Metabolic and genetic determinants for progression to severe liver disease in subjects with obesity from the UK Biobank

Background Obesity is among the main determinants of nonalcoholic fatty liver disease progression towards severe liver disease (SLD). However, risk factors for SLD in individuals with obesity have not been examined. Objectives To identify the independent risk factors for SLD among participants with obesity from the UK Biobank. Methods A total of 80,224 UK Biobank participants with obesity (body mass index[BMI] > 30 kg/m(2)) and 242,822 without obesity, of European descent without clinical history of liver disease and liver cancer were prospectively followed for the onset of SLD, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma and/or liver transplantation. Risk factors for incident SLD were assessed by Cox proportional hazards models. Different clinical phenotypes were derived by latent class analysis (LCA). Results Obesity conferred a 2.6-fold increased risk for SLD that was abolished after the inclusion of waist circumference (WC) in the model. Among individuals with obesity, age (adjusted hazard ratio [aHR] 1.05, 95%CI 1.03-1.07, p = 3.9 * 10(-7)), type 2 diabetes (aHR 2.18, 95%CI 1.55-3.05, p = 6.2 * 10(-6)), PNPLA3 rs738409 (aHR 1.59, 95%CI 1.33-1.9, p = 3.1 * 10(-7)) and WC (aHR 1.04, 95%CI 1.02-1.06, p = 8.5 * 10(-6)) were independent predictors of SLD. BMI category-specific WC thresholds allowed a better risk stratification compared to traditional ones. By LCA, the clinical phenotype at highest risk for SLD was that with BMI < 35 kg/m(2) and WC above BMI-category specific thresholds. Conclusions Age, WC, type 2 diabetes, and the PNPLA3 variant are the main risk factors for SLD in individuals with obesity. WC is the principal mediator of SLD risk conveyed by increased BMI. BMI category-specific WC-thresholds may refine the SLD risk more accurately than traditional thresholds.