The independent and joint associations of vitamin B12 and methylmalonic acid on the risk of mortality in individuals with metabolic dysfunction-associated steatotic liver disease

Purpose To investigate the independent and joint associations of vitamin B12 and methylmalonic acid (MMA) with all-cause, cardiovascular disease (CVD), and cancer mortality in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods We included 6797 individuals with MASLD from the U.S. National Health and Nutrition Examination Survey. Serum MMA was measured using gas/liquid chromatography-mass spectrometry. Serum vitamin B12 was measured using commercial kits. The separate and joint associations of dietary intake and serum vitamin B12 (cutoff: 400 pg/mL) and MMA (cutoff: 250 nmol/L) levels with mortality were assessed by Cox proportional hazards regression. Results During a median follow-up of 9.3 years, 1604 deaths were documented, including 438 from CVD and 365 from cancer. In MASLD patients, dietary intake and serum vitamin B12 did not associate with mortality, while MMA was associated with a 1.35-fold increased risk of all-cause mortality (P-trend < 0.001). The adjusted hazard ratios for the joint association of vitamin B12 and MMA with all-cause and CVD mortality were 1 in the B12(low)MMA(low) group (reference), 1.02 (0.87-1.20) and 1.15 (0.90-1.47) in the B12(high)MMA(low) group, 1.55 (1.29-1.86) and 1.84 (1.28-2.65) in the B12(low)MMA(high) group, and 1.82 (1.49-2.21) and 2.28 (1.40-3.71) in the B12(high)MMA(high) group, respectively. The joint association was modified by serum folate (P-interaction = 0.001). Conclusions In MASLD patients, MMA rather than dietary and serum vitamin B12 was positively associated with all-cause mortality. The joint effect of high levels of MMA and vitamin B12 showed the strongest associations with all-cause and CVD mortality, with a significant interaction with serum folate.