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Noninvasive diagnosis of liver cirrhosis using DNA sequencer–based total serum protein glycomics

Abstract

We applied our 'clinical glycomics' technology, based on DNA sequencer/fragment analyzers, to generate profiles of serum protein N-glycans of liver disease patients. This technology yielded a biomarker that distinguished compensated cirrhotic from noncirrhotic chronic liver disease patients, with 79% sensitivity and 86% specificity (100% sensitivity and specificity for decompensated cirrhosis). In combination with the clinical chemistry–based Fibrotest biomarker, compensated cirrhosis was detected with 100% specificity and 75% sensitivity. The current 'gold standard' for liver cirrhosis detection is an invasive, costly, often painful liver biopsy. Consequently, the highly specific set of biomarkers presented could obviate biopsy in many cirrhosis patients. This biomarker combination could eventually be used in follow-up examinations of chronic liver disease patients, to yield a warning that cirrhosis has developed and that the risk of complications (such as hepatocellular carcinoma) has increased considerably. Our clinical glycomics technique can easily be implemented in existing molecular diagnostics laboratories.

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Figure 1: Examples of total serum protein N-glycan profiles.
Figure 2: Trends in derived diagnostic variables.
Figure 3: Classification efficiency.
Figure 4: Values of some glycome markers gradually increase with fibrosis stage.
Figure 5: Partial structural analysis of differentially regulated N-glycans.

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Acknowledgements

N.C. is a postdoctoral fellow with the Fund for Scientific Research Flanders. This work was supported by the Fund for Scientific Research Flanders and by Ghent University (GOA Grant 12052299). The authors thank all blood donors for their participation; B. Vandekerckhove of the Blood Transfusion Center of the Red Cross Ghent and F. Dekeyser of the Department of Internal Medicine of Ghent University hospital for their collaboration; A. Vandeputte for expert technical assistance; A. Bredan for manuscript editing; B. Wuyts and J. Penders for assistance; M. Aebi for making an ABI 310 available for some of our experiments; and the management and technology transfer team of the Flanders Interuniversity Institute for Biotechnology for their encouragement.

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Correspondence to Nico Callewaert or Roland Contreras.

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There is a patent application (WO 03/087833) connected to this work.

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Callewaert, N., Vlierberghe, H., Hecke, A. et al. Noninvasive diagnosis of liver cirrhosis using DNA sequencer–based total serum protein glycomics. Nat Med 10, 429–434 (2004). https://doi.org/10.1038/nm1006

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