As iron can readily donate and accept electrons, interconverting between ferrous (Fe2+
) and ferric (Fe3+
) forms, it is an important component of various cytochromes and is required for the functioning of a number of enzymes. However, this property also makes iron highly toxic, being able to catalyze the conversion of hydrogen peroxide into free-hydroxyl radical ions that can damage cellular membranes, proteins, and DNA [5
]. Under normal conditions, the potential toxicity of plasma iron is eliminated by sequestration into complexes with transferrin, the major plasma iron-binding protein. However, the presence of excess body iron can quickly saturate the available transferrin and result in the appearance of nontransferrin-bound iron (NTBI). The pathologically relevant component of NTBI is labile plasma iron (LPI), which encompasses organ-penetrating forms of iron that are redox active and directly chelatable [6
]. Generation of LPI leads to unregulated iron uptake and subsequent intracellular storage either within ferritin molecules or as hemosiderin, an iron storage complex. When the sequestering capacity of iron-binding proteins is exceeded, excessive labile iron pools develop, which are the mediators of organ toxicity in iron-overloaded patients [7
]. In the absence of treatment the toxic effects of the stored iron will result in ongoing tissue damage and ultimately organ dysfunction and failure [4
]. Therefore, the adverse consequences of iron overload can arise from the elevation of NTBI and LPI in plasma, as well as due to organ damage mediated by the accumulation of tissue iron in target organs. The sources of elevated NTBI in HSCT patients are summarized in .
Causes of increased NTBI in HSCT recipients.
Iron from red cell transfusions initially accumulates bound to ferritin in the macrophages of tissues such as liver, spleen, and bone marrow. Iron export into plasma from iron-loaded macrophages as well as duodenal enterocytes (in the case dietary iron absorption) occurs via the iron export protein ferroportin located on the membrane of these cells [9
]. Ferroportin expression in turn is negatively regulated by hepatic production of hepcidin, a key hormone that regulates iron metabolism by inducing the internalization and degradation of ferroportin [10
]. Serum hepcidin-25 levels have been shown to negatively correlate with the degree of erythropoiesis in the HSCT setting [11
]. Thus, the degree of erythropoietic activity after HSCT appears to be the major regulator of hepcidin level which in turn may determine plasma iron levels in the HSCT setting.
The conditioning regimen itself can also contribute to the increase in NTBI levels, partly due to inhibition of erythropoiesis, the main route of iron utilization. In one study, NTBI peaked as early as 4 days prior to transplantation, and was detectable for 6–18 days in all patients [12
] (). Other studies have shown similar results [13
]. In addition, stored iron can be released from the liver as a result of tissue injury that can occur during conditioning [12
]. Transferrin levels can drop as an acute phase reaction, and transferrin saturation can increase during chemoradiotherapy, often reaching indexes of more than 80% and leading to increased levels of NTBI [12
]. Conditions in the peritransplantation period can therefore result in elevated NTBI and LPI levels in the plasma, which persist at least until engraftment.
Figure 2 Mean ± SD serum level of the calculated transferrin saturation in 10 allogenic SCT patients during the peritransplantation period. Arrow indicates onset of the conditioning regimen .
Normally, endogenous antioxidants also play a role in scavenging free radicals and preventing cell damage [17
]. However, in patients undergoing HSCT, chemotherapy or radiotherapy-based conditioning regimens can result in a prooxidant status, as indicated by a reduced total radical antioxidant parameter of plasma (TRAP), a measure of the overall capacity of human plasma to inhibit free radical-induced lipid peroxidation [14
]. In one study, assessment of the antioxidant status before and after HSCT showed a breakdown in plasma antioxidant defense and an inverse correlation between levels of NTBI and TRAP. Recent data have also demonstrated a prooxidant state in patients conditioned with chemoradiotherapy, indicated by significant increases in malondialdehyde (an indicator of oxidative stress and lipid peroxidation), glutathione peroxidase, and super oxide dismutase [19
]. Decreased levels of other endogenous antioxidants such as α
-tocopherol and β
-carotene have also been noted [14
]. The disturbance of pro-oxidative/antioxidative balance in the plasma of patients undergoing HSCT may augment the toxicity of LPI and suggests that the adminstration of antioxidants, such as N-acetylcysteine or glutamine (glutathione precursor), may, therefore, be beneficial [14
In addition to performing a vital role in the human body, iron is an important element for the growth of pathogenic microorganisms [21
]. High plasma iron levels can therefore not only promote microbial growth but can also directly increase susceptibility to infection by inhibiting the function of the immune system. High intracellular iron levels have been shown to result in the direct impairment of innate and acquired immune responses [21