Noninvasive proteomic biomarkers for alcohol-related liver disease

作者：Lili Niu, Maja Sofie Thiele, Philipp Emanuel Geyer, Ditlev Nytoft Rasmussen, Henry Emanuel Webel, Alberto Santos, Rajat Gupta, Florian Meier, Maximilian T. Strauss, Maria Kjærgaard, Katrine Prier Lindvig, Suganya Jacobsen, Simon Rasmussen, Torben F. Hansen, Aleksander Ahm Krag, Matthias Mann · 发表于：Nature Medicine · 年份：2022 · DOI：10.1038/s41591-022-01850-y · 被引用次数：336 · 研究领域：Liver Disease Diagnosis and Treatment、Alcohol Consumption and Health Effects、Endoplasmic Reticulum Stress and Disease

Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease-fibrosis, inflammation and steatosis-remains incomplete. Here, we present a paired liver-plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic-area under the curve (ROC-AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC-AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong's test, P < 0.05). These biomarker panels were found to be accurate in prediction of future liver-related events and all-cause mortality, with a Harrell's C-index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver ...