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.

Trial registration: ClinicalTrials.gov NCT00677313.

Figure 1

Cohort of 50 patients with baseline liver biopsy and the subset of 27 patients included in the analysis of the effects of metreleptin on liver histology.

Figure 2

Improvement of histology on leptin therapy. Patient NIH-56. Panel A shows characteristic changes of steatohepatitis prior to leptin therapy. Panel B shows resolution of steatosis and ballooning injury on follow-up biopsy. (H&E, 400x magnification).

Figure 3

Nonalcoholic fatty liver disease activity score difference (ΔNAS) before and after metreleptin therapy versus time on metreleptin replacement. Black squares represent patients with congenital generalized lipodystrophy, red circles are patients with familial partial lipodystrophy, and blue triangles are patients with acquired lipodystrophy (generalized and partial). There was not a statistically significant correlation between ΔNAS and the duration of metreleptin treatment.