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C. Camaschella et al.
synthesis of erythropoietin is mediated by HIF-2α. In iron deficiency, IRP1 binding to HIF-2α 5’IRE represses the lat- ter’s translation and decreases erythropoietin production, to limit erythropoiesis and iron consumption. When the mechanism fails, as in Irp1-knockout mice, a transient polycythemia occurs in the relatively iron-deficient young animals, which reverts in adult mice with iron suf- ficiency.64,65 In this context prolyl hydroxylase, the enzyme that induces degradation of HIF-2α, is iron- dependent and is thus inactive in iron deficiency.
Second, in in vitro studies, iron deprivation induced a block of early erythroid progenitors, by inactivating mito- chondrial aconitase;66 this block could be overcome by isocitrate supplementation.67 Finally the erythroid response to iron restriction is optimized by the iron sen- sor TFR2, a partner of erythropoietin receptor.10 Loss of bone marrow TFR2 in mice increases the sensitivity of erythroblasts to erythropoietin, which causes erythrocy- tosis, especially in iron deficiency.68 Liver TFR2 upregu- lates hepcidin and TFR2 mutations cause hemochromato- sis.69 As a sensor of iron-bound transferrin, erythroid TFR2 regulates erythropoiesis, while liver TFR2, control- ling hepcidin, modulates iron acquisition according to erythropoietic needs. The recently demonstrated TFR2 expression in osteoclasts and osteoblasts70 places this iron sensor at the crossroads of red cell production, iron homeostasis and bone turnover.
While iron regulates erythropoiesis, the reverse is also true. The old hypothesis that the erythropoietic drive controls iron absorption through an erythroid regulator71 was confirmed by the discovery of ERFE, the best exam- ple of tissue-mediated regulation of hepcidin. ERFE is a member of the tumor-necrosis factor (TNF)-α family, pro- duced by several tissues, but increased in response to ery- thropoietin only in erythroid precursors. ERFE sequesters BMP receptor ligands, especially BMP6,72 inhibiting BMP- SMAD signaling and hepcidin. However, ERFE fails to suppress hepcidin when the BMP pathway is overactive.73 Erfe-knockout mice are not anemic, indicating that ERFE has a modest effect on hepcidin repression in steady state. However, ERFE contributes to iron loading in mice with β-thalassemia.74
Iron disorders
The improved understanding of iron physiology has pro- foundly changed the modern approach to iron disorders, known historically for centuries as iron deficiency (chloro- sis) in young females and hemochromatosis (bronze dia- betes) in middle-age males. We now suspect hemochro- matosis based on iron parameters and confirm the diagno- sis by genetic testing well before the development of iron overload and organ damage. We are aware that anemia is a complication of iron deficiency, though not the only one, since other tissues/organs may be iron-depleted before anemia develops, as occurs in chronic heart failure.75
Hepcidin is tightly controlled to maintain body iron balance. Loss of this control leads to opposite genetic or acquired disorders (Table 1).
Genetic disorders
Hereditary hemochromatosis
The pathophysiology and diagnosis of hemochromato- sis were profoundly influenced by the cloning of the HFE
gene76 and the definition of the genetic heterogeneity of the disease (Table 1). Overall hemochromatosis is due to “insufficient hepcidin production” or exceptionally to “hepcidin resistance”.77 Mutations in genes of the hep- cidin-ferroportin axis disrupt iron homeostasis, leading to increased iron absorption, high transferrin saturation and increased toxicity from non-transferrin bound iron (NTBI) species.78 The commonest form of hemochromatosis in Caucasians is due to homozygous HFE(C282Y) muta- tions. Genetic tests allow early diagnosis so that individ- uals with the affected genotypes show high biochemical penetrance (increased transferrin saturation ± increased serum ferritin) but low clinical expression. Loss-of-func- tion mutations of HJV, TFR2 and HAMP (encoding hep- cidin) lead to more severe diseases, collectively called “non-HFE hemochromatosis”. In all the recessive forms hepcidin is inappropriately low in comparison with iron excess and the onset and severity of iron overload corre- late with the hormone deficiency.79 The implementation of next-generation sequencing in familial and isolated cases of iron overload80 has enabled the identification of mutations in more than one gene and provided examples of digenic inheritance. Both genetic and acquired modi- fiers contribute to the penetrance of HFE-hemochromato- sis, interfering with hepcidin expression: e.g., alcohol aggravates the iron burden, whereas blood donations attenuates it.77
Ferroportin mutations are inherited in a dominant man- ner (Table 1). The different effects of these mutations account for the controversy in disease nomenclature. Loss-of-function mutations impair iron export, are associ- ated with iron accumulation in Küpffer cells and require no or reduced phlebotomy therapy, representing the true “ferroportin disease”.81 Gain-of-function mutations lead to hepcidin resistance and the release of too much iron, as occurs in hemochromatosis.
The clinical severity of hemochromatosis is related to NTBI, a toxic iron species bound to low molecular weight molecules, easily taken up by hepatocytes and pancreatic cells via ZIP14 transporter82 and by cardiomyocytes through other transporters.83 While iron uptake by trans- ferrin receptor is tightly regulated, the uptake of NTBI is not and persists in iron overload. NTBI leads to the gen- eration of reactive oxygen species and cell damage, caus- ing liver fibrosis (which may progress to cirrhosis and hepatocellular carcinoma), chronic heart failure, diabetes, hypopituitarism and other complications of iron load- ing.77,79
Iron-refractory iron-deficiency anemia
This form of iron deficiency anemia (IRIDA) was recog- nized after the discovery of hepcidin as being due to mutations of its inhibitor TMPRSS6.50 High hepcidin levels lead to a phenotype opposite to that of hemochromatosis, reminiscent of anemia of inflammation.84 The anemia is refractory to oral iron and may require intravenous thera- py, especially when iron demand is high.85 TMPRSS6 genetic variants modulate iron and hematologic traits in several genome-wide association studies,58 alter hepcidin levels in normal subjects86 and might confer susceptibili- ty/resistance to iron deficiency, as observed in blood donors.87
Other rare recessive disorders of the transferrin receptor pathway – such as hypotransferrinemia and DMT1 muta- tions – lead to “atypical microcytic anemia” with
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haematologica | 2020; 105(2)