Analysis Says Excessive Vitamin B12 Concentration Can Increase Mortality Risk

Researchers have discovered a positive association between serum vitamin B₁₂ concentration and all-cause mortality risk, especially among older adults. Additionally, while vitamin B₁₂ deficiency has been previously linked to increased risk of cardiovascular disease and cancer, current evidence regarding the correlation between serum vitamin B₁₂ concentration and cardiovascular mortality was mixed, and there was limited research available on its link with cancer mortality, leading to inconclusive findings for these risks.

These findings are based on a comprehensive dose-response meta-analysis published in Archives of Gerontology and Geriatrics, which looked at 22 cohort studies encompassing 92,346 individuals with 10,704 all-cause deaths.

Vitamin B12 | Image credit: Katsiaryna Hatsak – stock.adobe.com

The analysis revealed that for every 100 pmol/L increase in serum vitamin B₁₂ concentration, there was a 4% higher risk of all-cause mortality in the general population and a 6% higher risk in older adults. The meta-analysis also indicated a positive correlation between high serum vitamin B₁₂ concentration (>600 pmol/L) and all-cause mortality, as well as cardiovascular mortality. Serum vitamin B₁₂ concentrations ranging from 400 to 600 pmol/L were also associated with increased all-cause mortality. However, there was no significant association found between serum vitamin B₁₂ concentration and cancer mortality.

The findings indicate varying associations between serum B₁₂ concentrations and all-cause mortality risk. Serum B₁₂ levels below 200 pmol/L or within the range of 200-400 pmol/L did not show significant associations with increased mortality risk. However, concentrations ranging from 400-600 pmol/L were linked to a significantly higher risk of all-cause mortality, with a similar trend observed for levels exceeding 600 pmol/L.

Subgroup analyses based on patient type revealed no heterogeneity for lower concentration segments but showed significant heterogeneity for higher segments, with inpatients exhibiting a higher mortality rate than outpatients. Additionally, analysis based on the source of vitamin B₁₂ revealed higher mortality rates associated with supplemental B₁₂ intake in the <200 pmol/L segment, while no significant heterogeneity was observed across different concentration segments.

“Because the reference range for vitamin B₁₂ is between 200 and 1000(pg/ml), high B₁₂ levels may not always be associated with worse prognosis, depending on the underlying cause (new studies designed for are necessary),” the authors said. “In addition, we stratify the included studies based on the source of vitamin B₁₂ (dietary intake or supplements). Our results suggest that for concentrations less than 200 pg/ml, vitamin B₁₂ from supplements may increase all-cause mortality, but not from diet.”

The association between elevated vitamin B₁₂ levels and mortalities lacks clear mechanistic explanations, but the authors proposed several hypotheses. Liver dysfunction may contribute, as it affects B₁₂ metabolism and can lead to increased circulating B₁₂ levels. Additionally, conditions such as chronic renal failure or genetic polymorphisms may influence vitamin B₁₂ transporters and contribute to elevated serum levels, potentially exacerbating risks for cardiovascular diseases and cancers. Subgroup analyses revealed heterogeneity between outpatient and inpatient populations, with higher mortality rates associated with elevated B₁₂ levels particularly in inpatients, possibly due to underlying conditions like hepatic insufficiency or chronic renal failure.

The source of vitamin B₁₂, whether from dietary intake or supplements, may influence mortality risk. While low levels of supplementation (<200 pg/ml) were associated with increased mortality, dietary sources did not show the same effect. However, for concentrations exceeding 400 pg/ml, dietary intake of vitamin B₁₂ was linked to higher mortality rates, possibly due to associated factors like cardiovascular disease or obesity, which are often linked to diets rich in food containing vitamin B₁₂. These findings highlight the complexity of vitamin B₁₂'s role in health outcomes and suggest the need for further research, particularly in understanding its relationship with mortality risk across different patient populations and dietary sources.

This meta-analysis has several limitations worth noting. First, the included studies were observational and deemed low quality by the analysis authors, leaving room for residual confounders that were not fully accounted for. Second, there was significant heterogeneity among the studies, likely due to variations in population characteristics and statistical methods employed across different studies. Despite attempts to adjust for these differences, moderate to high heterogeneity persisted, though subgroup and sensitivity analyses largely corroborated the main findings, mitigating the impact of heterogeneity. Additionally, as this was a research-level meta-analysis rather than an individual patient-level analysis, more detailed subgroup analyses were not feasible.

Reference

Liu K, Yang Z, Lu X, et al. The origin of vitamin B₁₂ levels and risk of all-cause, cardiovascular and cancer specific mortality: A systematic review and dose-response meta-analysis. Arch Gerontol Geriatr. 2024;117:105230. doi:10.1016/j.archger.2023.105230