Noninvasive proteomic biomarkers for alcohol-related liver disease

Lili Niu, Maja Thiele, Philipp E. Geyer, Ditlev Nytoft Rasmussen, Henry Emanuel Webel, Alberto Santos, Rajat Gupta, Florian Meier, Maximilian Strauss, Maria Kjaergaard, Katrine Lindvig, Suganya Jacobsen, Simon Rasmussen, Torben Hansen, Aleksander Krag, Matthias Mann

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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 disease testing.

Original languageEnglish
JournalNature Medicine
Volume28
Issue number6
Pages (from-to)1277-1287
Number of pages26
ISSN1078-8956
DOIs
Publication statusPublished - Jun 2022

Keywords

  • Biomarkers/metabolism
  • Biopsy
  • Humans
  • Inflammation/pathology
  • Liver Cirrhosis/diagnosis
  • Liver Diseases/metabolism
  • Liver/metabolism
  • Proteomics

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