Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis.
Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis.
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DOI：
10.1136/gutjnl-2022-327498
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发表时间：
2023-02
期刊：
影响因子：
24.5
通讯作者：
Mingrone, Geltrude
中科院分区：
文献类型：
--
作者：
Angelini, Giulia;Panunzi, Simona;Castagneto-Gissey, Lidia;Pellicano, Francesca;De Gaetano, Andrea;Pompili, Maurizio;Riccardi, Laura;Garcovich, Matteo;Raffaelli, Marco;Ciccoritti, Luigi;Verrastro, Ornella;Russo, Maria Francesca;Vecchio, Fabio Maria;Casella, Giovanni;Casella-Mariolo, James;Papa, Luigi;Marini, Pier Luigi;Rubino, Francesco;le Roux, Carel W.;Bornstein, Stefan;Mingrone, Geltrude
非酒精性脂肪性肝炎（NASH）的临床诊断和新药批准需要侵入性肝活检。我们研究的目的是确定NASH和/或肝纤维化的非侵入性生物标志物。该多中心研究包括250例患者（发现队列，n=100例受试者（减肥手术与非酒精性脂肪性肝炎- BRAVES试验）;验证队列，n=150例（NASH和肝纤维化液体活检- LIBRA试验）），经组织学证实为非酒精性脂肪肝（NAFL）或NASH伴或不伴纤维化。使用iTRAQ-纳米液相色谱-质谱/质谱法（LC-MS/MS）在单核细胞和肝星状细胞（HSC）中进行蛋白质组学研究，而流式细胞术测量外周血CD 14 + CD 16 −单核细胞中的周脂蛋白2（PLIN 2）和RAB 14。神经网络分类器用于预测NASH和NASH阶段的存在/不存在。Logistic Bootstrap回归用于衡量预测肝纤维化的准确性。使用PLIN 2平均荧光强度（MFI）结合腰围、甘油三酯、丙氨酸氨基转移酶（ALT）和存在/不存在糖尿病作为协变量的NASH算法在发现队列中具有93%的准确性，并且在验证队列中具有92%的准确性。发现队列的灵敏度和特异性分别为95%和90%，验证队列的灵敏度和特异性分别为88%和100%。NAS水平预测的受试者工作特征下面积（AUROC）范围为发现队列的83.7%（CI 75.6%至91.8%）至验证队列的97.8%（CI 95.8%至99.8%）。该算法包括RAB 14 MFI、年龄、腰围、高密度脂蛋白胆固醇、血糖和ALT水平作为协变量，以预测肝纤维化的存在，在发现队列和验证队列中分别产生95.9%（CI 87.9%至100%）和99.3%（CI 98.1%至100%）的AUROC。发现队列的准确性为99.25%，灵敏度为100%，特异性为95.8%，验证队列为97.6%，99%和89.6%。这种新的生物标志物上级于目前使用的FIB 4、非酒精性脂肪肝疾病纤维化评分和天冬氨酸转氨酶（AST）与血小板比率，并且与超声二维剪切波弹性成像相当。所提出的新型液体活检在诊断NASH或肝纤维化的存在和严重程度方面是准确、敏感和特异的，并且比目前使用的生物标志物更可靠。发现多中心队列：减肥手术与非酒精性脂肪性肝炎，BRAVES，ClinicalTrials.gov标识符：NCT 03524365。确认多中心队列：NASH和纤维化液体活检，LIBRA，ClinicalTrials.gov标识符：NCT 04677101。
Clinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis. This multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16− monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis. The algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively. The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort. The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography. The proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers. Discovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365. Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.
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影响因子：
--
作者：
He L;Deng L;Zhang Q;Guo J;Zhou J;Song W;Yuan F
通讯作者：
Yuan F
DOI：
10.1002/hep.29477
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Friedman SL;Ratziu V;Harrison SA;Abdelmalek MF;Aithal GP;Caballeria J;Francque S;Farrell G;Kowdley KV;Craxi A;Simon K;Fischer L;Melchor-Khan L;Vest J;Wiens BL;Vig P;Seyedkazemi S;Goodman Z;Wong VW;Loomba R;Tacke F;Sanyal A;Lefebvre E
通讯作者：
Lefebvre E
影响因子：
6.7
作者：
Bedossa, Pierre
通讯作者：
Bedossa, Pierre
影响因子：
13.5
作者：
Bedossa, P;Poynard, T
通讯作者：
Poynard, T
影响因子：
29.4
作者：
Angulo P;Kleiner DE;Dam-Larsen S;Adams LA;Bjornsson ES;Charatcharoenwitthaya P;Mills PR;Keach JC;Lafferty HD;Stahler A;Haflidadottir S;Bendtsen F
通讯作者：
Bendtsen F