A thesis presented in partial fulfilment of the requirements for the degree of Doctor of Medicine at the University of the Witwatersrand, Johannesburg. / The quantity of iron in the body is regulated largely by the amount absorbed from the gut as the body's capacity to excrete it seems to be very limited. However three conditions have been described in which enormous amounts of iron may accumulate. Such a finding is characteristic of idiopathic haemochromatosis, it is present in a proportion of malnourished South African and is seen also in cases of refractory anaemia treated over long periods with blood transfusions. / IT2018

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Iron is essential for virtually all organisms, yet it can be highly toxic if not properly regulated. Only the Lyme disease pathogen Borrelia burgdorferi has evolved to not require iron (Aguirre et al., 2013).Recent findings have characterised elements of the iron metabolism network, but understanding of systemic iron regulation remains poor. To improve understanding and provide a tool for in silico experimentation, a computational model of human iron metabolism has been constructed. COPASI was utilised to construct a model that included detailed modelling of iron metabolism in liver and intestinal cells. Inter-cellular interactions and dietary iron absorption were included to create a systemic computational model. Parameterisation was performed using a wide variety of literature data. Validation of the model was performed using published experimental and clinical findings, and the model was found to recreate quantitatively and accurately many results. Analysis of sensitivities in the model showed that, despite enterocytes being the only route of iron uptake, almost all control over the system is provided by reactions in the liver. Metabolic control analysis identified key regulatory factors and potential therapeutic targets. A virtual haemochromatosis patient was created and compared to a simulation of a healthy human. The redistribution of control in haemochromatosis was analysed in order to improve our understanding of the condition and identify promising therapeutic targets. Cellular prion protein (PrP) is an enigmatic protein, implicated in disease when misfolded, but its physiological role remains a mystery. PrP was recently found to have ferric-reductase capacity. Potential sites of ferric reduction were simulated and the findings compared to PrP knockout mice experiments. I propose that the physiological role of PrP is in the chemical reduction of endocytosed ferric iron to its ferrous form following transferrin receptor-mediated uptake.

[Truncated abstract. Please see the pdf format for the complete text.] The discovery of the C282Y mutation and its role in the development of hereditary haemochromatosis has allowed a greater understanding into the effects of iron overload and its involvement in other conditions such as diabetes and heart disease. It has also allowed the better classification of heterozygotes, who were previously only diagnosed through the use of family studies. There are however, areas of conflict between phenotyping and genotyping methods. My research involved examining the relationship between Haemochromatosis and certain diseases such as diabetes and heart disease; genotyping versus phenotyping discrepancies and the possible interaction of secondary mutations. In Chapter 3 a population study was undertaken with the aim of comparing genotyping versus phenotyping methods as well as increasing general practitioner awareness regarding hereditary haemochromatosis and its diagnosis. It was determined that a minimum of 5000 subjects would be required to give the study sufficient power. Individuals were to be between the ages of 20—40 years, and thus presumably presymptomatic. Participation was entirely voluntary and a consent form was to be signed. Recruitment of subjects proved to be difficult and there was a selective bias towards individuals already displaying symptoms of haemochromatosis. In total less than a 100 subjects were recruited for the study. There were several issues encountered in the implementation of this study. Firstly the number of GPs participating was probably insufficient to recruit the subjects required. A more extensive campaign was probably required to enroll more GPs. Secondly it is very difficult for a busy GP to find the time necessary to explain the study to each of his patients and to get them to sign the consent form. Finally a bias developed in some of the requests. The subjects participating in this study were supposed to be random but in many cases the GPs had enrolled them in the study because they had symptoms of iron overload. In effect the biggest obstacle this study faced was the recruitment of subjects. Due to the small number of subjects little statistical data could be obtained from this study. It was noted, however, that genotyping methods detected two individuals who were homozygous for the C282Y mutation. Both also had increased transferrin saturation levels. Phenotyping detected 5 individuals with increased transferrin saturation. The three others detected via phenotyping were C282Y heterozygotes. Haemochromatosis has long been though to be related to the development of diabetes due to the effect of iron overload on the pancreas. If this is so it would be logical to assume that the prevalence of haemochromatosis would be higher in a diabetic population. Chapter 4 examined the possibility that diabetics have a higher frequency of the C282Y mutation. A population group consisting of 1355 diabetics was genotyped for the C282Y mutation and iron studies were performed on all heterozygotes and C282Y homozygotes. Initial findings indicated that there was a significant difference between the diabetic and control population. However, this finding was the opposite of what was expected, there seemed to be a decreased frequency of the Y allele in the diabetic population rather than an increased one. The control and diabetic populations were not matched in terms of ethnicity. The removal of the ethnic bias in the diabetic population altered the statistics so there was no longer a significant difference between the two groups. This study highlighted the importance of using appropriate control populations as comparison groups. The final results of the study indicated that there was no significant difference between the diabetic population and the control population. This would seem to indicate that there is not an increased occurrence of the C282Y mutation in the diabetic population when compared to the control group. Chapter 5 considered the possible association between C282Y heterozygosity and cardiovascular disease as well as the potential for early mortality. Several recent studies have indicated that C282Y heterozygosity may be a risk factor for the development of atherosclerosis, possibly on the basis of increased iron loading. Using a control population and a population of individuals with known coronary events the incidence of the C282Y mutation was compared against other risk factors. C282Y heterozygosity did not appear to be a risk factor for atherosclerosis. There was however, a statistically significant link between increased ferritin in women and carotid plaques. A population of elderly women was genotyped in order to examine the effects of C282Y heterozygosity on longevity. The first hypothesis addressed in chapter 5 was that C282Y heterozygosity was a risk factor for the development of coronary heart disease.