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
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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
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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
Vilar-Gomez, E., Martinez-Perez, Y., Calzadilla-Bertot, L., Torres-Gonzalez, A., Gra-Oramas, B., Gonzalez-Fabian, L., Friedman, S. L., Diago, M., & Romero-Gomez, M. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.005 · Cited by 2,492
Nonalcoholic Fatty Liver Disease: From Steatosis to Cirrhosis
Farrell, G. C., & Larter, C. Z. (2006) · Hepatology · doi:10.1002/hep.20973 · Cited by 2,428
Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., & Shoelson, S. E. (2005) · Nature Medicine · doi:10.1038/nm1166 · Cited by 2,245
“We isolated IKK complexes from mouse liver lysates using anti-IKK-γ antibodies (PharMingen) coupled to protein A-Sepharose, and conducted in vitro kinase assays at 30 °C by adding [γ-32P]ATP and 2 μg of GST-IκBα (1-54)12.”
MethodSampling Variability of Liver Biopsy in Nonalcoholic Fatty Liver Disease
Ratziu, V., Charlotte, F., Heurtier, A., Gombert, S., Giral, P., Bruckert, E., Grimaldi, A., Capron, F., & Poynard, T. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.03.084 · Cited by 2,106
Fat and Beyond: The Diverse Biology of PPARγ
Tontonoz, P., & Spiegelman, B. M. (2008) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.77.061307.091829 · Cited by 2,085
A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis
Belfort, R., Harrison, S. A., Brown, K., Darland, C., Finch, J., Hardies, J., Balas, B., Gastaldelli, A., Tio, F., Pulcini, J., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa060326 · Cited by 1,827
Yki-Järvinen, H. (2004) · New England Journal of Medicine · doi:10.1056/nejmra041001 · Cited by 1,830
Molecular mediators of hepatic steatosis and liver injury
Browning, J. D., & Horton, J. D. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422422 · Cited by 1,772
“Pilot studies in humans using pioglitazone (57, 58) and rosiglitazone (59) have demonstrated the efficacy of these agents in reducing hepatic fat, presumably as a consequence of the molecular events summarized in Figure 2.”
Nonalcoholic fatty liver disease
Adams, L. A. (2005) · Canadian Medical Association Journal · doi:10.1503/cmaj.045232 · Cited by 1,658
“sitivity by activating the peroxisome proliferator-activated receptor gamma (PPARγ) and have shown promise in pilot trials involving patients with NASH, although weight gain has been a troublesome side effect.(78,79) In addition, the initial PPARγ agonist troglitazone was withdrawn because of its hepatotoxic effects.”
BackgroundRandomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis
Promrat, K., Kleiner, D. E., Niemeier, H. M., Jackvony, E., Kearns, M., Wands, J. R., Fava, J. L., & Wing, R. R. (2010) · Hepatology · doi:10.1002/hep.23276 · Cited by 1,330
Self-citationPostic, C., & Girard, J. R. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34275 · Cited by 1,243
Cusi, K., Orsak, B., Bril, F., Lomonaco, R., Hecht, J., Ortiz-Lopez, C., Tio, F., Hardies, J., Darland, C., Musi, N., et al. (2016) · Annals of Internal Medicine · doi:10.7326/m15-1774 · Cited by 1,024
“001 Aspartate aminotransferase level, U/L 38 (31) 29 (10) −14 (−22 to −6) 0.”
Targher, G., Bertolini, L., Padovani, R., Rodella, S., Tessari, R., Zenari, L., Day, C. P., & Arcaro, G. (2007) · Diabetes Care · doi:10.2337/dc06-2247 · Cited by 1,004
Beyond insulin resistance in NASH: TNF-α or adiponectin?
Hui, J. M., Hodge, A., Farrell, G. C., Kench, J. G., Kriketos, A., & George, J. (2004) · Hepatology · doi:10.1002/hep.20280 · Cited by 942
Insulin resistance: a metabolic pathway to chronic liver disease
Bugianesi, E., McCullough, A. J., & Marchesini, G. (2005) · Hepatology · doi:10.1002/hep.20920 · Cited by 900
The Role of Insulin Resistance in Nonalcoholic Fatty Liver Disease
Utzschneider, K. M., & Kahn, S. E. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-0587 · Cited by 874
PPAR and human metabolic disease
Semple, R. K. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28003 · Cited by 833
Mitochondrial dysfunction in Nash: causes, consequences and possible means to prevent it
Begriche, K., Igoudjil, A., Pessayre, D., & Fromenty, B. (2006) · Mitochondrion · doi:10.1016/j.mito.2005.10.004 · Cited by 753
Aithal, G. P., Thomas, J. A., Kaye, P. V., Lawson, A., Ryder, S. D., Spendlove, I., Austin, A. S., Freeman, J. G., Morgan, L., & Webber, J. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.047 · Cited by 721
Bugianesi, E., Gentilcore, E., Manini, R., Natale, S., Vanni, E., Villanova, N., David, E., Rizzetto, M., & Marchesini, G. (2005) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2005.41583.x · Cited by 690
“However, the use of use of enzyme levels as surrogate markers is supported by the association of higher aminotransferases with more severe histological findings in cross-sectional studies (4), and by the finding that reduced aminotransferases are associated with improved histology in intervention studies (7, 12, 13, 2…”
BackgroundMethodRecent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD)
Musso, G., Gambino, R. J., & Cassader, M. (2008) · Progress in Lipid Research · doi:10.1016/j.plipres.2008.08.001 · Cited by 691
Ratziu, V., Giral, P., Jacqueminet, S., Charlotte, F., Hartemann–Heurtier, A., Serfaty, L., Podevin, P., Lacorte, J., Bernhardt, C., Bruckert, E., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.03.078 · Cited by 625
Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis
Vuppalanchi, R., & Chalasani, N. (2008) · Hepatology · doi:10.1002/hep.22603 · Cited by 568
Ding, X., Saxena, N. K., Lin, S., Gupta, N., & Anania, F. A. (2006) · Hepatology · doi:10.1002/hep.21006 · Cited by 557
“peptide-1(7-37) does not stimulate either hepatic glycogenolysis or keto-”
BackgroundSystematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis
Argo, C. K., Northup, P. G., Al‐Osaimi, A. M. S., & Caldwell, S. H. (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.03.019 · Cited by 560
“This group consisted of studies of lifestyle interventions (reduced calorie diets and physical activity, either alone or in combination [45–52]) and medications (thiazolidinediones [53–60], metformin”
BackgroundNon-alcoholic fatty liver disease and increased risk of cardiovascular disease
Targher, G., & Arcaro, G. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.08.021 · Cited by 551
Tolman, K. G., Fonseca, V. A., Dalpiaz, A. S., & Tan, M. H. (2007) · Diabetes Care · doi:10.2337/dc06-1539 · Cited by 533
Harnois, D. M. (2009) · Yearbook of Gastroenterology · doi:10.1016/s0739-5930(09)79298-0 · Cited by 505
Farzaei, M. H., Zobeiri, M., Parvizi, F., El‐Senduny, F. F., Marmouzi, I., Coy-Barrera, E. D., Naseri, R., Nabavi, S. M., Rahimi, R., & Abdollahi, M. R. (2018) · Nutrients · doi:10.3390/nu10070855 · Cited by 489
“Thiazolidinediones (TZD) increases insulin sensitivity and lipid oxidation; preventing their accumulation in the liver [26,27].”
BackgroundRotman, Y., Koh, C., Zmuda, J. M., Kleiner, D. E., & Liang, J. T. (2010) · Hepatology · doi:10.1002/hep.23759 · Cited by 479
“Gamma glutamyl transferase 45 (5-793) 33 (5-208) 0.”
Self-citationNatural history of nonalcoholic steatohepatitis: A longitudinal study of repeat liver biopsies
Fassio, E., �lvarez, E., Dom�nguez, N., Landeira, G., & Longo, C. (2004) · Hepatology · doi:10.1002/hep.20410 · Cited by 470
Pathology of Nonalcoholic Fatty Liver Disease
Yeh, M. M., & Brunt, E. M. (2007) · American Journal of Clinical Pathology · doi:10.1309/rtpm1py6ygbl2g2r · Cited by 469
Yokohama, S., Yoneda, M., Haneda, M., Okamoto, S., Okada, M., Aso, K., Hasegawa, T., Tokusashi, Y., Miyokawa, N., & Nakamura, K. (2004) · Hepatology · doi:10.1002/hep.20420 · Cited by 459
Non-alcoholic fatty liver disease, obesity and the metabolic syndrome
Dietrich, P., & Hellerbrand, C. (2014) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2014.07.008 · Cited by 468
Histopathology of nonalcoholic fatty liver disease
Brunt, E. M. (2010) · World Journal of Gastroenterology · doi:10.3748/wjg.v16.i42.5286 · Cited by 448
Huang, M. A., Greenson, J. K., Chao, C., Anderson, L., Peterman, D., Jacobson, J. A., Emick, D. M., Lok, A. S.-F., & Conjeevaram, H. S. (2005) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2005.41334.x · Cited by 441
“Despite variations in criteria used to define histologic improvement, the proportion of patients in our study who successfully completed therapy and showed a histologic response was remarkably similar to the two recent studies on thiazolidinediones, 60% versus 67% and 59% (14, 15).”
BackgroundResultSanyal, A. J., MOFRAD, P., Contos, M. J., Sargeant, C., Luketic, V. A., Sterling, R. K., Stravitz, R. T., Shiffman, M. L., Clore, J. N., & Mills, A. S. (2004) · Clinical Gastroenterology and Hepatology · doi:10.1016/s1542-3565(04)00457-4 · Cited by 436
Chen, J., Talwalkar, J. A., Yin, M., Glaser, K. J., Sanderson, S. O., & Ehman, R. L. (2011) · Radiology · doi:10.1148/radiol.11101942 · Cited by 434
Kim, C.-W., Addy, C., Kusunoki, J., Anderson, N. N., Deja, S., Fu, X., Burgess, S. C., Li, C., Ruddy, M., Chakravarthy, M., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.009 · Cited by 419
“A pioglitazone arm was included as a comparator since it has previously been shown to reduce liver TGs and fibrosis (Bajaj et al., 2003; Belfort et al., 2006; Cusi et al., 2016; Musso et al., 2017; Promrat et al., 2004; Sanyal et al., 2010).”
InfluentialNonalcoholic fatty liver disease and the metabolic syndrome
Marchesini, G., Marzocchi, R., Agostini, F., & Bugianesi, E. (2005) · Current Opinion in Lipidology · doi:10.1097/01.mol.0000174153.53683.f2 · Cited by 421
Liver Markers and Development of the Metabolic Syndrome
Hanley, A. J., Williams, K., Festa, A., Wagenknecht, L. E., D’Agostino, R. B., & Haffner, S. M. (2005) · Diabetes · doi:10.2337/diabetes.54.11.3140 · Cited by 421
Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease
Rotman, Y., & Sanyal, A. J. (2016) · Gut · doi:10.1136/gutjnl-2016-312431 · Cited by 420
Nonalcoholic Fatty Liver Disease: Pathologic Patterns and Biopsy Evaluation in Clinical Research
Kleiner, D. E., & Brunt, E. M. (2012) · Seminars in Liver Disease · doi:10.1055/s-0032-1306421 · Cited by 402
Self-citationPortal chronic inflammation in nonalcoholic fatty liver disease (NAFLD)
Brunt, E. M., Kleiner, D. E., Wilson, L., Ünalp, A., Behling, C. A., Lavine, J. E., & Neuschwander‐Tetri, B. A. (2008) · Hepatology · doi:10.1002/hep.22724 · Cited by 387
Self-citationNonalcoholic Fatty Liver Disease: Cytokine-Adipokine Interplay and Regulation of Insulin Resistance
Tilg, H., & Hotamışlıgil, G. S. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.05.054 · Cited by 391
Elevations in Markers of Liver Injury and Risk of Type 2 Diabetes
Hanley, A. J., Williams, K., Festa, A., Wagenknecht, L. E., D’Agostino, R. B., Kempf, J., Zinman, B., & Haffner, S. M. (2004) · Diabetes · doi:10.2337/diabetes.53.10.2623 · Cited by 386
Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis
Anderson, N., & Borlak, J. T. (2008) · Pharmacological Reviews · doi:10.1124/pr.108.00001 · Cited by 395
Evolving Concepts in the Pathogenesis of NASH: Beyond Steatosis and Inflammation
Peverill, W., Powell, L. W., & Skoien, R. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15058591 · Cited by 387
“in abstract form only, of 18 months of pioglitazone in diabetic or pre-diabetic patients with biopsy-proven NASH demonstrated a significant reduction in fibrosis versus placebo in addition to other markers of disease activity [360].”
BackgroundMetformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial
Nair, S., Diehl, A. M., Wiseman, M., Farr, G. H., & Perrillo, R. P. (2004) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2004.02025.x · Cited by 369
PPARs: diverse regulators in energy metabolism and metabolic diseases
Wang, Y.-X. (2010) · Cell Research · doi:10.1038/cr.2010.13 · Cited by 366
Ratziu, V., Charlotte, F., Bernhardt, C., Giral, P., Halbron, M., Naour, G. L., Hartemann–Heurtier, A., Bruckert, É., & Poynard, T. (2009) · Hepatology · doi:10.1002/hep.23270 · Cited by 366
“Steatosis, % 53 (18) 43 (21) 30 (17) 47 (22) 32 (20) 35 (15) NAS score 3.”
Dufour, J., Oneta, C. M., Gonvers, J., Bihl, F. K., Cerny, A., Cereda, J., Zala, J., Helbling, B., Steuerwald, M., & Zimmermann, A. (2006) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2006.09.025 · Cited by 360
Diagnosis and Therapy of Nonalcoholic Steatohepatitis
Torres, D. M., & Harrison, S. A. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.02.077 · Cited by 359
Effects of probiotics on nonalcoholic fatty liver disease: A meta-analysis
Ma, Y.-Y. (2013) · World Journal of Gastroenterology · doi:10.3748/wjg.v19.i40.6911 · Cited by 352
Nonalcoholic fatty liver disease: A review of current understanding and future impact
Charlton, M. (2004) · Clinical Gastroenterology and Hepatology · doi:10.1016/s1542-3565(04)00440-9 · Cited by 351
Nonalcoholic Fatty Liver Disease: A Review and Update
Lewis, J. R., & Mohanty, S. R. (2010) · Digestive Diseases and Sciences · doi:10.1007/s10620-009-1081-0 · Cited by 350
“[152], in a series of 18 patients, showed that treatment for 48 weeks with pioglitazone resulted in significant improvements in LFTs, steatosis, inflammation, and fibrosis.”
BackgroundTreatment of non-alcoholic fatty liver disease
Adams, L. A., & Angulo, P. (2006) · Postgraduate Medical Journal · doi:10.1136/pgmj.2005.042200 · Cited by 350
Quantification of Liver Fat with Magnetic Resonance Imaging
Reeder, S. B., & Sirlin, C. B. (2010) · Magnetic Resonance Imaging Clinics of North America · doi:10.1016/j.mric.2010.08.013 · Cited by 343
Abnormal Lipid and Glucose Metabolism in Obesity: Implications for Nonalcoholic Fatty Liver Disease
Parekh, S., & Anania, F. A. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.055 · Cited by 344
Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets
Brown, J. D., & Plutzky, J. (2007) · Circulation · doi:10.1161/circulationaha.104.475673 · Cited by 345
Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?
Asrih, M., & Jornayvaz, F. R. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.02.018 · Cited by 336
“Also, glitazones, which are peroxisome proliferatoractivated receptor g (PPARg) agonists, were found to be efficient in managing NAFLD, by notably decreasing liver fibrosis (Promrat et al., 2004).”
BackgroundMethodMerriman, R. B., Ferrell, L. D., Patti, M. G., Weston, S. R., Pabst, M. S., Aouizerat, B. E., & Bass, N. M. (2006) · Hepatology · doi:10.1002/hep.21346 · Cited by 325
Recent concepts in non‐alcoholic fatty liver disease
Adams, L. A., & Angulo, P. (2005) · Diabetic Medicine · doi:10.1111/j.1464-5491.2005.01748.x · Cited by 330
Boettcher, E., Csako, G., Pucino, F., Wesley, R., & Loomba, R. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2011.04912.x · Cited by 318
Leuschner, U. F. H., Lindenthal, B., Herrmann, G., Arnold, J. C., Rössle, M., Cordes, H., Zeuzem, S., Hein, J., & Berg, T. (2010) · Hepatology · doi:10.1002/hep.23727 · Cited by 317
Elevated Liver Function Tests in Type 2 Diabetes
Harris, E. H. (2005) · Clinical Diabetes · doi:10.2337/diaclin.23.3.115 · Cited by 307
Yokoo, T., Bydder, M., Hamilton, G., Middleton, M. S., Gamst, A. C., Wolfson, T. J., Hassanein, T., Patton, H. M., Lavine, J. E., Schwimmer, J. B., et al. (2009) · Radiology · doi:10.1148/radiol.2511080666 · Cited by 303
Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis
LOOMBA, R., LUTCHMAN, G., KLEINER, D. E., RICKS, M., FELD, J. J., BORG, B. B., MODI, A., NAGABHYRU, P., SUMNER, A. E., LIANG, T. J., et al. (2009) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2008.03869.x · Cited by 299
Self-citationYoneda, M., Mawatari, H., Fujita, K., Iida, H., Yonemitsu, K., Kato, S., Takahashi, H., Kirikoshi, H., Inamori, M., Nozaki, Y., et al. (2007) · Journal of Gastroenterology · doi:10.1007/s00535-007-2060-x · Cited by 294
Preiss, D., & Sattar, N. A. (2008) · Clinical Science · doi:10.1042/cs20070402 · Cited by 297
Histological assessment of non‐alcoholic fatty liver disease
Hübscher, S. G. (2006) · Histopathology · doi:10.1111/j.1365-2559.2006.02416.x · Cited by 292
“A number of systems have been proposed for assessing the severity of fatty liver disease.(31,42,100,104,147,148) The main features of a scheme devised by Brunt and colleagues, which has been most widely used for assessing disease severity in non-alcoholic steatohepatitis, are summarized in Table 4.”
BackgroundGastaldelli, A., Harrison, S. A., Belfort-Aguilar, R., Hardies, L. J., Balas, B., Schenker, S., & Cusi, K. (2009) · Hepatology · doi:10.1002/hep.23116 · Cited by 285
Valenti, L. V. C., Fracanzani, A. L., Dongiovanni, P., Bugianesi, E., Marchesini, G., Manzini, P. M., Vanni, E., & Fargion, S. R. (2007) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2007.01192.x · Cited by 289
Nonalcoholic Fatty Liver Disease
Adams, L. A., & Lindor, K. D. (2007) · Annals of Epidemiology · doi:10.1016/j.annepidem.2007.05.013 · Cited by 291
The role of the lipogenic pathway in the development of hepatic steatosis
Postic, C., & Girard, J. R. (2008) · Diabetes & Metabolism · doi:10.1016/s1262-3636(08)74599-3 · Cited by 307
“They can reduce hepatic and peripheral insulin resistance, decrease hepatic steatosis and attenuate the infl ammatory response [4-6].”
BackgroundHepatic MRI for Fat Quantitation
Fishbein, M. H., Castro, F., Cheruku, S. M., Jain, S., Webb, B., Gleason, T., & Stevens, W. R. (2005) · Journal of Clinical Gastroenterology · doi:10.1097/00004836-200508000-00012 · Cited by 277
Nonalcoholic Fatty Liver Disease: A Clinical Review
Sass, D. A., Chang, P., & Chopra, K. B. (2005) · Digestive Diseases and Sciences · doi:10.1007/s10620-005-1267-z · Cited by 267
“A small pilot study with pioglitazone for 1 year in 18 NASH patients without diabetes also resulted in significant improvements in insulin sensitivity, serum ALT, and histologic features (70).”
Fat in the liver and insulin resistance
Yki‐Järvinen, H. (2005) · Annals of Medicine · doi:10.1080/07853890510037383 · Cited by 269
“Two uncontrolled 48-week studies have examined whether patients with NASH benefit from pioglitazone or rosiglitazone treatment (73,74).”
BackgroundReview article: drug hepatotoxicity
Chang, C., & Schiano, T. D. (2007) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2007.03307.x · Cited by 268
Pathogenesis and management issues for non-alcoholic fatty liver disease
Duvnjak, M. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i34.4539 · Cited by 266
Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence
Cheng, H. S., Tan, W., Low, Z. S., Marvalim, C., Lee, J. Y. H., & Tan, N. S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205055 · Cited by 282
Foster, T., Budoff, M. J., Saab, S., Ahmadi, N., Gordon, C., & Guerci, A. D. (2010) · The American Journal of Gastroenterology · doi:10.1038/ajg.2010.299 · Cited by 260
Highly Purified Eicosapentaenoic Acid Treatment Improves Nonalcoholic Steatohepatitis
Tanaka, N., Sano, K., Horiuchi, A., Tanaka, E., Kiyosawa, K., & Aoyama, T. (2008) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0b013e31815591aa · Cited by 248
“Recently, there have been several reports demonstrating the efficacy of pioglitazone for NASH.(7-9) In contrast with EPA, the chief pharmacological effect of pioglitazone is an adiponectin-mediated improvement in insulin sensitivity and enhancement of hepatic fatty acid metabolism rather than modulation of proinflamma…”
BackgroundAthyros, V. G., Mikhailidis, D. P., Didangelos, T., Γιουλεμέ, Ό., Liberopoulos, E. N., Karagiannis, A. I., Kakafika, A. I., Τζιόμαλος, Κ., Burroughs, A. K., & Elisaf, M. (2006) · Current Medical Research and Opinion · doi:10.1185/030079906x104696 · Cited by 248
The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis†
Lutchman, G. A., Modi, A. A., Kleiner, D. E., Promrat, K., Heller, T., Ghany, M. G., Borg, B. B., Loomba, R. S., Liang, T. J., Premkumar, A., et al. (2007) · Hepatology · doi:10.1002/hep.21661 · Cited by 240
Self-citationTargher, G. (2007) · Diabetic Medicine · doi:10.1111/j.1464-5491.2007.02025.x · Cited by 245
Tanwar, S., Rhodes, F., Srivastava, A., Trembling, P. M., & Rosenberg, W. M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i2.109 · Cited by 261
Cross‐Talk between PPARγand Insulin Signaling and Modulation of Insulin Sensitivity
Leonardini, A., Laviola, L., Perrini, S., Natalicchio, A., & Giorgino, F. (2009) · PPAR Research · doi:10.1155/2009/818945 · Cited by 254
Pathology of fatty liver disease
Brunt, E. M. (2007) · Modern Pathology · doi:10.1038/modpathol.3800680 · Cited by 238
Therapies in non‐alcoholic steatohepatitis ( NASH )
Oseini, A. M., & Sanyal, A. J. (2017) · Liver International · doi:10.1111/liv.13302 · Cited by 244
Approach to the Pathogenesis and Treatment of Nonalcoholic Steatohepatitis
Medina, J., Fernández-Salazar, L. I., García-Buey, L., & Moreno‐Otero, R. (2004) · Diabetes Care · doi:10.2337/diacare.27.8.2057 · Cited by 229
Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy†
Javor, E. D., Ghany, M. G., Cochran, E. K., Oral, E. A., DePaoli, A. M., Premkumar, A., Kleiner, D. E., & Gorden, P. (2005) · Hepatology · doi:10.1002/hep.20672 · Cited by 228
Self-citationSafety and Tolerability of Pioglitazone in High-Risk Patients with Type 2 Diabetes
Dormandy, J., Bhattacharya, M., & van Troostenburg, A. (2009) · Drug Safety · doi:10.2165/00002018-200932030-00002 · Cited by 227
Insulin Resistance Accelerates a Dietary Rat Model of Nonalcoholic Steatohepatitis
Ota, T., Takamura, T., Kurita, S., Matsuzawa, N., Kita, Y., Uno, M., Akahori, H., Misu, H., Sakurai, M., Zen, Y., et al. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.10.014 · Cited by 227
Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes
DeFronzo, R. A., Inzucchi, S., Abdul-Ghani, M., & Nissen, S. E. (2019) · Diabetes and Vascular Disease Research · doi:10.1177/1479164118825376 · Cited by 223
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.
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