Background and Aims: Little is known about the role of low-carbohydrate diets (LCDs) in the development of hepatocellular carcinoma (HCC). We prospectively evaluated the associations between plant-based and animal-based LCDs and risk of HCC in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Approach and Results: Dietary intake was assessed every 4 years using validated food frequency questionnaires. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). HRs are shown for a 1-standard deviation (SD) increment with variables modeled as continuous. During 3,664,769 person-years of follow-up, there were 156 incident HCC cases. Although there were no associations between overall or animal-based LCD score and risk of HCC, plant-based LCD score was inversely associated with HCC risk (HR, 0.83; 95% CI, 0.70-0.98; Ptrend = 0.03). Carbohydrate intake, especially from refined grains (HR, 1.18; 95% CI, 1.00-1.39; Ptrend = 0.04), was positively, while plant fat (HR, 0.78; 95% CI, 0.65-0.95; Ptrend = 0.01) was inversely associated with HCC risk. Substituting 5% of energy from plant fat and protein for carbohydrate (HR, 0.74; 95% CI, 0.58-0.93; Ptrend = 0.01) or refined grains (HR, 0.70; 95% CI, 0.55-0.90; Ptrend = 0.006) was associated with lower HCC risk. In conclusion, a plant-based LCD and dietary restriction of carbohydrate from refined grains were associated with a lower risk of HCC. Substituting plant fat and protein for carbohydrate, particularly refined grains, may decrease HCC incidence. Conclusions: Our findings support a potential benefit in emphasizing plant sources of fat and protein in the diet for HCC primary prevention; additional studies that carefully consider hepatitis B and C virus infections and chronic liver diseases are needed to confirm our findings.
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