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Norberg B. Deficiency of vitamin B12 and folate – the branded generic for optimal oral therapy [editorial]. Rondel 2008; 28. URL: http://www.rondellen.net

Deficiency of vitamin B12 and folate
The branded generic for optimal oral therapy


Summary
The risk groups for health lesions by deficiency of vitamin B12 and/or folate are fertile women and elderly persons. It is suggested that population prevention is managed by breakfast cereals and porridges. In deficiency stages, it is suggested that a prescription-free TwoBee combination, containing cyanocobalamin 1 mg and folic acid, 0.5 mg, is made available. (Figure: The sales are shown of oral cyanocobalamin, 1 mg (upper line 2005), and parenteral cobalamins (lowest line 2005) in patient years in the period 1990-2005 in Sweden (cf 1, Table).

Back to basics
The homocysteine model of vascular disease has collapsed; it is not expected to be resuscitated during the first decennium of our nearest future (1-3). The reason is that four randomised and controlled prospective trials have failed to show positive results of homocysteine lowering by B vitamins (2). Furthermore, two other studies of the same quality, the FACIT trial and the WENBIT trial, have also failed according to congress reports and Internet summaries. Nevertheless, some brave souls still nourish a smouldering hope (4-6).

The concept of prevention of overt B vitamin deficiency is now threatened by a discussion of possible cancer risks associated with B vitamin prevention (7-11). The exception is women in fertile age, the foetuses of whom may develop neural tube defects and other damages due to incipient deficiency of vitamin B12 and folate. Thus, time is ripe to return from the prevention of future deficiency to the treatment of actual deficiency.

The detection of B vitamin deficiency
A deficiency of B vitamins is generally due to deficient diet, quantitatively or qualitatively, defects of uptake, increased want, and/or increased excretion (12,13). Deficiency of vitamin B12 as an absorption defect is thought to have been described 1850 by Thomas Addison and 1872 by Anton Biermer. The industrial preparation of foods demonstrated deficiency states of thiamine (beriberi), riboflavin (lesions in skin and mucous membranes), and niacin (pellagra) from 1900 and forth (12,13).

Raw liver therapy for pernicious anaemia (vitamin B12 deficiency) was reported in 1926. Beside cobalamins, the liver preparations contained considerably amounts of folate, iron, pyridoxine, and other micronutrients. In 1931, Lucy Wills and co-workers reported observations due to the series coupling between folate and vitamin B12 in human metabolism (14). Later, therapy trials with folic acid only in pernicious anaemia proved disastrous (15). Thus, folate therapy should be safeguarded by cobalamin therapy (13).

The existence of folate deficiency in a post-industrial society was a matter of dispute until about 2000; the development of homocysteine as a deficiency marker has clarified this point. At least 2/38 representative probands over 70 years of age had a development of homocysteine signalling folate deficiency, while treated with vitamin B12 only (16, page 22, Fig 7). Thus, vitamin B12 therapy should always be safeguarded by folate therapy.

The role of pyridoxine was obscure until about 1950. Then meat production showed that pyridoxine was necessary for optimal growth. Furthermore, infants fed on pyridoxine-free diet developed microcytic anaemia and convulsions (13). The presence of pyridoxine deficiency in a modern post-industrial society is a matter of controversy.

Oral vitamin B12 therapy
Sweden is a country with comprehensive experience of oral vitamin B12 therapy, 1 mg daily (Fig 1); the experience comprises approximately three million patient years. In 2005, three out of four patients were treated with tablets. Among citizens over 70 years of age, 14% were treated with cobalamins, among younger 1%. The value of the sales was approximately three million Euro per one million of citizens (1).

USA is another country with extensive experience of oral B vitamin treatment. There are at least two combination tablets with cobalamin 2 mg, folic acid 2.5 mg, and pyridoxine 25 mg (Foltx, Pamlab, Covington, Louisiana, Folbee, Breckenridge Pharmaceuticals, Boca Raton, Florida). Behind this combination, there is a patent, which embodies cyanocobalamin 0.3 – 10 mg, folic acid 0.1 – 10 mg, and pyridoxine, 5-75 mg.

The patent is a continuation of four earlier patents on the metabolites homocysteine, cystathione, methylmalonic acid, and 2-methylcitric acid for diagnostic and therapeutic purposes (17). These patents are thought to claim prior arts and laws of nature; their legal validity is dubious, particularly outside USA.

Strategy for oral deficiency treatment
The potential for oral treatment of deficiency of cobalamin and folate is thought to be approximately 80% of all cases (3). The great risk groups are women in fertile age and persons older than 70 years. About every second pregnancy is more or less unplanned. Thus, it is suggested that the vast majority of fertile women are safeguarded by individual information letters each year, recommending fortified cereals for breakfast or minor meals, such as Cornflakes, Special K Classic, or All Bran Regular.

The coupling of micronutrients to breakfast cereals and porridges is expected to hamper excessive intake. Women actively planning pregnancy could support their body stores of cobalamins and folates with ordinary deficiency treatment.

Other persons with negative B12-folate balance are candidates for deficiency treatment. The optimal oral dose of vitamin B12 is cyanocobalamin, 1 mg daily, according to present documentation (3). Lower doses are not documented (1), higher doses imply increasing urinary losses. Thus, the brand generic for deficiency treatment is proposed to contain cyanocobalamin, 1 mg, and folic acid, 0.5 mg (cf 1-3). The suggested TwoBee combination  is safer than any single preparation available at present and should be sold over the counter (OTC) without mandatory prescription by a doctor.

Conclusion
Vitamin B12 and folate are the only B vitamins, the deficiency of which provides health risks in post-industrial societies for the time being. On a population basis, it is suggested that the risks are managed by fortified breakfast cereals and porridges and in deficiency groups by a TwoBee OTC combination, prescription-free. A few persons still need the attention of a qualified physician.

Bo Norberg

References 

  1. Liedholm H. Clinical effects of overfilling – vitamin B12 and folate repletion in non-deficient elderly [debate]. Rondel 2007; 27. URL: http://www.rondellen.net/debate27_eng.htm
  2. Björkegren K. The future of homocysteine – paradigm shift in homocysteine research [editorial]. Rondel 2007; 27. URL: http://www.rondellen.net/publisher27_eng.htm
  3. Norberg B. Provocative proposal – global guidelines for oral vitamin B12 therapy [editorial]. Rondel 2006; 26. URL: http://www.rondellen.net/publisher26_eng.htm
  4. Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007; 369:1876-82
  5. Carlsson CM. Lowering homocysteine for stroke prevention. Lancet 2007; 369:1841-2
  6. Ray JG, Kearon C, Yi Q, Sheridan P, Lonn E. Homocysteine-lowering therapy and risk for venous thromboembolism: a randomized trial. Ann Intern Med 2007; 146:761-7
  7. Kim Y-I. Folate: a magic bullet or a double edged sword for colorectal cancer prevention. Gut 2006; 55:1387-9
  8. Van Guelpen BR, Virén SM, Bergh ARJ, Hallmans G, Statin PE, Hultdin J. Polymorphisms of methylenetetrahydrofolate reductase and the risk of prostate cancer: A nested case-control study. Eur J Cancer Prevention 2006; 15:46-50
  9. Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E, Winkvist A. Low folate levels may protect against colorectal cancer. Gut 2006; 55:1461-6
  10. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, et al. Folic acid for the prevention of colorectal adenomas. JAMA 2007; 297:2351-9
  11. Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating improtant biological principles: A hypothesis. Biomarkers Prev 2007; 16(7):1325-9
  12. Boyd W. Pathology – an introduction to medicine. Chapter 15. Deficiency diseases, pp 377-92. 7th ed. Lea &, Philadelphia 1961
  13. Lee GR, Bitchell TC, Forster J, Athens JW, Lukens JN (eds). Wintrobe´s Clinical Hematology, Ed 9, Philadelphia: Lea & Febiger; 1993.
  14. Wills L, Cantab MA, Lond BS. Treatment of “pernicious anaemia of pregnancy” and “tropical anaemia”. BMJ 1931, 1:1059-84
  15. Fuld H. Effect of vitamin B12 on neuropathy in pernicious anaemia treated with folic acid. BMJ 1950; 2:147-8
  16. Björkegren K. Studies on vitamin B12 and folate deficiency markers in the elderly. A population-based study. Dissertation. Uppsala Universitet 2003
  17. Patents to Metabolite Laboratories, Denver, Colorado (Dr Robert H Allen and Dr Sally P Stabler):

US 5,563,126, application filed on Dec 29, 1992
US 5,795,873, filed on Aug 2, 1996*
US 6,207,651, filed on Jan 26, 1998
US 6,297,224, filed on March 22, 1999*
US 6,528,496, filed on Febr 26, 2001, issued on March 4, 2003**
*challenged by LabCorp
**settlement between PamLab and Breckenridge 

Published January 10, 2007