Advanced Age As a Risk Factor for Folate-Induced Cobalamin (Cbl) Deficiency

Abstract 5268

Folate therapy can induce or exacerbate neuro-cognitive changes in patients with clinically significant Cbl deficiency. High serum folate (sFol) values in subjects with low Cbl levels have also been associated with increases in the Cbl-dependent metabolite, methylmalonic acid (MMA) as well as with hematologic, neuro-cognitive and fetal abnormalities, raising concerns about the use of both folate supplements and folate-fortified grains. However, in a more recent study of young adults, MMA values were unaffected by high sFol values. Significantly, advanced age is also linked to increased MMA values even when Cbl values are normal. Thus, a retrospective study was performed of 91 non-diabetic subjects with normal renal function and low-normal Cbl values (201–300 pg/ml) who were evaluated for Cbl deficiency in an ambulatory care setting over a 10 year period to determine if age is a significant determinant of the metabolic interaction of sFol and Cbl when Cbl levels are within the normal reference range. In older individuals (≥60 yrs) with low-normal serum Cbl values, the geometric mean MMA value was significantly higher (401 nmol/l; n=11) when sFol values were elevated (>20 ng/ml) than when sFol values were normal (298 nmol/l; n=35)(p<0.025). In contrast, in younger subjects, mean MMA values were similar in both high and normal sFol groups (302 nmol/l; n=15 vs 270 nmol/l; n=30)(p=0.52). There was no correlation between MMA and sFol when sFol values were within the normal range in either age group (r≤0.07). Finally, when sFol levels were elevated, Cbl therapy significantly decreased MMA values in 8 of 9 younger subjects (89%) and in all 7 older individuals (100%) studied. It is concluded that: 1) MMA values are increased when sFol levels are elevated and Cbl values are low-normal but this effect is age-dependent; 2) the effect of sFol on MMA is not progressive but occurs only at sFol values above the normal range; and 3) Cbl therapy decreases MMA values in almost all subjects regardless of pretreatment sFol values. Since these findings may have clinical significance, caution in the use of folate supplements is advised.