Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease

Objective: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children. Design and methods: In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R: IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp): glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients. Results: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children: diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 4 1 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score I to 17.4 +/- 6.9 in score 2 (P=0.01) and 22.2 +/- 6.8ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 1.7 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.8 1 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to 18.3 +/- 6.9: P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 0 7 7: P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 6.9 (P = 0.01); score 5-7: 2 2.9 +/- 7.5 ng/ml (P = 0.03): FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P=0.01 and P=0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(o)=0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(o)=0.4, P < 0.0001), steatosis (r(o)=0.5, P < 0.0001) and NAS score (r(o)=0.5, P < 0.0001.). Conclusions: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.