Non-alcoholic fatty liver disease: beyond the liver is an emerging multifaceted systemic disease

Non-alcoholic fatty liver disease (NAFLD) has become the most frequent liver disease in the world and is characterized by an accumulation of intrahepatic triglycerides above 5% of hepatocytes in the absence of significant alcohol use and other causes recognized to induce fatty liver (1). Its prevalence is increasing, reflecting the global epidemic of obesity and type 2 diabetes (T2D). Although NAFLD occurs in all age groups, its peak is observed in individuals over 60 years of age. Men are more likely to develop NAFLD, but this predisposition disappears in diabetic patients (2). In the general population, the prevalence of NAFLD is reported in a wide range from 6.3% to 51%, with an average global prevalence of 25% (3). This wide variability depends on the diagnostic method used and the population and ethnic group studied. Ultrasonography, the most frequently used diagnostic tool, is operator-dependent and less sensitive than MR spectroscopy, which is expensive and not available in all facilities. Furthermore, the occurrence of NAFLD varies in different countries, with the highest prevalence reported in the Middle East and South America and the lowest in Africa (3); in Europe and the United States it is reported in 25–30% of subjects (3). However, the prevalence of NAFLD increases up to 80–90% in cohorts of subjects with dysmetabolic conditions such as overweight/obesity, T2D and metabolic syndrome (MetS) (2), emphasizing the primary role of metabolic factors in its development. It has been shown that NAFLD occurs in 10–15% of normal-weight subjects (4) in whom the disease can remain undiagnosed over a long period of time. Recent studies have shown that even lean subjects with NAFLD have excess visceral adiposity and some features of MetS (4), and such patients are often referred to as “metabolically obese, normal weight”