Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, Gastaldelli A, Tio F, Pulcini J, Berria R, Ma JZ, Dwivedi S, Havranek R, Fincke C, DeFronzo R, Bannayan GA, Schenker S, Cusi K. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297-2307. (Reprinted by Permission)
Background No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus.
Methods We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion).
Results Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P<0.001), normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels (by 40% vs. 21%, P=0.04), decreased alanine aminotransferase levels (by 58% vs. 34%, P<0.001), decreased hepatic fat content (by 54% vs. 0%, P<0.001), and increased hepatic insulin sensitivity (by 48% vs. 14%, P=0.008). Administration of pioglitazone, as compared with placebo, was associated with improvement in histologic findings with regard to steatosis (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 differ significantly from that in the placebo group (P=0.08). Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone; no other adverse events were observed.
Conclusions In this proof-of-concept study, the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. (ClinicalTrials.gov number, NCT00227110 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the United States.1 It is now regarded as a manifestation of the metabolic syndrome, which includes insulin resistance, central obesity and dyslipidemia. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD. An essential feature of NASH is hepatocyte injury and is represented histologically as ballooning degeneration with or without fibrosis, Mallory's hyaline, and lobular inflammation. Steatosis without evidence of hepatic injury seems to have a relatively benign course, with cirrhosis developing in fewer than 3% of patients; by contrast, up to 25% of patients with NASH have been estimated to develop cirrhosis.2
Insulin resistance (IR) plays a central role in NAFLD. IR causes impaired metabolic clearance of glucose, hyperinsulinemia, and lipolysis. Increased lipolysis leads to increased plasma free fatty acids (FFAs); increased hepatic uptake of FFAs results in steatosis. The progression of steatosis to steatohepatitis is not well defined but is believed to involve cytokine-mediated inflammation, lipid peroxidation, and apoptosis.3 The association of IR with NAFLD has led to the hypothesis that medical therapy directed at improving insulin sensitivity may be beneficial in alleviating NAFLD. Thiazolidinediones (TZDs) are agonists for the peroxisome proliferator-activated receptor γ (PPARγ), which is a nuclear receptor expressed in adipose tissue, muscle, and liver. This receptor is highly expressed in adipocytes, where it stimulates cell differentiation and decreases lipolysis and FFA release.4 Troglitazone, the first TZD, was found to lower serum aminotransferase levels and improve hepatic histology in NASH, but was removed from clinical use secondary to hepatotoxicity.5 Subsequently, there have been 4 more pilot studies conducted to assess whether other TZDs have a therapeutic role in treatment of NASH.
Neuschwander-Tetri et al. administered rosiglitazone for 48 weeks to 30 patients who had evidence of NASH on prior biopsy.6 Complete data were available on 22 patients who met published criteria for NASH on reevaluation of baseline biopsy and posttreatment biopsies. All patients were overweight and half had glucose intolerance or diabetes. The authors found a statistically significant improvement in steatosis, inflammation, and hepatocellular ballooning. In addition, mean serum alanine aminotransferase (ALT) levels and markers of insulin sensitivity improved. Although there was not a significant improvement in fibrosis score, the authors felt there was a change in the pattern and character of fibrosis observed with rosiglitazone treatment. Patients with zone 3 perisinusoidal fibrosis had a shift from dense collagen bands to more delicate deposition of collagen. It was noted that the benefits from therapy were not sustainable because the ALT levels and glycemic control reverted to pretreatment values 6 months after discontinuing rosiglitazone. Even more importantly, there was significant weight gain with therapy, occurring in almost two-thirds of the study group with a median increase of 7.3%.
Promrat et al. also performed a prospective study evaluating the use of pioglitazone in NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone for 48 weeks.7 Treatment was associated with improvement in all the component features of NASH, including steatosis, inflammation, hepatocyte injury, and even fibrosis. Serum ALT levels and markers of insulin sensitivity improved with therapy. Again, the main side effect was weight gain, occurring in three-quarters of the patients. Because follow-up data were not provided, it is not clear whether these benefits persisted after treatment was discontinued.
It has been proposed that the transition from steatosis to steatohepatitis involves a variety of inflammatory mediators, lipid peroxidation, and apoptosis; therefore, antioxidants have been proposed as an adjunctive therapy for NASH. Sanyal et al. conducted a randomized, prospective trial to compare the efficacy of vitamin E alone and vitamin E and piogliatzone in the treatment of NASH.8 Ten nondiabetic subjects with NASH were randomized to each treatment arm for 6 months, and then underwent posttreatment liver biopsies. They found that vitamin E only decreased the amount of steatosis. Combination therapy, however, resulted in a decrease in steatosis, hepatocyte ballooning, and fibrosis. Combination therapy also improved metabolic clearance of glucose and resulted in a decrease in FFA. The decrease in FFA and insulin were found to independently predict improvement in hepatic steatosis and cytologic ballooning. Treatment was discontinued in one patient because a marked increase in ALT and liver biopsy revealed cholestatic hepatitis consistent with drug toxicity. A major limitation of previous therapeutic trials in NASH has been the lack of a control group. This seems particularly important in NASH, given the dynamic nature of the histologic features, as documented by recent studies of the natural history of this condition.9 This is evidenced by the fact that the published placebo-controlled trial of ursodeoxycholic acid as treatment for NASH showed biochemical and histological improvement in both groups but no significant difference between the ursodeoxycholic acid and placebo groups.10
Belfort et al. report the first randomized, double-blind, placebo-controlled trial of pioglitazone in patients with biopsy-proven NASH.11 A total of 55 patients with glucose intolerance or type 2 diabetes were placed on a hypocaloric diet (a net reduction of 500 kcal/day) and pioglitazone (45 mg/day) or placebo for 6 months. Endpoints measured included liver histology, hepatic fat content assessed by magnetic resonance spectroscopy, and glucose turnover. Pioglitazone therapy was associated with a number of favorable outcomes, including improved glucose tolerance and greater hepatic insulin sensitivity along with decreased hepatic fat by magnetic resonance spectroscopy (54% versus 0%). These changes were accompanied by a significant improvement in serum ALT and AST levels, as well as in liver histology. There was significant reduction in steatosis, ballooning degeneration, and necroinflammatory changes (85% versus 38%); however, there was no significant reduction in hepatic fibrosis score compared to placebo-treated patients (P = 0.08). Pioglitazone also resulted in decreased TNF-α and TGF-β levels and increased serum adiponectin levels. There was a net decrease in weight among subjects who received placebo (average 4% decrease in mean body fat and 3.2 ± 0.5 kg of body weight) whereas subjects who received pioglitazone experienced weight gain (2.5 ± 0.5 kg) and increase in body fat 1.5 ± 0.5% (P < 0.01).
The study by Belfort provides the first placebo-controlled evidence that TZDs decrease insulin resistance and may be beneficial in the treatment of NASH. In all 4 studies reported to date, TZDs improved steatosis and necroinflammation scores in all; however, improvement in fibrosis was noted in only half the studies. In addition, it is not clear whether the benefits gained with TZD therapy are sustainable. Neuschwander-Tetri et al. discovered that serum ALT levels and markers of glucose metabolism reverted back to baseline levels after discontinuation of rosiglitazone. Another concern with long-term use of TZDs is weight gain, which is a common side effect.
In conclusion, the study by Belfort and colleagues provides the first controlled data that treatment with a thiazolidinedione can result in improvement in features of NASH among patients with glucose intolerance. Based on these findings, it seems reasonable to recommend that TZDs become part of the therapeutic regimen for patients with type 2 diabetes and evidence of NAFLD and, in particular, NASH. However, it appears premature to extrapolate these data to the therapy of NASH patients without type 2 diabetes. A large-scale study of pioglitazone compared to vitamin E or placebo in more than 240 subjects with NASH but without diabetes is currently underway under the auspices of the NIDDK-funded NASH Clinical Research Network. Meanwhile, it is reasonable to focus the management of NASH in nondiabetic patients around nonpharmacologic means to improve insulin resistance such as weight loss, exercise, and therapy of hyperlipidemia.