Low-normal vitamin B12 levels are not associated with clinically meaningful anemia or macrocytosis

Vitamin B12 deficiency is a well-known cause of macrocytic anemia. Low-normal levels of vitamin B12 are also often believed to cause macrocytic anemia, but data to support this are lacking. In this study, we aimed to determine whether low-normal vitamin B12 levels (211-399 pg/mL) are associated with clinically meaningful anemia, macrocytosis, or elevated methylmalonic acid (MMA) compared to normal vitamin B12 levels. This is a retrospective single-institution TriNetX study including adults with low and normal vitamin B12 levels who had hemoglobin and mean corpuscular volume (MCV) measured within 1 month of the B12 level. Patients were grouped into low B12 (<211 pg/mL), low-normal B12 (211-399 pg/mL), or normal B12 (400-911 pg/mL). The low B12 and low-normal B12 groups were individually compared to the normal B12 group following propensity-score matching. A total of 129,360 patients were included in the study, comprising 3,530 low B12, 39,190 low-normal B12, and 86,640 normal B12. There was no difference in macrocytosis between the low-normal B12 and normal B12 groups (4.6% of each group; RR 1.00; 95% CI 0.94-1.07). Anemia was present in 20.4% and 19.3% of the low-normal and normal groups, respectively (RR 1.06; 95% CI 1.03-1.09; absolute risk increase 1.1%). The median MMA levels of the low-normal and normal B12 groups were 185 nmol/L and 146 nmol/L (p<0.0001) but both were well below the upper limit of normal (400 nmol/L). These findings demonstrate that low-normal B12 levels are not associated with a clinically meaningful increase in macrocytosis or anemia.