Abstract
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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a considerable public health concern, and is the commonest cause for chronic liver disease in the developed world [1,2]
In addition to this there are recognised situations whereby there is an apparent disconnect between NAFLD and insulin resistance/metabolic syndrome features, and these generally arise as a result of particular genetic polymorphisms such as in the patatin-like phospholipase domain-containing protein-3 (PNPLA3) gene
It is clear from the literature that there is a complicated causal relationship between NAFLD and the metabolic syndrome
Summary
Non-alcoholic fatty liver disease (NAFLD) is a considerable public health concern, and is the commonest cause for chronic liver disease in the developed world [1,2]. There is a growing body of evidence supporting the idea that there is a bidirectional relationship between NAFLD and features of the metabolic syndrome, with insulin resistance being the central pathophysiological process common to both conditions. A recent study has demonstrated a reciprocal causality between NAFLD and metabolic syndrome in a Chinese population, with metabolic syndrome being found to have a greater effect on incident NAFLD in terms of causality than NAFLD does on incident metabolic syndrome [9] In addition to this there are recognised situations whereby there is an apparent disconnect between NAFLD and insulin resistance/metabolic syndrome features, and these generally arise as a result of particular genetic polymorphisms such as in the patatin-like phospholipase domain-containing protein-3 (PNPLA3) gene. This review will attempt to review the available evidence regarding the bidirectional relationship between NAFLD and components of the metabolic syndrome, as well as to explore the potential disconnects that may exist between the two due to genetic variability and inherited metabolic disease
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