Albertine Donker

Chapter 1 26 brain. The normal decline in Hb due to the breakdown of fetal Hb significantly increases iron stores in newborns. Moreover, despite the low iron content, the iron- binding protein lactoferrin in breastmilk facilitates iron absorption, resulting in a higher bioavailability than the iron from formula milk and cowmilk. 70,71 Therefore, healthy, term and breastfed infants are initially independent of additional external iron and can double their birth weight before iron stores are depleted. 57,58 Studies in human infants suggest that homeostatic regulation of iron absorption is absent in young infants but matures and is present at nine months of age. 72 Experimental studies in suckling rat pups show similar results; at the age of 10 days when fully nursing, iron absorption is independent of iron status, suggesting a lack of sensing and/or regulation of iron import. At the age of 20 days when pups are partially weaned from breastmilk, ID strongly up-regulates and iron supplementation strongly down- regulates the expression of both DMT1 and FPN suggesting homeostatic regulation of iron absorption that develops and matures during infancy. 73 Furthermore rodent studies have shown that iron absorption is refractory to hepcidin in suckling rats, in spite of intact hepcidin signaling. 74,75 This might be part of an adaptive mechanism to absorb as much iron as possible during the suckling period when milk, which has a low iron content, is the main food. However, this phenomenon might also illustrate the inability to regulate iron absorption by the gut according to physiologic need, which may render the neonate susceptible to iron excess and which can compromise growth and predispose to bacterial infections. 76,77 Regarding the extracellular transport of iron in the circulation, infants have low levels of ceruloplasmin that is required to oxidize Fe 2+ to Fe 3+ in order to enable binding to Tf after cellular iron export. Since also Tf is relatively low in the infant, both the affinity and the capacity to bind free iron is reduced, making the young child vulnerable to damage by NTBI. 78-80 Studies on the intracellular iron metabolism in infants are scarce. 65 Whether further developmental changes in systemic and cellular iron metabolism occur after infancy, during middle and later childhood, is unclear. 81 During adolescence hepcidin levels decrease in response to stimulation of endogenous production of both estrogens and testosterone. Sex hormones result in an increase of growth hormone, 82,83 which in turn also suppresses hepcidin production. 84 This suggests a regulatory mechanism in order to adapt to increased iron demands due to rapid growth and development during puberty in both boys and girls and due to menstrual blood loss in girls. 85,86