Sugar Rationing in the First 1000 Days After Conception and Long-Term Risk of Metabolic Dysfunction-Associated Steatotic Liver Disease and Major Adverse Liver Outcomes: A Natural Experiment Study.
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BACKGROUND & AIMS: The first 1000 days of life are critical for shaping long-term metabolic and organ health. We aimed to evaluate whether sugar restriction during the first 1000 days of life, due to the United Kingdom sugar rationing policy (1942-1953), reduced the risk of metabolic dysfunction-associated steatotic liver disease (MASLD) and related liver outcomes in adulthood. METHODS: We conducted a quasi-natural experiment using UK Biobank data, comparing individuals exposed to sugar rationing in utero and early childhood with those born after rationing ended. Primary outcomes included severe MASLD, major adverse liver outcomes, cirrhosis, and liver cancer, with secondary outcomes assessed by biochemical and imaging biomarkers. Mediation analysis was performed to examine the role of metabolic syndrome traits. RESULTS: Among 63,698 participants, early-life sugar rationing was associated with a 30% reduced risk of MASLD (hazard ratio, 0.70; 95% confidence interval, 0.58-0.85 for in utero plus 1-2 years exposure), 17% lower risk of metabolic dysfunction-associated steatotic liver disease with alcohol consumption, 35% for major adverse liver outcomes, and 32% for cirrhosis. The protective effect increased with longer exposure. Mediation analysis indicated that metabolic syndrome traits explained over 60% of the protective association. Improved liver biomarkers and imaging findings (magnetic resonance imaging-proton density fat fraction reduced by 0.50% and cT1 by 52.2 ms) in the rationed group supported these results. Findings were consistent across genotypes (PNPLA3, TM6SF2) and alcohol intake (metabolic dysfunction-associated steatotic liver disease with alcohol consumption) subgroups. CONCLUSIONS: Early-life sugar restriction during critical developmental windows is associated with lower adult risk of MASLD and liver complications, primarily mediated by improved metabolic profiles. Policy efforts targeting sugar intake in pregnancy and early childhood may provide durable benefits for liver and metabolic health.