Albertine Donker

Chapter 8 276 ABSTRACT Pathogenic TMPRSS6 variants impairing matriptase 2 function result in inappropriately high serum hepcidin levels relative to body iron status, leading to the clinical phenotype of Iron Refractory Iron Deficiency Anemia (IRIDA). Due to its genotypical and phenotypical heterogeneity, diagnosing IRIDA can be challenging. Therefore, we aimed to assess the transferrin saturation (TSAT)/hepcidin ratio as tool to distinguish TMPRSS6 -related IRIDA from TMPRSS6 -unrelated iron deficiency anemia (IDA). TSAT/hepcidin ratios were determined in 21 IRIDA patients and 39 IDA controls, both with CRP ≤10 mg/L. IRIDA cases had mono- or biallelic pathogenic TMPRSS6 variants combined with microcytic anemia, TSAT <10% and a poor response to oral iron treatment. IDA controls had microcytic anemia, TSAT ≤15%, absence of iron therapy <3 months, severe renal impairment or chronic liver disease. In all patients and controls, serum hepcidin-25 levels were measured by the same isotope dilution mass spectrometry assay. IRIDA cases showed significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.7 %/nM (range 0.1-9.1 %/nM) and 16.7 %/nM (8.0-44.0 %/nM, p =0.000), respectively. The area under the ROC-curve for the TSAT/hepcidin ratio was 0.99 with a specificity of 100% (95%-CI, 93-100%) and a sensitivity of 95% (95% CI, 79-100%) at an optimal cut-off point of 5.9%/nM to differentiate between IRIDA and IDA. We conclude that the TSAT/hepcidin ratio is an effective tool in distinghuishing TMPRSS6- related IRIDA from multi-causal IDA with high specificity, in which a ratio ≤5.9%/nM strongly indicates the presence of IRIDA, provided inflammatory parameters are low and no iron therapy has been given recently.