- Email: [email protected]
Pioglitazone: The beginning of a new era for NASH?
Journal of Hepatology 47 (2007) 160–162 www.elsevier.com/locate/jhep
Journal Club Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro
Pioglitazone: The beginning of a new era for NASH? Lawrence Serfaty* Hepatology Unit, Saint-Antoine Hospital, INSERM U680, Pierre&Marie Curie University, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. 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. Background/Aims: 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 non-alcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal/d 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%, *
Tel.: +33 1 49 28 29 23; fax: +33 1 49 28 21 07. E-mail address: [email protected]
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 non-alcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. [Abstract reproduced by permission of N Engl J Med 2006;355:2297–2307]
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury in Western countries with an estimated prevalence of 10–24% in the general population [1]. Although, most often, fatty liver does not progress to more severe liver disease, approximately 20–30% of patients have histologic signs of fibrosis and necroinflammation, indicating the presence of non-alcoholic steatohepatitis (NASH) [1]. These patients are at higher risk of developing cirrhosis, terminal liver failure, and hepatocellular carcinoma [1]. Insulin resistance is central to the pathogenesis of NAFLD, and data indicate that NASH should be considered as the hepatic manifestation of the insulin resistance syndrome [2]. Experimental data suggest that insulin
0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.03.002
L. Serfaty / Journal of Hepatology 47 (2007) 160–162
resistance may promote not only steatosis through increased peripheral lipolysis and hepatic lipogenesis, but also necroinflammation through IKK-b activation and NF-jB translocation leading to proinflammatory cytokine production such as TNF-a [2,3]. Low level of adiponectin associated with insulin resistance may also favor liver steatosis and inflammation [2]. The possible causal nature of insulin resistance has provided rationale for therapeutic interventions aimed at improving insulin sensitivity in patients with NASH. Weight reduction associated with increased physical exertion is the gold standard method to reverse insulin resistance but difficult to obtain in clinical practice. Liver injury improvement has been observed in patients with NASH who underwent bariatric surgery but such a method is available only in the subgroup of patients with severe obesity [4]. Correction of obstructive sleep apnea associated with insulin resistance has been proposed as a therapeutic option in patients with NASH [5]. Among insulin sensitizing drugs, thiazolinedinediones (TZD) are a new therapeutic class which are selective agonists for the peroxisome proliferator-activated receptor-gamma (PPAR-c). By reducing insulin resistance at adipose tissue, muscle and liver levels, TZD are now widely used for treatment of type 2 diabetes. Besides improving insulin resistance, several other properties of PPAR-c agonists may have potential interest in the treatment of NASH: direct antisteatotic effect by inhibiting hepatic lipogenic transcription factors through activation of AMP-activated kinase, and/or direct antifibrogenic effects by inducing the reversion of activated hepatic stellate cells toward a quiescent state [6,7]. Troglitazone was the first TZD tested in the treatment of NASH but was withdrawn because of hepatotoxicity [8]. Pioglitazone and rosiglitazone, which showed a safer profile in diabetic patients included in trials, were further tested in small open label trials in NASH patients [4]. One pilot study including 18 patients showed that a 48-week treatment with pioglitazone 30 mg/d was associated with normalization of aminotransferase levels in 72% of cases, and with a significant improvement of steatosis, necroinflammatory injury and fibrosis, concomitantly to improvement of insulin sensitivity, supporting the role of insulin resistance in the pathogenesis of NASH. In a small randomized trial including 20 patients, it was shown that a combination of pioglitazone 30 mg/d and vitamin E over a 6-month period produced a greater improvement in NASH histology than vitamin E alone. Similar results were found in 30 NASH patients treated with a 48-week course of rosiglitazone at the dosage of 4 mg twice daily. While the majority of study patients had aminotransferase levels higher than 2.5 the upper limit of normal at baseline, two patients – one treated with pioglitazone, one with rosiglitazone-discontinued treatment because of a marked
161
rise in aminotransferase levels. Although encouraging, these results should be tempered by the small size of the study groups and the lack of control placebo group. Indeed, the analysis of histological course in 103 NAFLD patients who underwent serial liver biopsies (mean interval 3.2 ± 3 years) in the absence of effective treatment showed significant improvement of steatosis, inflammation and hepatocyte ballooning, in parallel with significant decrease of aminotransferase levels, likely reflecting diet changes in patients [8]. Moreover, progression of fibrosis was highly variable among patients, fibrosis regressing in 29% of cases. In the present placebo-controlled trial, Belfort et al. have investigated whether a 6-month course of pioglitazone 45 mg/d with low calorie diet was more effective than diet alone in 55 patients with biopsy proven NASH [9]. In fact, only 47 patients finished the treatment and were analyzed. Metabolic investigations were of high quality including assessment of glucose clearance and hepatic insulin sensitivity by using a double-tracer oral glucose tolerance test. Histopathological changes were determined according to Kleiner et al. criteria, a semiquantitative scoring system for NAFLD validated by a US network of pathologists. In the placebo group, low calorie diet ( 500 kcal/d) had limited effect on metabolic variables and was only associated with lobular inflammation improvement, despite significant decrease of aminotransferase levels. Results were not modified when analyzing the subgroup of 12/21 patients who lost a mean of 3.2 ± 0.5 kg in body weight. The short duration of the study and the relatively slight reduction of weight in the placebo group may partly explain these results. Conversely, compared to the placebo group, patients who received pioglitazone had significant improvement of aminotransferase levels as well as all metabolic and histological variables, except for fibrosis (P = 0.08). Normalization of aminotransferase levels correlated with improved hepatic insulin sensitivity and adiponectin level, which significantly increased under pioglitazone, was inversely related with reduction of hepatic fat content measured by spectrometry. In terms of histological response, the percentages of patients in pioglitazone and placebo groups having P2 reduction of steatosis, necroinflammation or fibrosis scores were 43 vs. 0%, 46 vs. 14% and 42 vs. 17%, respectively. Unfortunately, data on relationships between histological response and aminotransferase course as well as metabolic changes are lacking. Treatment was well tolerated despite significant mean weight increase at the end of follow-up. No patient experienced rise in aminotransferase levels and treatment was discontinued in one patient with fatigue and mild lower-extremity edema. Compared to previous studies, these results are rather spectacular regarding the far shorter duration of treatment (6 vs. 12 months). This may have at least two
162
L. Serfaty / Journal of Hepatology 47 (2007) 160–162
explanations. First, patients received a higher dosage of pioglitazone (45 vs. 30 mg/d), likely more effective on insulin resistance. Second, only patients with aminotransferase levels lower than 2.5, the upper limit of normal, were randomized, probably in accordance with the guidelines for the treatment of diabetic patients with TZD. A clear relationship between aminotransferase levels and the severity of liver injuries has been established in NASH patients [10]. Accordingly, only 19% of patients had bridging fibrosis at baseline, compared to 50% in previous pilot studies. Another important issue with this study is the selection of patients according to the presence of diabetes or impaired glucose tolerance (still in accordance with guidelines), while it has been shown that 50% of patients with NASH have no evident glucose intolerance [11]. In summary, Belfort et al. provide strong arguments in favor of treatment of NASH with pioglitazone. However, because we cannot generalize the results of this proof-of-concept study to the overall population of patients with NASH, larger trials in unselected population are needed. Given the majority of patients with NASH are obese, long-term weight gain under treatment should be viewed with caution. Another major point of interest of this placebo-controlled study is a better understanding of the pathogenesis of NASH. Despite the lack of data on relationships between histological response and metabolic changes, the correlation between normalization of aminotransferase levels and improved hepatic insulin sensitivity is an indirect argument for the role of hepatic insulin resistance in the pathogenesis of NASH. The significant increase of circulating adiponectin levels associated with reduction of liver fat content may suggest the antisteatotic properties of this adipokine while the significant decrease of circulating TNF-a levels in treated patients may also suggest a role of this proinflammatory cytokine in the pathogenesis of NASH. However, changes at the hepatic level should be investigated before drawing definitive conclusions. Other insulin sensitizing drugs are currently evaluated in the treatment of NASH. The efficacy of rosiglitazone was recently investigated in a placebo-controlled trial [12]. Regarding histological response following one-year course of treatment, only steatosis was significantly improved. This apparently lower efficacy of rosiglitazone compared to pioglitazone may be due to the study population which was unselected in the former case. Specific PPAR-a agonist property of pioglitazone may be another explanation. Metformin has been shown to improve biochemical markers but with more variable improvement in histology [4]. Despite previous negative results in NASH patients, the beneficial effect of ursodeoxycholic acid (UDCA) recently shown in ob/ob mice provides a new rationale for this molecule in the treatment of NASH [4,13]. Accordingly, a placebo-con-
trolled trial assessing high dosage of UDCA is currently being conducted in France. Efficacy of rimonabant, a selective antagonist of cannabinoid receptors (CB1), should be soon evaluated in NASH. In conclusion, management of NASH patients should be deeply modified in the near future regarding the number of new potentially efficient drugs. As in chronic hepatitis C several years ago, the emergence of effective treatments should transform our view on NASH and should persuade the physician to no longer consider this chronic liver disease as a ‘‘benign, not to detect because no treatment’’ disease. Future issues to be resolved will be assessment of predictive factors of response to treatment, duration of treatment and combination therapies. The new era of NASH is coming soon. References [1] Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–1231. [2] Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005;42:987–1000. [3] Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293:1673–1677. [4] Siebler J, Galle PR. Treatment of nonalcoholic fatty liver disease. World J Gastroenterol 2006;12:2161–2167. [5] Tanne F, Gagnadoux F, Fleury B, Wendum D, Lasnier I, Chazouille`res O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology 2005;41:1290–1296. [6] Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun 2004;314:580–585. [7] Hazra S, Xiong S, Wang J, Rippe RA, Krishna V, Chatterjee K, et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 2004;279:11392–11401. [8] Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of non-alcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42:132–138. [9] Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. N Engl J Med 2006;355: 2297–2307. [10] Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121:91–100. [11] Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379. [12] Ratziu V, Charlotte F, Jacqueminet S, Podevin P, Serfaty L, Bruckert E, et al. A one year randomized placebo-controlled, double-blind trial of pioglitazone in nonalcoholic steatohepatitis: results of the FLIRT. Hepatology 2006;44:201A. [13] Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006;313:1137–1140.
Journal Club Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro
Pioglitazone: The beginning of a new era for NASH? Lawrence Serfaty* Hepatology Unit, Saint-Antoine Hospital, INSERM U680, Pierre&Marie Curie University, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France
A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. 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. Background/Aims: 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 non-alcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal/d 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%, *
Tel.: +33 1 49 28 29 23; fax: +33 1 49 28 21 07. E-mail address: [email protected]
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 non-alcoholic steatohepatitis. Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone. [Abstract reproduced by permission of N Engl J Med 2006;355:2297–2307]
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury in Western countries with an estimated prevalence of 10–24% in the general population [1]. Although, most often, fatty liver does not progress to more severe liver disease, approximately 20–30% of patients have histologic signs of fibrosis and necroinflammation, indicating the presence of non-alcoholic steatohepatitis (NASH) [1]. These patients are at higher risk of developing cirrhosis, terminal liver failure, and hepatocellular carcinoma [1]. Insulin resistance is central to the pathogenesis of NAFLD, and data indicate that NASH should be considered as the hepatic manifestation of the insulin resistance syndrome [2]. Experimental data suggest that insulin
0168-8278/$32.00 Ó 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2007.03.002
L. Serfaty / Journal of Hepatology 47 (2007) 160–162
resistance may promote not only steatosis through increased peripheral lipolysis and hepatic lipogenesis, but also necroinflammation through IKK-b activation and NF-jB translocation leading to proinflammatory cytokine production such as TNF-a [2,3]. Low level of adiponectin associated with insulin resistance may also favor liver steatosis and inflammation [2]. The possible causal nature of insulin resistance has provided rationale for therapeutic interventions aimed at improving insulin sensitivity in patients with NASH. Weight reduction associated with increased physical exertion is the gold standard method to reverse insulin resistance but difficult to obtain in clinical practice. Liver injury improvement has been observed in patients with NASH who underwent bariatric surgery but such a method is available only in the subgroup of patients with severe obesity [4]. Correction of obstructive sleep apnea associated with insulin resistance has been proposed as a therapeutic option in patients with NASH [5]. Among insulin sensitizing drugs, thiazolinedinediones (TZD) are a new therapeutic class which are selective agonists for the peroxisome proliferator-activated receptor-gamma (PPAR-c). By reducing insulin resistance at adipose tissue, muscle and liver levels, TZD are now widely used for treatment of type 2 diabetes. Besides improving insulin resistance, several other properties of PPAR-c agonists may have potential interest in the treatment of NASH: direct antisteatotic effect by inhibiting hepatic lipogenic transcription factors through activation of AMP-activated kinase, and/or direct antifibrogenic effects by inducing the reversion of activated hepatic stellate cells toward a quiescent state [6,7]. Troglitazone was the first TZD tested in the treatment of NASH but was withdrawn because of hepatotoxicity [8]. Pioglitazone and rosiglitazone, which showed a safer profile in diabetic patients included in trials, were further tested in small open label trials in NASH patients [4]. One pilot study including 18 patients showed that a 48-week treatment with pioglitazone 30 mg/d was associated with normalization of aminotransferase levels in 72% of cases, and with a significant improvement of steatosis, necroinflammatory injury and fibrosis, concomitantly to improvement of insulin sensitivity, supporting the role of insulin resistance in the pathogenesis of NASH. In a small randomized trial including 20 patients, it was shown that a combination of pioglitazone 30 mg/d and vitamin E over a 6-month period produced a greater improvement in NASH histology than vitamin E alone. Similar results were found in 30 NASH patients treated with a 48-week course of rosiglitazone at the dosage of 4 mg twice daily. While the majority of study patients had aminotransferase levels higher than 2.5 the upper limit of normal at baseline, two patients – one treated with pioglitazone, one with rosiglitazone-discontinued treatment because of a marked
161
rise in aminotransferase levels. Although encouraging, these results should be tempered by the small size of the study groups and the lack of control placebo group. Indeed, the analysis of histological course in 103 NAFLD patients who underwent serial liver biopsies (mean interval 3.2 ± 3 years) in the absence of effective treatment showed significant improvement of steatosis, inflammation and hepatocyte ballooning, in parallel with significant decrease of aminotransferase levels, likely reflecting diet changes in patients [8]. Moreover, progression of fibrosis was highly variable among patients, fibrosis regressing in 29% of cases. In the present placebo-controlled trial, Belfort et al. have investigated whether a 6-month course of pioglitazone 45 mg/d with low calorie diet was more effective than diet alone in 55 patients with biopsy proven NASH [9]. In fact, only 47 patients finished the treatment and were analyzed. Metabolic investigations were of high quality including assessment of glucose clearance and hepatic insulin sensitivity by using a double-tracer oral glucose tolerance test. Histopathological changes were determined according to Kleiner et al. criteria, a semiquantitative scoring system for NAFLD validated by a US network of pathologists. In the placebo group, low calorie diet ( 500 kcal/d) had limited effect on metabolic variables and was only associated with lobular inflammation improvement, despite significant decrease of aminotransferase levels. Results were not modified when analyzing the subgroup of 12/21 patients who lost a mean of 3.2 ± 0.5 kg in body weight. The short duration of the study and the relatively slight reduction of weight in the placebo group may partly explain these results. Conversely, compared to the placebo group, patients who received pioglitazone had significant improvement of aminotransferase levels as well as all metabolic and histological variables, except for fibrosis (P = 0.08). Normalization of aminotransferase levels correlated with improved hepatic insulin sensitivity and adiponectin level, which significantly increased under pioglitazone, was inversely related with reduction of hepatic fat content measured by spectrometry. In terms of histological response, the percentages of patients in pioglitazone and placebo groups having P2 reduction of steatosis, necroinflammation or fibrosis scores were 43 vs. 0%, 46 vs. 14% and 42 vs. 17%, respectively. Unfortunately, data on relationships between histological response and aminotransferase course as well as metabolic changes are lacking. Treatment was well tolerated despite significant mean weight increase at the end of follow-up. No patient experienced rise in aminotransferase levels and treatment was discontinued in one patient with fatigue and mild lower-extremity edema. Compared to previous studies, these results are rather spectacular regarding the far shorter duration of treatment (6 vs. 12 months). This may have at least two
162
L. Serfaty / Journal of Hepatology 47 (2007) 160–162
explanations. First, patients received a higher dosage of pioglitazone (45 vs. 30 mg/d), likely more effective on insulin resistance. Second, only patients with aminotransferase levels lower than 2.5, the upper limit of normal, were randomized, probably in accordance with the guidelines for the treatment of diabetic patients with TZD. A clear relationship between aminotransferase levels and the severity of liver injuries has been established in NASH patients [10]. Accordingly, only 19% of patients had bridging fibrosis at baseline, compared to 50% in previous pilot studies. Another important issue with this study is the selection of patients according to the presence of diabetes or impaired glucose tolerance (still in accordance with guidelines), while it has been shown that 50% of patients with NASH have no evident glucose intolerance [11]. In summary, Belfort et al. provide strong arguments in favor of treatment of NASH with pioglitazone. However, because we cannot generalize the results of this proof-of-concept study to the overall population of patients with NASH, larger trials in unselected population are needed. Given the majority of patients with NASH are obese, long-term weight gain under treatment should be viewed with caution. Another major point of interest of this placebo-controlled study is a better understanding of the pathogenesis of NASH. Despite the lack of data on relationships between histological response and metabolic changes, the correlation between normalization of aminotransferase levels and improved hepatic insulin sensitivity is an indirect argument for the role of hepatic insulin resistance in the pathogenesis of NASH. The significant increase of circulating adiponectin levels associated with reduction of liver fat content may suggest the antisteatotic properties of this adipokine while the significant decrease of circulating TNF-a levels in treated patients may also suggest a role of this proinflammatory cytokine in the pathogenesis of NASH. However, changes at the hepatic level should be investigated before drawing definitive conclusions. Other insulin sensitizing drugs are currently evaluated in the treatment of NASH. The efficacy of rosiglitazone was recently investigated in a placebo-controlled trial [12]. Regarding histological response following one-year course of treatment, only steatosis was significantly improved. This apparently lower efficacy of rosiglitazone compared to pioglitazone may be due to the study population which was unselected in the former case. Specific PPAR-a agonist property of pioglitazone may be another explanation. Metformin has been shown to improve biochemical markers but with more variable improvement in histology [4]. Despite previous negative results in NASH patients, the beneficial effect of ursodeoxycholic acid (UDCA) recently shown in ob/ob mice provides a new rationale for this molecule in the treatment of NASH [4,13]. Accordingly, a placebo-con-
trolled trial assessing high dosage of UDCA is currently being conducted in France. Efficacy of rimonabant, a selective antagonist of cannabinoid receptors (CB1), should be soon evaluated in NASH. In conclusion, management of NASH patients should be deeply modified in the near future regarding the number of new potentially efficient drugs. As in chronic hepatitis C several years ago, the emergence of effective treatments should transform our view on NASH and should persuade the physician to no longer consider this chronic liver disease as a ‘‘benign, not to detect because no treatment’’ disease. Future issues to be resolved will be assessment of predictive factors of response to treatment, duration of treatment and combination therapies. The new era of NASH is coming soon. References [1] Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221–1231. [2] Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005;42:987–1000. [3] Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001;293:1673–1677. [4] Siebler J, Galle PR. Treatment of nonalcoholic fatty liver disease. World J Gastroenterol 2006;12:2161–2167. [5] Tanne F, Gagnadoux F, Fleury B, Wendum D, Lasnier I, Chazouille`res O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology 2005;41:1290–1296. [6] Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun 2004;314:580–585. [7] Hazra S, Xiong S, Wang J, Rippe RA, Krishna V, Chatterjee K, et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J Biol Chem 2004;279:11392–11401. [8] Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of non-alcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42:132–138. [9] Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with non-alcoholic steatohepatitis. N Engl J Med 2006;355: 2297–2307. [10] Dixon JB, Bhathal PS, O’Brien PE. Nonalcoholic fatty liver disease: predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 2001;121:91–100. [11] Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373–379. [12] Ratziu V, Charlotte F, Jacqueminet S, Podevin P, Serfaty L, Bruckert E, et al. A one year randomized placebo-controlled, double-blind trial of pioglitazone in nonalcoholic steatohepatitis: results of the FLIRT. Hepatology 2006;44:201A. [13] Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 2006;313:1137–1140.