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Jansson J-H. Hypothesis on shaky pillars –homocysteine and vascular disease [evaluation]. Rondel 2004; 21. URL: http://www.rondellen.net

Hypothesis on shaky pillars
Homocysteine and vascular disease

Editorial prologue At the National Meeting of the Swedish Medical Association in Gothenburg Nov 24-26, 2004, the Section of Family Medicine arranged a symposium about "Homocysteine – from cradle to grave". Dr Karin Björkegren was moderator (cf 1). The lecture hall was overcrowded with about 300 listeners, 240 (80%) general practitioners, of whom 168 (70%) believed that homocysteine is a causal risk factor for vascular disease just before the speech of Jansson. The present paper is based on Janson´s lecture.

As all of us saw, about 70% of the general practitioners in this hall believe that homocysteine is a causal risk factor for vascular disease. This view is common, a working hypothesis generated by leading researchers with an honest hope to benefit large groups of patients. The idea was supported by "observation studies", which showed an association between homocysteine values and risk of thrombo-embolic events.

However, an association is not equivalent with a causal risk factor. A general deficiency of the epidemiological studies in the period 1990-2000 was an incomplete adjustment for traditional risk factors for vascular disease. Furthermore, kidney function and albumin correlate with both homocysteine and vascular disease; adjustment for kidney function and albumin is usually lacking in studies from the period 1990-2000.

The definition of a causal risk factor is that a modification of the risk factor reduces the morbidity and mortality associated with the risk factor. In case homocysteine is a causal risk factor for vascular disease, a lowering of plasma homocysteine, e.g. by vitamins, should reduce the risk for vascular disease in randomized and controlled trials (RCT). Now four such studies have been reported (2-5).

The four RCTs on homocystein lowering now available have some features in common – moderate decrease of homocysteine, and moderate effects on risk for events, if any (2-5). The largest RTC hitherto (5) comprised 3680 patients, who had survived an ischaemic stroke. The test group was treated with high-dose B vitamins for two years, the control group with low-dose B vitamins. The homocysteine was on an average 2 micromoles lower in the test group than in the control group after treatment. Nevertheless, recurrent cerebral infarction was as common in the test group as in the control group; nor did subgroup analyses reveal any differences. However, homocysteine before randomization was associated with risk of new vascular events or death (5).

In the other RCT of 2004, homocysteine lowering by cobalamin, folate and pyridoxine significantly increased the risk of restenosis in the stent and the need of repeated revascularization (4). The intervention studies of 2004 (4,5) suggest that B vitamin therapy lowers homocysteine without improvement of the vascular disease. In the worst scenario, homocysteine lowering might be a disadvantage for some patients (4). Thus, it is reasonable to suggest that moderately elevated homocysteine should be subject to further research, not to B vitamin therapy. A homocysteine value above 25 micromoles/L usually signals cobalamin/folate deficiency (6).

Then, why did 70% of the general practitioners in this hall believe that homocysteine is a causal risk factor for vascular disease 10 minutes ago? The simple answer appears to be "fraud marketing since 1998 by a seller of a combination preparation (cobalamin, folic acid, pyridoxine) for homocysteine lowering and deficiency treatment". The industrial disinformation has evoked an intense debate (7-9) and is at present subject to scrutiny by regulatory authorities.

1. Björkegren K. Studies on vitamin B12 and folate deficiency markers in elderly: A population-based study. Dissertation, Uppsala 2003
2. Schnyder G, Roffi M, Pin R, Flammer Y, Lange H, Eberli FR, Meier B. Turi ZG, Hess OM. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001; 345:1593-6000
3. Schnyder G, Rofi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin 6 on clinical outcome after percutaneous coronary intervention. JAMA 2002; 288:973-9
4. Lange H, suryapramata H, Luca G, Börmer C, Dille J, Kallmeyer K, Pasalary MN, Scherer E, Darmbrink JHE. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med 2004; 350:2673-81
5. Toole JF, Malinov MR, Chambless LE, Spence JD, Petigrew LC, Howard VJ, Sides EG, Wang CH, Stampfer M. Lowering homocysteine in patients with ischemic stroke to prevent recurrient stroke, myocardial infarction, and death. The vitamin intervention for stroke prevention (VISP) randomized controlled trial. JAMA 2004; 297:565-75
6. Hultdin J. Högt homocystein hos gamla [ledare]! Rondellen 2003; 14. URL: http://www.rondellen.net/publisher14_swe.htm
7. Rosenberg P, Hernborg A, Håkansson J, Skoglund I, Svartholm R, Söderström U, Wahlström L. B vitamins and dementia – lack of evidence in Cochrane analysis [debate]. Rondel 2004; 19. URL: http://www.rondellen.net/debate19_eng.htm
8. Nilsson-Ehle H. High homocysteine – prophylaxis and treatment [debate]. Rondel 2004; 21. URL: http://www.rondellen.net/debate21_eng.htm
9. Norberg B. Safety and reliability of oral cobalamin [editorial]. Rondel 2004; 21. URL: http://www.rondellen.net/publisher21_eng.htm

Published December 31, 2004