Iron-refractory iron deficiency anemia: new molecular mechanisms

Abstract

Iron deficiency anemia is a common complication in end-stage renal disease (ESRD) and impairs the therapeutic efficacy of recombinant erythropoietin. Oral or parental iron supplements usually are effective in treating iron deficiency anemia. Some patients, however, respond poorly to iron supplements and are diagnosed as having iron-refractory iron deficiency anemia. The condition exacerbates ESRD but its underlying mechanism was unclear. Hepcidin is a central player in iron homeostasis. It downregulates the iron exporter ferroportin, thereby inhibiting iron absorption, release, and recycling. In ESRD, plasma hepcidin levels are elevated, which contributes to iron deficiency in patients. Matriptase-2, a liver transmembrane serine protease, has been found to have a major role in controlling hepcidin gene expression. In mice, defects in the Tmprss6 gene encoding matriptase-2 result in high hepcidin expression and cause severe microcytic anemia. Similarly, mutations in the human TMPRSS6 gene have been identified in patients with iron-refractory iron deficiency. Thus, matriptase-2 is critical for iron homeostasis and may have an important role in ESRD.

Figure 1. Hepcidin down-regulates ferroportin expression on the cell surface

Ferroportin (FPN) is expressed on the surface of enterocytes, hepatocytes and tissue macrophages. The binding of hepcidin to FPN leads to its phosphorylation, internalization, and degradation. Low levels of FPN expression reduce iron absorption in the gut, lower iron release from the liver, and prevent iron recycling by tissue macrophages.

Figure 2. Matriptase-2 domain structure and mutants identified in patients with IRIDA

Matriptase-2 consists of an N-terminal transmembrane domain (TM), one SEA domain, two CUB domains, three LDL receptor repeats (LDLR), and a C-terminal trypsin-like protease domain. Relative positions of nonsense (♠), missense (◆), splicing junction (♣) and frameshift (♥) mutations identified in patients with IRIDA are indicated.

Figure 3. Regulation of hepcidin expression by matriptase-2

Matriptase-2 prevents hepcidin overexpression by degrading hemojuvelin (HJV), which acts as a co-receptor for BMP to promote Hamp gene expression (panel A). In matriptase-2 deficiency (panel B), high levels of HJV enhances the BMP signaling pathway, leading to overexpression of hepcidin. Hepcidin inhibits iron absorption, release and recycling, thereby causing IRIDA.