Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Abstract

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.

Keywords: benign condition; cardiovascular risk; disease progression; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis.

Figure 1

Factors contributing to development of NASH or progression of NAFL to NASH. NAFLD develops due to excess calorie intake, which leads to adipose tissue hypertrophy. Adipose tissue confronted with nutrient overload will increase lipolysis and change secretion of adipokines. This altered systemic situation of nutrients, lipids and adipokines, ultimately resulting in NAFLD, is modulated by genetic, epigenetic, environmental and metabolic factors (outer ring). Various molecular and cellular mechanisms (cogs) interact in development of NAFLD and NASH. Abbrevations: ATP: adenosine triphosphate; β-oxidation: beta oxidation of lipid components within mitochondria; DNL: de novo lipogenesis; ER stress: endoplasmatic reticulum stress; FFA: free fatty acids; UPR: unfolded protein response.