Association of Low Serum Vitamin B12 Concentration with Colorectal Cancer Risk and All-Cause Mortality: A Global Multi-Institutional Retrospective Cohort Study

BACKGROUND: The association between vitamin B12 deficiency and colorectal cancer (CRC) risk remains uncertain. We evaluated the association between low serum vitamin B12 concentration (<200 pg/mL) and CRC incidence and all-cause mortality, using a midrange reference group (400-600 pg/mL). METHODS: In this retrospective propensity score-matched cohort study, adults with serum B12 measurements between 2006 and 2020 were identified from the TriNetX Global Collaborative Network. Patients with any neoplasm diagnosis within 5 years before the index date (first B12 measurement) were excluded. Patients with B12 <200 pg/mL were matched 1:1 to those with 400-600 pg/mL and followed for up to 10 years. Time-stratified, landmark, subgroup, E-value, and outcome-control analyses were performed. RESULTS: After matching, 184,126 pairs were included. Low serum B12 was associated with higher CRC risk (HR 1.16; 95% CI, 1.09-1.23) and all-cause mortality (HR 1.16; 95% CI, 1.14-1.18). The CRC association persisted at the 2-year landmark (HR 1.16; 95% CI, 1.07-1.26) but attenuated at the 3-year (HR 1.07; 95% CI, 0.98-1.18) and 5-year (HR 1.12; 95% CI, 0.99-1.25) landmarks, whereas all-cause mortality remained elevated across all landmarks. The appendicitis negative control was null (HR 0.92; 95% CI, 0.84-1.02), whereas clavicle fracture was weakly positive (HR 1.08; 95% CI, 1.01-1.16). CONCLUSIONS: Low serum vitamin B12 was associated with higher all-cause mortality; its association with CRC was less robust at longer landmarks. IMPACT: The mortality association was more robust; the CRC finding requires prospective confirmation with serial B12 measurements.