Elevated Serum Vitamin B12 Concentrations Are Nonlinearly Associated with Cancer Incidence and All-Cause Mortality: A retrospective analysis of the global multi-institutional cohort study.

Background

Serum vitamin B12 is among the most frequently ordered laboratory tests, and both low and high concentrations have been linked to cancer and mortality. However, the full dose-response shape and the contribution of reverse causation remain unclear.

Objective

We aimed to characterize the dose-response shape and temporal structure of the associations of serum vitamin B12 with cancer incidence and all-cause mortality.

Methods

We conducted a retrospective propensity score-matched cohort study of 3,950,497 adults from the TriNetX Global Collaborative Network (169 healthcare organizations, 19 countries, 2006-2020). Adults were classified into six baseline serum B12 strata, with the 400-600 pg/mL stratum as the reference. Overall cancer incidence and all-cause mortality were assessed over 10 years. Dose-response, time-stratified, landmark, subgroup, and negative control analyses were performed to address reverse causation.

Results

Overall cancer incidence increased modestly above the reference (adjusted hazard ratio [aHR] 1.05-1.08), with no association in the deficiency range. All-cause mortality followed a J-shaped pattern, with elevations at both extremes. The elevated-end cancer association attenuated to near-null after excluding the first two years of follow-up (>1,000 pg/mL: aHR 1.07 to 1.02), whereas the deficiency-end mortality association showed the least attenuation (<200 pg/mL: aHR 1.26 at 1 year to 1.18 at 10 years).

Conclusions

Cancer incidence was modestly higher at elevated serum vitamin B12 concentrations but attenuated after exclusion of early events, whereas the mortality association at deficiency-range concentrations persisted. These observational findings do not justify discontinuing clinically indicated vitamin B12 therapy.