Steatosis and steatohepatitis: complex disorders

Abstract

Non-alcoholic fatty liver disease (NAFLD) which includes steatosis and steatohepatitis, in particular non-alcoholic steatohepatitis (NASH), is a rising health problem world-wide and should be separated from alcoholic steatohepatitis (ASH). NAFLD is regarded as hepatic manifestation of the metabolic syndrome (MetSy), being tightly linked to obesity and type 2 diabetes mellitus (T2DM). Development of steatosis, liver fibrosis and cirrhosis often progresses towards hepatocellular carcinogenesis and frequently results in the indication for liver transplantation, underlining the clinical significance of this disease complex. Work on different murine models and several human patients studies led to the identification of different molecular key players as well as epigenetic factors like miRNAs and SNPs, which have a promoting or protecting function in AFLD/ASH or NAFLD/NASH. To which extent they might be translated into human biology and pathogenesis is still questionable and needs further investigation regarding diagnostic parameters, drug development and a better understanding of the genetic impact. In this review we give an overview about the currently available knowledge and recent findings regarding the development and progression of this disease.

Figure 1

Schematic illustration of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) progression. A lifestyle with a balanced diet, moderate alcohol consumption and regular exercise supports the maintenance of an intact liver function. The intake of high energy food, less exercise and/or enhanced drinking of alcohol (light blue rectangle and arrow) leads to increased amounts of triglycerides (TG) in the liver which are stored as lipid droplets (yellow dots). Over time the degree of fatty change might reach an extent of hepatic steatosis. Concomitant effects like insulin resistance, obesity, type 2 diabetes mellitus (T2DM) and hyperlipidemia have a promoting effect (red arrows). It is under debate if the development of steatosis and NAFLD/NASH is the result of a “two” or “multiple hit event’’ (red rectangle). Adipocytokines, endoplasmic reticulum (ER) stress, endotoxins from gut bacteria, reactive oxygen species (ROS) and epigenetic modifications (dark blue rectangle and arrows) are potential mediators promoting the development from hepatic steatosis to steatohepatitis and liver fibrosis and/or cirrhosis. Under physiological conditions fatty acid metabolism is tightly controlled by antagonists such as adiponectin and antioxidants (green rectangle and arrows) which are involved in insulin tolerance, glucose consumption and fatty acid oxidation as well as in elimination of ROS.