Inborn and acquired risk factors for severe liver disease in Europeans with type 2 diabetes from the UK Biobank

Background & Aims: Type 2 diabetes is a major driver of fatty liver disease and its long-term complications. The aim of this study was to investigate the individual contribution of inborn and acquired risk factors for severe liver disease in individuals with type 2 diabetes from the UK Biobank study. Methods: A total of 22,812 UK Biobank participants of European descent without clinical history of liver disease and liver cancer were prospectively followed for the development of severe liver disease, defined as a composite diagnosis of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation from the National Health Service records. The contribution of inborn and acquired risk factors to the risk of incident severe liver disease was assessed by Cox proportional hazards models. Results: During a median follow-up of 8.9 years (IQR 8.1–9.6), there were 279 individuals with severe liver disease, including 255 with cirrhosis and/or decompensated liver disease, 47 with hepatocellular carcinoma, and 5 with liver transplantation; death from severe liver disease occurred in 83 individuals. Risk factors independently associated with increased risk of incident severe liver disease included abnormal aspartate aminotransferase (adjusted hazard ratio [aHR] 4.85, 95% CI 2.76–8.54), decrease in serum albumin (aHR 2.39, 95% CI 1.76–3.24) and platelet count (aHR 1.12, 95% CI 1.09–1.16), cardiovascular disease (aHR 1.86, 95% CI 1.23–2.79), microalbuminuria (aHR 1.55, 95% CI 1.04–2.30), PNPLA3 rs738409 (aHR 1.67, 95% CI 1.27–2.18) and TM6SF2 rs58542926 (aHR 1.63, 95% CI 1.12–2.39), while the net effect of male sex was protective (aHR 0.49, 95% CI 0.26–0.94). Conclusions: These findings may help in clinical care to identify individuals with type 2 diabetes at risk of severe liver disease, in turn leading to personalised risk prediction and prevention strategies. Lay summary: Type 2 diabetes is a key driver of severe liver disease, namely cirrhosis, hepatocellular carcinoma, and liver-related mortality. In Europeans with type 2 diabetes from the prospective UK Biobank study, abnormal liver function, cardiovascular disease, microalbuminuria, and genetic variants in PNPLA3 and TM6SF2 genes are the major independent risk factors for severe liver disease. These findings may contribute in clinical care to identify and closely monitor individuals with type 2 diabetes at risk of developing severe liver disease, requiring more intensive follow-up strategies.