PERSISTENTLY raised vitamin B12 levels may in some cases be explained by macro B12, potentially reducing the need for invasive investigations such as bone marrow biopsy.
Elevated vitamin B12 concentration can result from supplementation, liver disease, kidney disease, or myeloid malignancies. However, sustained unexplained increases often cause concern and may prompt extensive diagnostic work up. A proposed benign explanation is macro B12, a complex formed by vitamin B12, transcobalamin, and immunoglobulins. Although this complex is not biologically active, it can increase measured plasma vitamin B12 concentrations because of reduced clearance.
Macro B12 As a Cause of Raised Vitamin B12
Researchers evaluated the use of polyethylene glycol precipitation as a laboratory method to support suspicion of macro B12. A clinical case was described in which this approach could potentially have prevented an unnecessary bone marrow biopsy.
The investigators also assessed the presence of macro B12 in patients with and without myeloid malignancy. Among 72 individuals with vitamin B12 concentrations >1476 pmol/L, macro B12 was identified in 24%. In one of these patients, functional vitamin B12 deficiency was confirmed by an elevated methylmalonic acid concentration, indicating that raised total vitamin B12 does not exclude underlying deficiency.
Importantly, macro B12 was not detected in eight patients with a myeloid malignancy, suggesting that the presence of macro B12 may help differentiate benign from malignant causes of raised vitamin B12 in selected clinical contexts.
Implications For Clinical Practice
The findings suggest that in patients with persistently raised vitamin B12 and low clinical suspicion of a myeloid malignancy, polyethylene glycol precipitation may help clarify the cause of the abnormal result. By identifying macro B12 as a benign explanation, clinicians may be able to avoid unnecessary invasive investigations, including bone marrow puncture.
These data support consideration of macro B12 in the differential diagnosis of unexplained vitamin B12 elevation, particularly when other causes have been excluded and the likelihood of haematological malignancy is low.
Reference
Hurkmans EGE et al. Unexplained elevated vitamin B12: consider macro-B12. International Journal of Laboratory Hematology. 2026;0:1-6.
