Impact of Evolutionary Changes in Nonalcoholic Fatty Liver Disease on Lung Function Decline

Background/Aims: A relationship between fatty liver and lung function impairment has been identified, and both are independently associated with metabolic dysfunction. However, the temporal relationship between changes in fatty liver status and lung function and their genome-wide association remain unclear. Methods: This longitudinal cohort consisted of subjects who received serial health check-ups, including liver ultrasonography and spirometry, for >= 3 years between 2003 and 2015. Lung function decline rates were classified as "slow" and "accelerated" and compared among four different sonographic changes in steatosis status: "normal," "improved," "worsened," and "persistent." A genome-wide association study was conducted between the two groups: normal/improved steatosis with a slow decline in lung function versus worsened/persistent steatosis with an accelerated decline in lung function. Results: Among 6,149 individuals, the annual rates of decline in forced vital capacity (FVC) and forced expiratory volume measured in the first second of exhalation (FEV1) were higher in the worsened/persistent steatosis group than in the normal/improved steatosis group. In multi-variable analysis, persistent or worsened status of fatty liver was significantly associated with accelerated declines in FVC (persistent status, odds ratio [OR]=1.22, 95% confidence interval [CI]=1.04-1.44; worsened status, OR=1.30, 95% CI=1.12-1.50), while improved status of fatty liver was significantly associated with slow declines in FEV1 (OR=0.77, 95% CI=0.64-0.92). The PNPLA3 risk gene was most strongly associated with steatosis status change and accelerated declines in FVC (rs12483959, p=2.61x10(-7)) and FEV1 (rs2294433, p=3.69x10(-8)). Conclusions: Regression of fatty liver is related to lung function decline. Continuing efforts to improve fatty liver may preserve lung function, especially for subjects with a high genetic risk.