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Hepatology. Author manuscript; available in PMC 2013 Oct 1.
Find articles by Sriya Muralidharan
1 Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN, USA
2 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3 Virginia Commonwealth University, Richmond, VA, USA
4 Virginia Mason Medical Center, Seattle, WA, USA
5 Saint Louis University School of Medicine, St. Louis, MO, USA
6 Washington University School of Medicine, St. Louis, MO, USA
7 Cleveland Clinic Foundation, Cleveland, OH, USA
8 University of California San Francisco, San Francisco, CA, USA
9 Duke University School of Medicine, Durham, NC, USA
10 National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
Corresponding Author : Naga Chalasani, MD, Division of Gastroenterology/Hepatology, Indiana University School of Medicine, 1050 Wishard Blvd., RG 4100, Indianapolis, IN 46202, Tel: (317) 278-0414, Fax: (317) 278-1949, ude.iupui@asalahcn
* Members of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) are listed in the Appendix .
The publisher's final edited version of this article is available at Hepatology
Keywords: Nonalcoholic steatohepatitis, vitamin E, pioglitazone, insulin resistance, adipose tissue
§ Conversion factor used for calculation of Adipo-IR: 1 µU/ml insulin = 6 pM.
* For the means of outcome measures, p values were derived from multiple linear regression models with two indicator variables for the effect of treatment versus placebo.
** For the mean change in scores, p values were calculated with multiple linear regression models with two indicator variables for the effect of treatment versus placebo, adjusting for the baseline value of the outcome.
* P values were from multiple linear regression model, regressing the logarithm of Adipo-IR at baseline on the listed correlates at baseline.
‡ P values were from multiple linear regression model, regressing the logarithm of Adipo-IR at 96 weeks on the listed correlates at 96 weeks.
∥ Histologic Improvement required improvement by 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and either a decrease in the activity score for nonalcoholic fatty liver disease to a score of 3 points or less or a decrease in the activity score of at least 2 points, with at least a 1-point decrease in either the lobular inflammation or steatosis score.
† The binary change variables for histology scores are defined as improvement versus no improvement. For each histology score, improvement is: at least a 1-point decrease in the Steatosis score; at least a 1-point decrease in the lobular inflammation score; improvement of 1 or more points in the hepatocellular ballooning score; no increase in the fibrosis score; and at least 2 points decrease in the NAS score, respectively.
* Geometric means estimated as exponentiated regression coefficients from the multiple linear regression model for log-transformed Adipo-IR (see Methods).
‡ P values are from multiple linear regression models, regressing the log of the ratio between the outcome variables at 16 weeks and baseline on the five indicator variables for improvement in the histologic features at 96 weeks, the two indicator variables for treatment, the deltas for BMI, and ALT at 16 weeks, adjusting for baseline Adipo-IR, ethnicity, and baseline BMI. N=191; R 2 =0.39; RMSE=0.81.
¶ P values are from multiple linear regression models, regressing the log of the ratio between the outcome variables at 96 weeks and baseline on the five indicator variables for improvement in the histologic features at 96 weeks, the two indicator variables for treatment, the deltas for BMI, and ALT at 96 weeks, adjusting for baseline Adipo-IR, ethnicity, and baseline BMI. N=205; R 2 =0.29; RMSE=0.93.
MetroHealth Medical Center, Cleveland, OH: Arthur J. McCullough, MD; Patricia Brandt; Diane Bringman, RN (2004–2008); Srinivasan Dasarathy, MD; Jaividhya Dasarathy, MD; Carol Hawkins, RN; Yao-Chang Liu, MD (2004–2009); Nicholette Rogers, PhD, PA-C (2004–2008)
Cleveland Clinic Foundation, Cleveland, OH: Arthur J. McCullough, MD; Srinivasan Dasarathy, MD; Mangesh Pagadala, MD; Ruth Sargent, LPN; Lisa Yerian, MD; Claudia Zein, MD
1. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010; 362 :1675–1685. [ PMC free article ] [ PubMed ] [ Google Scholar ]
2. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001; 50 :1844–1850. [ PubMed ] [ Google Scholar ]
3. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001; 120 :1183–1192. [ PubMed ] [ Google Scholar ]
4. McClain CJ, Mokshagundam SP, Barve SS, Song Z, Hill DB, Chen T, Deaciuc I. Mechanisms of non-alcoholic steatohepatitis. Alcohol. 2004; 34 :67–79. [ PubMed ] [ Google Scholar ]
5. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002; 87 :3023–3028. [ PubMed ] [ Google Scholar ]
6. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia. 2005; 48 :634–642. [ PubMed ] [ Google Scholar ]
7. Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, Buzzigoli E, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007; 133 :496–506. [ PubMed ] [ Google Scholar ]
8. Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology. 2008; 134 :1369–1375. [ PMC free article ] [ PubMed ] [ Google Scholar ]
9. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355 :2297–2307. [ PubMed ] [ Google Scholar ]
10. Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, Cusi K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology. 2009; 50 :1087–1093. [ PubMed ] [ Google Scholar ]
11. Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J, Kleiner DE, Unalp A, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009; 30 :88–96. [ PMC free article ] [ PubMed ] [ Google Scholar ]
12. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41 :1313–1321. [ PubMed ] [ Google Scholar ]
13. Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with NAFLD. Hepatology. 2011 Dec 20; [Epub ahead of print] [ PubMed ] [ Google Scholar ]
14. Marchesini G, Pacini G, Bianchi G, Patrono D, Cobelli C. Glucose disposal, beta-cell secretion, and hepatic insulin extraction in cirrhosis: a minimal model assessment. Gastroenterology. 1990; 99 :1715–1722. [ PubMed ] [ Google Scholar ]
15. Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G. Mechanisms of hyperinsulinemia in Child's Disease grade B liver cirrhosis investigated in free liver conditions. Gut. 2002; 51 :870–875. [ PMC free article ] [ PubMed ] [ Google Scholar ]
1. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010; 362 :1675–1685. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
2. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001; 50 :1844–1850. [ PubMed ] [ Google Scholar ] [ Ref list ]
4. McClain CJ, Mokshagundam SP, Barve SS, Song Z, Hill DB, Chen T, Deaciuc I. Mechanisms of non-alcoholic steatohepatitis. Alcohol. 2004; 34 :67–79. [ PubMed ] [ Google Scholar ] [ Ref list ]
3. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001; 120 :1183–1192. [ PubMed ] [ Google Scholar ] [ Ref list ]
5. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002; 87 :3023–3028. [ PubMed ] [ Google Scholar ] [ Ref list ]
9. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, Balas B, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006; 355 :2297–2307. [ PubMed ] [ Google Scholar ] [ Ref list ]
10. Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, Cusi K. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology. 2009; 50 :1087–1093. [ PubMed ] [ Google Scholar ] [ Ref list ]
7. Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, Buzzigoli E, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007; 133 :496–506. [ PubMed ] [ Google Scholar ] [ Ref list ]
11. Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J, Kleiner DE, Unalp A, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009; 30 :88–96. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
12. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41 :1313–1321. [ PubMed ] [ Google Scholar ] [ Ref list ]
13. Lomonaco R, Ortiz-Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with NAFLD. Hepatology. 2011 Dec 20; [Epub ahead of print] [ PubMed ] [ Google Scholar ] [ Ref list ]
14. Marchesini G, Pacini G, Bianchi G, Patrono D, Cobelli C. Glucose disposal, beta-cell secretion, and hepatic insulin extraction in cirrhosis: a minimal model assessment. Gastroenterology. 1990; 99 :1715–1722. [ PubMed ] [ Google Scholar ] [ Ref list ]
15. Greco AV, Mingrone G, Mari A, Capristo E, Manco M, Gasbarrini G. Mechanisms of hyperinsulinemia in Child's Disease grade B liver cirrhosis investigated in free liver conditions. Gut. 2002; 51 :870–875. [ PMC free article ] [ PubMed ] [ Google Scholar ] [ Ref list ]
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1 Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN, USA
2 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
1 Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN, USA
1 Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN, USA
1 Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN, USA
2 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3 Virginia Commonwealth University, Richmond, VA, USA
4 Virginia Mason Medical Center, Seattle, WA, USA
5 Saint Louis University School of Medicine, St. Louis, MO, USA
7 Cleveland Clinic Foundation, Cleveland, OH, USA
8 University of California San Francisco, San Francisco, CA, USA
9 Duke University School of Medicine, Durham, NC, USA
2 The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
1 Division of Gastroenterology/Hepatology, Indiana University, Indianapolis, IN, USA
The PIVENS [Pioglitazone versus Vitamin E versus Placebo for the Treatment of Non-diabetic Patients with Nonalcoholic Steatohepatitis (NASH)] trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees but mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological end points. Adipo-IR [fasting non-esterified fatty acids (NEFA) × fasting insulin] was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either vitamin E group ( p =0.34) or pioglitazone group ( p =0.29).). Baseline Adipo-IR was significantly associated with fibrosis score (p=0.017) but not with other histological features or NAFLD activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had significant reduction in Adipo-IR (−15.7 vs. −1.91, p=0.02) but this effect did not persist at 96 weeks (−3.25 vs. −4.28, p=0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (p=0.70) or after 96 weeks (p=0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (p=0.02), fibrosis (p=0.004), and NAFLD activity score (p=0.01).
Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.
Despite the increasing incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), there are no therapies currently approved for treatment of these common liver disorders. Recently published results from the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) clinical trial showed that pioglitazone and vitamin E improved liver histology to varying degrees ( 1 ). Of particular interest is the fact that pioglitazone and vitamin E may target different mechanistic pathways (insulin sensitivity and oxidative stress, respectively) implicated in the pathogenesis of NASH ( 2 – 4 ), but liver histology improved in both treatment groups. Furthermore, although insulin resistance is thought to be directly involved in the development of NASH, liver histology improved in patients taking vitamin E despite no change in general insulin sensitivity as measured by Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index ( 1 ). Delineation of mechanisms involved in the development, progression, and improvement of NASH are clearly needed to better understand natural history and treatment options for this increasingly prevalent disease.
While hepatic and muscle insulin resistance are established hallmark features of NAFLD and NASH ( 2 , 3 , 5 – 9 ), a report by Gastaldelli et al . highlighted an additional component, adipose tissue insulin resistance (Adipo-IR), as an important contributor to the pathogenesis and treatment of NASH ( 10 ). In this study, patients with NASH had elevated fasting concentrations of non-esterified fatty acids (NEFA) compared to control subjects, and an index of Adipo-IR, calculated as the product of fasting NEFA×fasting insulin ( 7 , 10 ), was significantly elevated in NASH patients independent of the degree of obesity. Interestingly, treatment with pioglitazone decreased NEFA concentrations, resulting in a significant reduction in Adipo-IR, and decreases in Adipo-IR were correlated with improvements in hepatic steatosis and necroinflammation. Overall, this study suggests a central role for reduction of adipose tissue insulin resistance in pioglitazone-induced improvement of liver histology in patients with NASH.
The intriguing relationship between changes in adipose tissue insulin resistance and improvements in liver histology ( 10 ) led us to investigate Adipo-IR in patients who participated in the PIVENS clinical trial. Specifically, the aims of this study were to: ( 1 ) examine the predictors of Adipo-IR at baseline and after 96 weeks, ( 2 ) assess changes in Adipo-IR in the placebo, pioglitazone, and vitamin E groups after 16 and 96 weeks of therapy, and ( 3 ) determine if early (after 16 weeks) or long term (after 96 weeks) changes in Adipo-IR correlate with changes in liver histology.
Data included in this analysis were obtained from patients who participated in the PIVENS trial, an adult treatment trial conducted by the No
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