How we wish to be cited:
Schneede J. Homocysteine hypotheses - “virgin but not fanatic” [editorial]. Rondel 2005; 25. URL: http://www.rondellen.net

Homocysteine hypotheses
“Virgin but not fanatic”

Editorial orientation From the start 1999, the policy of The Rondel is to regard homocysteine mainly as a marker of vitamin B12 and/or folate deficiency. The attitude is skeptic concerning claims of a causal role of homocysteine in disease processes of old age. With the negative findings of the VISP study and of the NORVIT study, time is now ripe for consideration in order not to throw the baby out with the bathwater. The guest editor is a pioneer in the clinical application of homocysteine research. (Illustration: “Homocysteine debate in Sweden ” by Bodil Norberg)

  Introduction  

Current debate on homocysteine has been rather fierce and dogmatic in Sweden . The role of homocysteine in vascular disease (1-3), dementia (4), depression (5), and osteoporosis (6) is still not generally accepted. Another closely related issue is the use of homocysteine as diagnostic marker of B-vitamin deficiency and for dose finding studies (6). Optimal dosage and composition of B-vitamins is crucial for proper design of future intervention studies.  

The aim of this communication is to try to balance the debate and possibly to find the smallest common denominator of accepted knowledge on homocysteine in clinical practice.  

 Cardiovascular disease, dementia and depression are multifactorial diseases, and homocysteine may contribute to the development of disease - not necessarily as the primary cause, but as one of many causative factors. To indisputably proof the causal involvement of a risk factor which contributes possibly to only 10-20% of the total risk is very demanding, as very large sample sizes and long follow-up times are needed. On the other hand, this endeavor may still be worthwhile, as homocysteine concentrations are modifiable by simple means, and treatment of hyperhomocysteinemia is cheap and may thus represent a valuable complement to traditional treatment.  No single intervention study is expected to have sufficient statistical power to proof or reject the homocysteine hypothesis. Thus, the current situation calls for patience and scientists should keep an open mind while awaiting the results of large meta-analyses from ongoing intervention trials. However, we should also endorse the established knowledge on homocysteine based on more than 20 years of intense scientific activity.

 Homocysteine as vitamin deficiency marker

Homocysteine as a biochemical test is more reliable and sensitive than traditional markers of B-vitamin deficiency. It is possible to reduce laboratory costs by using homocysteine as first-line screening test, followed by serum cobalamin and serum folate according to certain algorithms. It has been estimated that use of homocysteine can reduce laboratory costs by 30%, provided that further testing of serum cobalamin and serum folate is reserved for homocysteine values above 9 micromol/L (7).

Homocysteine as risk marker  

The concept of homocysteine lowering in association with prevention of vascular disease is still unresolved. It should, however, be emphasized that the results of the NORVIT study are preliminary and unpublished and do not repudiate a causal role of homocysteine in vascular disease (3). Likewise, a revision of the results of the VISP trial underlines the importance of prudent patient selection (8). A subgroup analysis in 2155 subjects unlikely to have B₁₂ malabsorption (serum cobalamin above 250 pmol/L) and unlikely to receive cobalamin supplementation (serum cobalamin below 637 pmol/L) suggests that B-vitamin therapy could reduce the risk of recurrent vascular events (8). This “subgroup” comprised a major part of the total study population.  

Optimal dosage of oral B vitamins

Unfortunately, the B-vitamin doses used in the different homocysteine lowering studies have not been harmonized. This could relate to the fact that dose-finding studies for oral B-vitamins using clinical end-points as response parameters are scarce. Homocysteine has normally been used as an effect parameter for defining optimal doses. In patients with B₁₂-malabsorption, the optimal dosage of oral vitamin B12 appears to be about 1 mg daily (6). The optimal dosage of oral folic acid seems to lie between 0.4-1 mg daily (6). The optimal dosage of vitamin B6 in patients with cardiovascular disease is not established, but high doses in large excess of RDA-values may be problematic (3). Cardiovascular disease carries many aspects of an inflammatory disease and B-vitamins have the potential to facilitate inflammation.

Discussion and conclusions

Now, after the arrival of the results of the first intervention trials it is time for reflection and reconsideration. It appears that the design of many intervention studies may not have been optimal both with regard to selection of patients, B-vitamin doses used and the length of follow-up time. It is desirable that the doses and composition of vitamin supplements in future intervention trials should be tailored based on results of dose-finding studies with clinical parameters as endpoints, and that the supplementation regiments should be harmonized between the studies.

The homocysteine hypothesis is too well-founded to be rejected on the basis of the results of single intervention studies. Most likely, final conclusions can only be drawn on from large meta-analyses, which should be available within the next 3-4 years. Until then, we should not be tempted to jump to premature conclusions: The results of meta-analyses are worth waiting for! Both “believers” and “non-believers” should try to remain unprejudiced. The situation reminds me of the timid response of a girl to a young, attractive gentleman-in-waiting: “You should understand that I’m a virgin, but not a fanatic.”

Jörn Schneede, MD

Medical Bioscience, Clinical Chemistry
University Hospital of Northern Sweden
SE-901 85 Umeå, Sweden

E-mail: jorn.schneede@medbio.umu.se

References

1.      Jansson J-H. Hypothesis on shaky pillars –homocysteine and vascular disease [evaluation]. Rondel 2004; 21. URL: http://www.rondellen.net/evaluation21_eng.htm

2.      Zylberstein DE. Homocysteine – biological and statistical risk [evaluation]. Rondel 2005; 23. URL: http://www.rondellen.net/evaluation23_eng.htm

3.      Schneede J. Preliminary conclusions from the NORVIT study [evaluation]. Rondel 2005; 24. URL: http://www.rondellen.net/evaluation24_eng.htm

4.      Nägga K. Homocysteine in dementia diagnostics [debate]. Rondel 2005; 24. URL: http://www.rondellen.net/debate24_eng.htm

5.      Norberg B. Folate and cobalamin deficiency – depressive and cognitive symptoms [debate]. Rondellen 2004; 20. URL: http://www.rondellen.ne/debate20_eng.htm

6.      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

7.      Schedvin G, Jones I, Hultdin J, Nilsson TK. A laboratory algorithm with homocysteine as the primary parameter reduces the cost of investigation of folate and cobalamin deficiency. Clin Chem Lab Med 2005; 43(10):1065-8

8.      Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin intervention for stroke prevention trial. An efficacy analysis. Stroke 2005; 36:2404-9

Published December 31, 2005