Although the independent roles of T2D, IR, and the several polymorphisms in the pathogenesis and natural history of NASH have been widely investigated [22], to the best of our knowledge, there are no reports addressing the interaction of PNPLA3 and TM6SF2 gene variants with T2D and IR in the pathophysiology of NASH and their role in advanced liver fibrosis. This evidence concerns the gene PNPLA3 and metabolic dysfunction-associated steatohepatitis.