Prevalence of Functional Cobalamin Deficiency and Relevant Mortality Risk in the General Population: An Unheeded Phenotype Distinct from Cobalamin Deficiency

Background: Current guidelines prioritize monitoring and managing cobalamin (Cbl) deficiency but insufficiently address the issue of functional Cbl deficiency (decreased Cbl sensitivity). This study aims to investigate the prevalence burden of functional Cbl deficiency and to examine its prospective association with mortality risk, compared to Cbl deficiency, among United States (US) adults. Method: The cohort study included 22,513 US participants aged >= 20 years from 1999 to 2014 and was followed up through December 31, 2019. Cbl sensitivity was assessed using a combination of binary classifications for Cbl and methylmalonic acid (MMA) levels, with cutoff values set at 400 pg/mL for Cbl and 250 nmol/L for MMA. Functional Cbl deficiency was defined as elevated MMA and Cbl levels. Serum Cbl levels <148 pmol/L (200 pg/mL) were classified as Cbl deficiency. Results: In this study, approximately 2.1% of US adults had Cbl deficiency, while the age-adjusted prevalence of functional Cbl deficiency was 4.5%, corresponding to an estimated 10 million US adults. Over a median follow-up period of 10.7 years, there were 4636 recorded deaths. Compared to the MMA(low)Cbl(low) group (MMA <= 250 nmol/L, Cbl <= 400 pg/mL), the multivariable-adjusted hazard ratios for all-cause, cardiovascular, and cancer-related mortality in the MMA(high)Cbl(high) group were 1.76 (95% confidence interval [CI]: 1.53-2.02, p < 0.001), 2.17 (95% CI: 1.78-2.67, p < 0.001), and 1.38 (95% CI: 0.95-2.00, p = 0.089). In contrast, the mortality risk associated with Cbl deficiency became insignificant after adjusting for similar confounders. While Cbl supplementation or dietary intake above recommended levels might alleviate Cbl deficiency, they do not appear to reduce the prevalence of functional Cbl deficiency or its associated mortality risk. Conclusion: Compared with Cbl deficiency, functional Cbl deficiency is more frequent and is significantly associated with increased mortality risk in the general population.