Targeted quantitative lipidomic uncovers lipid biomarkers for predicting the presence of compensated cirrhosis and discriminating decompensated cirrhosis from compensated cirrhosis
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Yongbin Zeng
and Yongjun Zeng
Abstract
Objectives
This study aimed to characterize serum lipid metabolism and identify potential biomarkers for compensated cirrhosis (CC) predicting and decompensated cirrhosis (DC) discrimination using targeted quantitative lipidomics and machine learning approaches.
Methods
Serum samples from a cohort of 120 participants was analyzed, including 90 cirrhosis patients (45 CC patients and 45 DC patients) and 30 healthy individuals. Lipid metabolic profiling was performed using targeted LC-MS/MS. Two machine learning methods, least absolute shrinkage and selection operator (LASSO), and random forest (RF) were applied to screen for candidate metabolite biomarkers.
Results
The metabolic profiling analysis showed a significant disruption in patients with CC and DC. Compared to the CC group, the DC group exhibited a significant upregulation in the abundance of glycochenodeoxycholic acid (GCDCA), glyco-ursodeoxycholic acid (GUDCA), glycocholic acid (GCA), phosphatidylethanolamine (PE), N-acyl-lyso-phosphatidylethanolamine (LNAPE), and triglycerides (TG), and a significant downregulation in the abundance of ceramides (Cer) and lysophosphatidylcholines (LPC). Machine learning identified 11 lipid metabolites (abbreviated as BMP11) as potential CC biomarkers with excellent prediction performance, with an AUC of 0.944, accuracy of 94.7 %, precision of 95.6 %, and recall of 95.6 %. For DC discrimination, eight lipids (abbreviated as BMP8) were identified, demonstrating strong efficacy, with an AUC of 0.968, accuracy of 92.2 %, precision of 88.0 %, and recall of 97.8 %.
Conclusions
This study unveiled distinct lipidomic profiles in CC and DC patients and established robust lipid-based models for CC predicting and DC discrimination.
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: 82172338
Award Identifier / Grant number: 82202596
Award Identifier / Grant number: 82372316
Acknowledgments
The authors thank all the participants in this study for their cooperation in sample preparation.
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Research ethics: The study was approved by the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (MTCA, ECFAH of FMU [2021] 047).
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Informed consent: Written informed consent was obtained from each patient.
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Author contributions: Yongbin Zeng, Ya Fu and Li Zhang: Data analysis, Manuscript writing; Zhiyi Zheng and Jingyi Su: Data collection; Yongbin Zeng, Yongjun Zeng and Qishui Ou: Project development, Manuscript editing; Kun Lin and Huanhuan Huang: Samples preparation; Tianbin Chen and Can Liu: Laboratory testing.
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Competing interests: The authors declare that they have no conflicts of interest regarding the publication of this article.
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Research funding: The study is supported by grants from National Natural Science Foundation of China (82172338, 82202596, 82372316).
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Data availability: The raw data can be obtained on request from the corresponding author.
References
1. Huang, DQ, Terrault, NA, Tacke, F, Gluud, LL, Arrese, M, Bugianesi, E, et al.. Global epidemiology of cirrhosis – aetiology, trends and predictions. Nat Rev Gastroenterol Hepatol 2023;20:388–98. https://doi.org/10.1038/s41575-023-00759-2.Search in Google Scholar PubMed PubMed Central
2. Schneider, ARP, Schneider, CV, Schneider, KM, Baier, V, Schaper, S, Diedrich, C, et al.. Early prediction of decompensation (EPOD) score: non-invasive determination of cirrhosis decompensation risk. Liver Int 2022;42:640–50. https://doi.org/10.1111/liv.15161.Search in Google Scholar PubMed
3. D’Amico, G, Morabito, A, D’Amico, M, Pasta, L, Malizia, G, Rebora, P, et al.. Clinical states of cirrhosis and competing risks. J Hepatol 2018;68:563–76. https://doi.org/10.1016/j.jhep.2017.10.020.Search in Google Scholar PubMed
4. D’Amico, G. The clinical course of cirrhosis. Population based studies and the need of personalized medicine. J Hepatol 2014;60:241–2. https://doi.org/10.1016/j.jhep.2013.10.023.Search in Google Scholar PubMed
5. Wishart, DS. Metabolomics for investigating physiological and pathophysiological processes. Physiol Rev 2019;99:1819–75. https://doi.org/10.1152/physrev.00035.2018.Search in Google Scholar PubMed
6. Tzeng, HT, Chyuan, IT, Chen, WY. Shaping of innate immune response by fatty acid metabolite palmitate. Cells 2019;8:1633. https://doi.org/10.3390/cells8121633.Search in Google Scholar PubMed PubMed Central
7. Armour, SM, Remsberg, JR, Damle, M, Sidoli, S, Ho, WY, Li, Z, et al.. An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides. Nat Commun 2017;8:549. https://doi.org/10.1038/s41467-017-00772-5.Search in Google Scholar PubMed PubMed Central
8. Schuppan, D, Afdhal, NH. Liver cirrhosis. Lancet 2008;371:838–51. https://doi.org/10.1016/s0140-6736(08)60383-9.Search in Google Scholar
9. Shama, S, Jang, H, Wang, X, Zhang, Y, Shahin, NN, Motawi, TK, et al.. Phosphatidylethanolamines are associated with nonalcoholic fatty liver disease (NAFLD) in obese adults and induce liver cell metabolic perturbations and hepatic stellate cell activation. Int J Mol Sci 2023;24:1024. https://doi.org/10.3390/ijms24021034.Search in Google Scholar PubMed PubMed Central
10. Su, D, Liao, Z, Feng, B, Wang, T, Shan, B, Zeng, Q, et al.. Pulsatilla chinensis saponins cause liver injury through interfering ceramide/sphingomyelin balance that promotes lipid metabolism dysregulation and apoptosis. Phytomedicine 2020;76:153265. https://doi.org/10.1016/j.phymed.2020.153265.Search in Google Scholar PubMed
11. Wang, Y, Aoki, H, Yang, J, Peng, K, Liu, R, Li, X, et al.. The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology 2017;65:2005–18. https://doi.org/10.1002/hep.29076.Search in Google Scholar PubMed PubMed Central
12. Yuan, Z, Wang, J, Zhang, H, Chai, Y, Xu, Y, Miao, Y, et al.. Glycocholic acid aggravates liver fibrosis by promoting the up-regulation of connective tissue growth factor in hepatocytes. Cell Signal 2022;101:110508. https://doi.org/10.1016/j.cellsig.2022.110508.Search in Google Scholar PubMed
13. Hernandez-Lara, MA, Yadav, SK, Shah, SD, Okumura, M, Yokoyama, Y, Penn, RB, et al.. Regulation of airway smooth muscle cell proliferation by diacylglycerol kinase: relevance to airway remodeling in asthma. Int J Mol Sci 2022;23:11868. https://doi.org/10.3390/ijms231911868.Search in Google Scholar PubMed PubMed Central
14. Reeves, HL, Thompson, MG, Dack, CL, Burt, AD, Day, CP. The role of phosphatidic acid in platelet-derived growth factor-induced proliferation of rat hepatic stellate cells. Hepatology 2000;31:95–100. https://doi.org/10.1002/hep.510310116.Search in Google Scholar PubMed
15. Wu, X, Yao, Z, Zhao, L, Zhang, Y, Cao, M, Li, T, et al.. Phosphatidylserine on blood cells and endothelial cells contributes to the hypercoagulable state in cirrhosis. Liver Int 2016;36:1800–10. https://doi.org/10.1111/liv.13167.Search in Google Scholar PubMed
16. Serag, WM, Mohammed, BSE, Mohamed, MM, Elsayed, BE. Predicting the risk of portal vein thrombosis in patients with liver cirrhosis and hepatocellular carcinoma. Heliyon 2020;6:e04677. https://doi.org/10.1016/j.heliyon.2020.e04677.Search in Google Scholar PubMed PubMed Central
17. Han, X, Wang, J, Gu, H, Guo, H, Cai, Y, Liao, X, et al.. Predictive value of serum bile acids as metabolite biomarkers for liver cirrhosis: a systematic review and meta-analysis. Metabolomics 2022;18:43. https://doi.org/10.1007/s11306-022-01890-y.Search in Google Scholar PubMed
18. He, X, Zhou, MX, Cheng, C, Li, SS, Gao, Y, Ma, ZT, et al.. Metabolomic profiling for histologically fibrotic stage in chronic drug-induced liver injury. Front Pharmacol 2022;13:896198. https://doi.org/10.3389/fphar.2022.896198.Search in Google Scholar PubMed PubMed Central
19. Vasavan, T, Deepak, S, Jayawardane, IA, Lucchini, M, Martin, C, Geenes, V, et al.. Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations. J Hepatol 2020;74:1087–96. https://doi.org/10.1016/j.jhep.2020.11.038.Search in Google Scholar PubMed PubMed Central
20. Miao, J, Guo, L, Cui, H, Wang, L, Zhu, B, Lei, J, et al.. Er-chen decoction alleviates high-fat diet-induced nonalcoholic fatty liver disease in rats through remodeling gut microbiota and regulating the serum metabolism. Evid Based Complement Alternat Med 2022;2022:6221340. https://doi.org/10.1155/2022/6221340.Search in Google Scholar PubMed PubMed Central
21. Claria, J, Curto, A, Moreau, R, Colsch, B, Lopez-Vicario, C, Lozano, JJ, et al.. Untargeted lipidomics uncovers lipid signatures that distinguish severe from moderate forms of acutely decompensated cirrhosis. J Hepatol 2021;75:1116–27. https://doi.org/10.1016/j.jhep.2021.06.043.Search in Google Scholar PubMed
22. Sehrawat, TS, Arab, JP, Liu, M, Amrollahi, P, Wan, M, Fan, J, et al.. Circulating extracellular vesicles carrying sphingolipid cargo for the diagnosis and dynamic risk profiling of alcoholic hepatitis. Hepatology 2020;73:571–85. https://doi.org/10.1002/hep.31256.Search in Google Scholar PubMed PubMed Central
23. Pan, X, Dutta, D, Lu, S, Bellen, HJ. Sphingolipids in neurodegenerative diseases. Front Neurosci 2023;17:1137893. https://doi.org/10.3389/fnins.2023.1137893.Search in Google Scholar PubMed PubMed Central
24. Cartier, A, Hla, T. Sphingosine 1-phosphate: lipid signaling in pathology and therapy. Science 2019;366:6463. https://doi.org/10.1126/science.aar5551.Search in Google Scholar PubMed PubMed Central
25. Yu, S, Wang, K, Li, Q, Wei, Y, Li, Y, Zhang, Q, et al.. Nonalcoholic steatohepatitis critically rewires the ischemia/reperfusion-induced dysregulation of cardiolipins and sphingolipids in mice. Hepatobiliary Surg Nutr 2023;12:3–19. https://doi.org/10.21037/hbsn-21-133.Search in Google Scholar PubMed PubMed Central
26. Höring, M, Peschel, G, Grimm, J, Krautbauer, S, Müller, M, Weigand, K, et al.. Serum ceramide species are associated with liver cirrhosis and viral genotype in patients with hepatitis C infection. Int J Mol Sci 2022;23:9806. https://doi.org/10.3390/ijms23179806.Search in Google Scholar PubMed PubMed Central
Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/cclm-2023-0798).
© 2023 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Editorial
- Unraveling the mystery of blood groups and COVID-19
- Reviews
- Serum hepcidin levels in chronic liver disease: a systematic review and meta-analysis
- Platelet distribution width (PDW) as a significant correlate of COVID-19 infection severity and mortality
- Mini Reviews
- ABO blood group-related mechanism of infection of SARS-CoV-2: an overview of systematic reviews
- Opinion Paper
- Personalized laboratory medicine in the digital health era: recent developments and future challenges
- Guidelines and Recommendations
- Algorithm of differential diagnosis of anemia involving laboratory medicine specialists to advance diagnostic excellence
- General Clinical Chemistry and Laboratory Medicine
- Rescaling creatinine makes GFR estimation equations generally applicable across populations – validation results for the Lund-Malmö equation in a French cohort of sub-Saharan ancestry
- Periodic verification of results’ comparability between several analyzers: experience in the application of the EP31-A-IR guideline
- Machine learning to optimize cerebrospinal fluid dilution for analysis of MRZH reaction
- Diagnostic performance of automated red cell parameters in predicting bone marrow iron stores
- Reliability of hemoglobin A2 value as measured by the Premier Resolution system for screening of β-thalassemia carriers
- Amino acid sequence homology of monoclonal serum free light chain dimers and tissue deposited light chains in AL amyloidosis: a pilot study
- Development of high-performance point-of-care aqueous VEGF detection system and proof-of-concept validation in RVO patients
- Detection rate of IGF-1 variants and their implication to protein binding: study of over 240,000 patients
- Analysis of a second-tier test panel in dried blood spot samples using liquid chromatography-tandem mass spectrometry in Catalonia’s newborn screening programme
- Targeted quantitative lipidomic uncovers lipid biomarkers for predicting the presence of compensated cirrhosis and discriminating decompensated cirrhosis from compensated cirrhosis
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- Establishment of reference intervals for free light chains and immunoglobulins in Saudi population
- Cancer Diagnostics
- A predictive and prognostic model for surgical outcome and prognosis in ovarian cancer computed by clinico-pathological and serological parameters (CA125, HE4, mesothelin)
- M-protein diagnostics in multiple myeloma patients using ultra-sensitive targeted mass spectrometry and an off-the-shelf calibrator
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- Infectious Diseases
- Monocyte distribution width as an early predictor of short-term outcome in adult patients with sepsis
- Analytical and clinical evaluations of SNIBE Maglumi chemiluminescent immunoassay for the detection of SARS-CoV-2 antigen in salivary samples
- Letters to the Editor
- Predicting hemoglobinopathies using ChatGPT
- Managing the Quality Control of multiple instruments
- Lipid droplets may interfere with urinary red blood cell and crystal counts by urinary flow cytometry
- Assessment of the lipemia index determined by the Atellica CH 930 analyzer for the detection of monoclonal immunoglobulins
- Concerning quality demands of arterial partial pressure of oxygen
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