Long Term Effects of Leptin on Hepatic Fibrosis in Generalized Lipodystrophy
Journal of the Endocrine Society(2021)
摘要
Abstract Lipodystrophy syndromes are caused by deficiency of adipose tissue leading to severe insulin resistance, hypertriglyceridemia, and non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. Advanced fibrosis/cirrhosis was previously thought to be irreversible; however, eradication of hepatitis C or long-term viral suppression of hepatitis B can reverse cirrhosis. Metreleptin treatment in patients with lipodystrophy improves liver transaminases and NAFLD activity score (NAS) after a mean of 2 years, but the latter improvements were due to lower inflammation and steatosis, with no change in fibrosis. The long-term effects of metreleptin in subjects with advanced fibrosis are unknown. We analyzed 24 subjects with advanced fibrosis (NAS stage 3 or 4) prior to metreleptin. Seven had liver biopsies both before and after ≥ 3 years of metreleptin with mean treatment duration 7.8±2.9 years. Five of six subjects with stage 3 fibrosis at baseline had improved fibrosis scores after metreleptin, and 0 of 1 with stage 4 fibrosis improved. 17 patients (8 with stage 3, 9 stage 4) did not have follow up biopsies after ≥3 years. Of these 17, 4 (all stage 4) died from end stage liver disease, and 1 (stage 3) from other causes. There was no clinical indication for repeat biopsy in 6 patients (2 stage 3, 4 stage 4). 6 were lost to follow up. Of the 24 patients with advanced fibrosis, 13 had congenital generalized lipodystrophy (CGL), 7 had acquired generalized lipodystrophy (AGL), 3 had familial partial lipodystrophy (FPL) and 1 had acquired partial lipodystrophy (APL). Of the 5 subjects with improvement in their fibrosis score, 2 had AGL, 2 had CGL, and one had a novel FPL mutation (1). Of the two patients that did not improve, one had FPL and one had CGL. In conclusion, subjects with stage 3 fibrosis due to lipodystrophy may have regression of fibrosis after long-term metreleptin treatment. This improvement may be secondary to near-elimination of the inciting factors (excess nutrient intake leading to ectopic lipid storage in the liver), analogous to clearance of Hepatitis C infection. However, additional data is needed to determine if metreleptin can reverse fibrosis in subjects with stage 4 fibrosis.
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