Bidirectional Relationships and Disconnects Between NAFLD and Features of the Metabolic Syndrome

Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of liver disease from simple steatosis, to steatohepatitis, (both with and without liver fibrosis), cirrhosis and end-stage liver failure. NAFLD also increases the risk of hepatocellular carcinoma (HCC) and both HCC and end stage liver disease may markedly increase risk of liver-related mortality. NAFLD is increasing in prevalence and is presently the second most frequent indication for liver transplantation. As NAFLD is frequently associated with insulin resistance, central obesity, dyslipidaemia, hypertension and hyperglycaemia, NAFLD is often considered the hepatic manifestation of the metabolic syndrome. There is growing evidence that this relationship between NAFLD and metabolic syndrome is bidirectional, in that NAFLD can predispose to metabolic syndrome features, which can in turn exacerbate NAFLD or increase the risk of its development in those without a pre-existing diagnosis. Although the relationship between NAFLD and metabolic syndrome is frequently bidirectional, recently there has been much interest in genotype/phenotype relationships where there is a disconnect between the liver disease and metabolic syndrome features. Such potential examples of genotypes that are associated with a dissociation between liver disease and metabolic syndrome are patatin-like phospholipase domain-containing protein-3 (PNPLA3) (I148M) and transmembrane 6 superfamily member 2 protein (TM6SF2) (E167K) genotypes. This review will explore the bidirectional relationship between metabolic syndrome and NAFLD, and will also discuss recent insights from studies of PNPLA3 and TM6SF2 genotypes that may give insight into how and why metabolic syndrome features and liver disease are linked in NAFLD.