Homocysteine
Biological and statistical risk

Editorial background Dimitri Zylberstein was born 1951 in Poland. He studied medicine in Gothenburg, Sweden, 1974-80 and became a specialist in internal medicine and hematology 1990 and in family medicine in 1992. He has worked as a general practitioner in primary health care at Mölndal Health Center since 1994 and started his scientific training 2001. Now he analyses current state of homocysteine as a biological and statistical risk of vascular disease. Previous contributions in this series were written by Rosenberg and co-workers (debate19_eng.htm), Jansson (evaluation21_eng.htm), and Norberg (publisher22_eng.htm).

Homocysteine (tHcy) has become a token challenged in modern medicine (1-9). For the last 50 years, it has been obvious that patients with inborn errors of metabolism, tHcy range 300-500 micromol/L, are prone to die from thrombo-embolic disorders during their first 30-40 years of life. About 1990, the technical improvement made it possible to test the hypothesis that lower levels of tHcy, close to the decision level of 15 micromol/L, might increase vascular morbidity and mortality.

Homocysteine levels are easily lowered by cobalamin and folate. Thus, health profits could easily be obtained in case homocysteine should prove a causal biological risk factor. The literature on the topic has exploded (1-9). The aim of the present analysis is to elucidate some basic features of present debate.

The experimental studies on adverse effects of homocysteine have suggested toxic effects on endothelium cells and thrombin metabolism (3). Furthermore, the levels of tHcy are proportional to the levels of asymetric methylarginine (ADMA), which decreases e.g. the production of nitrite oxide in endothelial cells (4). The interpretation of these studies is cumbersome due to high concentrations of homocysteine and short exposure times. In vivo studies were performed on chicken embryos with homocysteine concentrations (30 micromol/L) corresponding to the concentrations seen in cases of mild to moderate hyperhomocysteinemia (3). Another biological model in man is an MTHFR(C677T) polymorphism (5), which in homozygote form increases tHcy (approximately 10% of the Swedish population).

There is a correlation between elevated tHcy and vascular disease; the nature of this correlation is still subject to debate. The first studies of the correlation were of case-control type. Then prospective studies with multivariate regression models came. The follow-up period of these studies is at best 13 years for women, 15 years for men, most of them 3-5 years. Most endpoints of such studies – stroke, myocardial infarct, morbidity, mortality – are correlated to several risk factors, e.g. age, blood lipids, blood pressure, smoking, body mass index. In addition to established risk factors, tHcy is also affected by vitamin state, kidney function, albumin levels in serum, and consumption of coffee. Thus, it is negatively correlated to levels of folate and cobalamin.

Our contribution (1) was a population-based prospective study of a representative sample of healthy women (n=1,368) followed for 24 years, with acute myocardial infarction (AMI) as end-point. We confirmed that tHcy is an independent risk factor for AMI. However, the association between homocysteine (over 14.2 micromol/L, fifth quintile) and AMI became evident after 15 years of observation. Cobalamin and folate data could not explain the association between tHcy and AMI in our study.

The role of tHcy as a possible independent risk factor in epidemiological models is accepted by most scientists. However, those findings might mirror other factors overlooked or non-caught. In our study, homocysteine stands out as a sole significant risk factor in the Cox regression analyses with correction for age, risk factors, and tHcy modifiers such as renal function, B vitamins, and coffee consumption (1). Multivariate regression models provide powerful tools for scientific analysis. Nevertheless, like other tools they have their restrictions and limitations. Thus, it is essential not to confuse statistical independence with biological causality. The causality problems have to be solved by other methods.

A possible causal role of homocysteine in vascular disease could be elucidated by randomized controlled prospective intervention trials on patiens with vascular disease. Such studies have been performed, others are in progress. Hitherto, the results of homocysteine lowering vary from deterioration to moderate improvement (6-9).

It should be emphasized that the null hypothesis is a villain, who at best can be acquitted short of evidence. Thus, the objections against B vitamin therapy for homocysteine lowering in vascular disease have limited value (2); treatment time was short and vitamin dose dubious. Nevertheless, the senders of new messages have to shoulder the burden of evidence; honesty is the best policy. Therapy recommendations have to be based on sound evidence.

Present knowledge, like past knowledge, is imperfect. Science provides a path forth, towards a deeper understanding of realities now barely imagined. For the time being, homocysteine is an independent risk factor in a statistical context. A causal role of homocysteine in the biological context of vascular disease is still a subject of debate.

Dimitri E Zylberstein
E-mail: dimitri.zylberstein@allmed.gu.se
The Sahlgren Academy of Gothenburg University
Section of Primamary Health Care
P O Box 454
SE-405 30 Göteborg, Sweden

1. Zylberstein DE, Bengtsson C, Bjorkelund C, Landaas S, Sundh V, Thelle D, Lissner L.

Serum homocysteine in relation to mortality and morbidity from coronary heart disease: a 24-year follow-up of the population study of women in Gothenburg. Circulation. 2004 Feb 10;109(5):601-6

2. Malouf R, Grimley Evans J, Areosa Sastre A. Folic acid with or without vitamin B12 for cognition and dementia (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

3. Splaver A, Lamas GA, Hennekens CH
Homocysteine and cardiovascular disease: biological mechanisms, observational epidemiology, and the need for randomized trials. Am Heart J. 2004 Jul;148(1):34-40..

4. Sydow K, Hornig B, Arakawa N, Bode-Boger SM, Tsikas D, Munzel T, Boger RH.

Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med. 2004 May;9(2):93-101

5. Spotila LD, Jacques PF, Berger PB, Ballman KV, Ellison RC, Rozen R.

Age dependence of the influence of methylenetetrahydrofolate reductase genotype on plasma homocysteine level. Am J Epidemiol. 2003 Nov 1;158(9):871-7

6. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy with folic acid, vitamin B(12), and vitamin B(6) on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. Jama. 2002;288:973-9.

7. Willems FF, Aengevaeren WR, Boers GH, et al. Coronary endothelial function in hyperhomocysteinemia: improvement after treatment with folic acid and cobalamin in patients with coronary artery disease. J Am Coll Cardiol. 2002;40:766-72.

8. 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

9. Toole JF, Malinow 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

Published May 8, 2005