Dear Editor
Whenever Vitamin B12 deficiency is characterised as a disorder typically associated with macrocytosis[1], the caveat that should apply is that the majority of vitamin B12 deficient subjects have a normocytic haematological profile[2]. In the latter retrospective study, which enrolled Indian subjects, serum vitamin B12 levels were measured by an assay in which the normal range for serum vitamin B12 was 239-931 pg/ml. Among 868 subjects who were deemed to be Vitamin B12 deficient, 664 were characterised by a mean corpuscular volume (MCV) in the range 80-100 fl. An MCV >100 fl was documented in 90 subjects, and an MCV < 80 fl in 114 subjects[2].
In a prospective study which enrolled Indian adolescent girls aged 10-18, vitamin B12 deficiency was defined as a serum vitamin B12 level < 200 pmol/l. In that study macrocytosis was prevalent in 10% of 290 subjects with Vitamin B12 deficiency . The sensitivity and specificity of macrocytosis to screen out vitamin B12 deficiency amounted to 10.14%, with a specificity of 92.8%. Positive predictive value amounted to 65.91%, with a negative predictive value of 43.01% [3].
These observations have been replicated in other populations as follows:-
A prospective study which enrolled female Chinese vegetarians utilised both subnormal serum vitamin B12 levels and raised methyl malonic acid (MMA) levels as markers of of vitamin B12 deficiency. Although the lower limit of normal in the assay was a serum vitamin B12 level of 187 pmol/L, a serum vitamin B12 level < 150 pmol/l was the one defined as being indicative of vitamin B12 deficiency. The combination of serum B12 < 150 pnol/L and raised MMA was the defining feature of definite vitamin B12 deficiency in that study. Macrocytosis was documented in only 16% of subjects with definite vitamin B12 deficiency[4].
In a Canadian study macrocytosis was documented in only 12.5% of 96 subjects with vitamin B12 deficiency anaemia[5].
A systematic review of the diagnostic value of macrocytosis (MCV > 100 fl) for vitamin B12 deficiency, both in anaemic and in nonanaemic subjects, generated a 17% prevalence of macrocytosis in vitamin B12 deficient subjects but this increased to 30% prevalence in the anaemic subgroup of vitamin B12 deficient subjects[6].
Microcytosis can also be a feature of vitamin B12 deficiency[2],[6], especially when the underlying cause is autoimmune gastritis[7]. In Hershko et al, among 160 patients with autoimmune gastritis, 29 had macrocytosis (MCV > 100 fl), 48 had a normocytic haematological profile (MCV 80-100 fl), and 83 had microcytosis (MCV < 80 fl). All 29 of the patients with macrocytosis had vitamin B12 deficiency.
Among the 48 with a normocytic profile, 44 (92%) were vitamin B12 deficient.
Among the 83 with microcytic profile 38 (46%) were vitamin B12 deficient[7].
Accordingly, “MCV should not be the only criterion to order vitamin B12[measurement] for anemia under evaluation”[2].
I have no conflict of interest
References
[1] Wolffenbatel B et al. Vitamin B12. BMJ 2023;383: e071725
[2] Jain R., Kapil M., Gupta GN. MCV should not be the only criterion to order vitamin B12 for anemia under evaluation. Open Journal of Gastroenterology 2012;2:187-190
[3] Patel S., Dhupar P., Bjattar A. Diagnostic accuracy of mean corpuscular volume in delineating vitamin B12 deficiency. Annals of Clinical Laboratory Research 2017. ISSN 2386-5180. DOI:10.21767/2386-5180.1000195
[4] Kwok T., Cheng G., Woo J., Lai WK., Pang CP. Independent effect of vitamin B12 deficiency on hematological status in older Chinese vegetarian women. Am J Hematol 2002;70:186-190
[5] Gupta M., Copley K., Keeney M., Chin-Yee I. Does cell size matter? Utilizing mean cell volume as a screen to determine common causes of anemia including iron deficiency anemia, vitamin B12 and folate deficiency
Blood 2016;128:2338
[6] Oosterhuis WP., Niessen RWL., Bossuyt PMM., Sanders GTB., Sturk A. Diagnostic value of the mean corpuscular volume in the detection of vitamin B12 deficiency. Scandinavian Journal of Clinical and Laboratory Investigation 2000;60:9-18
[7] Hershko C., Ronson A., Souroujon M et al. Variable hematological presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion. Blood 2006;107:1673-1679
Re: Vitamin B12 and the association with macrocytosis, normocytic features, and microcytosis, respectively