Albertine Donker

Chapter 4 162 severe α –thalassemia (HbH disease) patients have relatively low serum hepcidin levels due to an ineffective erythropoiesis. 47,48 In β-thalassemia mice, TMRPSS6 defects counteract the low serum hepcidin levels, thereby attenuating iron overload and anemia. 37,39.50 Alternatively, since Plasmodium falciparum has been reported to infect iron-deficient erythrocytes less efficiently, TMPRSS6 defects may also directly protect against malaria. 51 Altogether, these data suggest a survival benefit for patients with malaria or thalassemia syndromes that also harbor a TMPRSS6 defect. Taken together, in the present study we further substantiate previous observations that i) mono-allelic TMPRSS6 defect may result in a clinical phenotype of IRIDA that is generally milder than in patients with a bi-allelic TMPRSS6 defect, ii) IRIDA is a defect of cellular iron release as shown by ferrokinetic studies, iii) despite the acronym IRIDA, some patients benefit from treatment with oral iron, iv) IRIDA due to (a) TMPRSS6 defect(s) is a phenotypically and genotypically heterogeneous disease. Our novel observations include: i) identification of nine not previously described TMPRSS6 defects, ii) the presence of country/region specific TMPRSS6 defects, iii) a relatively high number of patients (all females) were only mono-allelically affected and iv) in the absence of inflammation, a low TSAT/hepcidin ratio was associated with TMPRSS6 defects and an IRIDA phenotype, even after iron supplementation has been given. Implications of our findings for clinical management of IRIDA patients may comprise: i) the TSAT/hepcidin ratio may prove to be a suitable parameter to detect IRIDA patients among patients presenting with unexplained microcytic anemia with a low TSAT and ii) oral iron with vitamin C treatments should be (re)considered prior to starting intravenous iron. In time, suppression of the hepcidin pathway may become an alternative therapeutic approach, especially for severely affected patients to prevent iron overload, but to date safety and benefits remain unknown, especially for pediatric patients. Further studies are required to i) assess the value of the TSAT/hepcidin ratio in the differential diagnosis of microcytic anemia, ii) elucidate the contribution of other (epi) genetic and environmental factors in the pathophysiology and clinical penetrance of TMPRSS6 defects and to iii) determine the optimal treatment regimen. However, in order to prevent misdiagnosis and unnecessary invasive diagnostic work up, the first challenge for the clinician remains the recognition of the disorder and differentiation from other common causes of microcytic anemia.