Nonalcoholic fatty liver disease: Evolving paradigms

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.