Homocysteine and methylmalonate: when should I measure them and what do they mean?

Plasma total homocysteine has traditionally been considered a risk factor for atherosclerosis. More recently, it is being adopted as a marker of vitamin B12 deficiency. The association between mild hyperhomocysteinaemia (HHC) and vascular disease appears increasingly uncertain.1 However, as the test is available in most hospital laboratories, plasma total homocysteine is being used as a ‘screening’ test when vascular disease or vitamin deficiency are suspected, or indeed when ‘metabolic’ causes are being considered for a wide range of non-specific clinical presentations. Plasma total homocysteine levels (reflecting both free-bound and protein-bound homocysteine) are determined by a complex interaction of genetic and environmental factors. Finding mild HHC (12–30 µmol/L) in a patient with cerebrovascular disease may be regarded as an ‘expected’ result as HHC is risk factor for cerebrovascular disease (though it might reflect vitamin B12 deficiency). However, occasional patients have moderate (30–100 µmol/L) or severe (>100 µmol/L) HHC: their raised plasma total homocysteine may point to an underlying condition that could be contributing to the clinical presentation and might be amenable to treatment. These patients need to be investigated further and this requires an understanding of the underlying biochemistry. Homocysteine is not a structural amino acid and is not found in protein (figure 1). It is derived from the essential amino acid methionine via the important intermediate S-adenosylmethionine. This acts as a methyl donor in many important biochemical processes including DNA methylation and creatine and phosphatidylcholine synthesis; levels of S-adenosylmethionine are closely regulated.2 Homocysteine itself can either be converted to cysteine by transsulfuration, or it can be remethylated back to methionine. Figure 1 The methionine and folate cycles. Defects in either of these pathways can lead to the accumulation of homocysteine and its upstream precursor, adenosyl homocysteine. Homocysteine is directly toxic to endothelium and neural tissue. Adenosyl homocysteine potently inhibits many methyltransferases, …