LAUSR

BACKGROUND & AIMS Obesity in adulthood has been associated with increased risk of liver-related mortality. Whether higher levels of physical activity counteract the excess risk conferred by obesity remains unknown. We simultaneously evaluated the long-term impact of physical activity and adiposity on liver-related mortality, within two nationwide populations. METHODS We conducted a prospective cohort study of 77,238 women and 48,026 men, with detailed, validated assessments of weekly physical activity (metabolic equivalent task [MET]-hours]), adiposity (body mass index [BMI], waist circumference), and diet, alcohol use and clinical comorbidities, biennially from 1986 through 2012. Using Cox proportional hazards regression models, we calculated multivariable adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for liver-related mortality, including death from hepatocellular carcinoma (HCC) and other cirrhosis complications. RESULTS Over 1,856,226 person-years, we recorded 295 liver-related deaths (108 HCC; 187 cirrhosis). Risk of liver-related mortality increased monotonically with higher BMI during adulthood (Ptrend<0.0001) and with weight gain during early-adulthood (Ptrend<0.0001). The risk of liver-related mortality also declined progressively, with increasing physical activity (Ptrend=0.0003); the aHRs across increasing physical activity quintiles were: 1.0, 0.70 (95%CI=0.51-0.96), 0.59 (95%CI=0.42-0.84), 0.52 (95%CI=0.36-0.74) and 0.46 (95%CI=0.31-0.66). Compared to lean-active adults (BMI<25; ≥18 MET-hours/week), the aHRs for obese-active, lean-sedentary, and obese-sedentary adults were: 1.04 (95%CI=0.73-1.37), 2.08 (95%CI=1.21-3.33) and 3.40 (95%CI=2.06-5.56), respectively. Findings were similar for HCC-specific and cirrhosis-specific mortality. Overall, engaging in average-pace walking for >3 hours/week could have prevented 25% of liver-related deaths (95%CI=0.12-0.38). CONCLUSIONS In two prospective, nationwide cohorts, both excess adiposity and reduced PA were significant predictors of liver-related mortality. Achieving higher PA levels counteracted the excess liver-related risks associated with obesity.