Circulating homocysteine is derived from dietary methionine. Homocysteine, in turn, is metabolized either into cystathionine or back into methionine (Fig. 33.4). The latter process involves the enzyme methionine synthase. Methionine synthase requires donation of a methyl group from 5-methyltetrahydrofolate to produce methionine, and the enzyme MTHFR is involved in the production of 5-methyltetrahydrofolate from dietary folate sources (20). The nutritional supplements folic acid, vitamins B2,B6, and vitamin B12 are all required for proper metabolism of homocysteine; therefore, their deficiency is associated with acquired elevations in circulating homocysteine levels (21,29,59). Although heritable deficiencies in the enzymes required for metabolism of homocysteine have been described for the pathways leading to cystathionine
Figure 33.4 Homocysteine metabolism. Dietary methionine is metabolized either to cysteine or back into methionine. Homocysteine, a prothrombotic metabolite, is an intermediate in this process. Conversion of homocysteine to methionine requires transfer of a methyl group from 5-methyltetrahydrofolate. The conversion of folate to 5-methyltetrahydrofolate is a multistep process requiring vitamin B2 as a cofactor for the enzyme, methylene tetrahydrofolate reductase (MTHFR). Vitamin B12 is a required cofactor for the enzyme methionine synthase. Vitamin B6 is also required for metabolism of sulfur containing amino acids such as methionine.
formation and those involved in reconversion to methionine, mutations in MTHFR have received the most attention (20,59–61). Point mutations in MTHFR are surprisingly common, are associated with hyperhomocysteinemia, and are linked to thrombosis (22,29,59–61).
Those heritable thrombophilias most often linked to recurrent pregnancy loss include hyperhomocysteinemia, activated protein C resistance associated with mutations in factor V, deficiencies in proteins C and S, mutations in prothrombin, and mutations in antithrombin. These inherited disorders are mainly autosomal dominant and display a wide variation in prevalence and in the severity of morbidity associated with gene carriage. The latter two characteristics have direct reciprocal correlations in white populations. In agreement with general thrombotic risk data, carriage of combinations of two or more inherited thrombophilic defects has particularly strong association with adverse pregnancy outcome (22,24,30,62). Acquired thrombophilias associated with recurrent pregnancy loss include hyperhomocysteinemia and activated protein C resistance. The vast majority of the data linking thrombophilic states to recurrent fetal loss consist of small-to moderate-sized prevalence studies (62–70). Recent attempts to pool these data into meta-analyses have led to more informed recommendations on the testing of patients presenting with recurrent pregnancy loss (71–73). Taken together, these studies suggest that testing for the factor V Leiden mutation, protein S levels, prothrombin promoter mutations, homocysteine levels, and global activated protein C resistance is of use in white patients with a history of repetitive first or second trimester losses. These recommendations do not apply to patients who are nonwhite. Data directly linking hyperhomocysteinemia, folic acid, vitamin B12, and MTHFR mutations to recurrent pregnancy loss have been contradictory (41,43,60–62,65,66,68). Studies have evaluated pooled data from previous investigations (one via meta-analysis) and show these disorders to be linked to risk for recurrent pregnancy loss (72).