Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
Clin Gastroenterol Hepatol. 2020 Oct;18(11):2592-2599.e10. doi: 10.1016/j.cgh.2020.02.011. Epub 2020 Feb 13.
BACKGROUND & AIMS: There are no biomarkers of nonalcoholic steatohepatitis (NASH) that are ready for routine clinical use. We investigated whether an analysis of PNPLA3 and TM6SF2 genotypes (rs738409 and rs58542926) can be used to identify patients with nonalcoholic fatty liver disease (NAFLD), with and without diabetes, who also have NASH.
We collected data from the Boramae registry in Korea on 453 patients with biopsy-proven NAFLD with sufficient clinical data for calculating scores. Patients enrolled from February 2014 through March 2016 were assigned to cohort 1 (n = 302; discovery cohort) and patients enrolled thereafter were assigned to cohort 2 (n = 151; validation cohort). DNA samples were obtained from all participants and analyzed for the PNPLA3 rs738409 C>G, TM6SF2 rs58542926 C>T, SREBF2 rs133291 C>T, MBOAT7-TMC4 rs641738 C>T, and HSD17B13 rs72613567 adenine insertion (A-INS) polymorphisms. We used multivariable logistic regression analyses with stepwise backward selection to build a model to determine patients' risk for NASH (NASH PT) using the genotype and clinical data from cohort 1 and tested its accuracy in cohort 2. We used the receiver operating characteristic (ROC) curve to compare the diagnostic performances of the NASH PT and the NASH scoring systems.
We developed a NASH PT scoring system based on PNPLA3 and TM6SF2 genotypes, diabetes status, insulin resistance, and levels of aspartate aminotransferase and high-sensitivity C-reactive protein. NASH PT scores identified patients with NASH with an area under the ROC (AUROC) of 0.859 (95% CI, 0.817-0.901) in cohort 1. In cohort 2, NASH PT scores identified patients with NASH with an AUROC of 0.787 (95% CI, 0.715-0.860), which was significantly higher than the AUROC of the NASH score (AUROC, 0.729; 95% CI, 0.647-0.812; P = .007). The AUROC of the NASH PT score for detecting NASH in patients with NAFLD with diabetes was 0.835 (95% CI, 0.776-0.895) and in patients without diabetes was 0.809 (95% CI, 0.757-0.861). The negative predictive value of the NASH PT score <-0.785 for NASH in patients with NAFLD with diabetes reached 0.905.
We developed a scoring system, based on polymorphisms in PNPLA3 and TM6SF2 and clinical factors that identifies patients with NAFLD, with or without diabetes, who have NASH, with an AUROC value of 0.787. This system might help clinicians better identify NAFLD patients at risk for NASH.
目前尚无适用于常规临床应用的非酒精性脂肪性肝炎（NASH）生物标志物。本研究旨在探讨分析载脂蛋白基因 3（PNPLA3）和 6 号跨膜丝氨酸蛋白酶 2（TM6SF2）基因（rs738409 和 rs58542926）的基因型能否用于识别患有非酒精性脂肪性肝病（NAFLD）且伴有或不伴有糖尿病的 NASH 患者。
我们从韩国的波拉美医院注册中心收集了 453 例经活检证实的 NAFLD 患者的数据，这些患者有足够的临床数据来计算评分。2014 年 2 月至 2016 年 3 月期间入组的患者被分配到队列 1（n=302；发现队列），此后入组的患者被分配到队列 2（n=151；验证队列）。所有参与者均获得了 DNA 样本，并对 PNPLA3 rs738409 C>G、TM6SF2 rs58542926 C>T、SREBF2 rs133291 C>T、MBOAT7-TMC4 rs641738 C>T 和 HSD17B13 rs72613567 腺嘌呤插入（A-INS）多态性进行了分析。我们使用多变量逻辑回归分析，采用逐步向后选择方法，构建了一个模型，以确定队列 1 中基因型和临床数据患者的 NASH 风险（NASH PT），并在队列 2 中检验其准确性。我们使用接收者操作特征（ROC）曲线比较了 NASH PT 和 NASH 评分系统的诊断性能。
我们基于 PNPLA3 和 TM6SF2 基因型、糖尿病状态、胰岛素抵抗以及天冬氨酸转氨酶和高敏 C 反应蛋白水平，开发了一种 NASH PT 评分系统。NASH PT 评分在队列 1 中识别 NASH 患者的曲线下面积（AUROC）为 0.859（95%CI，0.817-0.901）。在队列 2 中，NASH PT 评分识别 NASH 患者的 AUROC 为 0.787（95%CI，0.715-0.860），显著高于 NASH 评分的 AUROC（AUROC，0.729；95%CI，0.647-0.812；P=0.007）。NASH PT 评分用于检测糖尿病合并 NAFLD 患者 NASH 的 AUROC 为 0.835（95%CI，0.776-0.895），用于无糖尿病合并 NAFLD 患者 NASH 的 AUROC 为 0.809（95%CI，0.757-0.861）。NASH PT 评分< -0.785 用于诊断糖尿病合并 NAFLD 患者 NASH 的阴性预测值达到 0.905。
我们基于 PNPLA3 和 TM6SF2 多态性和临床因素开发了一种评分系统，用于识别伴有或不伴有糖尿病的 NAFLD 患者中患有 NASH 的患者，其 AUROC 值为 0.787。该系统可能有助于临床医生更好地识别患有 NASH 的 NAFLD 患者。
