Visceral adiposity: a key driver of non-alcoholic fatty liver disease

Liver fat accumulation/non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition and has become a major cause of liver failure. Imaging studies have shown that excess liver fat is frequently accompanied by an excess of abdominal visceral adipose tissue. Excess visceral adiposity is associated with an increased risk of type 2 diabetes and cardiovascular disease. Although NAFLD is clearly a risk factor for type 2 diabetes, whether excess liver fat increases cardiovascular disease risk independently of excess visceral adiposity remains uncertain.

As an approach to get further insight into the causality of these associations, a team of investigators led by Dr. Benoit Arsenault at the Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec – Université Laval has performed Mendelian randomization analyses and the results were published in Communications Medicine. Mendelian randomization can be viewed as a randomized control trial where subjects are naturally randomized based on the absence or presence of genetic variants affecting traits such as abdominal adiposity or liver fat. Previous Mendelian randomization studies had suggested that subjects with genetic variants related to high levels of abdominal adiposity (as estimated by the waist-to-hip ratio) were at increased risk of type 2 diabetes and coronary artery disease. Whether similar findings would be observed for NAFLD was not known.

Using the available genome-wide association study summary statistics of the UK Biobank (n=461,460) and of NAFLD (8434 cases and 770,180 controls), a multivariable Mendelian randomization approach showed that waist circumference was associated with the risk of NAFLD even after control for the body mass index (BMI) whereas the BMI per se did not increase NAFLD risk after control for waist circumference. Furthermore, in multivariable Mendelian randomization analyses accounting for liver fat, waist circumference was strongly associated with type 2 diabetes and coronary artery disease.

Thus, this analytical approach provides further evidence that people who inherit gene variants associated with increased visceral adiposity are at increased risk of developing NAFLD. These results also show the major limitation of using BMI to document the association between obesity and various health outcomes such as liver fat, type 2 diabetes and coronary artery disease. A paradigm shift is therefore needed to properly assess the health risk associated with increased adiposity.