*Liver Research Unit, Bambino Gesù Children's Hospital and Research Institute, Roma †Department of Pathophysiology and Transplantation, section Internal Medicine, Universita' degli Studi di Milano, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milan ‡Scientific direction, Bambino Gesù Children's Hospital and Research Institute, Roma, Italy.
J Pediatr Gastroenterol Nutr. 2014 May;58(5):632-6. doi: 10.1097/MPG.0000000000000279.
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in industrialized countries in adults and children, following the trail of the epidemic diffusion of obesity. Nonalcoholic steatohepatitis (NASH) is a potentially serious form of NAFLD linked with a significant increase in overall and liver-related morbidity and mortality. Because diagnosis still requires liver biopsy, there is urgent need of developing noninvasive early markers. The aim of the present study was to assess whether the simultaneous detection of genetic risk factors could predict NASH.
We enrolled 152 untreated, consecutive obese children and adolescents with biopsy-proven NAFLD and increased liver enzymes. The PNPLA3 rs738409 C>G (I148 M), SOD2 rs4880 C>T, KLF6 rs3750861 G>A, and LPIN1 rs13412852 C>T polymorphisms were detected by Taqman assays.
A multivariate logistic model based on the genetic risk factors significantly predicted NASH (area under the receiver-operating characteristic curve [AUC] 0.75, 95% confidence interval [CI] 0.67-0.82, P < 0.0001), performing better than a clinical risk score identified at stepwise regression based on age, aspartate aminotransferase levels, and diastolic blood pressure (AUC 0.66, 95% CI 0.57-0.75). A single cutoff value of the genetic risk score had 90% sensitivity and 36% specificity for NASH. A risk score combining the clinical and genetic risk factors resulted in an AUC of 0.80 (95% CI 0.73-0.87).
A score based on genetic risk factors significantly predicts NASH in obese children with increased liver enzymes, representing a proof-of-principle that genetic scores may be useful to predict long-term outcomes of the disease and guide clinical management.
非酒精性脂肪性肝病 (NAFLD) 已成为工业化国家成年人和儿童中最常见的慢性肝病病因，紧随肥胖症流行的脚步。非酒精性脂肪性肝炎 (NASH) 是一种潜在严重的 NAFLD 形式，与总死亡率和肝脏相关死亡率的显著增加有关。由于诊断仍然需要肝活检，因此迫切需要开发非侵入性的早期标志物。本研究旨在评估同时检测遗传危险因素是否可以预测 NASH。
我们纳入了 152 名未经治疗的连续肥胖儿童和青少年，这些患者患有经活检证实的 NAFLD 和肝酶升高。通过 Taqman 分析检测 PNPLA3 rs738409 C>G（I148 M）、SOD2 rs4880 C>T、KLF6 rs3750861 G>A 和 LPIN1 rs13412852 C>T 多态性。
基于遗传危险因素的多变量逻辑模型显著预测了 NASH（受试者工作特征曲线下面积 [AUC] 0.75，95%置信区间 [CI] 0.67-0.82，P<0.0001），表现优于逐步回归基于年龄、天冬氨酸转氨酶水平和舒张压确定的临床风险评分（AUC 0.66，95%CI 0.57-0.75）。遗传风险评分的单一截断值对 NASH 的敏感性为 90%，特异性为 36%。结合临床和遗传危险因素的风险评分得出 AUC 为 0.80（95%CI 0.73-0.87）。
基于遗传危险因素的评分可显著预测肝酶升高的肥胖儿童中的 NASH，这证明了遗传评分可能有助于预测疾病的长期结局并指导临床管理。
