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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that is predicted to become also the most frequent indication for liver transplantation by 2030. Over the last decade, it has been shown that the clinical burden of NAFLD is not only confined to liver-related morbidity and mortality, but there is now growing evidence that NAFLD is a multisystem disease, affecting extra-hepatic organs and regulatory pathways. For example, NAFLD increases risk of type 2 diabetes mellitus (T2DM), cardiovascular (CVD) and cardiac diseases, and chronic kidney disease (CKD). Although the primary liver pathology in NAFLD affects hepatic structure and function to cause morbidity and mortality from cirrhosis, liver failure and hepatocellular carcinoma, the majority of deaths among NAFLD patients are attributable to CVD. This narrative review focuses on the rapidly expanding body of clinical evidence that supports the concept of NAFLD as a multisystem disease. The review discusses the factors involved in the progression of liver disease in NAFLD and the factors linking NAFLD with other extra-hepatic chronic diseases, such as T2DM, CVD, cardiac diseases and CKD. The review will not discuss NAFLD treatments as these are discussed elsewhere in this issue of the Journal. For this review, PubMed was searched for articles using the keywords "non-alcoholic fatty liver disease" or "fatty liver" combined with "diabetes", "cardiovascular (or cardiac) disease", "cardiovascular mortality" or "chronic kidney disease" between 1990 and 2014. Articles published in languages other than English were excluded.

RESEARCH DESIGN AND METHODS -In the present study, we compared insulin sensitivity as assessed by a 4-h euglycemic ( 5 mmol/l) hyperinsulinemic ( 300 pmol/l) clamp with HOMA in 115 subjects with various degrees of glucose tolerance and insulin sensitivity.R E S U LT S -We found a strong correlation between clamp-measured total glucose disposal and HOMA-estimated insulin sensitivity (r = 0.820, P 0.0001), with no substantial diff e rences between men (r = 0.800) and women (r = 0.796), younger (aged 50 years, r = 0.832) and older (r = 0.800) subjects, nonobese (BMI 27 kg/m 2 , r = 0.800) and obese (r = 0.765) subjects, nondiabetic (r = 0.754) and diabetic (r = 0.695) subjects, and normotensive ( r = 0.786) and hypertensive (r = 0.762) subjects. Also, we found good agre ement between the two methods in the categorization of subjects according to insulin sensitivity (weighted k = 0.63).C O N C L U S I O N S -We conclude that the HOMA can be reliably used in large-scale or epidemiological studies in which only a fasting blood sample is available to assess insulin sensitivity. r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s Diabetes Care

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NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease).