Nobili Valerio, Manco Melania, Ciampalini Paolo, Diciommo Vincenzo, Devito Rita, Piemonte Fiorella, Comparcola Donatella, Guidi Roberto, Marcellini Matilde
Liver Unit, Research Institute, 'Bambino Gesù' Children's Hospital, S Onofrio 4 Square, 00165 Rome, Italy.
Eur J Endocrinol. 2006 Nov;155(5):735-43. doi: 10.1530/eje.1.02288.
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.
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.
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 41 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 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/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 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; 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: 22.9 +/- 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(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001).
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.
儿童非酒精性脂肪性肝病（NAFLD）的患病率正在急剧上升。目前尚不清楚为何一些患者会从脂肪变性发展为脂肪性肝炎（NASH）、纤维化和肝硬化，而另一些患者则不会。有观点认为瘦素发挥了作用。本研究旨在评估儿童瘦素、胰岛素抵抗（IR）与NAFLD之间的关系。
对72例经活检证实为NAFLD的儿童（年龄9 - 18岁；51名男性/21名女性）进行研究，检测空腹瘦素及其可溶性受体（sOB - R）；计算游离瘦素指数（FLI），即瘦素/sOB - R；采用稳态模型评估（HOMA - IR）和胰岛素敏感指数（ISI - comp）评估IR；通过口服葡萄糖耐量试验（OGTT）评估葡萄糖耐量。65例患者采用双能X线吸收法（DXA）测定全身脂肪百分比（TBF）。
糖尿病、空腹血糖受损和/或负荷后糖耐量受损的患病率为11%。HOMA - IR和ISI - comp值分别为2.55±1.39和4.4±2。38例儿童被诊断为NASH，25例为单纯性脂肪变性；29例儿童诊断不明确。41例患者观察到纤维化增加，大多为轻度。NAFLD活动度（NAS）评分中位数为3.42±1.60。根据组织学结果，随着脂肪变性程度加重（脂肪变性1级时瘦素为11.9±6.3，2级时为17.4±6.9（P = 0.01），3级时为22.2±6.8 ng/ml（P < 0.001）；FLI分别为2.56±1.40、3.57±0.34、4.45±0.64（P = 0.05））、气球样变（1级时为13.7±6.7，2级时为17±7.5（P = 0.001），3级时为22.1±7.1 ng/ml（P = 0.01）；FLI为2.81±1.50、3.40±1.65、4.57±1.67（0级与2级之间P = 0.01））、纤维化（从14.3±7至18.3±6.9；P = 0.03；FLI为3.03±1.57对3.92±0.77；P < 0.05）以及NAS评分（1 - 2分：12.9±6.9；3 - 4分：17±6.9（P = 0.01）；5 - 7分：22.9±7.5 ng/ml（P = 0.03）；FLI为2.70±1.53、3.12±1.53、4.58±1.57，1 - 2分与3 - 4分之间以及3 - 4分与5 - 7分之间P分别为0.01和0.05），瘦素和FLI水平均升高。较高的瘦素水平与更严重的脂肪变性、气球样变和NAS评分相关（r分别为0.6、0.4和0.6；均P < 0.001）；FLI与气球样变（r = 0.4，P < 0.0001）、脂肪变性（r = 0.5，P < 0.0001）和NAS评分（r = 0.5，P < 0.0001）相关。
在本研究中，瘦素与肝损伤的相关性独立于年龄、BMI和性别。然而，瘦素在NAFLD进展中的任何因果作用尚未确定。因此，需要开展研究以明确该激素在疾病中是否起主要作用。
