One-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study

Deficient intake of micronutrients involved in one-carbon metabolism (eg, choline, methionine, vitamin B₁₂ and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under-investigated in humans. We investigated the association between one-carbon metabolism-related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study. Dietary intakes and supplement use were ascertained at baseline using a food-frequency questionnaire. Total intake (diet plus supplements) of the following one-carbon metabolism-related micronutrients were calculated: folate, methionine and vitamins B₂ (riboflavin), B₃ (niacin), B₆ and B₁₂ . These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16-year follow-up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B₃ intake was associated with a lower HCC risk (HR_{Q5 vs Q1} = 0.60; 95% CI = 0.42-0.85; P_trend = .008), and the association remained significant when all six micronutrients were examined simultaneously (HR_{Q5 vs Q1} = 0.32; 95% CI = 0.18-0.55; P_trend < .0001). Among participants with >3 years of follow-up, higher total vitamin B₃ intake was again associated with lower risk (HR_{Q5 vs Q1} = 0.37; 95% CI = 0.20-0.68; P_trend = .001), whereas higher total vitamin B₆ intake was associated with higher risk (HR_{Q5 vs Q1} = 2.04; 95% CI = 1.02-4.07; P_trend = .04). Restricted cubic spline analyses showed a dose-response inverse association between total vitamin B₃ intake and HCC risk, and dose-response positive association between total vitamin B₆ intake and HCC risk. The study suggests that higher vitamin B₃ intake is associated with lower HCC risk, whereas higher vitamin B₆ intake is associated with increased risk.