How we wish to be cited:
Lökk J. Homocysteine lowering – from skunk to rose [debate]? Rondel 2003; 17. URL: http://www.rondellen.net

Homocysteine lowering – from skunk to rose?

The monocarbon metabolism is essential from conception to death (1). Cobalamin is a key coenzyme in the metabolic cycles of one-carbon moieties, folate a cornerstone substrate. Pyridoxine is another crucial coenzyme, which may cause neurotoxicity in over-dose (2). Homocysteine provides a sensitive marker for cobalamin/folate deficiency, even pre-clinical states of such deficiencies (3). In contrast, the role of pyridoxine in deficiency states and homocystein elevation is obscure at present (4).

During the 1990´ies, homocysteine was launched as a causal risk factor for cardiovascular disease. It was obvious around 1997 for the professional epidemiologists that the evidence for a causal role of homocysteine in cardiovascular risk was based on shaky pillars. At present, it is reasonable to assume that homocysteine serves as a marker for clicical and preclinical deficiency of cobalamin and/or folate - renal impairment, inborn errors of metabolism, some disease states, and interfering medication excluded (5-8).

The first commercial oral combination of cobalamin (0.5 mg), folate (0.8 mg) and pyridoxine (3 mg) was introduced on the Swedish market 1998 for prophylaxis of emerging deficiency states, not manifest disease. The marketing was dirty, ignorant, and arrogant, an insolence to the knowledge and competence of the prescribers. The main discredit of the launching of the combination was a ruthless exploitation of homocysteine as a causal risk factor of cardiovascular disease. A scientific hypothesis, as yet unverified, was blazoned as a selling argument; "the tail waved with the bear".

In contrast to the launching of the combination in Sweden, the scientific documentation of the combination is clean and solid, the text of which should be enjoyed in full (9). The evidence is based on 209 healthy subjects in a prospective randomized study during four months. The mean age of the probands was 76 years, range 70-93. As expected, cobalamin and folate increased in the treatment group, whereas homocysteine and methylmalonic acid decreased. It is reasonable to assume that the low pyridoxine content of the combination, equivalent to calculated daily requirement, is a special virtue of the present combination; pyridoxin is potentially neurotoxic and nowadays a popular fortification of cereals and supplements.

The oral treatment of cobalamin deficiency is a Swedish tradition (10). Since cobalamin and folate are linked by a series connection in the methionine cycle, the lack of one vitamin will block the effect of the other (3,10,11,12). Thus, it is an error of the art to treat folate deficiency without cobalamin – and vice versa. Such considerations are in favor of the combination, which is in the process of introduction on the world market. It should, however, be emphasized that the classical brands of oral high-dose cobalamin and oral high-dose folic acid are still competitive for structural reasons, as is the classical parenteral treatment. The future is interesting with a hope that the Swedish skunk will turn into an international rose.

Johan Lökk
Department of NEUROTEC
Karolinska Institute
Huddinge University Hospital, M98
SE-141 86 Stockholm, Sweden
E-mail: johan.lokk@hs.se

References

  1. Lökk J. Monocarbon metabolism – between conception and death [debate]. Rondel 2003; 14. URL: http://www.rondellen.net/debate14_eng.htm
  2. Hultdin J. Vitamin B6 and polyneuropathy [debate]? Rondel 2000; 4. URL: http://www.rondellen.net/debate04_eng.htm
  3. Hultdin J. High homocystiene levels in elderly [editorial]. Rondel 2003; 14. URL: http://www.rondellen.net/publisher14_eng.htm
  4. Norberg B. The rationale for B vitamin combinations [editorial]. Rondel 2000; 4. URL: http://www.rondellen.net/publisher04_eng.htm
  5. Norberg B. Painful sensory neuropathy [editorial]. Rondel 2003; 16. URL: http://www.rondellen.net/publisher16_eng.htm
  6. Bolander-Guaille C. Current state of homocysteine research [debate]. Rondel 2003; 16. URL: http://www.rondellen.net/debate16_eng.htm
  7. Neuman M. Homocysteine in moderation [editorial]. Rondel 2003; 17. URL: http://www.rondellen.net/publisher17_eng.htm
  8. Hultdin J. Down syndrome – should we increase homocysteine [debate]? Rondel 2001; 9. URL: http://www.rondellen.net/debate09_eng.htm
  9. Lewerin C, Nilsson-Ehle H, Matoucek M, Linderstedt G, Steen B. Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently health subjects after treatment with folic acid, vitamin B12, and vitamin B6: a randomised trial. Eur J Clin Nutr 2003; 57:1426-36
  10. Norberg B. Oral high-dose cobalamin – a contagious concept [editorial]. Rondel 2001; 8. URL: http://www.rondellen.net/publisher08_eng.htm
  11. Björkegren K. Studies on vitamin B12 and folate deficiency markers in the elderly. A population-based study (dissertation). Uppsala University, Uppsala, Sweden, 2003
  12. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1191-8

Published January 7, 2004