The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index; none of the 16 sources its claims cite is checked for support yet.
A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis
Open accessAbstract
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.)
Overview
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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Serum ALT levels fell from an average of 99 U/L at baseline to 40 U/L at 48 weeks (P Ͻ 0.01).”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Biochemical Responses (Table 2).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Waist circumferences did not change”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Anthropometric Results (Table 4).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“significant increases in total fat mass (ϩ3.1 Ϯ 3.6 kg, P ϭ 0.002)”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Anthropometric Results (Table 4).
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were no significant changes in total cholesterol, triglycerides, LDL and HDL cholesterol levels.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Biochemical Responses (Table 2).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ten of these 12 (83%) also had normal ALT levels at the end of therapy.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Histological Responses (Table 3).
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar improvements occurred in serum AST and alkaline phosphatase values.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Biochemical Responses (Table 2).
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fibrosis scores were unchanged in four (22%)”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Histological Responses (Table 3).
Strength:plain· not yet calibratedn = 4Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“little or no change in lean body mass (ϩ0.2 Ϯ 2.2 kg, P ϭ not significant)”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Anthropometric Results (Table 4).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“increased in three patients (17%)”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Histological Responses (Table 3).
Strength:plain· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“waist-to-hip ratios decreased significantly (P ϭ 0.004)”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Anthropometric Results (Table 4).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 20
- Probably not a substantial claim. 11
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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%).”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Anthropometric Results (Table 4).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Biochemical Responses (Table 2).
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Histological Responses (Table 3). · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The ALT decreases were gradual, beginning after 4 weeks of treatment, and reaching lowest levels between 40 and 48 weeks (Fig. 1).”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Biochemical Responses (Table 2).
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One patient had a myocardial infarction during therapy, and another suffered recurrent autoimmune uveitis during the study period.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Side Effects and Adverse Events.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No patient developed anemia or clinically apparent edema, reported side effects of pioglitazone.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Side Effects and Adverse Events.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Lean mass (kg) 56.4 Ϯ 12.1 56.6 Ϯ 11.9 0.640”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Frequently Sampled Intravenous Glucose Tolerance Test (Table 5).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All 18 patients enrolled had improvements in serum ALT levels, which became normal in 72%.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Anthropometric Results (Table 4). · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the main side effects were weight gain (averaging 4%) and an increase in total body adiposity”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Frequently Sampled Intravenous Glucose Tolerance Test (Table 5).
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Side Effects and Adverse Events.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One patient discontinued therapy after 3 weeks because of dizziness.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Side Effects and Adverse Events.
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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]”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Histological Analysis.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results underscore the importance of hepatic histology as an endpoint for trials of therapy in NASH.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Patient Population.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
What the sources say
- Not checked yetcites [18]
- Not checked yetcites [19]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
What the sources say
- Not checked yetcites [30] source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Another TZD, rosiglitazone has been shown to reduce hepatic fat content and improve biochemical evidence of hepatic inflammation in patients with NASH.18”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
What the sources say
- Not checked yetcites [18]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Patient Population.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Also stated in: § Histological Analysis. · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All data were analyzed on an intention-to-treat basis.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Statistical Analyses.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
What the sources say
- Not checked yetcites [17] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both adverse reactions were believed to be unrelated to pioglitazone therapy, and both patients continued to take pioglitazone during these episodes.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Side Effects and Adverse Events.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
What the sources say
- Not checked yetcites [12] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“The TZDs improve insulin resistance by increasing glucose disposal in muscle and decreasing hepatic glucose output.26”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
What the sources say
- Not checked yetcites [26] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Abstract
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ A Pilot Study of Pioglitazone Treatment for Nonalcoholic Steatohepatitis > Discussion
What the sources say
- Not checked yetcites [27]
- Not checked yetcites [28] source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.”
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?
In the citing paper
“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
MinorTable 3 reports NASH in 17 of 18 patients at baseline, whereas the Results state that liver histology showed NASH in all enrolled patients.
“Presence of NASH (%) 17 (94) 6 (33) <0.01”
“Liver histology showed NASH in all patients, with the NASH activity index ranging from 3 to 11.”
Citations
Cites
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Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
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Katz, A., Nambi, S. S., Mather, K., Baron, A. D., Follmann, D. A., Sullivan, G., & Quon, M. J. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.7.6661 · Cited by 3,931 · cited 1×
“Presence of NASH (%) 17 (94) 6 (33) <0.”
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
MATTEONI, C., YOUNOSSI, Z., GRAMLICH, T., BOPARAI, N., LIU, Y., & MCCULLOUGH, A. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70506-8 · Cited by 3,345
Ludwig, J., Viggiano, T. R., McGill, D. B., & Ott, B. J. (1980) · Mayo Clinic Proceedings · doi:10.1016/s0025-6196(24)00530-5 · Cited by 2,903
Nonalcoholic Fatty Liver Disease
Marchesini, G., Brizi, M., Bianchi, G., Tomassetti, S., Bugianesi, E., Lenzi, M., McCullough, A. J., Natale, S., Forlani, G., & Melchionda, N. (2001) · Diabetes · doi:10.2337/diabetes.50.8.1844 · Cited by 2,581
Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities
Sanyal, A. J., Campbell–Sargent, C., Mirshahi, F., Rizzo, W. B., Contos, M. J., Sterling, R. K., Luketic, V. A., Shiffman, M. L., & Clore, J. N. (2001) · Gastroenterology · doi:10.1053/gast.2001.23256 · Cited by 2,078
Powell, E. E., Cooksley, G. W. E., Hanson, R., Searle, J., Halliday, J. W., & Powell, L. W. (1990) · Hepatology · doi:10.1002/hep.1840110114 · Cited by 1,473
Flagged first, then by citations
Research works printed but not linked: 2
- Sanyal, 2002, A randomized controlled pilot study of pioglitazone and vitamin E versus Vitamin E for nonalcoholic steatohepatitis. abstract., HEPATOLOGY, 36, 875A
- Nair, 2002, Metformin in nonalcoholic steatohepatitis (NASH): efficacy and safety, a preliminary report. abstract., Gastroenterology, 122, 4A
Cited by
Sorted by citations
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y., Torbenson, M. S., Unalp‐Arida, A., et al. (2005) · Hepatology · doi:10.1002/hep.20701 · Cited by 10,791
Self-citationMechanisms of fatty acid-induced inhibition of glucose uptake.
Boden, G., Chen, X., Ruiz, J., White, J. V., & Rossetti, L. (1994) · Journal of Clinical Investigation · doi:10.1172/jci117252 · Cited by 3,720
Donnelly, K. L., Smith, C. I., Schwarzenberg, S. J., Jessurun, J., Boldt, M. D., & Parks, E. J. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23621 · Cited by 3,604
“Indeed, NAFLD patients treated with insulin-sensitizing agents show marked improvement in their condition (28, 30, 31).”
BackgroundPioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
Sanyal, A. J., Chalasani, N., Kowdley, K. V., McCullough, A., Diehl, A. M., Bass, N. M., Neuschwander-Tetri, B. A., Lavine, J. E., Tonascia, J., Unalp, A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0907929 · Cited by 3,327
Self-citationHepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver
Friedman, S. L. (2008) · Physiological Reviews · doi:10.1152/physrev.00013.2007 · Cited by 2,842
Metadata
- 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
- Published
- 2004-01
- Volume
- 39
- Issue
- 1
- Pages
- 188-196
- ISSN
- 0270-9139 (ISSN-L)
- 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
- bronze
- doi.org
- 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 › Hepatology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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