A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis

OBJECTIVES: Troglitazone is a thiazolidinedione and peroxisome proliferator -activated receptor gamma (PPAR gamma) ligand used to treat diabetes mellit us type II. Because hyper-insulinemia may be a factor in nonalcoholic steat ohepatitis (NASH), we postulated that troglitazone could have beneficial ef fects in this disorder. Our study was initiated before reports of idiosyncr atic hepatitis induced by this agent and was completed before its recent wi thdrawal from the market. METHODS: We studied 10 female patients (age 44 +/- 16) with histological NA SH. All but two were obese (mean body mass index, BMI = 38 +/- 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Trogli tazone was given at a dose of 400 mg/day for less than or equal to6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied . Paired specimens were compared in blinded fashion. Mitochondria were quan titated using ultrathin electron microscopy. RESULTS: Seven of ten patients responded with normal ALT at the end of trea tment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and t he ALT has remained at the baseline level with no other clinical or laborat ory findings. In the responders, ALT fell from 87 +/- 38 before to 39 +/- 9 at the end of treatment (p = 0.01), and AST decreased from 77 +/- 23 to 30 +/- 8 (p = 0.002). Biopsy comparisons before and after therapy showed pers istent steatohepatitis in all cases, although four of seven showed a one-po int improvement in the necroinflammatory grade. Electron microscopy reveale d elongation of the mitochondria after therapy. CONCLUSIONS: Normal ALT was seen in 70% of NASI-I patients at the end of tr eatment, but this biochemical response was associated with only mild histol ogical improvement, and all follow-up biopsies had evidence of NASH. Normal ization of the liver enzymes in patients with NASH who are treated with thi azolidinediones should be viewed with reservation. Follow-up biopsy is esse ntial to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest. (C) 2001 by Am. Cell. of Gastroente rology.