Associations between source-specific nitrate and nitrite intakes and metabolic dysfunction-associated steatotic liver disease in two prospective cohorts

Background and Aims<br/>Dietary nitrate and nitrite may have source-dependent effects on liver health: plant-sourced nitrate may confer hepatoprotective benefits via its conversion to nitric oxide, whereas nitrate and nitrite from animal foods, processed meats, or contaminated drinking water may promote liver injury via their conversion to N-nitrosamines. We aimed to examine associations between source-specific nitrate and nitrite intakes and incident metabolic dysfunction-associated steatotic liver disease (MASLD) in two large cohorts. Secondary aims were to assess associations with liver MRI biomarkers and to evaluate whether nitric oxide-pathway gene variants modify associations with plant-sourced nitrate/nitrite.<br/>Methods<br/>We analysed 53,854 participants from the Danish Diet, Cancer and Health (DCH) cohort and 197,198 from the UK Biobank. Source-specific nitrate and nitrite intakes were estimated using food frequency questionnaires (DCH) and 24-hour dietary assessments (UK Biobank) in combination with food composition databases and national water quality data. Associations with incident cases of severe MASLD—identified from hospital records—were examined using multivariable-adjusted Cox models, with fixed-effects meta-analysis. In the UK Biobank, analyses were stratified by nitric oxide pathway variants, and associations with liver imaging biomarkers were assessed using generalised regression models.<br/>Results<br/>Over 25.1 years (DCH) and 13.5 years (UK Biobank), 166 and 1,768 participants developed MASLD, respectively. Moderate plant-sourced nitrate intake was associated with lower MASLD rates [pooled HRQ3vsQ1 (95%CI): 0.84 (0.76-0.94)] with similar patterns for plant- and vegetable-sourced nitrite. No association was observed for animal-sourced nitrate, whereas higher intakes of animal-sourced nitrite [HRQ5vsQ1: 1.23 (1.09-1.39)] and additive permitted meat-sourced nitrate [HR T3vsT1: 1.21 (1.05-1.38)] were associated with higher rates. Plant nitrate intake was associated with more favourable liver imaging biomarkers, while animal- and additive-sourced exposures were linked to less favourable profiles. Protective associations of plant-sourced nitrate and nitrite were modified by nitric oxide pathway genetic variants.<br/>Conclusion<br/>The health impact of nitrate and nitrite depends on source: moderate plant-sourced intakes (∼1 cup baby spinach/day) were linked to lower MASLD rates, while higher intakes from animal and additive sources were associated with higher rates.