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Discriminatory Changes in Circulating Metabolites as a Predictor of Hepatocellular Cancer in Patients with Metabolic (Dysfunction) Associated Fatty Liver Disease

Lookup NU author(s): Professor Helen ReevesORCiD, Misti McCainORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


© 2022 Authors. Introduction: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC. Methods: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC. Results: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721-0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793-0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09-1.83, p < 0.01). Conclusion: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.

Publication metadata

Author(s): Lu H, George J, Eslam M, Villanueva A, Bolondi L, Reeves HL, McCain M, Chambers E, Ward C, Sartika D, Sands C, Maslen L, Lewis MR, Ramaswami R, Sharma R

Publication type: Article

Publication status: Published

Journal: Liver Cancer

Year: 2023

Volume: 12

Issue: 1

Pages: 19-31

Print publication date: 01/02/2023

Online publication date: 08/07/2022

Acceptance date: 25/06/2022

Date deposited: 14/03/2023

ISSN (print): 2235-1795

ISSN (electronic): 1664-5553

Publisher: S. Karger AG


DOI: 10.1159/000525911


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Funder referenceFunder name
C18342/A23390Cancer Research UK CRUK (open competition)
C9380/A18084Cancer Research UK CRUK (open competition)
HEALTH-F2-2009-241762Commission of the European Communities