Albertine Donker

General Introduction 29 1 On the other site of the spectrum, both the hepcidin/FPN axis and the IRE/IRP system operate in the opposite way in case of (imminent) iron surplus in order to prevent systemic and cellular overload. Tissue IO may occur when the hepcidin/FPN axis and the IRP system fail to maintain systemic and cellular iron levels below toxic levels. 96 Iron loading occurs in parenchymal tissues or in the reticulo-endothelial system (RES) or both, depending on the underlying pathophysiology. In hereditary hemochromatosis, a group of primary genetic disorders of hepcidin deficiency or resistance, hyper- absorption of dietary iron leads to primarily parenchymal iron accumulation in especially the liver. 97 A similar pattern is seen in iron loading anemias due to ineffective erythropoiesis with subsequently inappropriately decreased hepcidin levels. 98,99 IO of the RES corresponds to iron deposition within Kupffer cells or portal macrophages, and in the spleen, and is usually caused by excessive iron supply (i.e. repeated blood transfusions), infection or inflammation. 97 100 Massive iron surplus eventually results in a mixed type with iron loading in both the parenchyma tissues and the RES. 97 Iron deficiency anemia is the top-ranking cause of anemia worldwide and has a considerable impact on health ID affects more than 2 billion people worldwide, 101 and IDA remains the top cause of anemia with a prevalence of over 1.2 billion globally, as confirmed by the analysis of a large number of reports on the burden of disease in 187 countries between 1990 and 2010. 4 Many physiologic and pathologic causes exist that are mostly acquired and commonly occur simultaneously, like increased demands, insufficient dietary intake, malabsorption and/or chronic blood loss. 3,102 ID and IDA are associated with many adverse effects, depending on the age of the patient, the severity and the progress of the deficiency. ID can cause symptoms of fatigue and paleness, which may worsen to a reduced exercise capacity, cardiac palpitations and dizziness in the case of anemia. 12,103 Furthermore, the development and maturation of the central nervous system in infants and young children is highly dependent on iron-containing enzymes and proteins. ID might therefore have multiple and varied effects on neurocognitive development in children. 59,104 Besides the above-mentioned sequelae and the diverse effects on the central nervous system, ID in children is associated with growth retardation, breath holding spells and febrile convulsions. 2,105 Restless legs, impaired immune response and increased absorption of other metals like aluminum are also associated with decreased iron status in both children and adults. 105,106