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Cited by 228Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLipid metabolism and disorders

Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy†

Open access
Javor, Edward D., Ghany, Marc G., Cochran, Elaine K., Oral, Elif Arioglu, DePaoli, Alex M., Premkumar, Ahalya, Kleiner, David E., Gorden, Phillip·2005·Hepatology
DOI 10.1002/hep.20672
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Abstract

Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation. In the liver, this is associated with steatosis, potentially leading to nonalcoholic steatohepatitis (NASH). We investigated the prevalence of NASH and the effect of leptin replacement in these patients. Ten patients with either generalized lipodystrophy (8 patients) or Dunnigan's partial lipodystrophy (2 patients) were included in this analysis. Paired liver biopsy specimens were obtained at baseline and after treatment with recombinant methionyl human leptin (r-metHuLeptin), mean duration 6.6 months. 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. Histological disease activity was defined as the sum of ballooning, steatosis, and parenchymal inflammation scores. We concurrently tested serum triglycerides and aminotransferases and estimations of liver volume and fat content by magnetic resonance imaging. Eight of 10 patients met histological criteria for NASH at baseline. After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P = .006) and ballooning injury (P = .005), with a reduction of mean NASH activity by 60% (P = .002). Fibrosis was unchanged. Significant reductions were seen in mean serum triglycerides (1206-->226 mg/dL, P = .002), glucose (220-->144 mg/dL, P = .02), insulin (46.4-->24.8 muIU/mL, P = .004), ALT (54-->24 U/L, P = .02), AST (47-->22 U/L, P = .046), liver volume (3209-->2391 cm(3), P = .007), and liver fat content (31-->11%, P = .006). In conclusion, r-metHuLeptin therapy significantly reduced triglycerides, transaminases, hepatomegaly, and liver fat content. These reductions were associated with significant reductions in steatosis and the hepatocellular ballooning injury seen in NASH.

AI snapshot

Written from the paper’s full text.

TL;DR

In 10 patients with severe lipodystrophy and hypoleptinemia, recombinant methionyl human leptin (r-metHuLeptin) treatment was associated with significant histological improvement in nonalcoholic steatohepatitis (NASH), alongside reductions in liver fat, liver volume, triglycerides, and aminotransferases. Fibrosis did not change over the mean 6.6-month treatment period.

Key findings

  • Eight of 10 patients met histological criteria for NASH at baseline; after r-metHuLeptin, 6 of the 8 (75%) no longer met those criteria, and the group prevalence of NASH fell from 80% to 20% (P = .03).
  • Mean NASH activity score decreased by 60%, from 5.3 ± 0.8 to 2.1 ± 0.4 (P = .002), with significant improvements in steatosis (1.7 ± 0.4 to 0.4 ± 0.2; P = .006) and ballooning injury (1.5 ± 0.4 to 0.3 ± 0.2; P = .005); fibrosis was unchanged (1.9 ± 0.4 to 1.9 ± 0.5; P = .1).
  • Mean serum triglycerides fell from 1,206 ± 590 to 226 ± 57 mg/dL (P = .002), fasting glucose from 220 ± 27 to 144 ± 13 mg/dL (P = .02), fasting insulin from 46.4 ± 13.0 to 24.8 ± 7.4 IU/mL (P = .004), ALT from 54 ± 13 to 24 ± 4 U/L (P = .02), and AST from 47 ± 11 to 22 ± 2 U/L (P = .046).
  • Mean liver volume decreased from 3,209 ± 348 to 2,391 ± 254 cm³ (P = .007), and mean liver fat by MRI decreased from 31% ± 7% to 11% ± 6% (P = .006).

Methods

  • Open-label pilot study of r-metHuLeptin in 10 patients with severe lipodystrophy: 4 congenital generalized lipodystrophy, 4 acquired generalized lipodystrophy, and 2 Dunnigan’s partial lipodystrophy; 8 female and 2 male, age range 17–67 years.
  • Paired liver biopsies were obtained before and after treatment (mean duration 6.6 ± 1.4 months); biopsies were scored by a single hepatopathologist blinded to clinical data and biopsy sequence using a previously validated NASH scoring system.
  • Concurrent laboratory testing and MRI assessments of liver volume and liver fat were performed; paired t tests or Wilcoxon signed-rank tests compared baseline and post-treatment means, and Spearman rank correlation assessed relationships between NASH score and metabolic/imaging variables.

Limitations

  • The paper states limitations including relatively small sample size, variable interval between liver biopsies, study of a rare disease with uncertain general relationship to NASH, lack of placebo control, and no evidence that results in hypoleptinemic patients apply to broader NASH patients with higher serum leptin concentrations.
  • The authors also state that the short interval between biopsies was the primary factor limiting observed change in fibrosis.
  • Evident from the text: this was an open-label, single-arm pilot study without a placebo or untreated comparator, and the sample was predominantly female, which may limit generalizability.

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

Integrity signals

Registry

Crossref · 10.1002/hep.20672

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 13 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Mean fasting insulin decreased significantly after r-metHuLeptin therapy (P = .004).

    “Fasting insulin (IU/mL) 46.4 Ϯ 13.0 24.8 Ϯ 7.4 .004”
    Quote in the paperNot a substantial claim
  • Findingown data

    Reductions in NASH scores were strongly correlated with reductions in liver volumes, liver fat measured by MRI, serum transaminases, triglycerides, fasting insulin, and fasting glucose values.

    “The reductions in NASH scores were strongly correlated with reductions in liver volumes, liver fat measured by MRI, serum transami-nases, triglycerides, fasting insulin, and fasting glucose values (Table 3).”
    • Also stated in: § Discussion · plain
      “There were significant correlations between the NASH activity scores and MRI estimations of liver volume and fat content, serum transaminases, triglycerides, fasting insulin, and fasting glucose values.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Mean ALT decreased significantly after r-metHuLeptin therapy (P = .02).

    “ALT (U/L) 54 Ϯ 13 24 Ϯ 4 .02”
    Quote in the paperSubstantial claim
  • Findingown data

    Mean fasting glucose decreased significantly after r-metHuLeptin therapy (P = .02).

    “Fasting glucose (mg/dL) 220 Ϯ 27 144 Ϯ 13 .02”
    Quote in the paperNot a substantial claim
  • Findingown data

    After treatment with r-metHuLeptin, steatosis improved significantly (P = .006).

    “After treatment with r-metHuLeptin, repeat histological examinations showed significant improvements in steatosis (P ‫؍‬ .006)and ballooning injury (P ‫؍‬ .005),with a reduction of mean NASH activity by 60% (P ‫؍‬ .002).”
    • Also stated in: § Discussion · plain
      “Steatosis 1.7 Ϯ 0.4 0.4 Ϯ 0.2 .006”
    Quote in the paperSubstantial claim
  • May combine two claims. 3
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    Of the 8 patients with ballooning hepatocellular injury at baseline, only 3 had ballooning identified in follow-up, and in all 3 the degree was mild and confined to zone 3.

    “Similarly, of the 8 patients with ballooning hepatocellular injury, only 3 had ballooning identified in follow-up, and in all 3 the degree was mild and confined to zone 3.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Mallory bodies did not change significantly after treatment (P = .1).

    “Mallory bodies 0.6 Ϯ 0.3 0.2 Ϯ 0.2 .1”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All 8 patients with steatohepatitis had ballooning hepatocellular injury varying from mild changes only in zone 3 to diffuse, panacinar ballooning changes and fibrosis that varied from mild perisinusoidal zone 3 fibrosis to cirrhosis.

    “In addition to steatosis and inflammation, all 8 patients with steatohepatitis had ballooning hepatocellular injury varying from mild changes only in zone 3 to diffuse, panacinar ballooning changes and fibrosis that varied from mild perisinusoidal zone 3 fibrosis to cirrhosis.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Only 3 patients had identifiable Mallory bodies at baseline, despite staining all biopsy specimens with anti-ubiquitin.

    “Only 3 patients had identifiable Mallory bodies, despite staining all biopsy specimens with anti-ubiquitin.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The causative relationship of the correlations between NASH activity scores and metabolic parameters to the clinical situation remains uncertain.

    “However, the causative relationship of these correlations to the clinical situation remains uncertain.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    A liver specimen of at least 15 mm with a minimum of 10 portal tracts was considered adequate for evaluation.

    “A liver specimen of at least 15 mm with a minimum of 10 portal tracts was considered adequate for evaluation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The modified Dixon method was used to assess the hepatic fat fraction.

    “The modified Dixon method was used to assess the hepatic fat fraction.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] source

      Not checked in the free run.

    • cites [13] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] source

      Not checked in the free run.

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

    Premisecitation

    Steatosis is believed to sensitize the liver to metabolic injury, leading to inflammation, necrosis, and fibrosis.

    “Steatosis is believed to sensitize the liver to metabolic injury, leading to inflammation, necrosis, and fibrosis.2,[5][6][7]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] 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 conductnone given

    Liver biopsy specimens were scored prospectively by a single hepatopathologist blinded to the clinical data and sequence of the biopsies.

    “Biopsy specimens were scored prospectively by a single hepatopathologist blinded to the clinical data and sequence of the biopsies using a previously described scoring method developed for NASH.14”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The assessment and severity of NASH is made histologically based on the patterns and degrees of hepatic steatosis, inflammation, and injury, in the absence of significant alcohol consumption.

    “The assessment and severity of NASH is made histologically based on the patterns and degrees of hepatic steatosis, inflammation, and injury, in the absence of significant alcohol consumption.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] source

      Not checked in the free run.

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

    Study design and conductnone given

    The study was not placebo-controlled.

    “Other limitations of this study include its relatively small sample size, the variable interval between liver biopsies, the study of a rare disease in terms of its general relationship to NASH, and the fact that this study was not placebo-controlled.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Recent rodent studies suggest that leptin resistance can be potentially overcome with a high enough dose.

    “Recent rodent studies suggest that this can be potentially overcome with a high enough dose, 22,24 a theory similar to insulin resistance.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] source

      Not checked in the free run.

    • cites [24] source

      Not checked in the free run.

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

    Interpretationnone given

    Severe lipodystrophy is an exaggerated model of ectopic fat accumulation leading to an exaggerated form of the metabolic syndrome.

    “Severe lipodystrophy is an exaggerated model of ectopic fat accumulation leading to an exaggerated form of the metabolic syndrome.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    This may have broader implications for NASH in the general population, which is also characterized by ectopic triglyceride accumulation and secondary disorders such as insulin resistance.

    “This may have broader implications for NASH in the general population, which is also characterized by ectopic triglyceride accumulation and secondary disorders such as insulin resistance.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study had a relatively small sample size.

    “Other limitations of this study include its relatively small sample size, the variable interval between liver biopsies, the study of a rare disease in terms of its general relationship to NASH, and the fact that this study was not placebo-controlled.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The leptin and thiazolidinedione models both demonstrate the association of NASH with steatosis and the reversal of NASH by removing the fat.

    “The leptin and thiazolidinedione models both demonstrate the association of NASH with steatosis and the reversal of NASH by removing the fat.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    We have no evidence that the results achieved in this population of patients with hypoleptinemia are relevant to the broader group of NASH patients with higher serum leptin concentrations.

    “Furthermore, we have no evidence that the results achieved in this population of patients with hypoleptinemia are relevant to the broader group of NASH patients with higher serum leptin concentrations.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The study examined a rare disease in terms of its general relationship to NASH.

    “Other limitations of this study include its relatively small sample size, the variable interval between liver biopsies, the study of a rare disease in terms of its general relationship to NASH, and the fact that this study was not placebo-controlled.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Insulin resistance and NASH appear to develop in parallel rather than sequentially.

    “In other words, insulin resistance and NASH appear to develop in parallel rather than sequentially.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The interval between liver biopsies was variable.

    “Other limitations of this study include its relatively small sample size, the variable interval between liver biopsies, the study of a rare disease in terms of its general relationship to NASH, and the fact that this study was not placebo-controlled.”
    Quote in the paperNot a substantial claim
21 of 21

  • The paper relies on this without support.

    Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation.

    “Severe lipodystrophy is characterized by diminished adipose tissue and hypoleptinemia, leading to ectopic triglyceride accumulation.”

  • The paper relies on this without support.

    In the absence of adequate adipose tissue, combined with leptin deficiency, the liver becomes a major repository for triglycerides in lipodystrophic patients, often expanding far beyond the normal size.

    “In the absence of adequate adipose tissue, combined with leptin deficiency, the liver becomes a major repository for triglycerides in lipodystrophic patients, often expanding far beyond the normal size.”
2 of 2

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 humans with lipodystrophy, leptin therapy has demonstrated significant improvements in glycemia, dyslipidemia, and hepatic steatosis.

    “leptin therapy has been examined in several clinical trials in patients with lipodystrophy and these have demonstrated significant improvements in glycemia, dyslipidemia and hepatic steatosis (89, 90, 139, 142).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [90]

  • The reduction of hepatomegaly was associated with improvement of nonalcoholic steatohepatitis in patients with generalized lipodystrophy.

    “The reduction of hepatomegaly was associated with improvement of nonalcoholic steatohepatitis, a severe inflammatory manifestation of NAFLD (12).”

    From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [12]

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 liver-fat mean does not match individual MRI values

    Major

    The ten baseline liver-fat percentages in Table 1 average 57.1%, not the reported group mean of 31%. This changes a reported value used to describe the treatment effect.

    Reported 31 · recomputed 57.1

  • Stated age range excludes a listed patient

    Minor

    The stated maximum age is 67 years, but Table 1 lists a patient aged 68.

2 of 2

Cites

Flagged first, then by citations

2 of the 45 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Javor, E. D., Ghany, M. G., Cochran, E. K., Oral, E. A., DePaoli, A. M., Premkumar, A., Kleiner, D. E., & Gorden, P.
Affiliations
  • National Institutes of Health (US)
  • Amgen (United States) (US)
Corresponding author
Javor, Edward D.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2005-04
Volume
41
Issue
4
Pages
753-760
ISSN
0270-9139 (ISSN-L)
DOI
10.1002/hep.20672
OpenAlex
W2064309380
Semantic Scholar
ed56502ccbe96c2f2b6ef8670f3ba0436824e56d
Cited by
228
References
45
Citations by year
2025: 10 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 12 · 2020: 9 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 12 · 2014: 19 · 2013: 14 · 2012: 16
FWCI
11.71
Type
journal article
Language
en
Open access
Licence
doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 3805 d)
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
nonalcoholic steatohepatitis, generalized lipodystrophy, hepatic steatosis, hepatocyte ballooning, liver fibrosis, serum triglycerides, transaminases, liver fat, hepatomegaly, hypoleptinemia
MeSH terms
Adolescent, Adult, Aged, Transaminases, Fatty Liver, Female, Hepatitis, Humans, Lipodystrophy, Liver, Magnetic Resonance Imaging, Male, Middle Aged, Pilot Projects, Triglycerides, Hormone Replacement Therapy, Leptin

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