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. Published by Elsevier B.V.
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. Published by Elsevier B.V.
Authors: Robert K Semple; Alison Sleigh; Peter R Murgatroyd; Claire A Adams; Les Bluck; Sarah Jackson; Alessandra Vottero; Dipak Kanabar; Valentine Charlton-Menys; Paul Durrington; Maria A Soos; T Adrian Carpenter; David J Lomas; Elaine K Cochran; Phillip Gorden; Stephen O'Rahilly; David B Savage Journal: J Clin Invest Date: 2009-01-26 Impact factor: 14.808
Authors: David B Savage; Robert K Semple; Menna R Clatworthy; Paul A Lyons; B Paul Morgan; Elaine K Cochran; Phillip Gorden; Philippa Raymond-Barker; Peter R Murgatroyd; Claire Adams; Ian Scobie; Ghulam J Mufti; Graeme J M Alexander; Sathia Thiru; Incoronata Murano; Saverio Cinti; Afzal N Chaudhry; Kenneth G C Smith; Stephen O'Rahilly Journal: J Clin Endocrinol Metab Date: 2008-10-14 Impact factor: 5.958
Authors: Rebecca J Brown; Areli Valencia; Megan Startzell; Elaine Cochran; Peter J Walter; H Martin Garraffo; Hongyi Cai; Ahmed M Gharib; Ronald Ouwerkerk; Amber B Courville; Shanna Bernstein; Robert J Brychta; Kong Y Chen; Mary Walter; Sungyoung Auh; Phillip Gorden Journal: J Clin Invest Date: 2018-07-16 Impact factor: 14.808