In reply

Abstract

In reply:—Dr. Drinka addresses some interesting questions in his letter. We do not have an explanation for why subjects 12 and 28 had elevated metabolites, which fell with cobalamin therapy, at a time they had normal cobalamin levels. With the exception of volume depletion and renal failure, the only known causes of elevated methylmalonic acid are deficiencies of cobalamin and interference with cobalamin metabolism. Though elevated homocysteine levels may have several causes, we have previously shown that homocysteine elevations due to folate deficiency will not respond to cobalamin therapy and vice versa.1 We have shown previously that up to 5% of subjects with cobalamin deficiency may have normal cobalamin levels and elevated metabolites that respond to cobalamin.2, 3 In addition, in subjects known to malabsorb cobalamin, who received infrequent therapy, the serum methylmalonic acid was the most likely abnormal test both in patients with and without hematologic relapse. In contrast, the serum cobalamin was frequently normal when the methylmalonic acid level was increased. Thus, elevated methylmalonic acid was a sensitive indicator of impending clinical cobalamin deficiency in subjects dependent on replacement therapy.3 Most of the cobalamin measured in the serum is not bound to the physiologic transport protein transcobalamin II. The “superphysiologic” levels referred to by Dr. Drinka are usually transient, reflecting the recent injection of cobalamin. There is no storage form of cobalamin, 95% being bound to the two known cobalamin-dependent enzymes. One of those, the mutase, is only 5%–10% saturated with adenosylcobalamin. Indeed it appears that the amount of cobalamin available to the cell is rate-limiting on the activity of mutase. When extremely large amounts of cobalamin were infused into rats (10-fold the usual therapeutic dose in humans daily) serum methylmalonic acid decreased by 42% and homocysteine decreased by 26%.4 Therefore, it is possible to induce stimulation of the cobalamin dependent enzymes with massive amounts of cobalamin. How this relates to the usual therapeutic doses of cobalamin employed in our subjects is not known. We would agree with Dr. Drinka that more research needs to be done validating whether optimizing enzyme function with micronutrients will benefit our elderly subjects. Certainly there is a growing body of evidence that modest elevations of homocysteine are associated with vascular disease, but benefits of treatment have yet to be determined. We also thank Dr. Carmel for his comments.