The rationale for B vitamin combinations
Bo Norberg

A possible beneficial effect on vascular disease by homocysteine lowering with B vitamin therapy is subject to intensive investigation; reliable results are expected within a few years (1). Furthermore, homocysteine serves as a broad, sensitive and swift marker for pre-clinical stages of B vitamin deficiency. The plasma homocysteine levels are affected by cobalamin (B12), folate (B9) and pyridoxin (B6), one-vitamin deficiency or combined B vitamin deficiencies. Approximately 90-95 per cent of the homocysteine lowering is thought to be associated with cobalamin and folate; the role of pyridoxin is at present obscure (2).

Since November 1999, an intense debate has stormed in Sweden concerning prophylactic treatment of elevated homocysteine values in healthy elderly persons. The debate started when a combination tablet with cobalamin 0.5 mg, folate 0.8 mg, and pyridoxin 3 mg (TrioBe) was registered for prophylactic treatment of pre-clinical vitamin B deficiency, the deficiency marked by homocysteine elevation.

It should be emphasized that the criticism was directed towards the marketing methods, not towards the new combination. TrioBe was marketed far beyond its documentation and indications, as a remedy for clinical deficiencies and a salvation therapy for the possible vascular risks of moderate homocysteine elevations.

It is an old experience known by most physicians that deficiency of one nutrient tends to mask incipient deficiencies of other nutrients (3-7). It is for example considered an error of the art to prescribe folate without simultaneous treatment with cobalamin (6). Analogous ideas emerge concerning pyridoxin (cf. 4,5). Cobalamin monotherapy is also blocked in the presence of an incipient folate deficiency (3).

TrioBe is well composed for prophylactic treatment of pre-clinical stages of cobalamin-folate-pyridoxin deficiencies. However, it lacks documentation and indications for treatment of clinical deficiency states. It is reasonable to assume that such treatment will require at least a dose doubling. The doubling of dose is associated with a doubling of costs - as compared with the leading brands of oral high-dose cyanocobalamin (Behepan) and oral high-dose folic acid (Folacin).

With due regard to the close coupling of cobalamin and folate in methionine metabolism, it is remarkable that a combined advertisement for Behepan and Folacin recently was felled and fined by the Industrial Advertisement Controller (IGM); the reason for the fining was formal. The advertisement was incongruent with the official product monography (produktresumé) and the information of the manufacturer to physicians (Fass-text). "The sea trading authorities cannot accept the terrestrial globe, until the church authorities have incorporated the Galilean world conception." But verily, present presentations of oral high-dose cyanocobalamin and oral high-dose folic acid are in urgent need of renewal.

The local discussion in Sweden today may be the global discussion tomorrow, when the results of prospective randomized and placebo-controlled studies of the effect of homocysteine lowering emerge (cf. 1). It is reasonable to assume that low-dose oral B vitamin combinations will crush the concept of solely parenteral cobalamin therapy and prepare a global break-through for oral high-dose cyanocobalamin in clinical deficiency states.

References

1. Christen WG, Ajani UA, Lynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease. Causal or casual? Arch Intern Med 2000; 160;422-34.
2. den Heijer M, Brouwer IA, Bos GM, Blom HJ, van der Put NM, Spaans AP, Rosendaal FR, Thomas GM, Haak HL, GerritsWB. Vitamin supplementation reduces blood homocyseine levels: a controlled trial in patients with veneous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol 1998; 18(3):356-61.
3. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998; 92:1191-8.
4. Hoogeven EK, Kostense PJ, Valk GD, Bertelsmann FW, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouver DA. Hyperhomocysteinaemia is not related to risk of distal somatic polyneuropathy: The Hoorn Study. J Intern Med 1999; 246:561-6.
5. Mansoor MA, Kristensen O, Hervig T, Brates CJ, Pentieva K, Vefring H, Osland A, Drablös PA. Plasma homocyesteine response to oral doses of folic acid and pyridoxin hydrochloride (vitamin B6) in healthy individuals. Oral doses of vitamin B6 reduce concentrations of serum folate. Scand J Clin Lab Invest 1999; 59:139-46.
6. Lökk J, Nilsson M, Norberg B, Rudolphi O, Sandström H, Westman G. Controversies around vitamin B12 in Sweden. Attitudes and values behind clinical decision-making in primary health care 1996. Hematology 1997; 2:341-50.
7. Nilsson K, Gustafson L, Hultberg B. The plasma homocysteine concentration is better than that of methylmalonic acid as marker for sociopsychological performance in a psychogeriatric population. Clin Chem 2000; 46(5):691-6.

Updated September 30, 2000