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BACKGROUND: No pharmacologic therapy hasconclusively proved to be effective for the treatment of nonalcoholicsteatohepatitis, which is characterized by insulin resistance, steatosis, andnecroinflammation with or without centrilobular fibrosis. Pioglitazone is athiazolidinedione that ameliorates insulin resistance and improves glucose andlipid metabolism in type 2 diabetes mellitus. METHODS: We randomly assigned 55patients with impaired glucose tolerance or type 2 diabetes and liverbiopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with ahypocaloric diet (a reduction of 500 kcal per day in relation to the calculateddaily intake required to maintain body weight) plus pioglitazone (45 mg daily)or a hypocaloric diet plus placebo. Before and after treatment, we assessedhepatic histologic features, hepatic fat content by means of magnetic resonancespectroscopy, and glucose turnover during an oral glucose tolerance test([14C]glucose given with the oral glucose load and [3H]glucose given byintravenous infusion). RESULTS: Diet plus pioglitazone, as compared with dietplus placebo, improved glycemic control and glucose tolerance (P<0.001),normalized liver aminotransferase levels as it decreased plasma aspartateaminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanineaminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fatcontent (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity(by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared withplacebo, was associated with improvement in histologic findings with regard tosteatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008).Subjects in the pioglitazone group had a greater reduction in necroinflammation(85% vs. 38%, P=0.001), but the reduction in fibrosis did not differsignificantly from that in the placebo group (P=0.08). Fatigue and mildlower-extremity edema developed in one subject who received pioglitazone; noother adverse events were observed. CONCLUSIONS: In this proof-of-conceptstudy, the administration of pioglitazone led to metabolic and histologicimprovement in subjects with nonalcoholic steatohepatitis. Larger controlledtrials of longer duration are warranted to assess the long-term clinicalbenefit of pioglitazone. Leggil'articolo