Nonalcoholic fatty liver disease: Evolving paradigms

Figure 1 Nonalcoholic fatty liver disease as a pathogenically and clinically heterogeneous condition. Schematic representation of the pathogenic and clinical heterogeneity of different NAFLD populations. Left: “Metabolic” NAFLD is associated with adipose tissue dysfunction and IR and may progress towards hepatic and extrahepatic complications. Right: “Genetic” NAFLD seems to be disconnected from adipose tissue dysfunction and IR, is associated with an increased risk of liver disease progression but is probably spared from extrahepatic complications. NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; HCC: Hepatocellular carcinoma.

Figure 2 Nonalcoholic fatty liver disease pathogenesis: from two to multiple parallel hits. Schematic representation of the increasing grade of complexity gained in moving from earlier theories[27] to more updated pathogenic paradigms[28]. Top: Former “two hits” hypothesis: steatosis, the first ‘hit’, sensitizes the liver to the second “hits”: oxidative stress, endotoxin, ATP depletion and adduct formation[44]. Bottom: The "multiple hits" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include IR, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors[28]. NAFLD: Nonalcoholic fatty liver disease; TLRs: Toll-like receptors.

Figure 3 The closed loop nonalcoholic fatty liver disease-metabolic syndrome circuit. Schematic representation illustrating the mutual cause-and-effect relationship of NAFLD with the Metabolic syndrome[4,31,146,147]. NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis.