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Bolander-Gouaille C. Current state of homocysteine research [debate]. Rondel 2003; 16. URL: http://www.rondellen.net

Current state of homocysteine research

Christina Bolander-Goaauille has worked with pharmaceutical information for 25 years, the last15 years mainly with monocarbon metabolism and the vitamins, the deficiency of which affect methionine metabolism (1-5). She now summarizes some impressions from the 4^th International conference on Homocysteine Metaabolism, Basle, 29 June – 3 July, 2003 (cf 4).

The first of these international congresses on homocysteine was held in 1995. Since then the interest in this field of research has expanded very rapidly. This is mirrored by the fact that the number of publications on the topic that are now published each year has increased four-fold since 1995 to reach about 1 000.

In 1995 the main interest was in the association between hyperhomocysteinaemia and cardiovascular disease (CVD). There was only one presentation that addressed the association with neuropsychiatric disease. This year a substantial part of the program was about the association with dementia, but studies on the relationship with depression and schizophrenia were also presented.

Genetic polymorphisms that influence the homocysteine metabolism, and that may therefore be of importance for homocysteine-related disorders have also become a very active field of research. About 200 studies are published on just one of these polymorphisms. This common polymorphism results in a thermolabile form of methylentetrahydrofolate reductase (MTHFR), and reduced activity. MTHFR is crucial for the folate metabolism.

Meta-analyses of the studies on the association between hyperhomocysteinemia and the risk of CVD have yielded varying results. Some of the analyses found a rather modestly increased risk, others quite high. These analyses, however, are complicated not the least because several of the established risk factors cause increased homocysteine levels. Smoking and high alcohol intake, for instance, cause increased catabolism of folate, vitamin B6 and B12 and thereby increased homocysteine levels.

In contrast, all studies agree upon the finding that the risk associated with the established risk factors is strongly increased by concomitant elevated homocysteine levels. Several presented studies showed a strong synergistic effect. New data from The European Concerted Action Project (COMAC) demonstrated for instance a steeply increased risk of smoking, increased total cholesterol, LDL, triglycerides, and ApoB, if homocysteine levels are also elevated.

Another intervention study was presented. In a German placebo-controlled study 50 patients with intima media thickness (IMT) >1mm, were supplemented with 2.5 mg of folic acid, 0.5 mg of vitamin B12 and 25 mg of vitamin B6, or placebo daily for one year. The homocysteine level decreased from 10.5 m mol/L to 6.6 m mol/L in the active group. At the same time IMT decreased in the active group, whereas there was an increase of IMT in the placebo group. The difference between the groups was significant already after 6 months.

New data from 3 large American longitudinal studies and one Canadian study confirmed earlier findings of an association between homocysteine/vitamin status and the risk of dementia. Data from the Framingham Offspring Study, the Normative Aging Study and McArthur Studies of Successful Aging showed that baseline increased homocysteine/low levels of folate and/or vitamins B12 or B6 is associated to worse score of cognitive tests. Moreover baseline homocysteine/vitamin status is predictive of a more rapid cognitive impairment. The Canadian study also showed a more rapid cognitive impairment among subjects whose homocysteine levels increased during follow-up, than among those with stable homocysteine levels.

Also in this context there seems to be a synergistic effect with other risk factors. The Maine-Syracuse Study showed that high systolic blood pressure in combination with elevated homocysteine levels substantially increased the risk of loss of cognitive function. The effect was most pronounced among elderly and women.

Elevated homocysteine levels in schizophrenic patients have earlier been reported from 3 studies. In an Israeli study a large number of patients were screened. Young, male schizophrenics, in particular, had strongly increased homocysteine levels. The same group of researchers now reported on the effect of homocysteine-lowering treatment of 18 such patients. The study was placebo-controlled, double-blind and crossover. After treatment with 2 mg of folic acid, 0.4 mg of vitamin B12 and 25 mg of vitamin B6 daily for 3 months a 10% improvement of Positive and Negative Symptom Scale was found, whereas placebo was associated with an improvement of <2% (p<0.01).

Low folate/vitamin B12 levels are reported from several studies of depressive patients. Folic acid in addition to antidepressives is also found to improve treatment outcome in depression. New data from the large Norwegian Hordaland Study now showed that homocysteine levels ³ 15.0 m mol/L increased the risk of depression with 90%. Also the thermolabile form of MTHFR that impairs folate metabolism increased the risk. In contrast there was no significant association with folate or vitamin B12 levels. The reason for this might be that homocysteine is more sensitive, as it mirrors the interaction between the vitamins.

There is also a growing skepticism concerning the reliability of cobalamin determinations. The specificity seems to be low. Moreover plasma/serum levels do not necessarily mirror cellular status. Recently, determination of holoTC that is the fraction of the vitamin that is bound to TC and available for transport into the cell has become available for clinical practice. HoloTC is an early marker for negative B12 balance that may ameliorate the diagnosis.

Willianne Nelen from Nijmegen gave an overview of studies on birth defects and pregnancy complications associated with disturbed homocysteine metabolism. These studies show a clear relationship with not only NTD, but also cleft lip with or without cleft palate, heart malformations, low birth weight, spontaneous abortions and preeclampsia. Research within this field is intensive, not the least on the interactions between polymorphisms, homocysteine and the vitamins involved.

Data were presented that point at the importance of not only folate, but also vitamin B12, and stressing the view that women should receive vitamin supplementation not only before conception and during the 3 first months of pregnancy, but during the entire pregnancy. Furthermore a presented large Norwegian study did not demonstrate any increased incidence of twin births after folic acid supplementation before and during pregnancy. The result is in contrast to an earlier Swedish study but in accordance with an American and a Chinese study (cf 5).

1. Bolander-Gouaille C. Focus on homocysteine. Springer, Berlin 1999
2. Bolander-Gouaille C. Focus on homocysteine and the vitamins involved in its metabolism. Springer, Berlin 2002.
3. Bolander-Gouaille C, Bottiglieri T. Homocysteine, ralated vitamins, and neuropsychiatric disorders. Springer, Berlin 2003.
4. Norberg B. Painful sensory neuropathy [editorial]. Rondel 2003; 16. URL: http://www.rondellen.net/publisher16_eng.htm
5. Lökk J. Monocarbon metabolism – between conception and death [debate]. Rondel 2003; 14. URL: http://www.rondellen.net/debate14_eng.htm

Published October 3, 2003