Hyperhomocysteinemia and Disease—Is 10 μmol/L a Suitable New Threshold Limit?

Abstract

Hyperhomocysteinemia (HHcy) is a medical condition characterized by an abnormally high level of homocysteine (Hcy) in the blood. Homocysteine is a toxic sulfur-containing amino acid that is produced during the metabolism of methionine. Under normal circumstances, Hcy is recycled back to methionine via the remethylation pathway, through the action of various enzymes and vitamins, particularly folic acid (vitamin B9) and B12 used when intracellular methionine levels are low, thus restoring the necessary levels to correctly maintain active protein synthesis. A second pathway, used in cases of intracellular methionine excess, (the trans-sulfuration pathway) is the one that recycles Hcy into cysteine (a precursor of glutathione), first passing through cystathionine (via the enzyme cystathionine beta-synthase), a reaction that requires vitamin B6 in its active form. HHcy has been identified as a risk factor for a variety of disorders, including cardiovascular diseases, multiple sclerosis, diabetes, Alzheimer’s and Parkinson’s diseases, osteoporosis and cancer. However, it remains unclear whether the slightly elevated concentration of Hcy (Hcy 7–10 μmol/L) is a causative factor or simply a marker of these pathologies. In human plasma, the concentration of Hcy ([Hcy]) is classified as mild (15 to 30 μmol/L), moderate (30 to 100 μmol/L), and severe (greater than 100 μmol/L). Interestingly, many laboratories continue to consider 25 μmol/L as normal. This review seeks to examine the controversial literature regarding the normal range of HHcy and emphasizes that even a [Hcy] level of 10 μmol/L may contribute to the development of several diseases, aiming to discuss whether it would be appropriate to lower the threshold of HHcy normal values.