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Björkegren K. The future of homocysteine – paradigm shift in homocysteine research [editorial]. Rondel 2007; 27. URL: http://www.rondellen.net

The future of homocysteine
Paradigm shift in homocysteine research


Figure legend
Spring in Skane. Photo: Hans Liedholm (2).

Editorial background
The outcome of the first four large randomized and controlled clinical trials on homocysteine lowering in vascular disease constitutes a paradigm collapse with crisis and chaos. It also provides an opportunity for re-orientation and development. Karin Björkegren (1) suggests that future trials on homocysteine lowering should focus on patients with moderate homocysteinemia, tHcy 15-30 micromol/L, in clinical stady-state, in reversible stages of disease, with optimal and uniform doses of cobalamin, folate and pyridoxine.

The process of paradigm shift
The accepted concepts of a defined group are called a “paradigm” (3), the frame of reference, which guides our interpretations and anticipations. Many of the bricks in this building are defective due to age or erroneous interpretations in past and present. In spite of restrictions, limitations and frailties, the paradigm defends itself aggressively. Contradictory bricks are rejected. However, at last the building cracks due to own weight, own weaknesses, and external pressure.

The homocysteine model predicted that a measurable part of our vascular diseases is due to moderately elevated homocysteine levels, plasma values ranging between 15-30 micromol/L. The model was based on previous observations that patients with homocystinuria, an inborn error of metabolism with tHcy in plasma in the range 300-500 micromol/L, are prone to die in young years by vascular diseases. The model was also supported by the association between vascular disease and moderate elevations of homocysteine levels (see e.g. 4).

Four large randomised and controlled trials (RCTs) have hitherto failed to demonstrate any beneficial effect on vascular disease by homocysteine lowering with B vitamins (5-10). Such findings constitute a paradigm collapse or at least a paradigm crisis. Thus, it is time for reviewing past experience and suggesting fresh moves towards future.

Vascular diseases
The VISP study (5) was the first RCT to be concluded within the field of homocysteine lowering in vascular disease; it addressed patients with previous stroke. Beneficial effects of homocysteine lowering could not be demonstrated. An efficacy analysis suggested a key role of vitamin B12 deficiency in the study population (9); a higher dose than 0.4 mg daily might have improved the outcome in some patients.

The NORVIT study addressed patients with an acute myocardial infarction within seven days of randomisation (6); the results could not show any improvement by homocysteine lowering. However, it is noteworthy that pyridoxine (40 mg daily) did not lower homocysteine levels. The observation supports the conclusion of Brattström and co-workers that pyridoxine does not lower homocysteine levels in deficient and non-deficient probands without genetic disorders (11,12).

The HOPE-2 study addressed vascular risk patients in a broader sense (7). In contrast to VISP and NORVIT, the dosage of vitamin B12 in HOPE-2 was adequate for complete deficiency treatment, 1 mg daily (13,14). Nevertheless, the vitamin combination did not reduce the risk of major cardiovascular events in these patients (7). The editorial comments of Loscalzo on the NORVIT study and the HOPE-2 study are informative (10).

The VITRO study addressed patients with previous deep vein thrombosis and/or pulmonary embolism (8). A combination of cobalamin, folate, and pyridoxine did not significantly reduce the rate of relapses. Thus, the findings of four prospective RCTs (5-8) demonstrated homocysteine lowering by B vitamins without measurable effects on morbidity and mortality. Nor does homocysteine lowering influence other factors associated with vascular disease (4).

Cognition and motility
The cells, tissues and organs of cognition and motility are affected by vascular diseases. Nevertheless, homocysteine lowering has hitherto produced more positive results than in gross vascular diseases (5-8). Demented persons with tHcy above 20 micromol/L responded better to B12-folate treatment for two months than demented persons with lower homocysteine levels (15). However, the study does not meet the criteria of an RCT investigation.

The Lewerin dissertation (16) adds important pieces to the homocysteine puzzle. Essentially, the trial suggests that homocysteine lowering in non-deficient elderly does not influence the age-dependent deterioration of cognition and motility (2,17). Nor does B12-folate supplementation to non-deficient elderly improve cognition and motility (2,16,17). The Lewerin trial (16) meets the criteria of an RCT.

The FACIT study (18) reported that folic acid, 0.8 mg daily, significantly improved domains of cognitive function which tend to decline with age. The results are difficult to evaluate for an observer without special knowledge of the field. The absence of vitamin B12 in the trial provides a conservative bias (cf 12). The study meets the criteria of an RCT.

The Sato study (19) with hip fracture as hard endpoint provides the most convincing evidence hitherto in favour of motility improvement by homocysteine lowering; the rate of hip fractures was reduced from 43/1000 patient years to 10/1000 patient years (p<0.001) by vitamin B12 1.5 mg daily and folic acid 5 mg daily.

The mean homocysteine value at baseline was approximately 20 micromol/L in the Sato study (19). The study meets the criteria of an RCT. It should be emphasised that the beneficial effects of B12-folate in the Sato study might be interpreted as healing of nerve lesions in patients with mild deficiency, the healing resulting in better balance (20).

It is conceivable that moderate impairment of cognition and motility combined with tHcy in the range 15-30 micromol/L provide symptoms and signs of reversible B12-folate deficiency. At least, the findings in the Nilsson study (15) and in the Sato study (19) are compatible with this hypothesis. Thus, it is suggested that future studies on homocysteine lowering are focussed on such patients.

Take home messages from the past
One grim lesson from the past is never to draw conclusions about causes from epidemiological studies. Everybody knows that the correlation between priest salaries and whisky prices is complex. Thus, the joke of these days is that the correlation between old age and homocysteine reflects a “reverse causality”.

The previous RCTs on homocysteine lowering were based on the observation that there is a graded dose-dependent association between homocysteine levels and vascular disease. Thus, patients with low homocysteine levels were also included. The mean homocysteine value at baseline was approximately 12 in HOPE-2 (7), 13 in NORVIT (6), 14 in VISP (5) and VITRO (8), 15 in FACIT (18). It is reasonable to suggest that the participants of future studies on homocysteine lowering should have homocysteine levels between 15-30 micromol/L at baseline (cf 15,19,20).

Besides the selection of conclusive patients, it is essential that future trials of homocysteine lowering are conducted with optimal doses of oral vitamin B12, folic acid and (possibly) pyridoxine. One such combination would be cyanocobalamin, 1 mg daily, folic acid 0.4 - 1 mg daily, pyridoxine 0 - 3 mg daily (cf 2,13,14,21,22).

References

  1. Björkegren K. Studies on vitamin B12 and folate deficiency markers in the elderly. A population-based study. Dissertation, Uppsala University 2003. Copies may be requested from karin.bjorkegren@pubcare.uu.se.
  2. 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
  3. Kuhn TS. The structure of scientific revolutions (1962). 3rd ed. Chicago University Press 1996.
  4. Öhlin H. Homocysteine, vitamin therapy, and coronary heart disease [evaluation]. Rondel 2006; 26. URL: http://www.rondellen.net/evaluation26_eng.htm
  5. Toole JF, Malinow MR, Chambless RE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004; 291:565-75
  6. Bönaa KH, Njölstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354:1578-88
  7. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354:1567-77
  8. Heijer M, Willems HPJ, Blom HJ, Gerrits WBJ, Cattaneo M, Eichinger S, Rosendaal FR, Bos GMJ. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial. Blood 2007; 109(1):139-44
  9. Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin intervention for stroke prevention trial. An efficacy analysis. Stroke 2005; 36:2404-09
  10. Loscalzo J. Homocysteine trials – clear outcomes for complex reasons. N Engl J Med 2006; 354:1529-32
  11. Brattstöm L, Israelsson B, Norrving B, Bergqvist D, Thörne J, Hultberg B, Hamfelt A. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment. Atherosclerosis 1990; 81:51-60
  12. Brattström L. Vitamins as homocysteine-lowering agents. J Nutr. (suppl) 1996; 1276S-80S
  13. Eussen SJPM, Groot LCPG, Clarke R, Schneede J, Ueland PM, Hoefnagels WHL, Staveren WA. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency. A dose-finding trial. Arch Intern Med 2005; 165:1167-72
  14. Norberg B. Provocative proposal – global guidelines for oral vitamin B12 therapy [editorial]. Rondel 2006; 26. URL: http://www.rondellen.net/publisher26_eng.htm
  15. Nilsson K, Gustafson L, Hultberg B. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. Internat J Geriatr Psychiatry 2001; 16:609-14
  16. Lewerin C. Vitamin B12 and folate depletion in the elderly. Diagnosis, clinical correlates and causes. Dissertation, Göteborg University, Sweden 2006. ISBN 91-628-6999-X. Copies may be requested from catharina.lewerin@vgregion.se
  17. Schneede J. Vitamin B12 and folate depletion in the elderly. Diagnosis, clinical correlates and causes [evaluation]. Rondel 2007; 27. URL: http://www.rondellen.net/evaluation27_eng.htm
  18. Durga J, Boxtel MPJ, Schouten EG, Kok FJ, Joues J, Katan MB, Verhoef P. Effect of 3-year folic acid supplementation on cognitive function on older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 2007; 369:208-16
  19. Sato Y, Honda Y, Iwamoto J, Kanoko T, Satoh K. Effect of folate and mecobalamin on hip fractures in patients with stroke. A randomized controlled trial. JAMA 2005; 293:1082-8
  20. Norberg B. Oral high-dose vitamin B12 and folate – breakthrough by broken hips [editorial]. Rondel 2005; 24. URL: http://www.rondellen.net/publisher24_eng.htm
  21. Schneede J. Homocysteine hypotheses - “virgin but not fanatic” [editorial]. Rondel 2005; 25. URL: http://www.rondellen.net/publisher25_eng.htm
  22. Clarke R. Vitamin B12, folic acid, and the prevention of dementia. N engl J Med 2006; 354:2817-9

 

 

Published May 23, 2007