Albertine Donker

Increased Serum Hepcidin in Combination with TMPRSS6 Variants: not always IRIDA 199 5 TO THE EDITOR, With interest we read the article of Nie et a., 1 which describes a 15-months old girl with a severe microcytic anemia, neither responding to oral iron nor to a combination or intravenous iron and erythropoietin. The authors suggest that the patient suffers from Iron Refractory Iron Deficiency Anemia (IRIDA) due to a tri-allelic mutation in TMPRSS6 . We do not agree with this conclusion for several reasons. The phenotype is not very typical of IRIDA. Since the cardinal feature of IRIDA is impaired iron availability due to a reduced intestinal iron absorption and iron release from the macrophages as a result of the disproportionally high serum hepcidin level, transferrin saturation (TS) is very low (<5%). 2-4 In the described child, the TS is only moderately decreased compared to the severity of the anemia. Furthermore, serum hepcidin levels should always be interpreted in relation to serum inflammation parameters because hepcidin production by the liver is stimulated by cytokines, especially IL6. 5 The authors do not mention the results of CRP or ESR, but the sharp decline of the serum hepcidin level after glucocorticosteroids had been given, suggests that inflammation played a role in the high serum hepcidin level and subsequent anemia, a phenomenon, which is known as Anemia of Chronic Disease (ACD). As far as we know, splenomegaly is not characteristic for IRIDA. 6 However, our main comment concerns the genetic confirmation of the diagnosis of IRIDA. The occurrence of both the matriptase 2 changes K253E (rs2235324) and V736A (rs855791), found in the patient, depends on the ethnicity but is highly prevalent in all populations and does not correspond to the relatively low frequency of IRIDA. (CSHL-HAPMAP: HapMap HCB, describing the Chinese population: prevalence of homozygous K253E: 0.133; prevalence of heterozygous V736A: 0.044). Functional studies show that the matriptase 2 736A variant inhibits hepcidin more efficiently than 736 V variant. 7 This implicates that the presence of the 736A variant has a lower prevalence in the Chinese population than the 736V variant and protects against elevated hepcidin levels and iron deficiency!