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PILOT STUDY OF PIOGLITAZONE IN NONALCOHOLIC STEATOHEPATITIS
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Insulin resistance is common in patients with nonalcoholic steatohepatitis (NASH) and may be involved in the pathogenesis of this disease. Promrat and colleagues reported the results of pilot study at DDW (May, 2003) using pioglitazone (insulin-sensitizing agent in nondiabetic patients with histologic features of NASH (non-alcoholic steatosis hepatitis).
The purpose of the study was to determine if 1 year of treatment with the insulin sensitizing agent, pioglitazone will reduce hepatic steatosis, inflammation and fibrosis in patients with NASH.
Twenty patients (9 men) with biopsy-proven NASH without diabetes were treated with 30 mg of pioglitazone daily for 48 weeks. Medical evaluation and liver biopsy were performed before and at the end of treatment. Insulin sensitivity was assessed by oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Liver histology was scored for degree of steatosis, cellular injury, parenchymal and portal inflammation, Mallory bodies and fibrosis.
Nine patients have completed 48 weeks of treatment. Serum ALT decreased in all 9 and were normal in 7 (78%) at 48 wks; mean ALT decreasing from 90.6 to 34 U/L . Insulin sensitivity also improved with decreases in fasting insulin from 18.4 to 10.6 mIU/ml, C-peptide from 5.5 to 3.3ng/ml, and free fatty acids from 815.8 to 597.5 mEQ/L..
Also improved were estimates of insulin sensitivity including QUICKI (0.32 to 0.34), HOMA-IR (Homeostasis model assessment- insulin resistance index) (3.72 to 2.50) and insulin sensitivity derived from FSIGT (1.18 to 2.65 x 10-4 min-1._U-1.ml-1).
End-of-treatment liver biopsies showed significant improvements in steatosis, Mallory bodies and parenchymal inflammation. Fibrosis (0-4) improved from 2.3 to 1.8 P=0.10). Steatosis improved from 2.1 to 1.1 (p=0.02). Mallory bodies (0-4) improved from 2.1 to 1.1 (p=0.04). Parenchial inflammation (0-4) improved from 2.6 to 1.4 (p=0.05). Portal inflammation (0-4) improved from 2.0 to 1.8 p=0.58).
Five (56%) patients had improvements in at least three features of steatohepatitis. None had worsening of liver histology or fibrosis. The main side effect of pioglitazone was weight gain, which averaged 3.5 kg. All patients had increased total body fat by DEXA (31.7 to 33.7%, p=0.01), even among those who lost weight.
The authors concluded that in non-diabetic patients with NASH, a 48-week course of pioglitazone was associated with significant improvements in insulin sensitivity, serum ALT and histologic features of NASH but induced gain in adiposity.
Promrat K, Lutchman G, Kleiner DE, et al. Pilot study of pioglitazone in nonalcoholic steatohepatitis. Gastroenterology. 2003;124:A-708. DDW Conference, May 17-22, 2003, Orlando, FL [Abstract #334]
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