Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis

A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study

Lauren N. Bell, Jiangxia Wang, Sriya Muralidharan, Sadhana Chalasani, Allison M. Fullenkamp, Laura A. Wilson, Arun J. Sanyal, Kris V. Kowdley, Brent A. Neuschwander-Tetri, Elizabeth M. Brunt, Arthur J. McCullough, Nathan M. Bass, Anna Mae Diehl, Aynur Unalp-Arida, Naga Chalasani

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Abstract

The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the 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 endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × 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 the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -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 = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: 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.

Original languageEnglish
Pages (from-to)1311-1318
Number of pages8
JournalHepatology
Volume56
Issue number4
DOIs
StatePublished - Oct 2012

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pioglitazone
Vitamin E
Insulin Resistance
Adipose Tissue
Histology
Placebos
Liver
Therapeutics
Fibrosis
Fasting
Non-alcoholic Fatty Liver Disease

ASJC Scopus subject areas

  • Hepatology

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Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis : A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. / Bell, Lauren N.; Wang, Jiangxia; Muralidharan, Sriya; Chalasani, Sadhana; Fullenkamp, Allison M.; Wilson, Laura A.; Sanyal, Arun J.; Kowdley, Kris V.; Neuschwander-Tetri, Brent A.; Brunt, Elizabeth M.; McCullough, Arthur J.; Bass, Nathan M.; Diehl, Anna Mae; Unalp-Arida, Aynur; Chalasani, Naga.

In: Hepatology, Vol. 56, No. 4, 10.2012, p. 1311-1318.

Research output: Contribution to journalArticle

Bell, LN, Wang, J, Muralidharan, S, Chalasani, S, Fullenkamp, AM, Wilson, LA, Sanyal, AJ, Kowdley, KV, Neuschwander-Tetri, BA, Brunt, EM, McCullough, AJ, Bass, NM, Diehl, AM, Unalp-Arida, A & Chalasani, N 2012, 'Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis: A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study', Hepatology, vol. 56, no. 4, pp. 1311-1318. https://doi.org/10.1002/hep.25805
Bell, Lauren N. ; Wang, Jiangxia ; Muralidharan, Sriya ; Chalasani, Sadhana ; Fullenkamp, Allison M. ; Wilson, Laura A. ; Sanyal, Arun J. ; Kowdley, Kris V. ; Neuschwander-Tetri, Brent A. ; Brunt, Elizabeth M. ; McCullough, Arthur J. ; Bass, Nathan M. ; Diehl, Anna Mae ; Unalp-Arida, Aynur ; Chalasani, Naga. / Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis : A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study. In: Hepatology. 2012 ; Vol. 56, No. 4. pp. 1311-1318.
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abstract = "The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the 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 endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × 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 the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -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 = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: 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.",
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T2 - A pioglitazone versus vitamin E versus placebo for the treatment of nondiabetic patients with nonalcoholic steatohepatitis trial follow-up study

AU - Bell, Lauren N.

AU - Wang, Jiangxia

AU - Muralidharan, Sriya

AU - Chalasani, Sadhana

AU - Fullenkamp, Allison M.

AU - Wilson, Laura A.

AU - Sanyal, Arun J.

AU - Kowdley, Kris V.

AU - Neuschwander-Tetri, Brent A.

AU - Brunt, Elizabeth M.

AU - McCullough, Arthur J.

AU - Bass, Nathan M.

AU - Diehl, Anna Mae

AU - Unalp-Arida, Aynur

AU - Chalasani, Naga

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N2 - The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the 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 endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × 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 the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -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 = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: 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.

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