Albertine Donker

Chapter 2 72 Throughout the first 48 hours of life an acute hypo-ferremia occurs in children, 178,179 possibly due to a birth-related stress responsewith an increase of cytokines. The decline of serum ferritin levels is associated with increased serum hepcidin levels, suggesting intact hepcidin-mediated regulation of iron status in young infants. 10 This is supported by rodent studies in suckling rats. 180,181 However, both animal and human studies suggest that, despite intact hepcidin signaling, the interaction between hepcidin and ferroportin and the netto effect on enteral iron absorption changes and matures during early life. At the age of 10 days, when fully nursing, iron absorption was independent of iron status in suckling rat pups, suggesting a lack of sensing and/or regulation of iron import. Nonetheless, at the age of 20 days, when pups were partially weaned from breast milk, ID strongly up-regulated and iron supplementation strongly down-regulated the expression of both DMT1 and ferroportin, supporting the hypothesis of developmental iron homeostasis. 182 Interestingly, these studies also showed that DMT1 and ferroportin are expressed in all areas of the small intestines and colon of the suckling rat, in contrast to adult rats in whom iron absorption predominantly occurs in the duodenum, suggesting that surface area and time available to absorb iron are age dependent. 183 Of note, ferroportin was relatively insensitive to hepcidin during suckling, supporting the above- mentioned inability to regulate iron absorption by the gut according to physiologic needs in early life. Conversely it might suggest 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. In linewith the first-mentioned hypothesis, studies in human infants showed that fractional iron absorption was independent of oral iron supplementation in breastfed infants until the age of nine months, indicating that the ability to decrease iron absorption in case of a high iron supply matures during infancy. 184 This will render the infant susceptible to iron excess and its undesired consequences such as compromised growth, predisposition to bacterial infections and a disturbance of the gut microbiota. 106,119,185,186 Extracellular iron transport in infants Infants have low levels of ceruloplasmin that is required to oxidize Fe 2+ released from cells to Fe 3+ to enabling binding to circulating transferrin. Clinical studies demonstrate that also transferrin is relatively low in the infant, especially in the premature child, suggesting that both the affinity and the capacity to bind free iron is reduced, making especially the premature infant vulnerable to damage by NTBI. 187-189