Iron, hypoxia and chronic disease

The main theme of this thesis is centred around the physiology and pathophysiology of two elements essential for human life: oxygen and iron. The work presented here is focused on the complex regulatory mechanisms, the interactions between iron and oxygen and the perturbations within those pathways underlying various disease conditions. Translational applications are presented in the settings of chronic obstructive pulmonary disease (COPD), critical illness and hypoxic conditioning.
In Chapter 3, a randomised, controlled clinical trial investigating the effects of iron augmentation in patients with COPD is presented. In this study, 48 participants received a single dose of either intravenous iron (ferric carboxymaltose) or placebo. Over an eight-week period, oxygenation, exercise performance, symptomatology, health-related quality of life and lung function were assessed. Intravenous iron did not improve peripheral oxygen saturation. However, participants receiving an iron infusion walked farther and were less breathless. Six-minute walk distance improved by 14 ± 8 m after eight weeks following iron administration compared to placebo (p = 0.025). Improvements ≥ 40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after one week (p = 0.009). MRC dyspnoea scores were lower one week after iron treatment, with a larger fraction of participants reporting scores ≤ 1 in the iron group than in the placebo group (66.7% vs. 33.3%, p = 0.021). Adverse event rates were similar in both groups except for hypophosphataemia, a common and well-known side effect of ferric carboxymaltose, which occurred more frequently in the iron group (91.7% vs. 8.3%, p = 0.001). This decrease in serum phosphate levels remained asymptomatic.
Chapter 4 presents results from the retrospective analysis of iron status in critically ill patients. Inflammation commonly occurs in these patients as highlighted by elevated inflammatory markers C-reactive protein and interleukin-6. Several iron parameters, including serum iron, ferritin, hepcidin, transferrin, and transferrin saturation, strongly correlated with the increase in inflammatory markers. Anaemia, often a consequence of iron sequestration in systemic inflammation, was observed in nearly all patients.
Chapter 5 describes a small study investigating the effects of prolonged exposure to hypoxia in healthy 50–70-year-old volunteers. Using a residential hypoxia facility, eight participants were exposed to mild hypoxia for one week in a crossover study design. The exposure to 15% of inspired oxygen fraction resulted in physiological adaptations, including increased heart rate, respiratory rate, haemoglobin, and haematocrit. Erythropoietin, a marker of hypoxia signalling, and hepcidin, the main regulator of iron homeostasis, were assessed by enzyme-linked immunosorbent assay. While erythropoietin was significantly elevated in response to hypoxia, hepcidin levels decreased. The exposure to hypoxia was well-tolerated by all participants.
A main summary, overall conclusions, and an outlook are provided in Chapter 6.

Keywords: Ferric carboxymaltose
Hypoxia
Chronic obstructive pulmonary disease
Iron metabolism
Advisor: Robbins, P