Albertine Donker

Chapter 9 320 Decreased energy metabolism on the cellular level affecting multiple organ systems may play a role in the clinical phenotype of IRIDA Since the majority of iron in the human body is attributed to hemoglobin synthesis, a persistent deficit of iron will inevitably lead to IDA, with a decreased oxygen- transporting capacity to the tissues. Clinically, this will result in fatigue and decreased exercise intolerance, which are the most commonly heard complaints in IRIDA patients. However, in general we observe a more pronounced tiredness in our IRIDA patients compared to other patients suffering from a chronic anemia, e.g. sickle cell disease. The reason for the relatively mild complaints of fatigue in patients with chronic anemia lies in the shifting of the oxygen dissociation curve to the right, with a decreased affinity of Hb for oxygen. This is a physiologic adaptation mechanism in order to ensure sufficient oxygen supply to the tissues in conditions of impaired oxygen transporting capacity. However, ID does not only affect the hematopoietic system; virtually all organ systems in the human body are dependent of iron (see also Table 1 in Chapter 2 ). Importantly, myoglobin, which is crucial for the function of the muscular system, contains heme of which iron is a critical component. Iron is also involved in thyroid metabolism, whereas IDA is associated with thyroid dysfunction, especially (subclinical) hypothyroidism. 87 The mechanism by which IDA influences thyroid metabolism is still incompletely understood but seems to include an impaired function of the heme- containing enzyme thyroid peroxidase (TPO), a reduced tissue conversion of T4 to T3 and a decreased pituitary TSH secretion. 87 Importantly, on the cellular level, iron is indispensable for mitochondrial respiration, the process that is essential for the generation of adenosine tri phosphate (ATP) as the universal energy donor in the cell. 88 Furthermore, iron plays a crucial role in the citric acid cycle and oxidative phosphorylation. 89 We therefore hypothesize that the tiredness in IRIDA patients can be attributed to iron deficiency on multiple organ systems, apart from the iron deficit of the erythroblasts, leading to IDA. Results of in vitro and animal studies indeed indicate that ID negatively affects cellular oxidative metabolism, especially in the skeletal system that contains a very high concentration of mitochondria. 90,91 Noteworthy, in adult patients with heart failure, the administration of intravenous iron is associated with an improvement