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

doi:10.1002/hep.25805

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

Oral and Maxillofacial Surgery

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	1311-8
Number of pages	8
Journal	Hepatology
Volume	56
Issue number	4
DOIs	https://doi.org/10.1002/hep.25805
State	Published - Oct 2012

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

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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

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 et al.
In: Hepatology, Vol. 56, No. 4, 10.2012, p. 1311-8.

Research output: Contribution to journal › Article › peer-review

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, 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, vol. 56, no. 4, pp. 1311-8. https://doi.org/10.1002/hep.25805

Bell LN, Wang J, Muralidharan S, Chalasani S, Fullenkamp AM, Wilson LA et al. 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. 2012 Oct;56(4):1311-8. doi: 10.1002/hep.25805

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title = "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",

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.",

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",

author = "Bell, {Lauren N} and Jiangxia Wang and Sriya Muralidharan and Sadhana Chalasani and Fullenkamp, {Allison M} and Wilson, {Laura A} and Sanyal, {Arun J} and Kowdley, {Kris V} and Neuschwander-Tetri, {Brent A} and Brunt, {Elizabeth M} and McCullough, {Arthur J} and Bass, {Nathan M} and Diehl, {Anna Mae} and Aynur Unalp-Arida and Naga Chalasani and Bradley Aouizerat and {Nonalcoholic Steatohepatitis Clinical Research Network}",

note = "Copyright {\textcopyright} 2012 American Association for the Study of Liver Diseases.",

year = "2012",

month = oct,

doi = "10.1002/hep.25805",

language = "English (US)",

volume = "56",

pages = "1311--8",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

TY - JOUR

T1 - Relationship between adipose tissue insulin resistance and liver histology in nonalcoholic steatohepatitis

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

AU - Aouizerat, Bradley

AU - Nonalcoholic Steatohepatitis Clinical Research Network

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

KW - Adipose Tissue

KW - Adult

KW - Cross-Sectional Studies

KW - Dose-Response Relationship, Drug

KW - Drug Administration Schedule

KW - Fatty Liver

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin Resistance

KW - Male

KW - Middle Aged

KW - Non-alcoholic Fatty Liver Disease

KW - Reference Values

KW - Thiazolidinediones

KW - Time Factors

KW - Treatment Outcome

KW - Vitamin E

U2 - 10.1002/hep.25805

DO - 10.1002/hep.25805

M3 - Article

C2 - 22532269

SN - 0270-9139

VL - 56

SP - 1311

EP - 1318

JO - Hepatology

JF - Hepatology

IS - 4

ER -