Comprehensive Guide to Vitamins by Dr. James Meschino - HTML preview

Vitamin B₁₂ - Cobalamin

Introduction

Cobalamin is the generic name for Vitamin B₁₂ because of the presence of cobalt. Several of the different Cobalamin compounds exhibit Vitamin B₁₂ activity. Of these compounds, cyanocobalamin and hydroxycobalamin are the most active forms. Cyanocobalamin is the most stable form and therefore, the form in which the vitamin is produced commercially from bacterial fermentation. Vitamin B₁₂ is best known for its role in preventing pernicious anemia.

Absorption and Metabolism

Cobalamin is poorly absorbed from the intestinal tract unless the intrinsic factor in gastric secretion is present. Intrinsic factor binds with Vitamin B₁₂ forming a complex that binds with a specific receptor in the membrane of the ileum allowing its absorption into the blood stream to occur. Intrinsic factor is a mucoprotein enzyme made in the stomach. Vitamin B₁₂ injections are often given to prevent the development of pernicious anemia and other symptoms of Vitamin B₁₂ deficiency in certain individuals who are unable to synthesize intrinsic factor. In the absence of intrinsic factor only 1-3 percent of Vitamin B₁₂ can be absorbed via simple diffusion. Normal people absorb up to 30 percent of a test dose of Vitamin B₁₂. However, in individuals with low intakes, absorption may increase up to 70 percent.

There is an enteroheptatic circulation of B₁₂ that recycles it from bile and other intestinal secretions to the bloodstream from the intestinal tract. This is the reason why Vitamin B₁₂ deficiency takes so long to develop in humans, as a result of insufficient intake or age-related malabsorption.

Functions

In conjunction with folic acid, Vitamin B₁₂ enables each cell in the body to recycle homocysteine to methionine by providing an all-important methyl group. From methionine, the body easily makes S-adenosyl methionine by adding an adenosyl ring from ATP. Once formed, S-adenosyl methionine can transfer its methyl group to permit the synthesis of thymine nucleotides of DNA, neurotransmitters in the brain, creatine in the liver and other crucial functions, including a direct effect on detoxification reactions in the liver. A deficiency of either folic acid or Vitamin B₁₂ results in megaloblastosis, or the development of red blood cells that are enlarged because normal cell division has not taken place. Vitamin B₁₂ is also required by nerve cells as a stabilizer of glutathione, which is needed for carbohydrate metabolism. An absence of B₁₂ then hinders the energy metabolism of nerve cells. As well, in its methyl-form Vitamin B₁₂ is necessary for the formation and maintenance of myelin, the protective coating sheathing the axons of nerve cells. The B-vitamin biotin assists B₁₂ in this role.

Recommended Daily Allowance (Vitamin B12)

Vitamin B12 Deficiency

Unlike other water-soluble nutrients, Vitamin B₁₂ is stored in the liver, kidney, and other body tissues. As a result, signs and symptoms of Vitamin B₁₂ deficiency may not show themselves until 5 to 6 years of poor dietary intake or inadequate secretion of intrinsic factor. Lack of intrinsic factor occurs from an inborn error of metabolism and as a result of aging.

Pernicious Anemia

Although hereditary, it rarely manifests itself before age 35. Classic signs include megaloblastic anemia. The anemia may be severe, with a hematocrit as low as 10-15%. The megaloblastic state also produces changes in mucosal cells, leading to glossitis, as well as other vague GI disturbances such as anorexia and diarrhea. Vitamin B₁₂ deficiency also leads to a complex neurological syndrome, including peripheral paresthesia followed by poor balance due to involvement of the posterior column. In severe cases, cerebral function may be altered (e.g. dementia, other neuropsychiatric changes).

Of note is the fact that neurological involvement precedes the anemia. Therefore, in Vitamin B₁₂ deficiency the nervous system and brain are affected first. Note that a high intake of folic acid may mask a Vitamin B₁₂ deficiency because it prevents the changes in red blood cells, but does not counteract the deficiency in the brain and nervous system.¹

Supplementation Studies

Impaired Mental Function in the Elderly (Senility)

Impaired mental function in the elderly can be a result of reversible nutritional deficiencies. Several clinical trials have noted improvement in cognitive function in older persons when supplemented with Vitamin B₁₂ and/or folic acid. Supplements appear to be indicated in cases of high homocysteine and/or low blood levels of Cobalamin. A dosage of Vitamin B₁₂ is typically 100-500 mcg to correct the deficiency, then a maintenance dose of 25-75 mcg per day.^2-10

Diabetic Neuropathy

Some success has been realized using Vitamin B₁₂ supplementation in diabetic neuropathy. Injections are most common, but oral intake of 1.5 to 2.0 mg per day may produce the same results.^11-14

Multiple Sclerosis

Supplementing with methylocobalamin at 60 mg per day was shown to improve both visual and brainstem auditory-evoked potentials by nearly 30 percent. Motor function did not improve, indicating a benefit to afferent not efferent nerve pathways.¹⁵

Low Sperm Count

In men with a low sperm count (<20 million per ml or a motility rate of less than 50 percent), two studies have demonstrated improvement (achieved a total count of 100,000 million per ml) with daily doses of 1,000 mcg and 6,000 mcg of Vitamin B₁₂ daily (taken orally).^16,17

Vitamin B12 Toxicity

Vitamin B₁₂ is not known to have any toxic effects at any reasonable intake level.¹

Drug-Nutrient Interactions

The following drugs are reported to cause depletion of Vitamin B₁₂:

Oral contraceptives¹⁸

Antibiotics decrease the synthesis of various B-vitamins by the bacterial flora of the large intestine.^19,20

Antiviral drugs (didanosine, lamivudine, stavudine, salcitabine, zidovudine).²¹

Biguanides (e.g. metformin) may reduce Vitamin B₁₂ absorption in approximately 30% of patients.²²

Bile Sequestrants (cholestyramine, colestipol) decrease VitaminB₁₂ absorption.²³

Clofibrate and possible other fibrate drugs decrease Vitamin B₁₂ absorption.²⁴

Colchicine is reported to reduce Vitamin B₁₂ absorption.²⁵

H₂ Receptor Antagonists (cimetidine, famotidine, mizatidine, ranitidine) these drugs reduce VitaminB₁₂ absorption by decreasing stomach acidity.²⁶

Phenytoin (anti-consulsant) may decrease VitaminB₁₂ absorption.²⁷

Proton Pump Inhibitors may reduce Vitamin B₁₂ absorption by decreasing stomach acidity (e.g. lansoprazole, omeprazole, rabeprazole, pantoprazole).²⁸

Time-released potassium chloride, these medications can reduce stomach acidity and may decrease Vitamin B₁₂ absorption as a result.²⁹

Standard Textbooks of Nutritional Science:

-Shils M, Shike M, Olson J, Ross C. Modern Nutrition in Health and Disease. 9^th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1993.

-Escott-Stump S, Mahan LK, editors. Food, Nutrition and Diet Therapy. 10^th ed. Philadelphia, PA: W.B. -Saunders Company; 2000.

-Bowman B, Russell RM, editors. Present Knowledge in Nutrition, 8^th ed. Washington, DC:.ILSI Press; 2001.

-Kreutler PA, Czajka-Narins DM, editors. Nutrition in Perspective. 2^nd ed. Upper Saddle River, NJ: Prentice Hall Inc.; 1987.

van Goor L, Woiski MD, Lagaay AM, Meinders AE, Tak PP. Review, Cobalamin deficiency and mental impairment in elderly people. Age Ageing 1995;24:536-42.

Nilsson K, Gustafson L, Fäldt R, et al. Plasma homocysteine in relationship to serum Cobalamin and blood folate in a psychogeriatric population. Eur J Clin Invest 1994;24:600-6.

Healton EB, Savage DG, Brust CM, Garrett TJ, Lindenbaum J. Neurologic aspects of Cobalamin deficiency. Medicine 1991 ;70:229-45.

Martin DC, Francis J, Protech J, Huff FJ. Time dependency of cognitive recovery with Cobalamin replacement: a report of a pilot study. J Am Geriatric Soc 1992;40:168-72.

Levitt AJ, Karlinsky H. Folate, Vitamin B12 and cognitive impairment in patients with Alzheimer’s disease. Acta Psychiatr Scand 1995;86:301-5.

Abalan F, Delile JM. B12 deficiency in presenile dementia. Biol Psychiatry 1985;20:1247-51.

Cole MG , Parchal JF. Low serum Vitamin B12 in Alzheimer-type dementia. Age Ageing 1984;13:101-5.

Nilsson-Ehle H. Age-related changes in Cobalamin (Vitamin B12) handling. Implications for therapy. Drugs Aging 1998;12(4):277-92.

Delva MD. Vitamin B12 replacement. To B12 or not to B12? Can Fam Physician 1997;43:917-22.

Yoshioka K, Tanka K. Effect of methylcobalamin on diabetic neuropathy as assessed by power spectral analysis of heart rate variations. Horm Metab Res 1995;27:43-4.

Yaqub BA, Siddique A, Sulimani R Effects of methylcobalamin on diabetic neuropathy. Clin Neurol Neurosurg 1992;94:105-11.

Yamane K, Usui T, Yamamoto T, et al. Clinical efficacy of intravenous plus oral mecobalamin in patients with peripheral neuropathy using vibration perception thresholds as an indicator of improvement. Curr Ther Res 1995;56:656-70l.

Stracke H, Lindemann A, Federlin K. A befotiamine-Vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 1996;104(4):311-6.

Kira J, Tobimatsu S, GotoI. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Int Med 1994;33:82-6.

Sandler B, Faragher B. Treatment of oligospermia with Vitamin B12. Infertility 1984;7:133-8.

Kumamoto Y, Maruta H, Ishigami J, et al. Clinical efficacy of mecobalamin in treatment of oligospermia. Results of a double-blind comparative clinical study. Acta Urol Japan 1998;34:1109-32.

Webb JL. Nutritional effects of oral contraceptive use: a review. J Reprod Med 1980;25(4):150-6.

Cummings JH, Macfarlane G. Role of intestinal bacteria in nutrient metabolism. J Parenter Enteral Nutr 1997;21 (6):357-65.

Deguchi Y, Morishita T, Mutai M. Comparative studies on synthesis of water-soluble vitamins among species of bifidobacteria. Agric Biol Chem 1985;49(1):13-9.

Paltiel O, Falutz J, Veilleux M, Rosenblatt DS, Gordon K. Clinical correlates of subnormal Vitamin B12 levels in patients infected with the human immunodeficiency virus. Am J Hematol 1995;49(4):318-22.

Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Malabsorption of Vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia 1983;24(1):16-8.

Leonard JP, Desager JP, Beckers C, Harvengt C. In vitro binding of various biological substances by two hypocholesterolaemic resins. Cholestyramine and colestipol. Arzneimittelforschung 1979:29(7):979-81.

Robinson C, Weighly E. Clofibrate inhibits absorption of Vitamin B12. Basic Nutrition and Diet Therapy. New York: Macmillan; 1984.L Race TF, et al. Intestinal malabsorption induced by oral colchicines (comparison with neomycin and cathartic agents). Am J Med Sci 1970;259:32.

Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on Vitamin B12 absorption. Ann Pharmacother 1992;26(10):1283-6.

Latham J, Wickramasinghe G, Wickramasinghe SN. Effect of phenytoin sodium on doubling time, deoxyuridine suppression, 3H-methotrexate uptake and 57CO-cyanocobalamin uptake in HL60 cells. Clin Lab Haematol 1990;12(1):67-75.

Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin. Ann Intern Med 1994;129(3):211-5.

Palva IP, Salokannel SJ, Timonen T, et al. Drug-induced malabsorption of Vitamin B12. IV. Malabsorption and deficiency of B12 during treatment with slow-release potassium chloride. Acta Med Scand 1972;191 (4):355-7.