Risk Assessment in Non-Alcoholic Fatty Liver Disease: From Human Genetics to Novel Blood-Based Biomarkers

Paralleling the epidemics of obesity and type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease worldwide. Most individuals remain asymptomatic for long periods of time with slowly progressive disease, but a minority progress to cirrhosis, liver failure, and hepatocellular carcinoma. In this scenario, the identification of risk factors for liver disease progression is crucial. Additionally, given the huge number of individuals at high risk for NAFLD and the invasiveness of liver biopsy, accurate and affordable non-invasive strategies to screen for liver disease are urgently needed. In Paper I, we investigated the individual contribution of inborn and acquired risk factors for the development of severe liver disease (cirrhosis, decompensated liver disease, hepatocellular carcinoma, liver transplantation) in 22,812 Europeans with type 2 diabetes from the prospective UK Biobank study. Abnormal AST, decrease in serum albumin and platelet count, cardiovascular disease, microalbuminuria, and genetic variants in PNPLA3 and TM6SF2 genes were found to be the major independent risk factors for incident severe liver disease. In Paper II, we developed and validated the Fibrotic NASH Index (FNI), an accurate, simple, and affordable non-invasive score based on routine laboratory tests (AST, HDL cholesterol, HbA1c) to screen for fibrotic NASH in individuals with metabolic risk factors in primary healthcare and diabetology/endocrinology clinics. The derivation cohort included 264 morbidly obese individuals undergoing intraoperative liver biopsy in Rome, Italy. External validation was assessed in three independent European cohorts (Finland, n=370; Italy n=947; England n=5,368) of individuals at high risk for NAFLD. The model was developed using a bootstrapping stepwise logistic regression analysis. Performance was satisfactory in both derivation and external validation cohorts (AUROCs 0.78 and 0.80-0.95, respectively). In conclusion, these findings may contribute in clinical care to identify individuals at risk for severe liver disease, in turn leading to personalised risk prediction and prevention strategies.