This article was published in No 2 of The Rondel (Jan 5, 2000)
Håkan Odeberg, M.D, Dept Int Med, Karlskrona Hospital, S-371 65 Karlskrona, Sweden.
hakan.odeberg@blekinge.se
Homocysteine is a sulphydryl-containing amino acid. It is not found in food but formed from the esential amino acid methionine. The metabolite homocysteine is remethylated to methionine in a reaction dependent on cobalamin and methyltetrahydrofolate. In deficiency states of vitamin B12 or folate, the plasma levels of homocysteine increae. Plasma homocysteine (P-Hcy) has thus become a popular marker for non-specified deficiency.
Homocysteine may also be transsulphurated with serin to cystathione in a vitamin B6 dependent reaction, demanding the enzyme cystathionbetasynthetase (CBS). Highly elevated levels of homocysteine (hyperhomocysteinemia) with urinary excretion of homocysteine (homocystinuria) are caused by deficiency of the CBS enzyme. Homozygotes for CBS deficiency are prone to develop atherosclerosis and thrombosis in early ages. Recent studies have demonstrated an association between moderately elevated levels of P-Hcy and vascular disease.
In the 31 July issue of The Lancet (1), Graeme J Hankey and John W Eickelboom made a systematic analysis of the state of the art concerning homocysteine and vascular disease. The authors defined hyperhomocysteinemia and described factors influencing homocysteine metabolism, test methods for P-Hcy determination, prevalence studies of hyperhomocysteinemia, and the association between homocystein, thrombosis and embolism.
Elevated levels of P-Hcy are encountered in deficiency states of vitamin B12, folate, and vitamin B6. Isolaed deficiency of either B vitamin or combined deficiences of B vitamins produce hyperhomocysteinemia. It should, however, be emphasized that the role of vitamin B6 in this context is subject to debate.
Other etiologic factors of elevated P-Hcy levels is hereditary enzyme defects. The CBS mutation is already mentioned. The C677T mutation in the genes for thermolabile methylene tetrahydrofolate reductase (MTFR) is at present the most widely recognized of the hereditary defects affecting P-Hcy. Homozygotes for the C677T mutation provide 5-15% of different normal populations.
The view of Hankey and Eikelboom is that it is reasonable to define "hyperhomocysteinemia" as levels of P-Hcy correlated with increased risk of atherosclerotic and thrombotic vascular disease. The risk is "dose-related without cut-off value", just as in hypertonia and hypercholesterolemia. In comparison with blood pressure and serum cholesterol, the sampling and determination of P-Hcy is less standardized.
There is a large quantity of epidemiological data , which suggest that elevated levels of P-Hcy are correlated with an increased risk of atherosclerosis and thrombotic vascular disease – the higher the P-Hcy levels, the greater the risk (1). There are, however, high-quality prospective studies, which do not support this interpretation. Furthermore, several studies have been unable to demonstrate an association between the C677T mutation and vascular disease.
Experimental observations indicate destructive effects of of elevated homocysteine on endothelial cells and vascular tissue. Nevertheless, the authors (1) emphasize that corresponding evidence in clinical conditions in man are still lacking. Their view is supported by a list of nine on-going prospective controlled clinical trials.
In deficiency states, the B vitamins decrease P-Hcy levels. Folate is the single most potent homocysteine depressor. Vitamin B12 further decreases homocysteine levels in groups of patients and probands. The effect of vitamin B6 is negligible. It should, however, be noted that high levels of P-Hcy, around 100 micromol/L, have been observed in patients suffering from isolated vitamin B12 deficiency (cf. 2).
Hankey and Eikelboom (1) deem that time is not ripe for decision on homocysteine lowering with B vitamins, until the results of on-going controlled clinical trials are reported. The Bergen group of researchers, supported by Lars Brattström, came to the same conclusion in the November issue of Journal of Internal Medicine (3).
References
Updated november 06, 2003