Albertine Donker

General Discussion 305 9 X-linked Sideroblastic Anemia (XLSA) due to ALAS2 defects respectively, assessing age of presentation, clinical and biochemical features, genotype and treatment characteristics of the patients. The case study on IRIDA illustrates the clinical and genetic characteristics of inappropriately increased hepcidin levels relative to body iron. Conversely, the case series of XLSA demonstrates the clinical and genetic characteristics of inappropriately decreased hepcidin levels relative to body iron. Both studies exemplify the phenotypic andgenotypic heterogeneity of genetic disorders of ironmetabolismandheme synthesis, suggesting a complex interplay between (epi)genetic and environmental factors in the pathogenesis of these disorders. These factors still need elucidation, with the ultimate goal of determining the prognosis, optimal diagnostic approach and treatment regimen, tailored to the individual patient. Suggestions to achieve this goal, in particular for IRIDA, are discussed in this chapter. PART II: DIAGNOSTIC STUDIES: FOCUS ON IRON REFRACTORY IRON DEFICIENCY ANEMIA In the diagnostic part of this thesis ( PART II ) we described a study on serum hepcidin levels, hepcidin/ferritin ratios and transferrin saturation (TSAT)/hepcidin ratios in 266 healthy children aged 0.3-17 years, measured with a standardized assay, with the intention to facilitate the diagnosis of iron disorders in childhood ( Chapter 7 4 ). We demonstrated that serum hepcidin and also hepcidin relative to ferritin and TSAT is age dependent in children, suggesting that the set point of serum hepcidin relative to stored and circulating iron changes during childhood. This suggestion needs confirmation in a broader population as we elaborate on in this chapter. In Chapter 8 we performed a study assessing the value of the TSAT/hepcidin ratio in discriminating IRIDA from iron deficiency anemia (IDA) due to acquired causes e.g. gastro- intestinal or vaginal blood loss or malabsorption in 21 IRIDA patients and 39 IDA controls. We observed that the TSAT/hepcidin ratio was significantly lower in IRIDA patients compared to IDA controls. We therefore concluded that the TSAT/hepcidin ratio is able to differentiate between IRIDA and IDA-controls due to other reasons with high specificity and sensitivity in a broad iron-deficient population, provided moderate to severe inflammation is absent and no recent iron therapy has been given. Recommendations to validate the TSAT/hepcidin ratio in a populationwithout the above-mentioned restrictions are important in order to increase its usability in clinical practice. This is discussed in the discussion section of Chapter 8 .