McGlinchey Aidan J, Govaere Olivier, Geng Dawei, Ratziu Vlad, Allison Michael, Bousier Jerome, Petta Salvatore, de Oliviera Claudia, Bugianesi Elisabetta, Schattenberg Jörn M, Daly Ann K, Hyötyläinen Tuulia, Anstee Quentin M, Orešič Matej
School of Medical Sciences, Örebro University, Örebro, Sweden.
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
JHEP Rep. 2022 Mar 26;4(5):100477. doi: 10.1016/j.jhepr.2022.100477. eCollection 2022 May.
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis).
We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis.
Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered.
Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress.
The study is registered at Clinicaltrials.gov (NCT04442334).
Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.
非酒精性脂肪性肝病（NAFLD）是一种进展性肝病，可能会引发包括肝硬化和肝细胞癌在内的严重并发症。此前，我们已确定了与肝脏脂肪含量及非酒精性脂肪性肝炎（NASH）相关的循环脂质特征。在此，我们绘制了一幅涵盖NAFLD全谱的代谢组图谱，定义了脂肪变性（非酒精性脂肪肝、NASH和纤维化）相互关联的代谢特征。
我们对来自欧洲NAFLD注册研究的患者（n = 627）的血清样本进行了分子脂质和极性代谢物的质谱分析，这些样本代表了NAFLD的全谱。我们使用各种单变量、多变量和机器学习统计方法，从脂肪变性、NASH和纤维化这3个临床角度对代谢物进行了研究。
构建NAFLD代谢网络后，我们确定了15种脂肪变性特有的代谢物、18种NASH特有的代谢物和15种纤维化特有的代谢物，其中有27种是三者共有的。我们发现从F2期到F3期纤维化的进展与疾病自然史中的一个关键病理生理转变点相吻合，有73种代谢物发生了改变。
对循环代谢物的分析为NAFLD进展过程中的代谢变化提供了重要见解，揭示了NAFLD全谱的代谢特征以及NAFL、NASH和纤维化特有的特征。F2 - F3期转变标志着NAFLD发病机制中的一个关键代谢转变点，数据表明代谢应激尤其是氧化应激在病理生理学上具有重要意义。
该研究已在Clinicaltrials.gov注册（NCT04442334）。
非酒精性脂肪性肝病的特征是肝脏中脂肪堆积，进而发展为肝功能障碍、瘢痕形成和不可逆的肝衰竭，其在全球的患病率正在显著上升。在此，我们检测了血液中的脂质和其他小分子（代谢物），旨在全面分子层面概述脂肪堆积、肝纤维化及已确诊的严重程度。我们在肝损伤进展过程中确定了一个关键的代谢“分水岭”，将严重疾病与轻度疾病区分开来，并表明特定的脂质和代谢物谱有助于区分和/或界定这些病例。
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