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Clinical Chemistry 52: 950-968, 2006. First published April 20, 2006; 10.1373/clinchem.2006.068684
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(Clinical Chemistry. 2006;52:950-968.)
© 2006 American Association for Clinical Chemistry, Inc.

Review

Hereditary Hemochromatosis: Genetic Complexity and New Diagnostic Approaches

Dorine W. Swinkels1,a, Mirian C.H. Janssen2, Jürgen Bergmans1 and Joannes J.M. Marx1,3

Departments of1 Clinical Chemistry and 2 General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen.
3 Eijkman-Winkler Institute, University Medical Centre Utrecht, Utrecht, The Netherlands.

aAddress correspondence to this author at: Department of Clinical Chemistry 441, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Fax 31-24-541743; e-mail D.Swinkels{at}akc.umcn.nl.

Since the discovery of the hemochromatosis gene (HFE) in 1996, several novel gene defects have been detected, explaining the mechanism and diversity of iron-overload diseases. At least 4 main types of hereditary hemochromatosis (HH) have been identified. Surprisingly, genes involved in HH encode for proteins that all affect pathways centered around liver hepcidin synthesis and its interaction with ferroportin, an iron exporter in enterocytes and macrophages. Hepcidin concentrations in urine negatively correlate with the severity of HH. Cytokine-mediated increases in hepcidin appear to be an important causative factor in anemia of inflammation, which is characterized by sequestration of iron in the macrophage system. For clinicians, the challenge is now to diagnose HH before irreversible damage develops and, at the same time, to distinguish progressive iron overload from increasingly common diseases with only moderately increased body iron stores, such as the metabolic syndrome. Understanding the molecular regulation of iron homeostasis may be helpful in designing innovative and reliable DNA and protein tests for diagnosis. Subsequently, evidence-based diagnostic strategies must be developed, using both conventional and innovative laboratory tests, to differentiate between the various causes of distortions of iron metabolism. This review describes new insights in mechanisms of iron overload, which are needed to understand new developments in diagnostic medicine.




The following articles in journals at HighWire Press have cited this article:


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M. van Deuren, J. J. C. Kroot, and D. W. Swinkels
Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler's syndrome treated with IL-1 receptor antagonist
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Comment to: Hepcidin: from discovery to differential diagnosis. Haematologica 2008; 93:90-7
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E. H.J.M. Kemna, H. Tjalsma, H. L. Willems, and D. W. Swinkels
Hepcidin: from discovery to differential diagnosis
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E. H.J.M. Kemna, H. Tjalsma, V. N. Podust, and D. W. Swinkels
Mass Spectrometry-Based Hepcidin Measurements in Serum and Urine: Analytical Aspects and Clinical Implications
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M. V. Verga Falzacappa, M. Vujic Spasic, R. Kessler, J. Stolte, M. W. Hentze, and M. U. Muckenthaler
STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation
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