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Iron oxide deposits in iron overload diseases

Chua-anusorn, Wanida (1997) Iron oxide deposits in iron overload diseases. PhD thesis, Murdoch University.

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Iron overload diseases such as thalassaemia are a major public health problem in many parts of the world. Excess iron deposited in such tissues occurs in the form of ultrafine particles of iron oxyhydroxide. At low levels of iron loading, the iron(III) oxyhydroxide particles are mostly found in the iron storage protein, ferritin. At higher levels of loading, iron(III) oxyhydroxide particles are found in insoluble aggregates known as haemosiderin. Three different structures of these iron deposits are known: (i) ferrihydrite (5Fe203.9H20), (ii) poorly crystalline goethite (α-FeOOH), and (iii) non-crystalline hydrated iron(III) oxyhydroxide.

In this thesis, Mössbauer spectroscopy has been used to study the form of iron oxyhydroxide present in the tissues of thalassaemic patients who had undergone regular blood transfusion and chelation therapy as well as those receiving little, if any, such treatment. The data show a higher fraction of non-haem iron occurs as the goethite-like form in patients undergoing regular transfusion and chelation treatment. The poorly crystalline goethite form was not found in normal human tissues.

To define further some of the factors involved in the deposition of these different iron oxides, an iron-loaded rat system was established. Two routes of administration were chosen. The first involved regular administration of red blood cells injected intraperitoneally for up to one year. The second involved the oral administration of carbonyl-iron as a dietary supplement for nearly two years. Mössbauer spectra of livers and spleens at 78 K consisted of a relatively intense central doublet with spectral parameters indicative of paramagnetic or superparamagnetic high-spin iron(III). Many spectra obtained from parenterally iron-loaded spleens and dietary iron-loaded livers also showed a clear sextet at 78 K, which is indicative of the presence of the goethite-like form of iron oxyhydroxide. The relative intensity of this sextet spectral component in the livers from the dietary iron-loaded rats increased significantly with the age of rats. In order to distinguish iron present in the parenchymal versus non-parenchymal cells in the livers, an indirect quantitative assessment of the iron concentration was performed from liver histological sections using computer-assisted morphometric analysis. The goethite-like form increased significantly as the fraction of iron in non-parenchymal cells increased (r = 0.71, p < 0.005), suggesting that its formation may be associated with the nonparenchymal cells.

The ultrastructure of the iron oxide deposits and associated organic components was studied using a combination of scanning probe microscopy and transmission electron microscopy. Liver samples with ferrihydrite or goethite-like haemosiderin were studied as well as aggregated ferritin in the form of ferritin crystals, ferrihydrite-like form of haemosiderin shows topographies of iron aggregation similar to In contrast, liver with goethite-like form of Liver tissue with the that found in the ferritin crystals, haemosiderin showed a different topography.

Haemosiderin was isolated from a selection of tissues. Crude haemosiderin from patients who had undergone regular blood transfusion and chelation therapy showed a high fraction of goethite-like form of iron oxyhydroxide with a wide range of particle size. Infrared spectroscopy indicated that the iron oxyhydroxide in haemosiderins is associated with organic components. The availability of the different forms of iron oxyhydroxide present in different haemosiderins was assessed using the iron chelator desferrioxamine. The percentage of iron released showed a negative correlation (r = 0.82, p < 0.001) with the percentage of goethite-like iron oxyhydroxide present in these haemosiderins.

In summary, these studies indicate that the chemical forms of iron oxyhydroxide deposits are related to their deposition, toxicity and relative ease of removal. The study has implications for the clinical management of different groups of thalassaemic patients.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): Division of Science
Notes: Note to the author: If you would like to make your thesis openly available on Murdoch University Library's Research Repository, please contact: Thank you.
Supervisor(s): Webb, John and Macey, David
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