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Cited by 726Liver Disease Diagnosis and TreatmentLiver Diseases and ImmunityAlcohol Consumption and Health Effects

A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis

Open access
Promrat, Kittichai, Lutchman, Glen, Uwaifo, Gabriel I., Freedman, Renee J., Soza, Alejandro, Heller, Theo, Doo, Edward, Ghany, Marc +6 more·2004·Hepatology
DOI 10.1002/hep.20012
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Abstract

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease for which there is no known effective therapy. A proportion of patients with NASH progress to advanced fibrosis and cirrhosis. NASH is considered one of the clinical features of the metabolic syndrome in which insulin resistance plays a central role. This prospective study evaluates the role of insulin-sensitizing agent in treatment of NASH. Eighteen nondiabetic patients with biopsy-proven NASH were treated with pioglitazone (30 mg daily) for 48 weeks. Tests of insulin sensitivity and body composition as well as liver biopsies were performed before and at the end of treatment. By 48 weeks, serum alanine aminotransferase values fell to normal in 72% of patients. Hepatic fat content and size as determined by magnetic resonance imaging decreased, and glucose and free fatty acid sensitivity to insulin were uniformly improved. Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05). Using strict criteria, histological improvement occurred in two-thirds of patients. Pioglitazone was well tolerated; the main side effects were weight gain (averaging 4%) and an increase in total body adiposity. In conclusion, these results indicate that treatment with an insulin-sensitizing agent can lead to improvement in biochemical and histological features of NASH and support the role of insulin resistance in the pathogenesis of this disease. The long-term safety and benefits of pioglitazone require further study. (Hepatology 2004;39:188-196.)

AI snapshot

Written from the paper’s full text.

TL;DR

In this prospective pilot study, 18 nondiabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH) received pioglitazone 30 mg daily for 48 weeks. Pioglitazone improved serum aminotransferases, insulin sensitivity, hepatic fat by MRI, and multiple histological features of NASH, but caused weight gain and required further long-term study.

Key findings

  • Serum ALT normalized in 72% of patients (13/18); mean ALT fell from 99 U/L to 40 U/L (P < 0.01), and mean AST fell from 61 U/L to 34 U/L (P = 0.001).
  • The mean NASH activity index decreased from 8.0 at baseline to 4.0 at 48 weeks; using strict criteria, 12 patients (67%) had a histological response.
  • Steatosis, hepatocellular injury, parenchymal inflammation, Mallory bodies, and fibrosis all improved significantly (all P < 0.05); fibrosis improved in 11 patients (61%), was unchanged in 4 (22%), and increased in 3 (17%).
  • Insulin sensitivity improved: FSIGT S_I increased by 126% ± 78%, HOMA-IR fell from 4.3 to 2.6 (P < 0.001), and liver fat by MRI fell from 47.5% to 22.8% (P = 0.001), while weight increased by an average of 3.5 kg (4%) and total fat mass increased by 3.1 kg (P = 0.002).

Methods

  • Prospective, single-arm pilot study of 18 nondiabetic adults with biopsy-proven NASH, enrolled between March 2001 and April 2002; patients received pioglitazone 30 mg daily for 48 weeks.
  • Before and after treatment, patients underwent liver biopsy, oral glucose tolerance testing, frequently sampled intravenous glucose tolerance testing, MRI of the liver, and DEXA body composition measurement.
  • The primary outcome was improvement in hepatic histology using a predetermined NASH activity index; analyses were intention-to-treat, with paired t tests and nonparametric tests where appropriate.

Limitations

  • The paper states a major limitation was the lack of a concurrently followed control group, making spontaneous histological improvement difficult to exclude.
  • The paper states patients were treated for only 48 weeks, so long-term sustainability of biochemical and histological improvements is unclear; it also cautions that weight gain with pioglitazone may eventually reverse benefits.
  • Evident from the text: this was a small, single-arm pilot (n = 18), so findings are preliminary and cannot establish causality or generalizability without larger controlled trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1002/hep.20012

Cites

31 of 31 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 16 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Serum ALT levels fell from an average of 99 U/L at baseline to 40 U/L at 48 weeks (P < 0.01).

    “Serum ALT levels fell from an average of 99 U/L at baseline to 40 U/L at 48 weeks (P Ͻ 0.01).”
    Quote in the paperSubstantial claim
  • Findingown data

    Waist circumferences did not change during pioglitazone therapy.

    “Waist circumferences did not change”
    Quote in the paperNot a substantial claim
  • Findingown data

    Total fat mass increased significantly (+3.1 ± 3.6 kg, P = 0.002).

    “significant increases in total fat mass (ϩ3.1 Ϯ 3.6 kg, P ϭ 0.002)”
    Quote in the paperNot a substantial claim
  • Findingown data

    There were no significant changes in total cholesterol, triglycerides, LDL and HDL cholesterol levels.

    “There were no significant changes in total cholesterol, triglycerides, LDL and HDL cholesterol levels.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Ten of the 12 patients with histological response (83%) also had normal ALT levels at the end of therapy.

    “Ten of these 12 (83%) also had normal ALT levels at the end of therapy.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    The average increase in weight was 3.5 kg (range, -1.7 to +13.3), representing a 4% increase from baseline (range, -1.7% to +12.4%).

    “The average increase in weight was 3.5 (range, Ϫ1.7 to ϩ13.3) kilograms, which represented a 4% increase from baseline (range, Ϫ1.7% to ϩ12.4%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Indices of insulin resistance improved, including mean fasting insulin (21% decrease, P = 0.02) and C-peptide levels (29% decrease, P < 0.01).

    “indices of insulin resistance improved, including mean fasting insulin (21% decrease, P ϭ 0.02) and C-peptide levels (29% decrease, P Ͻ 0.01) (Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05).

    “Histological features of steatosis, cellular injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from baseline (all P < 0.05).”
    • Also stated in: § Histological Responses (Table 3). · plain
      “Each of the component features of the NASH activity index (steatosis, parenchymal inflammation, and hepatocellular injury) improved significantly, as did fibrosis and Mallory bodies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ALT decreases were gradual, beginning after 4 weeks of treatment, and reaching lowest levels between 40 and 48 weeks.

    “The ALT decreases were gradual, beginning after 4 weeks of treatment, and reaching lowest levels between 40 and 48 weeks (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    One patient had a myocardial infarction during therapy, and another suffered recurrent autoimmune uveitis during the study period.

    “One patient had a myocardial infarction during therapy, and another suffered recurrent autoimmune uveitis during the study period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    No patient developed anemia or clinically apparent edema.

    “No patient developed anemia or clinically apparent edema, reported side effects of pioglitazone.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Lean mass did not change significantly after 48 weeks (56.4 ± 12.1 to 56.6 ± 11.9 kg, P=0.640).

    “Lean mass (kg) 56.4 Ϯ 12.1 56.6 Ϯ 11.9 0.640”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All 18 patients enrolled had improvements in serum ALT levels, which became normal in 72%.

    “All 18 patients enrolled had improvements in serum ALT levels, which became normal in 72%.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Liver fat and liver volume as assessed by MRI both decreased significantly.

    “Hepatic fat content and size as determined by magnetic resonance imaging decreased”
    • Also stated in: § Anthropometric Results (Table 4). · plain
      “In contrast, liver fat and liver volume as assessed by MRI both decreased significantly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    83% of patients with a histological response had normal ALT levels, but so did 50% of patients who did not achieve a histological response.

    “Thus, 83% of patients with a histological response had normal ALT levels, but so did 50% of patients who did not achieve a histological response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The main side effects of pioglitazone were weight gain (averaging 4%) and an increase in total body adiposity.

    “the main side effects were weight gain (averaging 4%) and an increase in total body adiposity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Glucose effectiveness, acute insulin response to glucose, disposition index, and glucose disappearance rates did not change significantly after 48 weeks of pioglitazone treatment.

    “Glucose effectiveness (S G ) did not change significantly, nor did the acute insulin response to glucose (AIR G ), the disposition index (DI), or glucose disappearance (K G ) rates (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Weight gain was the major side effect of therapy, averaging 3.5 kg and occurring in 72% of patients.

    “Weight gain was the major side effect of therapy, averaging 3.5 kg and occurring in 72% of patients.”
    • Also stated in: § Discussion · plain
      “Furthermore, an important side effect of therapy was weight gain, which averaged 3.5 kg.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    One patient discontinued therapy after 3 weeks because of dizziness.

    “One patient discontinued therapy after 3 weeks because of dizziness.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    NASH can lead to progressive fibrosis and eventually cirrhosis.

    “While once thought to be a benign condition, there is increasing evidence that NASH can lead to progressive fibrosis and eventually cirrhosis.3,[5][6][7]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] source

      Not checked in the free run.

    • cites [5] source

      Not checked in the free run.

    • cites [6] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Liver biopsies were coded and read by a hepatic pathologist without knowledge of the patient or the sequence of the biopsy.

    “After conclusion of the study, all liver biopsies samples were coded and read by a hepatic pathologist (D.E.K) without the knowledge of the patient or the sequence of the biopsy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    These results underscore the importance of hepatic histology as an endpoint for trials of therapy in NASH.

    “These results underscore the importance of hepatic histology as an endpoint for trials of therapy in NASH.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The study protocol and consent forms were approved by the Institute Review Board of the NIDDK.

    “All patients gave written informed consent, and the protocol and consent forms were approved by the Institute Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Rosiglitazone and pioglitazone have a low rate of hepatotoxicity and have been reported to improve aminotransferase levels and hepatic steatosis in NASH.

    “Two newer TZDs, rosiglitazone and pioglitazone, have proven to have a low rate of hepatotoxicity and have been reported to improve aminotransferase levels and hepatic steatosis in NASH.18,19”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18]

      Not checked in the free run.

    • cites [19]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent placebo-controlled trial of ursodiol in NASH found that a proportion of patients receiving placebo had decreases in steatosis, but that improvements in inflammation and cell injury were uncommon.

    “A recent placebo-controlled trial of ursodiol in NASH found that a proportion of patients receiving placebo had decreases in steatosis, but that improvements in inflammation and cell injury were uncommon.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another TZD, rosiglitazone, has been shown to reduce hepatic fat content and improve biochemical evidence of hepatic inflammation in patients with NASH.

    “Another TZD, rosiglitazone has been shown to reduce hepatic fat content and improve biochemical evidence of hepatic inflammation in patients with NASH.18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The primary outcome measure was improvement in hepatic histology using predetermined criteria.

    “The primary outcome measure was an improvement in hepatic histology using predetermined criteria (see Histological Analysis section).”
    • Also stated in: § Histological Analysis. · plain
      “The primary outcome measure for this study was improvement in liver histology as assessed by the NASH activity index.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All data were analyzed on an intention-to-treat basis.

    “All data were analyzed on an intention-to-treat basis.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Troglitazone lowered serum aminotransferase levels and improved hepatic histology in patients with NASH.

    “Troglitazone, the first TZD to become commercially available, was found to lower serum aminotransferase levels and improve hepatic histology in patients with NASH, 17 but its potential for hepatotoxicity led to its subsequent withdrawal from use.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Both adverse reactions were believed to be unrelated to pioglitazone therapy.

    “Both adverse reactions were believed to be unrelated to pioglitazone therapy, and both patients continued to take pioglitazone during these episodes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The primary cause of steatosis is thought to be insulin resistance, which causes increased lipolysis and delivery of free fatty acids to the liver.

    “The primary cause of steatosis is thought to be insulin resistance, which causes increased lipolysis and delivery of free fatty acids to the liver.12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TZDs improve insulin resistance by increasing glucose disposal in muscle and decreasing hepatic glucose output.

    “The TZDs improve insulin resistance by increasing glucose disposal in muscle and decreasing hepatic glucose output.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Biguanides and thiazolidinediones have shown promising results in animal models of NASH and in small pilot studies in humans.

    “Indeed, both the biguanides and the thiazolidinediones (TZDs), two classes of antidiabetic drugs that increase insulin sensitivity, have shown promising results in animal models of NASH and in small pilot studies in humans.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] source

      Not checked in the free run.

    • cites [16] source

      Not checked in the free run.

    • cites [34]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PPARγ is expressed at the highest level in adipocytes, where it promotes cell differentiation and decreases lipolysis and free fatty acid release.

    “This nuclear receptor is expressed at the highest level in adipocytes, where it promotes cell differentiation 27 and decreases lipolysis and free fatty acid release.28”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27]

      Not checked in the free run.

    • cites [28] source

      Not checked in the free run.

29 of 29

  • The paper relies on this without support.

    There is no proven beneficial therapy for NASH.

    “While there is no proven beneficial therapy for NASH, its association with insulin resistance has provided the rationale for evaluation of medical therapies that increase insulin sensitivity.14”

  • The paper relies on this without support.

    A decrease in the NASH activity index of at least 3 points with improvements of at least 1 point in each of steatosis, parenchymal inflammation, and hepatocellular injury represents a clinically meaningful histological improvement.

    “Improvement was defined as a decrease in the NASH activity index of at least 3 points with improvements of at least 1 point for each of the three features.”

  • The paper relies on this without support.

    The natural progression of hepatic histology in NASH is not well defined.

    “The natural progression of hepatic histology in NASH is not well defined.”

  • The paper relies on this without support.

    A combination of histological improvements in all major components of NASH has not been found to improve spontaneously.

    “a combination of features that have not been found to improve spontaneously.”

  • The paper relies on this without support.

    Patients with NASH are usually overweight or obese.

    “Patients with NASH are usually overweight or obese, and therapies that lead to further weight gain must be viewed with caution.”

  • The paper relies on this without support.

    The mechanisms of action of the TZDs are not fully understood.

    “The mechanisms of action of the TZDs are not fully understood.”

  • The paper relies on this without support.

    PPARγ is expressed in adipose tissue, muscle, and the liver.

    “a nuclear receptor expressed in adipose tissue, muscle, and the liver.”

  • The paper relies on this without support.

    Serum ALT levels have been reported to improve with several medical therapies of NASH, including vitamin E, ursodiol, and metformin.

    “Serum ALT levels have been reported to improve with several medical therapies of NASH, including vitamin E, ursodiol, and metformin.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Liver biopsy specimens were scored using a previously validated system developed to assess NASH activity.

    “The extents of portal and parenchymal inflammation, steatosis, ballooning, presence of Mallory bodies, and fibrosis in liver biopsy specimens were scored using a previously validated system developed to assess NASH activity.”

    From Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy† (2005) · cites this paper as [14]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Baseline NASH count conflicts with patient description

    Minor

    Table 3 reports NASH in 17 of 18 patients at baseline, whereas the Results state that liver histology showed NASH in all enrolled patients.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Sanyal, 2002, A randomized controlled pilot study of pioglitazone and vitamin E versus Vitamin E for nonalcoholic steatohepatitis. abstract., HEPATOLOGY, 36, 875A
  2. Nair, 2002, Metformin in nonalcoholic steatohepatitis (NASH): efficacy and safety, a preliminary report. abstract., Gastroenterology, 122, 4A

Cited by

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Related

Authors
Promrat, K., Lutchman, G., Uwaifo, G. I., Freedman, R. J., Soza, A., Heller, T., Doo, E., Ghany, M., Premkumar, A., Park, Y., Liang, J. T., Yanovski, J. A., Kleiner, D. E., & Hoofnagle, J. H.
Affiliations
  • National Institutes of Health (US)
  • National Institute of Diabetes and Digestive and Kidney Diseases (US)
  • United States Department of Health and Human Services (US)
  • National Cancer Institute (MY)
Corresponding author
Hoofnagle, Jay H.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2004-01
Volume
39
Issue
1
Pages
188-196
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.20012
OpenAlex
W2029811522
Semantic Scholar
90426913059d50b66252bba9648512ab0bd3355c
Cited by
726
References
31
Citations by year
2026: 3 · 2025: 5 · 2024: 1 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 10 · 2019: 11 · 2018: 17 · 2017: 19 · 2016: 25 · 2015: 28 · 2014: 19 · 2013: 28 · 2012: 25
FWCI
66.35
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 4261 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health and Human Services
  • National Institutes of Health (Z01-HD-00641)
  • NIH Clinical Center
  • National Institute on Minority Health and Health Disparities
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (ZO1 HD00641, Z01HD000641)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
Keywords
nonalcoholic steatohepatitis, pioglitazone, insulin sensitizers, insulin resistance, metabolic syndrome, hepatic steatosis, liver fibrosis, alanine aminotransferase, body composition, adiposity, liver histopathology, drug safety
MeSH terms
Pioglitazone, Adult, Alanine Transaminase, Aspartate Aminotransferases, Fatty Liver, Female, Glucose Tolerance Test, Hepatitis, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Pilot Projects, Prospective Studies, Treatment Outcome, Thiazolidinediones

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