Hepcidin: analysis, regulation and clinical perspectives.
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RU Radboud Universiteit Nijmegen, 7 maart 2008
Promotor : Willems, J.L. Co-promotores : Swinkels, D.W., Tjalsma, H.
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SubjectUMCN 5.1: Genetic defects of metabolism
The major aim of this thesis was the development of a high through-put assay for hepcidin in order to study the regulation of this peptide, and to gain knowledge on the role of hepcidin in iron metabolism. Chapter 2 presents a novel urinary hepcidin assay exploiting surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). This assay showed to have a strong correlation with the only pre-existing antibody-based dotblot assay. As described in chapter 3, further analytical improvement of this assay expanded the usability of hepcidin analysis also for serum samples and made it possible to determine associations with other iron related parameters, especially in patients with distorted iron metabolism. By using this serum hepcidin assay chapter 4 shows that insights on hepcidin regulation, foremost gained form in vitro cell culture and mice studies, can indeed be translated to the human in vivo model. Besides this, chapter 4 also describes an algorithm, based on biochemical serum parameters reflecting the main hepcidin regulators, which is capable to predict highly accurate the measured serum hepcidin levels. Chapter 5, shows a time-course analysis of urinary hepcidin, serum iron and plasma cytokine levels in a human endotoxemia experiment that defines the temporal associations between Interleukin 6, hepcidin and iron during inflammation. Using this endotoxemia model, next to hepcidin the contribution of nitric oxide (NO) in the development of hypoferremia was assessed with the use of aminoguanidine as specific inducible NO synthase (iNOS) inhibitor during acute inflammation, as described in chapter 6. Finally, the clinical use of hepcidin in the pre-screening of non-HFE hemochromatosis patients is described in chapter 7. These results indicate a potential role for hepcidin measurements in clinical practice which has to be explored more intensively in the near future.
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