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Hepcidin and iron disorders
increased transferrin saturation and iron stores, because of decreased iron utilization by blunted erythropoiesis.85
Congenital sideroblastic anemia
Ringed sideroblasts are erythroblasts with iron-loaded mitochondria that, clustering around the nucleus, confer the appearance of a ring at Perls iron staining. Hereditary sideroblastic anemias are usually due to heme deficiency: X-linked sideroblastic anemia is caused by mutations in ALAS2, the first, rate-limiting enzyme of heme biosynthe- sis, while recessive forms are associated with mutations of mitochondria glycine importer solute carrier family 25 member 38.88 Rare severe cases result from mutations of Fe/S cluster proteins, such as GLRX589 or HSPA9,90 which decrease Fe/S groups and the activity of ferrochelatase, the last enzyme of the heme pathway. Another cause of low heme in GLRX5 deficiency is the overactive IRP1 that, not being converted to aconitase because of the Fe/S cluster deficit, blocks ALAS2 translation, thereby preventing heme formation. These disorders reveal the tight connec- tion of heme-Fe/S metabolism. Among syndromic forms, the X-linked ABCB7 deficiency reduces export of Fe/S clusters to the cytosol,91 while others are associated with immunodeficiency92 strengthening the need of Fe/S clus- ters in other cell types (Table 1). Those due to mitochon- drial protein mutations91 are not discussed here.
Acquired iron disorders
Iron deficiency
Iron deficiency, both isolated and associated with ane- mia, represents one of the five major causes of disability burden worldwide, especially in women.93 For discussions of the etiology, clinical presentation and treatment of iron deficiency with or without anemia readers are directed to specific reviews.94-96 In absolute iron deficiency low total body and serum iron fully suppress hepcidin, a mecha- nism of adaptation to increase iron absorption. In func- tional iron deficiency (e.g., in inflammation) total body iron is not decreased, but iron is sequestered in stores by the high hepcidin levels.84,97 This distinction strongly influ- ences the route of iron administration required to treat iron deficiency, as discussed below.
Anemia of inflammation
Proinflammatory cytokines such as IL-6 and IL-1β, pro- duced in chronic infections, autoimmunity, cancer, renal failure and other chronic disorders activate hepcidin expression leading to iron-restricted erythropoiesis and anemia of inflammation, once named anemia of chronic diseases.84,97,98 By withholding iron in macrophages, extra- cellular Gram-negative microorganisms are deprived of this essential nutrient.99,100 This is an innate defense mech- anism known as 'nutritional immunity'.101 A recent inter- pretation is that hypoferremia prevents the generation of NTBI that potentiates the pathogenicity of Gram-nega- tive bacteria.102 Anemia, usually moderate and normocyt- ic, is multifactorial, because of concomitant insufficient erythropoietin production and impaired early erythroid commitment.98 Microcytosis occurs in longstanding severe inflammation such as in Castleman disease, a lym- phoproliferative disorder in which high IL-6 production strongly enhances hepcidin synthesis103 or in patients with ectopic hepcidin expression by liver adenomas.104 Anemia reverts after anti-IL6 receptor treatment in Castleman disease or after surgical removal of the tumor
in the case of adenoma.
Anemia of inflammation regresses with control of the
disease. In selected cases intravenous iron or erythro- poiesis-stimulating agents are used. Since treatment is often unsatisfactory, manipulation of the hepcidin path- way (blocking either its production or function) is pro- posed as a novel therapeutic opportunity.97
Iron-loading anemias
Low hepcidin levels explain the iron overload that develops in the absence of blood transfusions in “iron- loading anemias”, i.e., anemias with ineffective erythro- poiesis (Table 1). ERFE, released by erythropoietin-stimu- lated erythroblasts, inhibits hepcidin, despite iron over- load. In non-transfusion-dependent β-thalassemia patients, serum ERFE levels are high,105 to ensure iron acquisition for the expanded erythropoiesis.106 However, since the erythropoiesis is inefficient, excess iron inter- feres with erythroblast maturation aggravating anemia in a vicious cycle.107 In patients with transfusion-dependent thalassemia, hepcidin increases following transfusions which partially suppress erythropoiesis.
ERFE contributes to the iron loading of some clonal myelodysplastic syndromes. Patients with the ringed sideroblasts subtype of myelodysplastic syndrome (once called refractory anemia with ringed sideroblasts) carry a somatic mutation in the spliceosome gene SF3B1.108 Among other abnormally spliced products, an elongated variant of ERFE is more efficient than the wildtype hor- mone in hepcidin repression.109
Diagnostic implications
Notwithstanding spectacular advances in our under- standing of iron metabolism and homeostasis our diag- nostic approach to iron disorders still relies mainly on three historical tests: serum iron, transferrin (or total iron binding capacity) and ferritin. Transferrin saturation (Tsat), i.e. the ratio of serum iron/total iron binding capac- ity and serum ferritin coupled with genetic testing and non-invasive magnetic resonance imaging measurements of liver iron content, define the nature and severity of iron loading in both hemochromatosis77 and thalassemia.110 Other useful markers are the level of serum soluble trans- ferrin receptor (sTFRC), related to the expansion of ery- thropoiesis or iron deficiency, the sTFRC/log ferritin ratio for the diagnosis of iron deficiency in inflammation98 and the Tsat/log hepcidin ratio to suspect IRIDA.111
Enzyme-linked immunosorbent assay kits can measure serum hepcidin levels. However, this does not provide any information additional to serum ferritin, since the two variables are tightly related.112,113 Some researchers propose determining hepcidin levels in order to choose the better therapeutic route of administration of iron supplementa- tion (oral vs. intravenous),114 as well as its correct timing115 and schedule.116 However, besides being subject to circadi- an oscillations, hepcidin levels change rapidly in response to activating and inhibitory signals, making their measure- ment useful in only a limited number of conditions.47 A kit to measure human serum ERFE concentration is available for research purposes. Whether the elongated ERFE iden- tified in individuals with SF3B1 mutations will become a biomarker of ringed sideroblast myelodysplastic syn- drome109 remains to be tested.
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