Tumor necrosis factor α promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease

Background & Aims: Nonalcoholic fatty liver disease, which can range from fatty liver alone to nonalcoholic steatohepatitis and cirrhosis, is related to insulin resistance. Tumor necrosis factor α (TNF-α) may induce insulin resistance, and polymorphisms of its promoter have been associated with an increased release of this cytokine. We analyzed (1) the prevalence of insulin resistance, (2) the prevalence of the 238 and 308 TNF-α polymorphisms, and (3) the relationship among TNF-α polymorphisms, insulin resistance, and the occurrence of steatohepatitis in 99 patients with nonalcoholic fatty liver diagnosed by ultrasonography and confirmed by histologic analysis in the 53 who underwent biopsy. Methods: Insulin resistance was evaluated by the homeostatic metabolic assessment insulin resistance indices and TNF-α polymorphisms by polymerase chain reaction and restriction fragment length polymorphism analysis. Results: Insulin resistance was detected in almost all of the patients and was more severe in those with steatohepatitis. The prevalence of the 238, but not of the 308, TNF-α polymorphism was higher in subjects with nonalcoholic fatty liver than in controls (31% vs. 15%; P <0.0001), and patients positive for TNF-α polymorphisms had higher insulin resistance indices, a higher prevalence of impaired glucose tolerance, and a lower number of associated risk factors for steatosis. Conclusions: TNF-α polymorphisms could represent a susceptibility genotype for insulin resistance, nonalcoholic fatty liver, and steatohepatitis.