Apoptosis and Disease Severity is Associated with Insulin Resistance in Nonalcoholic Fatty Liver Disease

Background & Aims : Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR). We evaluated whether IR contributes to hepatocyte apoptosis, inflammation, and fibrosis in NAFLD. Methods : Forty-four teetotaller patients with biopsy-proven diagnosis of NAFLD were enrolled. Twenty-eight NAFLD patients with IR were compared with 16 subjects without IR. For apoptotic activity caspase 3 and 8, transcription nuclear factor kB (NFkB), and anti-apoptotic Bcl-2 protein were determined through immunohistochemical methods. Results : HOMA-IR index was significantly correlated with the stage and caspase 3- and 8 levels (p= 0.001, 0.02, and 0.01, respectively). HOMA-IR index was independently associated with the severity of fibrosis (beta = 5.9, p = 0.001), caspase-3 (beta = 0.16 , p = 0.001), and caspase-8 (b = 0.032, p = 0.018) levels. TNF-sRp55 level was positively correlated with HOMA-IR index (p = 0.024). Patients with IR had significantly higher necroinflammatory grade, stage, caspase-3, and caspase-8 levels than those without IR (p = 0.022, 0.007, 0.031, and p = 0.011, respectively). HOMA-IR index had statistically significant values for distinguishing of severe necroinflammatory grade, stage and for differentiating NASH from simple fatty liver (AUC = 0.78, 0.76, and 0.82, respectively). Conclusion : This study demonstrates that IR in NAFLD is associated with enhanced hepatocyte apoptosis and histopathologic disease severity. These data indicate that NAFLD patients with IR may have increased risk for disease progression.