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Hyperhomocysteinaemia as a cardiovascular risk factor: an update
R van der Griend1, D H Biesma, J D Banga
1Department of Internal Medicine, Sint Antonius Hospital, Nieuwegein, The Netherlands. r.griend@digd.azu.nl
Insights
High homocysteine levels are linked to cardiovascular disease, but a direct cause-effect link is unproven. Folic acid supplementation shows promise for lowering homocysteine, but ongoing trials are needed to confirm its cardiovascular benefits.
Area of Science:
- Cardiovascular Science
- Metabolic Disorders
- Nutritional Biochemistry
Background:
- Hyperhomocysteinaemia is an independent cardiovascular risk factor, supported by epidemiological data.
- Acquired causes include B-vitamin deficiencies and renal insufficiency; a common inherited cause (MTHFR gene mutation) doesn't increase cardiovascular risk.
- The precise mechanism of homocysteine-induced cardiovascular disease remains unclear, though endothelial dysfunction is implicated.
Purpose of the Study:
- To review the evidence linking hyperhomocysteinaemia to cardiovascular risk.
- To discuss diagnostic methods and reference values for homocysteine.
- To evaluate homocysteine-lowering therapies, particularly folic acid supplementation.
Main Methods:
- Epidemiological evidence review.
- Discussion of diagnostic approaches including fasting homocysteine and methionine loading tests.
- Analysis of pathophysiological mechanisms and therapeutic interventions.
Main Results:
- Epidemiological data strongly associate hyperhomocysteinaemia with cardiovascular risk.
- Methionine loading tests identify more cases than fasting tests; significant intra-individual variability necessitates repeated sampling.
- Folic acid (0.5 mg daily) is an effective homocysteine-lowering therapy, except in renal failure patients.
Conclusions:
- Hyperhomocysteinaemia is a significant cardiovascular risk factor, despite unproven causality.
- Folic acid supplementation is a primary therapeutic strategy for reducing homocysteine levels.
- Further large-scale clinical trials are essential to determine the impact of homocysteine-lowering therapy on cardiovascular outcomes.
Abstract:
There is overwhelming epidemiological evidence that hyperhomocysteinaemia is an independent and graded cardiovascular risk factor, although a cause-and-effect relationship is still unproven. Acquired causes of hyperhomocysteinaemia include B-vitamin deficiencies and renal insufficiency. The most important inherited cause is a point mutation in methylenetetrahydrofolate reductase gene, which is, remarkably, not associated with an increased cardiovascular risk. A methionine loading test identifies substantially more subjects with hyperhomocysteinaemia compared with a fasting homocysteine determination alone. Repeated blood sampling is necessary due to an intra-individual variability in homocysteine concentrations up to 25%. A conservative reference value for fasting homocysteine is 15 micromol/l, although there seems to be no definite threshold in the presumed linear relation between homocysteine concentration and cardiovascular risk. The pathophysiological mechanism of homocysteine-induced cardiovascular disease is still not elucidated. The concept of endothelial dysfunction, demonstrated by impaired endothelium-dependent vasodilation, by oxidant damage has been confirmed in hyperhomocysteinaemic healthy adults. Folic acid supplementation (0.5 mg daily) can be considered the optimum homocysteine lowering therapy, with the exception of renal failure patients. Ongoing large prospective, randomised controlled clinical trials are investigating the potential beneficial effect of homocysteine lowering therapy on cardiovascular morbidity and mortality in subjects with hyperhomocysteinaemia.
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