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The liver diseases of lipodystrophy: the long-term effect of leptin treatment.

ABSTRACT: BACKGROUND & AIMS:Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement. METHODS:This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipodystrophy at the National Institutes of Health. Liver biopsies were performed at baseline (N=50) and after leptin replacement (N=27). NASH activity was assessed using the NASH Clinical Research Network (CRN) scoring system. Fasting blood glucose, triglyceride, hemoglobin A1c and liver enzymes were measured at baseline and at the time of the final liver biopsy. RESULTS:In leptin-treated patients, 86% met criteria for NASH at baseline, while only 33% had NASH after leptin replacement for 25.8 ± 3.7 months (mean ± SE, p=0.0003). There were significant improvements in steatosis grade (reduction of mean score from 1.8 to 0.9) and ballooning injury scores (from 1.2 to 0.4), with a 44.2% reduction in mean NAFLD activity score (p<0.0001). Patients who already had fibrosis remained stable on leptin replacement. We observed significant improvement in metabolic profile, ALT and AST. In addition to NASH, four patients with acquired generalized lipodystrophy (AGL) had autoimmune hepatitis. CONCLUSIONS:The fundamental liver disease of lipodystrophy is NASH, although autoimmune hepatitis was observed in some patients with AGL. Leptin appears to be a highly effective therapy for NASH in hypoleptinemic lipodystrophic patients.

SUBMITTER: Safar Zadeh E

PROVIDER: S-EPMC3924897 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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The liver diseases of lipodystrophy: the long-term effect of leptin treatment.

Safar Zadeh Elika E Lungu Andreea O AO Cochran Elaine K EK Brown Rebecca J RJ Ghany Marc G MG Heller Theo T Kleiner David E DE Gorden Phillip P

Journal of hepatology 20130221 1

<h4>Background & aims</h4>Lipodystrophies are hypoleptinemic conditions characterized by fat loss, severe insulin resistance, hypertriglyceridemia, and ectopic fat accumulation. Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are also features of this condition. We studied the spectrum of liver disease in lipodystrophy and the effects of leptin replacement.<h4>Methods</h4>This was an open-label, prospective study of leptin therapy in patients with inherited and acquired lipo ...[more]

PMID: 23439261

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Project description:ObjectiveTo evaluate the long-term clinical effect of treatment with metreleptin (an analogue of human leptin) on glycemic and lipid abnormalities and markers of hepatic steatosis in patients with inherited or acquired lipodystrophy.MethodsFifty-five patients (36 with generalized lipodystrophy and 19 with partial lipodystrophy) with at least 1 of 3 metabolic abnormalities (diabetes mellitus, fasting triglyceride level ≥200 mg/dL, and insulin resistance) and low leptin levels received subcutaneous injections of metreleptin once or twice daily in an ongoing clinical trial at the National Institutes of Health.ResultsAt baseline, hemoglobin A1c-8.5% ± 2.1% (mean ± standard deviation [SD])-and triglycerides-479 ± 80 mg/dL (geometric mean ± standard error [SE])-were substantially elevated. Robust and sustained reductions in both variables were evident for the observed patient population during a 3-year metreleptin treatment period (-2.1% ± 0.5% [mean ± SE] and -35.4% ± 13.7% [mean ± SE], respectively). Mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated at baseline (100 ± 120 U/L and 71 ± 77 U/L [mean ± SD], respectively) and decreased by -45 ± 19 U/L and -33 ± 14 U/L (mean ± SE), respectively, during the 3-year metreleptin treatment period. Improvements in hemoglobin A1c, triglycerides, ALT, and AST were more pronounced in the subsets of patients having elevated levels at baseline. The most notable adverse events observed in this patient population were likely attributable to underlying metabolic abnormalities or comorbidities.ConclusionMetreleptin treatment substantially reduced glycemic variables, triglycerides, and liver enzymes (ALT and AST) and demonstrated durability of response throughout a 3-year treatment period. These results support metreleptin as a potential treatment for certain metabolic disorders (for example, diabetes mellitus and hypertriglyceridemia) associated with lipodystrophy.

Project description:ContextLipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia.ObjectiveDetermine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy.MethodsOpen-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance.ResultsIn GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ± 1.7, 9.1 ± 1.3, 8.3 ± 1.7 mm, P < .01), and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e' velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD.ConclusionMetreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Project description:BACKGROUND:The long-term benefits of antiretroviral treatment (ART) are associated with metabolic complications, especially lipodystrophy, which has been well described among HIV-infected adults and children on ART in developed settings. Specifically, stavudine, and to a lesser extent zidovudine and protease inhibitors (PI), have been consistently implicated in the development of lipodystrophy. In 2006, following advice from the WHO, Senegal began phasing out stavudine from first-line ART. The objectives of this cross-sectional analysis are to assess and identify risk factors affecting the prevalence of lipodystrophy in Senegalese children and adolescents on long-term ART participating in a cohort study. METHODS:Lipodystrophy was clinically assessed in two- to 18-year-old children on ART for at least six months and with no concurrent severe acute malnutrition. Risk factors for lipodystrophy were identified using stepwise multivariable logistic regression. Explanatory variables included clinical and personal data, immunovirologic status, and therapeutic history. RESULTS:Overall, 254 children were assessed for lipodystrophy. The median age was 10.9 years (IQR: 8.1-14.2) and the median duration on ART was 54 months (32-84). Only 18% had been previously treated with stavudine, with a median treatment duration of 8 months (5-25). Ongoing treatment included 76% of children receiving zidovudine (median duration of 48 months (26-74)) and 27% receiving PI (lopinavir/ritonavir; median duration of 49 months (23-59)). Mild signs of lipodystrophy were observed in 33 children (13%): 28 with lipoatrophy, 4 with lipohypertrophy and one with combined type. Boys were more likely to present with lipoatrophy than girls (aOR: 4.3, 95% CI: 1.6-11.7). Children previously treated with stavudine for ?1 year had a greater risk for lipoatrophy than those never exposed (3.8, 1.0-14.0), although the association was weak. There was no association between lipodystrophy and age or current or cumulative treatment with lopinavir/ritonavir or zidovudine. CONCLUSIONS:We report low prevalence of mild lipodystrophy in children and adolescents on long-term ART receiving a stavudine-sparing regimen. These findings are reassuring for clinicians in low-income settings where zidovudine is massively prescribed and lopinavir/ritonavir is the only widely available PI. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01771562 (registration date: 01/18/2013).

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The liver diseases of lipodystrophy: the long-term effect of leptin treatment.

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The liver diseases of lipodystrophy: the long-term effect of leptin treatment.

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