Kilmer McCully, the first pioneer to study the role of hyperhomocysteinemia in the pathogenesis of arteriosclerosis, began by studying two children with two different forms of hereditary enzymatic defects which led to severe hyperhomocystenemia. Both these children presented with significant vascular disease at very young ages. In 1969, McCully concluded that the vascular damage in both cases was caused by an severely elevated homocysteine level and he suggested a possible similar mechanism in patients without genetic defects but who have mild to moderately elevated homocysteine levels . In the years that followed, a large number of studies supported the presence of a strong association between elevated homocysteine levels and various atherothrombotic diseases including stroke, venous thromboembolism (VTE) and ischemic cardiac disease [1–3]; a meta-analysis of clinical observational studies consistently found that a 25 percent reduction in the serum homocysteine concentration is associated with an 11 percent lower risk of ischemic heart disease (odds ratio, 0.89; 95% confidence interval, 0.83 to 0.96) and a 19 percent lower risk of stroke (odds ratio, 0.81; 95% confidence interval, 0.69 to 0.95) . Furthermore, in vitro studies and animal models of hyperhomocysteinemia have clearly shown multiple mechanisms of homocysteine induced vascular dysfunction. Inhibition of endothelial cell nitric oxide production, enhanced oxidative stress, IL-8 up-regulation leading to enhanced leukocyte recruitment, and up-regulation of tissue factor within the vasculature are among many mechanisms proposed underpinning homocysteine induced cell injury [12–15]. However, lowering mildly elevated homocysteine levels in patients with and without vascular disease using vitamin supplementation did not show a reduction in cardiovascular events in several prospective and randomized clinical studies [7–10]. Possibly harmful effects of vitamin therapy in certain settings have been suggested in some trials. For example, the folate after coronary intervention (FACIT) trial demonstrated that administration of folic acid, vitamin B12 and vitamin B6 after coronary stenting might increase the risk of in-stent restenosis and the need for target-vessel revascularization .
In contrast to those studies which included patients with mild to moderate elevations in homocysteine, our patient had a severely elevated homocysteine level. Interestingly, the etiology of the severity of hyperhomocysteinemia in this case is not exactly clear as isolated vitamin B12 deficiency due to pernicious anemia has not been reported to directly cause such unusually high homocysteine levels [17–19]. We did not identify other causes of hyperhomocysteinemia and genetic testing for the common C677T MTHFR gene mutation was negative. We realize the limitation of testing for only one gene mutation, given that a number of other genetic mutations in enzymes involved in homocysteine metabolism can contribute to an elevation in plasma homocysteine levels . However, the absence of a family history for atherothrombotic diseases together with the normalization of his homocysteine level after only ten days of parenteral vitamin B12 supplementation strongly support that indeed vitamin B12 malabsorption secondary to pernicious anemia is the underlying cause of his severe hyperhomocysteinemia. His normal folate level likely may have contributed to the severity of the homocysteine elevation by masking his megaloblastic anemia, and leading to a later presentation of a more severe neuropathy.
In fact, a recent study using data from the National Health and Nutrition Survey (NHANES) between 1999–2002 found that participants with vitamin B12 deficiency and high serum folate had increased homocysteine levels compared to participants who had the combination of vitamin B12 deficiency and low serum folate, suggesting a role of folate levels in vitamin B12's enzymatic functions . We speculate that his normal folate levels may have contributed to the delay in diagnosing pernicious anemia leading to severe hyperhomocysteinemia and the consequent development of vascular injury and hypercoaguability which presented as an acute myocardial infarction and multiple pulmonary emboli.