a health care professional. In most cases, no action is taken upon discovering the anomaly.|
However, careful enquiry very frequently demonstrates that no external human intervention explains the finding of high vitamin B12 levels. Thus the answer to the puzzle must be found within the body’s internal metabolic processes. It is clear that the amount of vitamin B12 excreted in human faeces does not only correspond to what was not absorbed in the ileum (the last of the three sections of the small intestine), but also reflects the production of significant amounts of cobalamin by the colonic microflora .
Intestinal Vitamin B synthesis
The fact that intestinal micro-organisms produce significant amounts of B vitamins is fully accepted and has been published in peer-reviewed international medical journals [2,3]. Intestinal bacterial B vitamin biosynthesis involves at least vitamin B1 (thiamine) , vitamin B2 (riboflavin) , vitamin B5 (pantothenic acid) , vitamin B8 (biotin) [6, 7], vitamin B9 (folic acid) [8,9],and vitamin B12 (cobalamin) . As a matter of fact, bacteria obtained from dairy and belonging to the genus Propionibacterium (also abundant in the human intestinal microflora) are extensively used for the biological production of cobalamin .
Concerning vitamin B8, also called biotin, “it has long been recognized that the normal microflora of the large intestine synthesize considerable amounts of biotin” . In fact, several studies have shown that the colon is capable of absorbing free biotin and HM Saidhas shown, for the first time in 1998, the functional existence of a specialized carrier-mediated system for biotin uptake in colonic epithelial cells . “In addition, the uptake process is shared by another water-soluble vitamin, pantothenic acid, (…) which is also synthesized by the normal microflora of the large intestine”, as biotin inhibited the uptake of vitamin B5 and vice versa .
The specialized vitamin B transporter has been cloned in the rabbit intestine by another team in 1999  and named the sodium-dependent multivitamin transporter (SMVT). This transporter is also highly expressed in human enterocytes (cells found in the internal lining of the intestines) [11,12], where it serves to take up not only pantothenate and biotin, but also lipoate (the ion from lipoic acid) .
Half a century ago, vitamin B2 (also called riboflavin) was known to be synthesized by intestinal bacteria and the amount provided by this source appears to become significantly higher when adhering to a vegetarian diet . Interestingly, as he did for other water-soluble vitamins B, HM Said demonstrated in 2000 “for the first time, the existence of a specialized carrier-mediated mechanism for riboflavin uptake in an in vitro cellular model of human colonocytes” (cells found in the lining of the colon) . Once again in 2001, HM Said showed that a model of human-derived colonic epithelial cells possesses a specific carrier-mediated system for thiamine (vitamin B1) uptake . “It is suggested that bacterially synthesized thiamine in the large intestine may contribute to thiamine nutrition of the host, especially towards (…) the local colonocytes” .
Certain bacterial species present in the rat colon are also capable of de novo synthesis of vitamin B9, better known as folic acid . As clearly evidenced by the use of tritiated (marked with radioactive hydrogen) para-aminobenzoic acid (3H PABA), the experimental “data provide direct evidence that some of the folate synthesized by the microflora in the rat large intestine is incorporated into the tissue folate of the host” .
More recently, the same methodology has been utilized with humans in order to determine whether folate synthesized by bacteria in the small intestine rather than in the colon is assimilated by the human host . Indeed, the perfusion of tritiated PABA, a classic precursor substrate for the bacterial folate synthesis, led to the identification of bacterially synthesized (as marked) folates aspirated from in the small intestine. Subsequently, tritiated 5-methyltetrahydrofolate, a major metabolite of folate, was isolated from the human host urine, demonstrating that the human host did absorb and consequently metabolized these bacterially synthesized folates .
Coming back to cobalamin, it has been shown, already in 1980, that “at least two groups of organisms in the small bowel,Pseudomonas and Klebsiella sp., may synthesize significant amounts of the vitamin [B12]” . Obviously, the two accepted dogma of vitamin B metabolism in the digestive tract don’t seem to correspond to reality: several compounds (vitamins B1, B2, B5, B8 and B9) supposedly absorbed by the small intestine may be assimilated by the colonocytes, while several compounds (vitamins B9 and B12) supposedly synthesized by colonic bacteria may actually be generated in the small intestine! Unfortunately, if we wanted to explain the high vitamin B12 blood levels by some colonic absorption, we must underline that absolutely nothing has been published about this and what seems true for other vitamins B would not be so for cobalamin.
Consequently, we should rather focus on the possibility that bacterially-produced vitamin B12 is absorbed in the small intestine, where most of the assimilation process of other B vitamins takes place. Two different specific proteins ensure the uptake of thiamine (vitamin B1) in the enterocytes of the proximal small intestine and are structurally close to a specific folic acid carrier . Indeed, the intestinal folate (vitamin B9) absorption process occurs via a specialized mechanism that involves the reduced folate carrier (RFC) in the jejunum (the middle part of the small intestine) [15, 16]. We have already mentioned earlier the existence, in the proximal small intestinal enterocytes, of a sodium-dependent multivitamin transporter (SMVT) taking care of biotin (vitamin B8) and of pantothenic acid (vitamin B5). The involvement of a specialized carrier-mediated mechanism for pyridoxine (vitamin B6) by the intestinal epithelial cells has been demonstrated for the first time in 2003 . Finally, a specialized carrier for niacin (vitamin B3) has been uncovered very recently, the article only being published in July 2005 .
In contrast to all the other B vitamins, cobalamin is not absorbed in the jejunum or in the proximal (first part of) ileum as they are, but only in the terminal ileum from a quite complex absorption process. This makes absorption very sensitive to diseases affecting specifically, or more frequently, this portion of the digestive tract such as Crohn’s disease.
Vitamin B12 Absorption
The term vitamin B12 or cobalamin actually refers to four different forms found in the diet and mostly bound to proteins:methylcobalamin, hydroxocobalamin, cyanocobalamin, and deoxyadenosylcobalamin.
The absorption process involves five steps:
- The cobalamins are released from their protein complexes through the action of acid or pepsin in the stomach.
- They bind to R proteins – cobalamin-binding glycoproteins secreted in saliva and in gastric juice.
- The cobalamin-protein complexes must then be degraded by pancreatic proteases. This important step may be jeopardized in case of pancreatic insufficiency .
- The free cobalamin combines in the duodenum with another glycoprotein called intrinsic factor which is secreted by the stomach parietal (oxyntic) cells; this glycoprotein dimerises and each part of the dimer binds one molecule of cobalamin, making the complex resistant to digestion . The formation of the cobalamin-intrinsic factor complex appears indispensable for the vitamin to be absorbed in the terminal ileum via an active transport system .
- The brush border membrane of the terminal ileum enterocytes contains a specific receptor for the dimeric complex and its importance in the process is shown by a congenital vitamin B12 malabsorption syndrome due to a defect in this receptor. The absorption is hampered by an abnormally low ileum pH, which may occur in some diseases such as the Zollinger-Ellison syndrome.
The problem with vitamin B12 absorption lies in the small safety margin between the dietary requirements for the vitamin and the maximal absorptive capacity of the five-step process outlined above. Cobalamins can also be absorbed passively, but the passive pathway only accounts for 1 or 2 % of the ingested vitamin, explaining the development of anemia when one of the five steps is not functioning properly . The most frequent cause for vitamin B12 malabsorption is represented by the lack of intrinsic factor , which may be explained by a genetic defect, an auto-immune condition (auto-antibodies targeting either the parietal cells or the intrinsic factor itself), or a surgical gastrectomy (removal of part or all of the stomach). But further problems can occur at the level of the blood carriers, transcobalamin I and transcobalamin II, which may be impaired .
Now, supposing that all these steps leading to an effective absorption of vitamin B12 function adequately, then the presence in significant amounts of bacteria producing cobalamin in the terminal ileum would explain - at least theoretically - a sharp increase in absorption and lead to higher blood levels of this vitamin. If we consider some specific circumstances in the above mentioned study about folate absorption , we might discover the mechanism which could lead to an excessive absorption of cobalamin and to an elevation of blood levels.
The Role of Small Intestinal Bacterial Overgrowth
In an exemplary functional medicine study, two groups of patients were involved - healthy volunteers and subjects suffering from gastric arthritis (inflammation of the stomach lining). The participants were evaluated before and after the administration of omeprazole (a proton pump inhibitor that turns off gastric acid production) . As expected, both patients with atrophic gastritis (chronic inflammation of the stomach lining) and those receiving omeprazole showed an increased duodenal pH (which stands for less acidity), but also an overgrowth of the small intestinal microflora . Under normal physiological conditions, bacterial growth in the small intestine is inhibited by the acidic environment caused by the presence of hydrochloric acid. However, with an increase in pH the small intestinal environment, normally hostile to the local microflora, becomes friendlier and enables what is called a “small intestinal bacterial overgrowth” (SIBO) either in case of atrophic gastritis  or in case of drug-induced hyperchlorhydria , especially among “subjects taking a hydrogen pump blocking agent [such as] omeprazole” . Interestingly, SIBO seems to provide “a unifying framework for understanding irritable bowel syndrome (IBS) and other functional disorders” , such as fibromyalgia [25, 26]. We come back once again to the experimentation with labelled folate to review its conclusions as presented in the corresponding abstract: “(1) Mild bacterial overgrowth caused by atrophic gastritis and administration of omeprazole are associated with de novo folate synthesis in the lumen of the small intestine; (2) the human host absorbs and uses some of these folates” . Indeed, the unexplained increase of blood levels that we are describing about vitamin B12 may also occur with folic acid. We present a first case study concerning a four-year old boy who suffered from diarrhoea and abdominal bloating. Celiac disease had been ruled out, but he showed an increase of specific urinary organic metabolites corresponding to a bacterial overgrowth, typically from Clostridium. This child had never been treated with vitamins at the time of his first blood check, though his erythrocytic folate level (folic acid in red blood cells) was measured at 913µg/l whereas 257µg/l - 582µg/l represents the lab’s normal range for the parameter. Besides, the plasma level of cobalamins was raised to 1324ng/l, contrasting with the laboratory’s normal range of 450ng/l to 1200ng/l. He was treated for intestinal dysbiosis and put on a casein-free diet, improved dramatically… and was not blood tested again!
Case Study involving Elevated Vitamin B 12 Levels
We present a second case study concerning a thirty-year old woman (in 1999) whose blood parameters were monitored for unrelated matters but strikingly presented repetitive high vitamin B12 levels without any related supplementation neither from the vitamin itself, nor through vitamin B complexes / multivitamin formulas.
The original data from our records follows [NOTE: All results for vitamin B12 are expressed in pg/ml and the normal range provided by the Belgian laboratory is 200pg/ml to 900pg/ml, even if the lower limit could be considered as too low to be compatible with optimal health].
The five first measurements, from February 1999 to April 2000, were quite consistently fluctuating around 2500pg/ml (respectively 2796pg/ml on 6/2/99, 2355pg/ml on 19/4/99, 2572pg/ml on 30/7/99, 2697pg/ml on 7/3/2000 and 2325pg/ml on 17/4/00), which is much too high! At the time, the patient’s blood had to be monitored in relation to a drug-based anti-epileptic treatment. However, the young woman was not complaining about her digestive system, even if she occasionally mentioned some severe but transitory abdominal cramps.
Her digestive problems started during the summer season in 2000, with IBS like symptoms, bloating, diarrhoea and excruciating pain in the belly. She was examined thoroughly and the gastroenterologist initially suspected Crohn’s disease due to the presence of mucosal ulcerations in the proximal small intestine. During that period of major clinical deterioration, blood vitamin B12 level increased even further as seen from two measurements performed on 25/08/00 (3220pg/ml) and on 28/11/00 (3221pg/ml). Then, she refused to take the corticoids prescribed by the specialist and went on a natural treatment based on diet modifications (exclusion of high IgG foods, in her case: dairy products, beef, bananas and black pepper), supplements (according to her biological results in blood and in 24-hour urine), antimicrobial herbs (such as grapefruit seed extracts) and probiotics.
She didn’t improve dramatically, but slowly started to complain less within a few weeks, then was feeling slightly better in March 2001 and significantly better when she came back five months later, in August 2001. Very interestingly, vitamin B12 blood levels started to decrease to 2740pg/ml on 24/3/01 and then down to 2132pg/ml on 22/08/01. In fact, the last result provided her lowest blood value since the beginning of the study. In September 2001, we then asked the gastroenterologist to perform a new endoscopy, in order to dismiss the diagnosis of Crohn’s disease and make sure that we were not harming her by not giving the prescribed drugs. The digestive exploration was then considered as normal, besides some “non specific mucosal inflammation”.
So the case was much less worrying and it took about seven months before she consulted again, in March 2003. She was symptom-free, finally expressing a much better digestive capacity since she was on this diet, even though she hadn’t renewed her supplements for a while. The cramps had disappeared and her blood reading for the vitamin B12 was 1001pg/ml on 26/3/02, almost back to the normal range. She definitely reached and stayed within the normal range on further checks with 726pg/ml on 31/08/02, 677npg/ml on 21/5/03 and finally 516pg/ml on 15/5/04. The last time, she was still symptom-free, but also dairy-free. She might have to consider taking vitamin B12 supplements one day in the future, but that’s another story…
About the author: Georges Mouton MD is a medical doctor specializing in functional medicine with practices in Brussels, London and Madrid. His website can be found at http://www.gmouton.com
- Albert, M.J., V.I. Mathan, and S.J. Baker, Vitamin B12 synthesis by human small intestinal bacteria. Nature, 1980. 283(5749): p. 781-2.
- Hill, M.J., Intestinal flora and endogenous vitamin synthesis. Eur J Cancer Prev, 1997. 6 Suppl 1: p. S43-5.
- Cummings, J.H. and G.T. Macfarlane, Role of intestinal bacteria in nutrient metabolism. JPEN J Parenter Enteral Nutr, 1997. 21(6): p. 357-65.
- Said, H.M., et al., Mechanism of thiamine uptake by human colonocytes: studies with cultured colonic epithelial cell line NCM460. Am J Physiol Gastrointest Liver Physiol, 2001. 281(1): p. G144-50.
- Said, H.M., et al., Riboflavin uptake by human-derived colonic epithelial NCM460 cells. Am J Physiol Cell Physiol, 2000. 278(2): p. C270-6.
- Said, H.M., Cellular uptake of biotin: mechanisms and regulation. J Nutr, 1999. 129(2S Suppl): p. 490S-493S.
- Said, H.M., et al., Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol, 1998. 275(5 Pt 1): p. C1365-71.
- Rong, N., et al., Bacterially synthesized folate in rat large intestine is incorporated into host tissue folyl polyglutamates. J Nutr, 1991. 121(12): p. 1955-9.
- Camilo, E., et al., Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology, 1996. 110(4): p. 991-8.
- Zarate, G., S. Gonzalez, and A.P. Chaia, Assessing survival of dairy propionibacteria in gastrointestinal conditions and adherence to intestinal epithelia. Methods Mol Biol, 2004. 268: p. 423-32.
- Prasad, P.D., et al., Molecular and functional characterization of the intestinal Na+-dependent multivitamin transporter. Arch Biochem Biophys, 1999. 366(1): p. 95-106.
- Balamurugan, K., A. Ortiz, and H.M. Said, Biotin uptake by human intestinal and liver epithelial cells: role of the SMVT system. Am J Physiol Gastrointest Liver Physiol, 2003. 285(1): p. G73-7.
- Iinuma, S., Synthesis of riboflavin by intestinal bacteria. J Vitaminol (Kyoto), 1955. 1(2): p. 6-13.
- Subramanian, V.S., J.S. Marchant, and H.M. Said, Targeting and trafficking of the human thiamine transporter-2 (hTHTR2) in epithelial cells. J Biol Chem, 2005.
- Matherly, L.H., Molecular and cellular biology of the human reduced folate carrier. Prog Nucleic Acid Res Mol Biol, 2001. 67: p. 131-62.
- Subramanian, V.S., N. Chatterjee, and H.M. Said, Folate uptake in the human intestine: promoter activity and effect of folate deficiency. J Cell Physiol, 2003. 196(2): p. 403-8.
- Said, H.M., A. Ortiz, and T.Y. Ma, A carrier-mediated mechanism for pyridoxine uptake by human intestinal epithelial Caco-2 cells: regulation by a PKA-mediated pathway. Am J Physiol Cell Physiol, 2003. 285(5): p. C1219-25.
- Nabokina, S.M., M.L. Kashyap, and H.M. Said, Mechanism and regulation of human intestinal niacin uptake. Am J Physiol Cell Physiol, 2005. 289(1): p. C97-103.
- Festen, H.P., Intrinsic factor secretion and cobalamin absorption. Physiology and pathophysiology in the gastrointestinal tract. Scand J Gastroenterol Suppl, 1991. 188: p. 1-7.
- Oh, R. and D.L. Brown, Vitamin B12 deficiency. Am Fam Physician, 2003. 67(5): p. 979-86.
- Carmel, R., et al., Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program), 2003: p. 62-81.
- Saltzman, J.R. and R.M. Russell, The aging gut. Nutritional issues. Gastroenterol Clin North Am, 1998. 27(2): p. 309-24.
- Pereira, S.P., N. Gainsborough, and R.H. Dowling, Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly. Aliment Pharmacol Ther, 1998. 12(1): p. 99-104.
- Paiva, S.A., et al., Interaction between vitamin K nutriture and bacterial overgrowth in hypochlorhydria induced by omeprazole. Am J Clin Nutr, 1998. 68(3): p. 699-704.
- Lin, H.C., Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. Jama, 2004. 292(7): p. 852-8.
- Pimentel, M., et al., A link between irritable bowel syndrome and fibromyalgia may be related to findings on lactulose breath testing. Ann Rheum Dis, 2004. 63(4): p. 450-2.
Vitamin B12: Odds and Ends
Vitamin B12 resolves shaky-leg syndrome
MADRID, SPAIN. Dr. Julian Benito-Leon MD, a physician at the Hospital General de Mostoles, reports the case of a 68-year-old man with the shaky-leg syndrome. The shaking (tremor) would begin immediately after the patient stood up and subside as soon as he began walking. A detailed examination revealed that the patient had a very low blood level of vitamin B12 (132 ng/L versus normal range of 222 to 753 ng/L) and a Schilling test demonstrated malabsorption of vitamin B12. The patient was put on the anticonvulsant clonazepam (1 mg/day) and was given vitamin B12 injections (1 mg daily for two weeks, then weekly for two months, and once a month thereafter). This treatment completely eliminated the tremor. After one year clonazepam was discontinued without reoccurrence of the shaky-leg syndrome. Dr. Benito-Leon and his colleagues conclude that the problem was a result of disturbances in the cerebellum or related brain structures caused by a vitamin B12 deficiency. They believe that the vitamin B12 injections were responsible for resolving it.
Benito-Leon, Julian and Porta-Etessam, Jesus. Shaky-leg syndrome and vitamin B12 deficiency. New England Journal of Medicine, Vol. 342, No. 13, 2000, p. 981 (correspondence)
Editor: William R. Ware PhD
International Health News is published 10 times a year by Hans R. Larsen MSc ChE
1320 Point Street, Victoria, BC, Canada V8S 1A5
International Health News does not provide medical advice. Do not attempt self- diagnosis or self-medication based on our reports.
Please consult your health-care provider if you wish to follow up on the information presented.