Homocysteine is generated during metabolism of methionine, an essential amino acid. In turn, it can be transformed into cystathionine, which is then used to manufacture cysteine, a nonessential amino acid that is ultimately broken down and excreted in the urine. An alternative pathway is a sort of salvage operation, incorporating homocysteine into the production of more methionine. An inherited metabolic fault or a nutritional deficiency can interfere with these processes, either because too little enzyme is available to catalyze the reactions or because the substances working in concert with the enzymes—cofactors and cosubstrates—are deficient. Homocysteine levels can build, resulting in homocystinuria (higher plasma levels of free homocysteine) or hyperhomocysteinemia (increased plasma total homocysteine, free and protein-bound), the latter of which is under scrutiny in premature vascular disease.8

For example, the enzyme 5-methyltetrahydrofolate reductase (MTHR) is essential in the conversion of homocysteine to methionine. Some 9% to 17% of the population is homozygous for a mutated form of MTHR that is heat-sensitive and unable to work effectively at normal body temperature; an estimated 30% to 41% of the population is thought to be heterozygous for this mutation.7 Similarly, a genetic deficiency of the enzyme cystathionine beta-synthase (CBS) disrupts the metabolism of homocysteine to cystathionine. More routine factors can boost homocysteine levels as well, including increasing age, tobacco use, certain medical disorders or medications, and deficiencies of folate or vitamin B12 (see Table 2).