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, Bradley Aouizerat, Nonalcoholic Steatohepatitis Clinical Research Network

Research output: Contribution to journalArticle

Abstract

UNLABELLED: 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 (US)
Pages (from-to)1311-8
Number of pages8
JournalHepatology
Volume56
Issue number4
DOIs
StatePublished - Oct 2012

    Fingerprint

Keywords

  • Adipose Tissue
  • Adult
  • Cross-Sectional Studies
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fatty Liver
  • Female
  • Follow-Up Studies
  • Humans
  • Hypoglycemic Agents
  • Insulin Resistance
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease
  • Reference Values
  • Thiazolidinediones
  • Time Factors
  • Treatment Outcome
  • Vitamin E

Cite this

Bell, L. N., Wang, J., Muralidharan, S., Chalasani, S., Fullenkamp, A. M., Wilson, L. A., Sanyal, A. J., Kowdley, K. V., Neuschwander-Tetri, B. A., Brunt, E. M., McCullough, A. J., Bass, N. M., Diehl, A. M., Unalp-Arida, A., Chalasani, N., Aouizerat, B., & Nonalcoholic Steatohepatitis Clinical Research Network (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, 56(4), 1311-8. https://doi.org/10.1002/hep.25805